Model-Drive Architecture for Agent-Based Systems

NASA Technical Reports Server (NTRS)

Gradanin, Denis; Singh, H. Lally; Bohner, Shawn A.; Hinchey, Michael G.

2004-01-01

The Model Driven Architecture (MDA) approach uses a platform-independent model to define system functionality, or requirements, using some specification language. The requirements are then translated to a platform-specific model for implementation. An agent architecture based on the human cognitive model of planning, the Cognitive Agent Architecture (Cougaar) is selected for the implementation platform. The resulting Cougaar MDA prescribes certain kinds of models to be used, how those models may be prepared and the relationships of the different kinds of models. Using the existing Cougaar architecture, the level of application composition is elevated from individual components to domain level model specifications in order to generate software artifacts. The software artifacts generation is based on a metamodel. Each component maps to a UML structured component which is then converted into multiple artifacts: Cougaar/Java code, documentation, and test cases.

A novel synthesis of malondialdehyde adducts of deoxyguanosine, deoxyadenosine, and deoxycytidine.

PubMed

Wang, Hao; Marnett, Lawrence J; Harris, Thomas M; Rizzo, Carmelo J

2004-02-01

Malondialdehyde (MDA) is a mutagenic product of lipid peroxidation and prostaglandin biosynthesis. MDA reacts with DNA bases to produce adducts of deoxyguanosine (M1G), deoxyadenosine (M1A), and deoxycytidine (M1C). A novel synthesis of these MDA nucleoside adducts has been developed, which significantly improves their availability. For the deoxyguanosine adduct, M1G, an amine equivalent to MDA, 4-amino-3-(phenylselenyl)butane-1,2-diol, was reacted with 2-fluoro-O6-(2-(trimethylsilyl)ethyl)-2'-deoxyinosine via a nucleophilic aromatic substitution reaction followed by acid hydrolysis of the O6-protecting group to give an N2-modified deoxyguanosine intermediate. Periodate oxidation of this intermediate under slightly acidic conditions gave M1G in good overall yield via cleavage of the vicinal diol unit and concomitant oxidation of the phenylselenide group to the corresponding selenoxide and syn beta-elimination. M1A and M1C were synthesized by the same strategy starting from 6-chloropurine 2'-deoxyriboside and 1-(2-deoxy-beta-d-erythro-pentofuranosyl)-4-(1H-1,2,4-triazol-1-yl)-2-(1H)pyrimidinone, respectively. An advantage of this approach is that similar chemistry has been shown to be directly applicable to the synthesis of site specifically adducted oligonucleotides containing activated nucleobases such as those used in this study. This strategy may offer an improved synthesis to oligonucleotides containing M1G and a feasible approach to M1A and M1C containing oligonucleotides.

Artemisinin combination therapy mass drug administration in a setting of low malaria endemicity: programmatic coverage and adherence during an observational study in Zanzibar.

PubMed

Ali, Abdullah S; Thawer, Narjis G; Khatib, Bakar; Amier, Haji H; Shija, Joseph; Msellem, Mwinyi; Al-Mafazy, Abdul-Wahid; Garimo, Issa A; Mkali, Humphrey; Ramsan, Mahdi M; Kafuko, Jessica M; Paxton, Lynn A; Reithinger, Richard; Ngondi, Jeremiah M

2017-08-14

Mass drug administration (MDA) appears to be effective in reducing the risk of malaria parasitaemia. This study reports on programmatic coverage and compliance of MDA using artemisinin-based combination therapy (ACT) in four shehias (smallest administration unit) that had been identified as hotspots through Zanzibar's malaria case notification surveillance system. Mass drug administration was done in four shehias selected on the basis of: being an established malaria hot spot; having had mass screening and treatment (MSaT) 2-6 weeks previously; and exceeding the epidemic alert threshold of 5 cases within a week even after MSaT. Communities were sensitized and MDA was conducted using a house-to-house approach. All household members, except pregnant women and children aged less than 2 months, were provided with ACT medicine. Two weeks after the MDA campaign, a survey was undertaken to investigate completion of ACT doses. A total of 8816 [97.1% of eligible; 95% confidence interval (CI) 96.8-97.5] people received ACT. During post MDA surveys, 2009 people were interviewed: 90.2% reported having completed MDA doses; 1.9% started treatment but did not complete dosage; 4.7% did not take treatment; 2.0% were absent during MDA and 1.2% were ineligible (i.e. infants <2 months and pregnant women). Main reasons for failure to complete treatment were experience of side-effects and forgetting to take subsequent doses. Failure to take treatment was mainly due to fear of side-effects, reluctance due to lack of malaria symptoms and caregivers forgetting to give medication to children. Mass drug administration for malaria was well accepted by communities at high risk of malaria in Zanzibar, with high participation and completion rates. Further work to investigate the potential of MDA in accelerating Zanzibar's efforts towards malaria elimination should be pursued.

Using Formal Game Design Methods to Embed Learning Outcomes into Game Mechanics and Avoid Emergent Behaviour

ERIC Educational Resources Information Center

Grey, Simon; Grey, David; Gordon, Neil; Purdy, Jon

2017-01-01

This paper offers an approach to designing game-based learning experiences inspired by the Mechanics-Dynamics-Aesthetics (MDA) model (Hunicke et al., 2004) and the elemental tetrad model (Schell, 2008) for game design. A case for game based learning as an active and social learning experience is presented including arguments from both teachers and…

Digital droplet multiple displacement amplification (ddMDA) for whole genome sequencing of limited DNA samples

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rhee, Minsoung; Light, Yooli K.; Meagher, Robert J.

Here, multiple displacement amplification (MDA) is a widely used technique for amplification of DNA from samples containing limited amounts of DNA (e.g., uncultivable microbes or clinical samples) before whole genome sequencing. Despite its advantages of high yield and fidelity, it suffers from high amplification bias and non-specific amplification when amplifying sub-nanogram of template DNA. Here, we present a microfluidic digital droplet MDA (ddMDA) technique where partitioning of the template DNA into thousands of sub-nanoliter droplets, each containing a small number of DNA fragments, greatly reduces the competition among DNA fragments for primers and polymerase thereby greatly reducing amplification bias. Consequently,more » the ddMDA approach enabled a more uniform coverage of amplification over the entire length of the genome, with significantly lower bias and non-specific amplification than conventional MDA. For a sample containing 0.1 pg/μL of E. coli DNA (equivalent of ~3/1000 of an E. coli genome per droplet), ddMDA achieves a 65-fold increase in coverage in de novo assembly, and more than 20-fold increase in specificity (percentage of reads mapping to E. coli) compared to the conventional tube MDA. ddMDA offers a powerful method useful for many applications including medical diagnostics, forensics, and environmental microbiology.« less

Digital droplet multiple displacement amplification (ddMDA) for whole genome sequencing of limited DNA samples

DOE PAGES

Rhee, Minsoung; Light, Yooli K.; Meagher, Robert J.; ...

2016-05-04

Here, multiple displacement amplification (MDA) is a widely used technique for amplification of DNA from samples containing limited amounts of DNA (e.g., uncultivable microbes or clinical samples) before whole genome sequencing. Despite its advantages of high yield and fidelity, it suffers from high amplification bias and non-specific amplification when amplifying sub-nanogram of template DNA. Here, we present a microfluidic digital droplet MDA (ddMDA) technique where partitioning of the template DNA into thousands of sub-nanoliter droplets, each containing a small number of DNA fragments, greatly reduces the competition among DNA fragments for primers and polymerase thereby greatly reducing amplification bias. Consequently,more » the ddMDA approach enabled a more uniform coverage of amplification over the entire length of the genome, with significantly lower bias and non-specific amplification than conventional MDA. For a sample containing 0.1 pg/μL of E. coli DNA (equivalent of ~3/1000 of an E. coli genome per droplet), ddMDA achieves a 65-fold increase in coverage in de novo assembly, and more than 20-fold increase in specificity (percentage of reads mapping to E. coli) compared to the conventional tube MDA. ddMDA offers a powerful method useful for many applications including medical diagnostics, forensics, and environmental microbiology.« less

Novel Therapeutic Approach for Breast Cancer

DTIC Science & Technology

2006-06-01

replication, mda-7/IL-24 expression, growth inhibition and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 into human breast cancer xenografts in athymic nude...CLASSIFICATION OF: 18 . NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b. ABSTRACT U c. THIS PAGE U UU 62 19b...breast cancer xenografts in athymic nude mice in vivo. Infection of this CRCA (designated Ad.PEG-E1A-mda-7) in normal mammary epithelial cells and

Assessing the interruption of the transmission of human helminths with mass drug administration alone: optimizing the design of cluster randomized trials.

PubMed

Anderson, Roy; Farrell, Sam; Turner, Hugo; Walson, Judd; Donnelly, Christl A; Truscott, James

2017-02-17

A method is outlined for the use of an individual-based stochastic model of parasite transmission dynamics to assess different designs for a cluster randomized trial in which mass drug administration (MDA) is employed in attempts to eliminate the transmission of soil-transmitted helminths (STH) in defined geographic locations. The hypothesis to be tested is: Can MDA alone interrupt the transmission of STH species in defined settings? Clustering is at a village level and the choice of clusters of villages is stratified by transmission intensity (low, medium and high) and parasite species mix (either Ascaris, Trichuris or hookworm dominant). The methodological approach first uses an age-structured deterministic model to predict the MDA coverage required for treating pre-school aged children (Pre-SAC), school aged children (SAC) and adults (Adults) to eliminate transmission (crossing the breakpoint in transmission created by sexual mating in dioecious helminths) with 3 rounds of annual MDA. Stochastic individual-based models are then used to calculate the positive and negative predictive values (PPV and NPV, respectively, for observing elimination or the bounce back of infection) for a defined prevalence of infection 2 years post the cessation of MDA. For the arm only involving the treatment of Pre-SAC and SAC, the failure rate is predicted to be very high (particularly for hookworm-infected villages) unless transmission intensity is very low (R 0 , or the effective reproductive number R, just above unity in value). The calculations are designed to consider various trial arms and stratifications; namely, community-based treatment and Pre-SAC and SAC only treatment (the two arms of the trial), different STH transmission settings of low, medium and high, and different STH species mixes. Results are considered in the light of the complications introduced by the choice of statistic to define success or failure, varying adherence to treatment, migration and parameter uncertainty.

Hotspot Selective Preference of the Chimeric Sequences Formed in Multiple Displacement Amplification.

PubMed

Tu, Jing; Lu, Na; Duan, Mengqin; Huang, Mengting; Chen, Liang; Li, Junji; Guo, Jing; Lu, Zuhong

2017-02-24

Multiple displacement amplification (MDA) is considered to be a conventional approach to comprehensive amplification from low input DNA. The chimeric reads generated in MDA lead to severe disruption in some studies, including those focusing on heterogeneity, structural variation, and genetic recombination. Meanwhile, the generation of by-products gives a new approach to gain insights into the reaction process of φ29 polymerase. Here, we analyzed 36.7 million chimeras and screened 196 billion chimeric hotspots in the human genome, as well as evaluating the hotspot selective preference of chimeras. No significant preference was captured in the distributions of chimeras and hotspots among chromosomes. Hotspots with overlaps for 12-13 nucleotides (nt) were most likely to be selected as templates in chimera generation. Meanwhile, a regularly selective preference was noticed in overlap GC content. The preferences in overlap length and GC content was shown to be pertinent to the sequence denaturation temperature, which pointed out the optimization direction for reducing chimeras. Distance preference between two segments of chimeras was 80-280 nt. The analysis is beneficial for reducing the chimeras in MDA, and the characterization of MDA chimeras is helpful in distinguishing MDA chimeras from chimeric sequences caused by disease.

Hotspot Selective Preference of the Chimeric Sequences Formed in Multiple Displacement Amplification

PubMed Central

Tu, Jing; Lu, Na; Duan, Mengqin; Huang, Mengting; Chen, Liang; Li, Junji; Guo, Jing; Lu, Zuhong

2017-01-01

Multiple displacement amplification (MDA) is considered to be a conventional approach to comprehensive amplification from low input DNA. The chimeric reads generated in MDA lead to severe disruption in some studies, including those focusing on heterogeneity, structural variation, and genetic recombination. Meanwhile, the generation of by-products gives a new approach to gain insights into the reaction process of φ29 polymerase. Here, we analyzed 36.7 million chimeras and screened 196 billion chimeric hotspots in the human genome, as well as evaluating the hotspot selective preference of chimeras. No significant preference was captured in the distributions of chimeras and hotspots among chromosomes. Hotspots with overlaps for 12–13 nucleotides (nt) were most likely to be selected as templates in chimera generation. Meanwhile, a regularly selective preference was noticed in overlap GC content. The preferences in overlap length and GC content was shown to be pertinent to the sequence denaturation temperature, which pointed out the optimization direction for reducing chimeras. Distance preference between two segments of chimeras was 80–280 nt. The analysis is beneficial for reducing the chimeras in MDA, and the characterization of MDA chimeras is helpful in distinguishing MDA chimeras from chimeric sequences caused by disease. PMID:28245591

Extracting business vocabularies from business process models: SBVR and BPMN standards-based approach

NASA Astrophysics Data System (ADS)

Skersys, Tomas; Butleris, Rimantas; Kapocius, Kestutis

2013-10-01

Approaches for the analysis and specification of business vocabularies and rules are very relevant topics in both Business Process Management and Information Systems Development disciplines. However, in common practice of Information Systems Development, the Business modeling activities still are of mostly empiric nature. In this paper, basic aspects of the approach for business vocabularies' semi-automated extraction from business process models are presented. The approach is based on novel business modeling-level OMG standards "Business Process Model and Notation" (BPMN) and "Semantics for Business Vocabularies and Business Rules" (SBVR), thus contributing to OMG's vision about Model-Driven Architecture (MDA) and to model-driven development in general.

Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis-inducing agents.

PubMed

Eldehna, Wagdy M; Almahli, Hadia; Al-Ansary, Ghada H; Ghabbour, Hazem A; Aly, Mohamed H; Ismael, Omnia E; Al-Dhfyan, Abdullah; Abdel-Aziz, Hatem A

2017-12-01

Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC 50  = 12.35 ± 0.12 and 12.00 ± 0.13 μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC 50  = 29.38 ± 1.24 μM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 10g showed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control).

Differentially expressed proteins in ER+ MCF7 and ER- MDA- MB-231 human breast cancer cells by RhoGDI-α silencing and overexpression.

PubMed

Hooshmand, Somayeh; Ghaderi, Abbas; Yusoff, Khatijah; Thilakavathy, Karuppiah; Rosli, Rozita; Mojtahedi, Zahra

2014-01-01

The consequence of Rho GDP dissociation inhibitor alpha (RhoGDIα) activity on migration and invasion of estrogen receptor positive (ER+) and negative (ER-) breast cancer cells has not been studied using the proteomic approach. Changes in expression of RhoGDIα and other proteins interacting directly or indirectly with RhoGDIα in MCF7 and MDA-MB-231, with different metastatic potentials is of particular interest. ER+ MCF7 and ER- MDA-MB-231 cell lines were subjected to two-dimensional electrophoresis (2-DE) and spots of interest were identified by matrix-assisted laser desorption/ionization time of- flight/time- of-flight (MALDI-TOF/TOF) mass spectrometry (MS) analysis after downregulation of RhoGDIα using short interfering RNA (siRNA) and upregulated using GFP-tagged ORF clone of RhoGDIα. The results showed a total of 35 proteins that were either up- or down-regulated in these cells. Here we identifed 9 and 15 proteins differentially expressed with silencing of RhoGDIα in MCF-7 and the MDA-MB-231 cells, respectively. In addition, 10 proteins were differentially expressed in the upregulation of RhoGDIα in MCF7, while only one protein was identified in the upregulation of RhoGDIα in MDA-MB-231. Based on the biological functions of these proteins, the results revealed that proteins involved in cell migration are more strongly altered with RhoGDI-α activity. Although several of these proteins have been previously indicated in tumorigenesis and invasiveness of breast cancer cells, some ohave not been previously reported to be involved in breast cancer migration. Hence, these proteins may serve as useful candidate biomarkers for tumorigenesis and invasiveness of breast cancer cells. Future studies are needed to determine the mechanisms by which these proteins regulate cell migration. The combination of RhoGDIα with other potential biomarkers may be a more promising approach in the inhibition of breast cancer cell migration.

International cooperation in space transportation

NASA Astrophysics Data System (ADS)

Carlson, C. R.

1997-01-01

International cooperation in the field of Space Transportation has become an accepted norm as companies and countries have come to understand the necessity of lower costs for launch services. Many different approaches have been attempted, some of which are more successful than others. This paper discusses the history of McDonnell Douglas Aerospace (MDA) launch vehicle cooperation with Japan, as well as how MDA developed Mitsubishi Heavy Industries (MHI) as a supplier for the Delta III program, and how MDA became a supplier for the Japanese H-2 vehicle.

Contextualizing Learning Scenarios According to Different Learning Management Systems

ERIC Educational Resources Information Center

Drira, R.; Laroussi, M.; Le Pallec, X.; Warin, B.

2012-01-01

In this paper, we first demonstrate that an instructional design process of Technology Enhanced Learning (TEL) systems based on a Model Driven Approach (MDA) addresses the limits of Learning Technology Standards (LTS), such as SCORM and IMS-LD. Although these standards ensure the interoperability of TEL systems across different Learning Management…

Inhibition of SIRT1 by a small molecule induces apoptosis in breast cancer cells.

PubMed

Kalle, Arunasree M; Mallika, A; Badiger, Jayasree; Alinakhi; Talukdar, Pinaki; Sachchidanand

2010-10-08

Overexpression of SIRT1, a NAD+-dependent class III histone deacetylases (HDACs), is implicated in many cancers and therefore could become a promising antitumor target. Here we demonstrate a small molecule SIRT1 inhibitor, ILS-JGB-1741(JGB1741) with potent inhibitory effects on the proliferation of human metastatic breast cancer cells, MDA-MB 231. The molecule has been designed using medicinal chemistry approach based on known SIRT1 inhibitor, sirtinol. The molecule showed a significant inhibition of SIRT1 activity compared to sirtinol. Studies on the antitumor effects of JGB on three different cancer cell lines, K562, HepG2 and MDA-MB 231 showed an IC₅₀ of 1, 10 and 0.5 μM, respectively. Further studies on MDA-MB 231 cells showed a dose-dependent increase in K9 and K382 acetylation of H3 and p53, respectively. Results also demonstrated that JGB1741-induced apoptosis is associated with increase in cytochrome c release, modulation in Bax/Bcl2 ratio and cleavage of PARP. Flowcytometric analysis showed increased percentage of apoptotic cells, decrease in mitochondrial membrane potential and increase in multicaspase activation. In conclusion, the present study indicates the potent apoptotic effects of JGB1741 in MDA-MB 231 cells. Copyright © 2010 Elsevier Inc. All rights reserved.

Oxidative status in different settings and with different methodological approaches compared by Receiver Operating Characteristic curve analysis.

PubMed

Cighetti, Giuliana; Bamonti, Fabrizia; Aman, Caroline S; Gregori, Dario; De Giuseppe, Rachele; Novembrino, Cristina; de Liso, Federica; Maiavacca, Rita; Paroni, Rita

2015-01-01

To test the performance of different analytical approaches in highlighting the occurrence of deregulated redox status in various physio-pathological situations. 35 light and 61 heavy smokers, 19 chronic renal failure, 59 kidney transplanted patients, and 87 healthy controls were retrospectively considered for the study. Serum oxidative stress and antioxidant status, assessed by spectrophotometric Reactive Oxygen Metabolites (d-ROMs) and Total Antioxidant Capacity (TAC) tests, respectively, were compared with plasma free (F-MDA) and total (T-MDA) malondialdehyde, both quantified by isotope-dilution-gas chromatography-mass spectrometry (ID-GC-MS). Sensitivity, specificity and cut-off points of T-MDA, F-MDA, d-ROMs and TAC were evaluated by both Receiver Operating Characteristic (ROC) analyses and area under the ROC curve (AUC). Only T-MDA assay showed a clear absence of oxidative stress in controls and significant increase in all patients (AUC 1.00, sensitivity and specificity 100%). Accuracy was good for d-ROMs (AUC 0.87, sensitivity 72.8%, specificity 100%) and F-MDA (AUC 0.82, sensitivity 74.7%, specificity 83.9%), but not high enough for TAC to show in patients impaired antioxidant defense (AUC 0.66, sensitivity 52.0%, specificity 92.9%). This study reveals T-MDA as the best marker to detect oxidative stress, shows the ability of d-ROMs to identify modified oxidative status particularly in the presence of high damages, and evidences the poor TAC performance. d-ROMs and TAC assays could be useful for routine purposes; however, for an accurate clinical data evaluation, their comparison versus a "gold standard method" is required. Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells.

PubMed

Talukdar, Sarmistha; Pradhan, Anjan K; Bhoopathi, Praveen; Shen, Xue-Ning; August, Laura A; Windle, Jolene J; Sarkar, Devanand; Furnari, Frank B; Cavenee, Webster K; Das, Swadesh K; Emdad, Luni; Fisher, Paul B

2018-05-14

Glioma stem cells (GSCs) comprise a small subpopulation of glioblastoma multiforme cells that contribute to therapy resistance, poor prognosis, and tumor recurrence. Protective autophagy promotes resistance of GSCs to anoikis, a form of programmed cell death occurring when anchorage-dependent cells detach from the extracellular matrix. In nonadherent conditions, GSCs display protective autophagy and anoikis-resistance, which correlates with expression of melanoma differentiation associated gene-9/Syntenin (MDA-9) (syndecan binding protein; SDCBP). When MDA-9 is suppressed, GSCs undergo autophagic death supporting the hypothesis that MDA-9 regulates protective autophagy in GSCs under anoikis conditions. MDA-9 maintains protective autophagy through phosphorylation of BCL2 and by suppressing high levels of autophagy through EGFR signaling. MDA-9 promotes these changes by modifying FAK and PKC signaling. Gain-of-function and loss-of-function genetic approaches demonstrate that MDA-9 regulates pEGFR and pBCL2 expression through FAK and pPKC. EGFR signaling inhibits autophagy markers (ATG5, Lamp1, LC3B), helping to maintain protective autophagy, and along with pBCL2 maintain survival of GSCs. In the absence of MDA-9, this protective mechanism is deregulated; EGFR no longer maintains protective autophagy, leading to highly elevated and sustained levels of autophagy and consequently decreased cell survival. In addition, pBCL2 is down-regulated in the absence of MDA-9, leading to cell death in GSCs under conditions of anoikis. Our studies confirm a functional link between MDA-9 expression and protective autophagy in GSCs and show that inhibition of MDA-9 reverses protective autophagy and induces anoikis and cell death in GSCs.

Experiences and perspectives of community health workers from implementing treatment for schistosomiasis using the community directed intervention strategy in an informal settlement in Kisumu City, western Kenya.

PubMed

Odhiambo, Gladys O; Musuva, Rosemary M; Odiere, Maurice R; Mwinzi, Pauline N

2016-09-15

The Community Directed Intervention (CDI) strategy has been used to conduct various health interventions in Africa, including control of Neglected Tropical Diseases (NTDs). Although the CDI approach has shown good results in the control of onchocerciasis and lymphatic filariasis with respect to treatment coverage using community drug distributors, its utility in the control of schistosomiasis among urban poor is yet to be established. Using a longitudinal qualitative study, we explored the experiences, opportunities, challenges as well as recommendations of Community Health Workers (CHWs) after participation in annual mass drug administration (MDA) activities for schistosomiasis using the CDI approach in an urban setting. Unstructured open-ended group discussions were conducted with CHWs after completion of annual MDA activities. Narratives were obtained from CHWs using a digital audio recorder during the group discussions, transcribed verbatim and translated into English where applicable. Thematic decomposition of data was done using ATLAS.ti. software, and themes explored using the principle of interpretative phenomenological analysis (IPA). From the perspective of the CHWs, opportunities for implementing CDI in urban settings, included the presence of CHWs, their supervisory structures and their knowledge of intervention areas, and opportunity to integrate MDA with other health interventions. Several challenges were mentioned with regards to implementing MDA using the CDI strategy among them lack of incentives, fear of side effects, misconceptions regarding treatment and mistrust, difficulties working in unsanitary environmental conditions, insecurity, and insufficient time. A key recommendation in promoting more effective MDA using the CDI approach was allocation of more time to the exercise. Findings from this study support the feasibility of using CDI for implementing MDA for schistosomiasis in informal settlements of urban areas. Extensive community sensitization and provision of incentives may help address the aforementioned challenges associated with implementing MDA using the CDI strategy. Opportunities highlighted in this study may be of value to other programmes that may be considering the adoption of the CDI strategy for rolling out interventions in the urban setting.

Integration of mass drug administration programmes in Nigeria: The challenge of schistosomiasis.

PubMed Central

Richards, Frank O.; Eigege, Abel; Miri, Emmanuel S.; Jinadu, M. Y.; Hopkins, Donald R.

2006-01-01

PROBLEM: Annual mass drug administration (MDA) with safe oral anthelminthic drugs (praziquantel, ivermectin and albendazole) is the strategy for control of onchocerciasis, lymphatic filariasis (LF) and schistosomiasis. District health officers seek to integrate treatment activities in areas of overlapping disease endemicity, but they are faced with having to merge different programmatic guidelines. APPROACH: We proceeded through the three stages of integrated MDA implementation: mapping the distribution of the three diseases at district level; tailoring district training and logistics based on the results of the mapping exercises; and implementing community-based annual health education and mass treatment where appropriate. During the process we identified the "know-do" gaps in the MDA guidelines for each disease that prevented successful integration of these programmes. LOCAL SETTING: An integrated programme launched in 1999 in Plateau and Nasarawa States in central Nigeria, where all three diseases were known to occur. RELEVANT CHANGES: Current guidelines allowed onchocerciasis and LF activities to be integrated, resulting in rapid mapping throughout the two states, and states-wide provision of over 9.3 million combined ivermectin-albendazole treatments for the two diseases between 2000 and 2004. In contrast, schistosomiasis activities could not be effectively integrated because of the more restrictive guidelines, resulting in less than half of the two states being mapped, and delivery of only 701,419 praziquantel treatments for schistosomiasis since 1999. LESSONS LEARNED: Integration of schistosomiasis into other MDA programmes would be helped by amended guidelines leading to simpler mapping, more liberal use of praziquantel and the ability to administer praziquantel simultaneously with ivermectin and albendazole. PMID:16917658

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine1[S

PubMed Central

Gonen, Ayelet; Hansen, Lotte F.; Turner, William W.; Montano, Erica N.; Que, Xuchu; Rafia, Apaїs; Chou, Meng-Yun; Wiesner, Philipp; Tsiantoulas, Dimitrios; Corr, Maripat; VanNieuwenhze, Michael S.; Tsimikas, Sotirios; Binder, Christoph J.; Witztum, Joseph L.; Hartvigsen, Karsten

2014-01-01

Immunization with homologous malondialdehyde (MDA)-modified LDL (MDA-LDL) leads to atheroprotection in experimental models supporting the concept that a vaccine to oxidation-specific epitopes (OSEs) of oxidized LDL could limit atherogenesis. However, modification of human LDL with OSE to use as an immunogen would be impractical for generalized use. Furthermore, when MDA is used to modify LDL, a wide variety of related MDA adducts are formed, both simple and more complex. To define the relevant epitopes that would reproduce the atheroprotective effects of immunization with MDA-LDL, we sought to determine the responsible immunodominant and atheroprotective adducts. We now demonstrate that fluorescent adducts of MDA involving the condensation of two or more MDA molecules with lysine to form malondialdehyde-acetaldehyde (MAA)-type adducts generate immunodominant epitopes that lead to atheroprotective responses. We further demonstrate that a T helper (Th) 2-biased hapten-specific humoral and cellular response is sufficient, and thus, MAA-modified homologous albumin is an equally effective immunogen. We further show that such Th2-biased humoral responses per se are not atheroprotective if they do not target relevant antigens. These data demonstrate the feasibility of development of a small-molecule immunogen that could stimulate MAA-specific immune responses, which could be used to develop a vaccine approach to retard or prevent atherogenesis. PMID:25143462

Mass Spectrometric Evidence of Malonaldehyde and 4-Hydroxynonenal Adductions to Radical-Scavenging Soy Peptides

PubMed Central

Zhao, Jing; Chen, Jing; Zhu, Haining; Xiong, Youling L.

2012-01-01

Antioxidative peptides in food systems are potential targets of lipid oxidation-generated reactive aldehydes, such as malonaldehyde (MDA) and 4-hydroxynonenal (HNE). In this study, covalent modifications on radical-scavenging peptides prepared from soy protein hydrolysate by MDA and HNE were characterized by liquid chromatography–electrospray ionization-mass spectrometry (LC-ESI-MS/MS). MS/MS analyses detected the formation of Schiff base type adducts of MDA on the side chain groups of lysine, histidine, arginine, glutamine, and asparagine residues as well as the N-termini of peptides. MDA also formed a fluorescent product with lysine residues. HNE adducted on lysine residues through Schiff base formation and on histidine, arginine, glutamine, and asparagine residues mainly through Michael addition. In spite of the extensive MDA modification, peptide cross-linking by this potential mechanism was undetectable. PMID:22946674

Population-based coverage survey results following the mass drug administration of azithromycin for the treatment of trachoma in Amhara, Ethiopia.

PubMed

Astale, Tigist; Sata, Eshetu; Zerihun, Mulat; Nute, Andrew W; Stewart, Aisha E P; Gessese, Demelash; Ayenew, Gedefaw; Melak, Berhanu; Chanyalew, Melsew; Tadesse, Zerihun; Callahan, E Kelly; Nash, Scott D

2018-02-01

Trachoma is the leading infectious cause of blindness worldwide. In communities where the district level prevalence of trachomatous inflammation-follicular among children ages 1-9 years is ≥5%, WHO recommends annual mass drug administration (MDA) of antibiotics with the aim of at least 80% coverage. Population-based post-MDA coverage surveys are essential to understand the effectiveness of MDA programs, yet published reports from trachoma programs are rare. In the Amhara region of Ethiopia, a population-based MDA coverage survey was conducted 3 weeks following the 2016 MDA to estimate the zonal prevalence of self-reported drug coverage in all 10 administrative zones. Survey households were selected using a multi-stage cluster random sampling design and all individuals in selected households were presented with a drug sample and asked about taking the drug during the campaign. Zonal estimates were weighted and confidence intervals were calculated using survey procedures. Self-reported drug coverage was then compared with regional reported administrative coverage. Region-wide, 24,248 individuals were enumerated, of which, 20,942 (86.4%) individuals were present. The regional self-reported antibiotic coverage was 76.8% (95%Confidence Interval (CI):69.3-82.9%) in the population overall and 77.4% (95%CI = 65.7-85.9%) among children ages 1-9 years old. Zonal coverage ranged from 67.8% to 90.2%. Five out of 10 zones achieved a coverage >80%. In all zones, the reported administrative coverage was greater than 90% and was considerably higher than self-reported MDA coverage. Main reasons reported for MDA campaign non-attendance included being physically unable to get to MDA site (22.5%), traveling (20.6%), and not knowing about the campaign (21.0%). MDA refusal was low (2.8%) in this population. Although self-reported MDA coverage in Amhara was greater than 80% in some zones, programmatic improvements are warranted throughout Amhara to achieve higher coverage. These results will be used to enhance community mobilization and improve training for MDA distributors and supervisors to improve coverage in future MDAs.

Impact of Six Rounds of Mass Drug Administration on Brugian Filariasis and Soil-Transmitted Helminth Infections in Eastern Indonesia

PubMed Central

Supali, Taniawati; Djuardi, Yenny; Bradley, Mark; Noordin, Rahmah; Rückert, Paul; Fischer, Peter U.

2013-01-01

Background The lymphatic filarial parasite Brugia timori occurs only in eastern Indonesia where it causes high morbidity. The absence of an animal reservoir, the inefficient transmission by Anopheles mosquitoes and the high sensitivity to DEC/albendazole treatment make this species a prime candidate for elimination by mass drug administration (MDA). Methodology/Principal Findings We evaluated the effect of MDA using DEC and albendazole on B. timori and soil transmitted helminths (STH) in a cross-sectional study of a sentinel village on Alor Island annually over a period of 10 years. Pre-MDA the microfilaria (MF) prevalence was 26% and 80% of the residents had filaria-specific IgG4 antibodies. In 2010, 34 months after the 6th round of MDA, MF and antibody rates were only 0.17% and 6.4%, respectively. The MDA campaign had also a beneficial effect on STH. Baseline prevalence rates for Ascaris, hookworm and Trichuris were 34%, 28%, and 11%, respectively; these rates were reduced to 27%, 4%, and 2% one year after the 5th round of MDA. Unfortunately, STH rates rebounded 34 months after cessation of MDA and approached pre-MDA rates. However, the intensity of STH infection in 2009 was still reduced, and no heavy infections were detected. Conclusions/Significance MDA with DEC/albendazole has had a major impact on B. timori MF and IgG4 antibody rates, providing a proof of principle that elimination is feasible. We also documented the value of annual DEC/albendazole as a mass de-worming intervention and the importance of continuing some form of STH control after cessation of MDA for filariasis. PMID:24349595

Impact of six rounds of mass drug administration on Brugian filariasis and soil-transmitted helminth infections in eastern Indonesia.

PubMed

Supali, Taniawati; Djuardi, Yenny; Bradley, Mark; Noordin, Rahmah; Rückert, Paul; Fischer, Peter U

2013-01-01

The lymphatic filarial parasite Brugia timori occurs only in eastern Indonesia where it causes high morbidity. The absence of an animal reservoir, the inefficient transmission by Anopheles mosquitoes and the high sensitivity to DEC/albendazole treatment make this species a prime candidate for elimination by mass drug administration (MDA). We evaluated the effect of MDA using DEC and albendazole on B. timori and soil transmitted helminths (STH) in a cross-sectional study of a sentinel village on Alor Island annually over a period of 10 years. Pre-MDA the microfilaria (MF) prevalence was 26% and 80% of the residents had filaria-specific IgG4 antibodies. In 2010, 34 months after the 6(th) round of MDA, MF and antibody rates were only 0.17% and 6.4%, respectively. The MDA campaign had also a beneficial effect on STH. Baseline prevalence rates for Ascaris, hookworm and Trichuris were 34%, 28%, and 11%, respectively; these rates were reduced to 27%, 4%, and 2% one year after the 5(th) round of MDA. Unfortunately, STH rates rebounded 34 months after cessation of MDA and approached pre-MDA rates. However, the intensity of STH infection in 2009 was still reduced, and no heavy infections were detected. MDA with DEC/albendazole has had a major impact on B. timori MF and IgG4 antibody rates, providing a proof of principle that elimination is feasible. We also documented the value of annual DEC/albendazole as a mass de-worming intervention and the importance of continuing some form of STH control after cessation of MDA for filariasis.

MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma.

PubMed

Das, Swadesh K; Bhutia, Sujit K; Azab, Belal; Kegelman, Timothy P; Peachy, Leyla; Santhekadur, Prasanna K; Dasgupta, Santanu; Dash, Rupesh; Dent, Paul; Grant, Steven; Emdad, Luni; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B

2013-01-15

Melanoma differentiation-associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma, and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, chorioallantoic membrane (CAM) assays and xenograft tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several proangiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/syntenin in which MDA-9/syntenin interacts with the extracellular matrix (ECM), activating Src and FAK resulting in activation by phosphorylation of Akt, which induces hypoxia inducible factor 1-α (HIF-1α). The HIF-1α activates transcription of insulin growth factor-binding protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell nonautonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (nonautonomous).

MDA-9/Syntenin and IGFBP-2 Promote Angiogenesis in Human Melanoma

PubMed Central

Das, Swadesh K.; Bhutia, Sujit K.; Azab, Belal; Kegelman, Timothy P.; Peachy, Leyla; Santhekadur, Prasanna K.; Dasgupta, Santanu; Dash, Rupesh; Dent, Paul; Grant, Steven; Emdad, Luni; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B.

2012-01-01

Melanoma differentiation associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacological approaches were employed to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, CAM assays and xenograft tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several pro-angiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/syntenin in which MDA-9/syntenin interacts with the ECM activating Src and FAK resulting in activation by phosphorylation of Akt, which induces HIF-1α. The HIF-1α activates transcription of Insulin Growth Factor Binding Protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell non-autonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (non-autonomous). PMID:23233738

Effects of malondialdehyde modification on the in vitro digestibility of soy protein isolate.

PubMed

Chen, Nannan; Zhao, Qiangzhong; Sun, Weizheng; Zhao, Mouming

2013-12-11

Soy protein isolate (SPI) was modified by lipid peroxidation product malondialdehyde (MDA), and the in vitro digestibility of modified SPI was investigated. Results indicated that incubation with increasing MDA concentration resulted in significant carbonyl group generation and loss of free amino groups of SPI. Fluorescence loss of natural tryptophan and formation of Schiff base were observed. Noncovalent interaction between molecules was enhanced and became the main force that led to the solubility reduction of MDA-modified SPI. Differential scanning calorimetry (DSC) indicated that SPI had higher thermal stability and lower total calorimetric enthalpy after MDA pretreatment. Electrophoresis showed that β-conglycinin was more sensitive to MDA modification. In vitro digestion indicated that MDA could induce non-disulfide covalent polymer of SPI, which could not be digested by pepsin and pancreatin. β subunits of β-conglycinin became more resistant to digestion with increasing MDA concentration. Evaluation of the free amino acid profile in the digests indicated that MDA-modified SPI had deteriorating nutritive quality.

Impact of the Mass Drug Administration for malaria in response to the Ebola outbreak in Sierra Leone.

PubMed

Aregawi, Maru; Smith, Samuel J; Sillah-Kanu, Musa; Seppeh, John; Kamara, Anitta R Y; Williams, Ryan O; Aponte, John J; Bosman, Andrea; Alonso, Pedro

2016-09-20

As emergency response to the Ebola epidemic, the Government of Sierra Leone and its partners implemented a large-scale Mass Drug Administration (MDA) with artesunate-amodiaquine (ASAQ) covering >2.7 million people in the districts hardest hit by Ebola during December 2014-January 2015. The World Health Organization (WHO) and the National Malaria Control Programme (NMCP) evaluated the impact of the MDA on malaria morbidity at health facilities and the number of Ebola alerts received at District Ebola Command Centres. The coverage of the two rounds of MDA with ASAQ was estimated by relating the number anti-malarial medicines distributed to the estimated resident population. Segmented time-series analysis was applied to weekly data collected from 49 primary health units (PHUs) and 11 hospitals performing malaria parasitological testing during the study period, to evaluate trends of malaria cases and Ebola alerts during the post-MDA weeks compared to the pre-MDA weeks in MDA- and non-MDA-cheifdoms. After two rounds of the MDA, the number of suspected cases tested with rapid diagnostic test (RDT) decreased significantly by 43 % (95 % CI 38-48 %) at week 1 and remained low at week 2 and 3 post-first MDA and at week 1 and 3 post-second MDA; RDT positive cases decreased significantly by 47 % (41-52 %) at week 1 post-first and remained lower throughout all post-MDA weeks; and the RDT test positivity rate (TPR) declined by 35 % (32-38 %) at week 2 and stayed low throughout all post-MDA weeks. The total malaria (clinical + confirmed) cases decreased significantly by 45 % (39-52 %) at week 1 and were lower at week 2 and 3 post-first MDA; and week 1 post-second MDA. The proportion of confirmed malaria cases (out of all-outpatients) fell by 33 % (29-38 %) at week 1 post-first MDA and were lower during all post-MDA weeks. On the contrary, the non-malaria outpatient cases (cases due to other health conditions) either remained unchanged or fluctuated insignificantly. The Ebola alerts decreased by 30 % (13-46 %) at week 1 post-first MDA and much lower during all the weeks post-second MDA. The MDA achieved its goals of reducing malaria morbidity and febrile cases that would have been potentially diagnosed as suspected Ebola cases with increased risk of nosocomial infections. The intervention also helped reduce patient case-load to the severely strained health services at the peak of the Ebola outbreak and malaria transmission. As expected, the effect of the MDA waned in a matter of few weeks and malaria intensity returned to the pre-MDA levels. Nevertheless, the approach was an appropriate public health intervention in the context of the Ebola epidemic even in high malaria transmission areas of Sierra Leone.

Multidrug-resistant malaria and the impact of mass drug administration.

PubMed

Zuber, Janie Anne; Takala-Harrison, Shannon

2018-01-01

Based on the emergence and spread throughout the Greater Mekong Subregion (GMS) of multiple artemisinin-resistant lineages, the prevalence of multidrug resistance leading to high rates of artemisinin-based combination treatment failure in parts of the GMS, and the declining malaria burden in the region, the World Health Organization has recommended complete elimination of falciparum malaria from the GMS. Mass drug administration (MDA) is being piloted as one elimination intervention to be employed as part of this effort. However, concerns remain as to whether MDA might exacerbate the already prevalent problem of multidrug resistance in the region. In this review, we briefly discuss challenges of MDA, the use of MDA in the context of multidrug-resistant malaria, and the potential of different drug combinations and drug-based elimination strategies for mitigating the emergence and spread of resistance.

Pharmacokinetic modeling of 4,4'-methylenedianiline released from reused polyurethane dialyzer potting materials.

PubMed

Do Luu, H M; Hutter, J C

2000-01-01

4, 4'-Methylenedianiline (MDA) is a hydrolysis degradation product that can be released from polyurethanes commonly used in medical device applications. MDA is mutagenic and carcinogenic in animals. In humans, it is hepatotoxic, a known contact and respiratory allergen, and a suspected carcinogen. A physiologically based pharmacokinetic (PBPK) model was developed to estimate the absorption, distribution, metabolism, and excretion of MDA in patients exposed to MDA leached from the potting materials of hemodialyzers. A worst-case reuse situation and a single use case were investigated. The PBPK model included five tissue compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues, and richly perfused tissues. Physiological and chemical parameters of a healthy individual used in the model were obtained from the literature. The model was calibrated using previously published kinetic studies of IV administered doses of (14) C-MDA to rats. The model was validated using independent data published for MDA-exposed workers. The PBPK results indicated that dialysis patients who are exposed to MDA released from dialyzers (new or reused) could accumulate low levels of MDA and metabolites (total MDA) over time. Copyright 2000 John Wiley & Sons, Inc.

Ionizing Radiation Enhances Adenoviral Vector Expressing mda-7/IL-24-mediated Apoptosis in Human Ovarian Cancer

PubMed Central

EMDAD, LUNI; SARKAR, DEVANAND; LEBEDEVA, IRINA V.; SU, ZAO-ZHONG; GUPTA, PANKAJ; MAHASRESHTI, PARAMESHWAR J.; DENT, PAUL; CURIEL, DAVID T.; FISHER, PAUL B.

2007-01-01

Ovarian cancer is the fifth most common cause of cancer-related death in women. Current interventional approaches, including debulking surgery, chemotherapy, and/or radiation have proven minimally effective in preventing the recurrence and/or mortality associated with this malignancy. Subtraction hybridization applied to terminally differentiating human melanoma cells identified melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), whose unique properties include the ability to selectively induce growth suppression, apoptosis, and radiosensitization in diverse cancer cells, without causing any harmful effects in normal cells. Previously, it has been shown that adenovirus-mediated mda-7/IL-24 therapy (Ad.mda-7) induces apoptosis in ovarian cancer cells, however, the apoptosis induction was relatively low. We now document that apoptosis can be enhanced by treating ovarian cancer cells with ionizing radiation (IR) in combination with Ad.mda-7. Additionally, we demonstrate that mda-7/IL-24 gene delivery, under the control of a minimal promoter region of progression elevated gene-3 (PEG-3), which functions selectively in diverse cancer cells with minimal activity in normal cells, displays a selective radiosensitization effect in ovarian cancer cells. The present studies support the use of IR in combination with mda-7/IL-24 as a means of augmenting the therapeutic benefit of this gene in ovarian cancer, particularly in the context of tumors displaying resistance to radiation therapy. PMID:16646087

Chromobacterium haemolyticum sp. nov., a strongly haemolytic species.

PubMed

Han, Xiang Y; Han, Faye S; Segal, Jonathan

2008-06-01

A Gram-negative bacterium, strain MDA0585(T), isolated from a sputum culture, was characterized by a polyphasic approach. The 16S rRNA gene and a conserved portion of the DNA gyrase A gene were sequenced and analysed phylogenetically. Strain MDA0585(T) showed the closest relationships with Chromobacterium violaceum ATCC 12472(T) and Chromobacterium subtsugae PRAA4-1(T) (96.1 % and 96.3 % 16S rRNA gene sequence similarity, respectively). The cellular fatty acids of strain MDA0585(T) consisted mainly of C(16 : 0), C(16 : 1)omega7c and C(16 : 1)omega6c (summed feature 3) and C(18 : 1)omega7c and C(18 : 1)omega6c (summed feature 8), a profile that was similar to, but distinguishable from, those of C. violaceum ATCC 12472(T) and C. subtsugae PRAA4-1(T). In culture, strain MDA0585(T) differed from C. violaceum and C. subtsugae in several ways: lack of violet pigmentation, the ability to haemolyse sheep blood, differences in several biochemical reactions and higher resistance to antibiotics. The culture supernatant of strain MDA0585(T) also caused remarkable haemolysis of human erythrocytes. These results suggest that strain MDA0585(T) represents a novel species within the genus Chromobacterium, for which the name Chromobacterium haemolyticum sp. nov. is proposed. The type strain is MDA0585(T) (=CCUG 53230(T)=JCM 14163(T)=DSM 19808(T)).

Caught in the middle with multiple displacement amplification: the myth of pooling for avoiding multiple displacement amplification bias in a metagenome.

PubMed

Marine, Rachel; McCarren, Coleen; Vorrasane, Vansay; Nasko, Dan; Crowgey, Erin; Polson, Shawn W; Wommack, K Eric

2014-01-30

Shotgun metagenomics has become an important tool for investigating the ecology of microorganisms. Underlying these investigations is the assumption that metagenome sequence data accurately estimates the census of microbial populations. Multiple displacement amplification (MDA) of microbial community DNA is often used in cases where it is difficult to obtain enough DNA for sequencing; however, MDA can result in amplification biases that may impact subsequent estimates of population census from metagenome data. Some have posited that pooling replicate MDA reactions negates these biases and restores the accuracy of population analyses. This assumption has not been empirically tested. Using mock viral communities, we examined the influence of pooling on population-scale analyses. In pooled and single reaction MDA treatments, sequence coverage of viral populations was highly variable and coverage patterns across viral genomes were nearly identical, indicating that initial priming biases were reproducible and that pooling did not alleviate biases. In contrast, control unamplified sequence libraries showed relatively even coverage across phage genomes. MDA should be avoided for metagenomic investigations that require quantitative estimates of microbial taxa and gene functional groups. While MDA is an indispensable technique in applications such as single-cell genomics, amplification biases cannot be overcome by combining replicate MDA reactions. Alternative library preparation techniques should be utilized for quantitative microbial ecology studies utilizing metagenomic sequencing approaches.

Periodic molybdenum disc array for light trapping in amorphous silicon layer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Jiwei; Deng, Changkai; Shanghai Advanced Research Institute, Chinese Academy of Sciences, 99 Haike Road, Shanghai, 201210 China

2016-05-15

We demonstrate the light trapping effect in amorphous silicon (a-Si:H) layer by inserting a layer of periodic molybdenum disc array (MDA) between the a-Si:H layer and the quartz substrate, which forms a three-layer structure of Si/MDA/SiO{sub 2}. The MDA layer was fabricated by a new cost-effective method based on nano-imprint technology. Further light absorption enhancement was realized through altering the topography of MDA by annealing it at 700°C. The mechanism of light absorption enhancement in a-Si:H interfaced with MDA was analyzed, and the electric field distribution and light absorption curve of the different layers in the Si/MDA structure under lightmore » illumination of different wavelengths were simulated by employing numerical finite difference time domain (FDTD) solutions.« less

Utilizing wide area maritime domain awareness (MDA) data to cue a remote surveillance system

NASA Astrophysics Data System (ADS)

Isenor, Anthony W.; Cross, Richard; Webb, Sean; Lapinski, Anna-Liesa S.

2013-10-01

Defence Research and Development Canada - Atlantic (DRDC Atlantic) is currently involved in research on the topic of northern Maritime Domain Awareness (MDA). One project, entitled Situational Information for Enabling Development of Northern Awareness (SEDNA), includes research on the exploitation of MDA data in northern areas. One aspect of this research is to utilize wide area MDA data to provide awareness to an unattended, land-based system. Wide area MDA is attained through the use of space-based AIS (SAIS) data, a data feed used by the Canadian Department of National Defence and supplied by the commercial provider exactEarth Ltd. The land-based surveillance system used is the remote northern system constructed within the DRDC Northern Watch Technology Demonstration Project. Northern Watch is a multi-year project intended to show state-of-the-art, unattended, surveillance capabilities in the Canadian north. The link between the SAIS and Northern Watch is provided by a research infrastructure that consists of an assembly of data sources, users, applications, and product management techniques that collectively support research in areas such as information management and MDA data exploitation. High-level descriptions of the systems are provided along with elaboration on the alerting algorithm, the notifications that would be sent to the Northern Watch southern command site, and the resulting actions that could be taken by the Northern Watch surveillance system.

Dermal uptake and excretion of 4,4'-methylenedianiline during rotor blade production in helicopter industry--an intervention study.

PubMed

Weiss, Tobias; Schuster, Hubert; Müller, Johannes; Schaller, Karl-Heinz; Drexler, Hans; Angerer, Jürgen; Käfferlein, Heiko U

2011-10-01

Workers using composite materials by fibre reinforced laminate technology are exposed to 4,4'-methylenedianiline (MDA), a liver toxicant and suspected human carcinogen, during the production of rotor blades in helicopter industry. The aim of the study presented here was to assess the internal dose of MDA and the suitability of various personal protection measures at the workplace. Ambient monitoring and biological monitoring was carried out by analysing MDA in air and urine samples in seven workers of a highly specialized workplace (rotor blade production). Three different concepts of personal protection measures were applied to study the route of uptake and to evaluate strategies in decreasing workplace exposure. In addition, elimination kinetics of MDA was studied in three workers who were exposed to MDA on three consecutive working days. Ambient monitoring consistently provided air levels at or below the limit of quantification of 0.1 μg m(-3). Nevertheless, MDA was detected in 89% of all post-shift urine samples and median concentration was 4.2 μg l(-1). MDA in urine were >20 times higher than expected on data from ambient monitoring alone. A significant decrease in exposure could be achieved when workers have worn MDA-protective overalls in combination with MDA-protective gloves and a splash protection shield (from 9.8 μg l(-1) down to 3.7 μg l(-1)). The results show that MDA is taken up primarily via the skin at the workplaces under study. The excretion of MDA in urine was observed to be delayed after dermal exposure. Exposure assessment of MDA should be carried out by biological monitoring rather than ambient monitoring. For this purpose, urine samples midweek or at the end of the week should be used based on the observed delay in the excretion of MDA after dermal absorption. Uptake of MDA via the skin could not be completely avoided even if state-of-the-art personal protection measures were applied.

Metabolically Generated Stable Isotope-Labeled Deoxynucleoside Code for Tracing DNA N6-Methyladenine in Human Cells.

PubMed

Liu, Baodong; Liu, Xiaoling; Lai, Weiyi; Wang, Hailin

2017-06-06

DNA N 6 -methyl-2'-deoxyadenosine (6mdA) is an epigenetic modification in both eukaryotes and bacteria. Here we exploited stable isotope-labeled deoxynucleoside [ 15 N 5 ]-2'-deoxyadenosine ([ 15 N 5 ]-dA) as an initiation tracer and for the first time developed a metabolically differential tracing code for monitoring DNA 6mdA in human cells. We demonstrate that the initiation tracer [ 15 N 5 ]-dA undergoes a specific and efficient adenine deamination reaction leading to the loss the exocyclic amine 15 N, and further utilizes the purine salvage pathway to generate mainly both [ 15 N 4 ]-dA and [ 15 N 4 ]-2'-deoxyguanosine ([ 15 N 4 ]-dG) in mammalian genomes. However, [ 15 N 5 ]-dA is largely retained in the genomes of mycoplasmas, which are often found in cultured cells and experimental animals. Consequently, the methylation of dA generates 6mdA with a consistent coding pattern, with a predominance of [ 15 N 4 ]-6mdA. Therefore, mammalian DNA 6mdA can be potentially discriminated from that generated by infecting mycoplasmas. Collectively, we show a promising approach for identification of authentic DNA 6mdA in human cells and determine if the human cells are contaminated with mycoplasmas.

Formalism Challenges of the Cougaar Model Driven Architecture

NASA Technical Reports Server (NTRS)

Bohner, Shawn A.; George, Boby; Gracanin, Denis; Hinchey, Michael G.

2004-01-01

The Cognitive Agent Architecture (Cougaar) is one of the most sophisticated distributed agent architectures developed today. As part of its research and evolution, Cougaar is being studied for application to large, logistics-based applications for the Department of Defense (DoD). Anticipiting future complex applications of Cougaar, we are investigating the Model Driven Architecture (MDA) approach to understand how effective it would be for increasing productivity in Cougar-based development efforts. Recognizing the sophistication of the Cougaar development environment and the limitations of transformation technologies for agents, we have systematically developed an approach that combines component assembly in the large and transformation in the small. This paper describes some of the key elements that went into the Cougaar Model Driven Architecture approach and the characteristics that drove the approach.

Improving Coverage and Compliance in Mass Drug Administration for the Elimination of LF in Two ‘Endgame’ Districts in Indonesia Using Micronarrative Surveys

PubMed Central

Krentel, Alison; Damayanti, Rita; Titaley, Christiana Rialine; Suharno, Nugroho; Bradley, Mark; Lynam, Timothy

2016-01-01

Background As the Global Programme to Eliminate Lymphatic Filariasis (LF) approaches its 2020 goal, an increasing number of districts will enter the endgame phase where drug coverage rates from mass drug administration (MDA) are used to assess whether MDA can be stopped. As reported, the gap between reported and actual drug coverage in some contexts has overestimated the true rates, thus causing premature administration of transmission assessment surveys (TAS) that detect ongoing LF transmission. In these cases, districts must continue with additional rounds of MDA. Two districts in Indonesia (Agam District, Depok City) fit this criteria—one had not met the pre-TAS criteria and the other, had not passed the TAS criteria. In both cases, the district health teams needed insight into their drug delivery programs in order to improve drug coverage in the subsequent MDA rounds. Methodology/Principal Findings To inform the subsequent MDA round, a micronarrative survey tool was developed to capture community members’ experience with MDA and the social realm where drug delivery and compliance occur. A baseline survey was implemented after the 2013 MDA in endemic communities in both districts using the EPI sampling criteria (n = 806). Compliance in the last MDA was associated with perceived importance of the LF drugs for health (p<0.001); perceived safety of the LF drugs (p<0.001) and knowing someone in the household has complied (p<0.001). Results indicated that specialized messages were needed to reach women and younger men. Both districts used these recommendations to implement changes to their MDA without additional financial support. An endline survey was performed after the 2014 MDA using the same sampling criteria (n = 811). Reported compliance in the last MDA improved in both districts from 57% to 77% (p<0.05). Those who reported having ever taken the LF drug rose from 79% to 90% (p<0.001) in both sites. Conclusions/Significance Micronarrative surveys were shown to be a valid and effective tool to detect operational issues within MDA programs. District health staff felt ownership of the results, implementing feasible changes to their programs that resulted in significant improvements to coverage and compliance in the subsequent MDA. This kind of implementation research using a micronarrative survey tool could benefit underperforming MDA programs as well as other disease control programs where a deeper understanding is needed to improve healthcare delivery. PMID:27812107

Real-time analysis of the carbohydrates on cell surfaces using a QCM biosensor: a lectin-based approach.

PubMed

Pei, Zhichao; Saint-Guirons, Julien; Käck, Camilla; Ingemarsson, Björn; Aastrup, Teodor

2012-05-15

A novel approach to the study of molecular interactions on the surface of mammalian cells using a QCM biosensor was developed. For this study, an epidermoid carcinoma cell line (A-431) and a breast adenocarcinoma cell line (MDA-MB-468) were immobilized onto polystyrene-coated quartz crystals. The binding and dissociation between the lectin Con A and the cells as well as the inhibition of the binding by monosaccharides were monitored in real time and provided an insight into the complex avidic recognition of cell glycoconjugates. The real-time lectin screening of a range of lectins, including Con A, DBA, PNA and UEA-I, enabled the accurate study of the glycosylation changes between cells, such as changes associated with cancer progression and development. Furthermore, the kinetic parameters of the interaction of Con A with MDA-MB-468 cells were studied. This application provides investigators in the field of glycobiology with a novel tool to study cell surface glycosylation and may also have impacts on drug discovery. Copyright © 2012 Elsevier B.V. All rights reserved.

The π-Tetrel Bond and its Influence on Hydrogen Bonding and Proton Transfer.

PubMed

Wei, Yuanxin; Li, Qingzhong; Scheiner, Steve

2018-03-19

The positive region that lies above the plane of F 2 TO (T=C and Si) interacts with malondialdehyde (MDA), which contains an intramolecular H-bond. The T atom of F 2 TO can lie either in the MDA molecular plane, forming a T⋅⋅⋅O tetrel bond, or F 2 TO can stack directly above MDA in a parallel arrangement. The former structure is more stable than the latter, and in either case, F 2 SiO engages in a much stronger interaction than does F 2 CO, reaching nearly 200 kJ mol -1 . The π-tetrel bond strengthens/weakens the MDA H-bond when the bond is formed to the hydroxyl/carbonyl group of MDA, and causes an accompanying inhibition/promotion of proton transfer within this H-bond; this effect is stronger for F 2 SiO. These same aspects can be tuned by substituents placed on any of the C atoms of MDA, although their effects are not fully correlated with the electron-withdrawing or electron-releasing properties of the substituent. A new type of π-π tetrel bond occurs when the π-hole on the T atom of F 2 TO approaches the middle carbon atom of MDA from above, and a similar configuration is also found between F 2 TO and benzene. Evidence for extensive C⋅⋅⋅C π-π tetrel bonding in crystal materials is presented. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

No apparent reduction in schistosome burden or genetic diversity following four years of school-based mass drug administration in mwea, central kenya, a heavy transmission area.

PubMed

Lelo, Agola E; Mburu, David N; Magoma, Gabriel N; Mungai, Ben N; Kihara, Jimmy H; Mwangi, Ibrahim N; Maina, Geoffrey M; Kinuthia, Joseph M; Mutuku, Martin W; Loker, Eric S; Mkoji, Gerald M; Steinauer, Michelle L

2014-10-01

Schistosomiasis is a debilitating neglected tropical disease that infects over 200 million people worldwide. To combat this disease, in 2012, the World Health Organization announced a goal of reducing and eliminating transmission of schistosomes. Current control focuses primarily on mass drug administration (MDA). Therefore, we monitored transmission of Schistosoma mansoni via fecal egg counts and genetic markers in a typical school based MDA setting to ascertain the actual impacts of MDA on the targeted schistosome population. For 4 years, we followed 67 children enrolled in a MDA program in Kenya. Infection status and egg counts were measured each year prior to treatment. For 15 of these children, for which there was no evidence of acquired resistance, meaning they became re-infected following each treatment, we collected microsatellite genotype data from schistosomes passed in fecal samples as a representation of the force of transmission between drug treatments. We genotyped a total of 4938 parasites from these children, with an average of 329.2 parasites per child for the entire study, and an average of 82.3 parasites per child per annual examination. We compared prevalence, egg counts, and genetic measures including allelic richness, gene diversity (expected heterozygosity), adult worm burdens and effective number of breeders among time points to search for evidence for a change in transmission or schistosome populations during the MDA program. We found no evidence of reduced transmission or schistosome population decline over the course of the program. Although prevalence declined in the 67 children as it did in the overall program, reinfection rates were high, and for the 15 children studied in detail, schistosome egg counts and estimated adult worm burdens did not decline between years 1 and 4, and genetic diversity increased over the course of drug treatment. School based control programs undoubtedly improve the health of individuals; however, our data show that in an endemic area, such a program has had no obvious effect on reducing transmission or of significantly impacting the schistosome population as sampled by the children we studied in depth. Results like these, in combination with other sources of information, suggest more integrated approaches for interrupting transmission and significantly diminishing schistosome populations will be required to achieve sustainable control.

Single-cell genomic sequencing using Multiple Displacement Amplification.

PubMed

Lasken, Roger S

2007-10-01

Single microbial cells can now be sequenced using DNA amplified by the Multiple Displacement Amplification (MDA) reaction. The few femtograms of DNA in a bacterium are amplified into micrograms of high molecular weight DNA suitable for DNA library construction and Sanger sequencing. The MDA-generated DNA also performs well when used directly as template for pyrosequencing by the 454 Life Sciences method. While MDA from single cells loses some of the genomic sequence, this approach will greatly accelerate the pace of sequencing from uncultured microbes. The genetically linked sequences from single cells are also a powerful tool to be used in guiding genomic assembly of shotgun sequences of multiple organisms from environmental DNA extracts (metagenomic sequences).

Oppenheimer's Box of Chocolates: Remediation of the Manhattan Project Landfill at Los Alamos National Laboratory - 12283

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allen, Donald L.; Ramsey, Susan S.; Finn, Kevin P.

2012-07-01

Material Disposal Area B (MDA B) is the oldest radioactive waste disposal facility at Los Alamos National Laboratory. Operated from 1944-48, MDA B was the disposal facility for the Manhattan Project. Recognized as one of the most challenging environmental remediation projects at Los Alamos, the excavation of MDA B received $110 million from the American Recovery and Reinvestment Act of 2009 to accelerate this complex remediation work. Several factors combined to create significant challenges to remediating the landfill known in the 1940's as the 'contaminated dump'. The secrecy surrounding the Manhattan Project meant that no records were kept of radiologicalmore » materials and chemicals disposed or of the landfill design. An extensive review of historical documents and interviews with early laboratory personnel resulted in a list of hundreds of hazardous chemicals that could have been buried in MDA B. Also, historical reports of MDA B spontaneously combusting on three occasions -with 50-foot flames and pink smoke spewing across the mesa during the last incident in 1948-indicated that hazardous materials were likely present in MDA B. To complicate matters further, though MDA B was located on an isolated mesa in the 1940's, the landfill has since been surrounded by a Los Alamos commercial district. The local newspaper, hardware store and a number of other businesses are located directly across the street from MDA B. This close proximity to the public and the potential for hazardous materials in MDA B necessitated conducting remediation work within protective enclosures. Potential chemical hazards and radiological inventory were better defined using a minimally intrusive sampling method called direct push technology (DPT) prior to excavation. Even with extensive sampling and planning the project team encountered many surprises and challenges during the project. The one area where planning did not fail to meet reality was safety. There were no serious worker injuries and the minor injuries recorded were those common to construction type activities. Extensive monitoring along the site boundary demonstrated that no hazardous chemicals were released and radiological dose to the public was within administrative limits. More than three years of effort by the LANL project team went into the planning for remediation of Material Disposal Area B. Hundreds of historical documents were reviewed; retired personnel were extensively interviewed and noninvasive techniques were used to characterize the site. The information collected was incorporated into the safety requirements, cost estimate, schedule and primary execution plan for the project. Ultimately the waste volume managed by the project approached 40000 m{sup 3}, more than double the original project estimate. This increase had a major impact on both project cost and schedule. Nuclear safety requirements for the project were based on an estimated MDA B radionuclide inventory of 12 PE-Ci. When excavation was complete over 123 PE-Ci had been removed from the trenches. The radionuclide inventory at MDA B was an order of magnitude higher than estimated. Work at MDA B could not have proceeded without the safety basis exemption from DOE-HQ. The one area where planning did not fail to meet reality was safety. There were no serious worker injuries and the minor injuries recorded were those common to construction type activities. Extensive monitoring along the site boundary demonstrated that no hazardous chemicals were released and radiological dose to the public was within administrative limits. (authors)« less

Obesity And Laboratory Diets Affects Tissue Malondialdehyde (MDA) Levels In Obese Rats

NASA Astrophysics Data System (ADS)

Chowdhury, Parimal; Scott, Joseph; Holley, Andy; Hakkak, Reza

2010-04-01

This study was conducted to investigate the interaction of obesity and laboratory diets on tissue malondialdehyde levels in rats. Female Zucker obese and lean rats were maintained on either regular grain-based diet or purified casein diet for two weeks, orally gavaged at day 50 with 65 mg/kg DMBA and sacrificed 24 hrs later. Malondialdehyde (MDA) levels were measured in blood and harvested tissues. Data were recorded as mean ± SEM and analyzed statistically. Results show that the obese group on purified casein diet had reduction of MDA levels in the brain, duodenum, liver, lung and kidney tissues as compared to lean group, p <0.05. Obese group on grain-based diet showed significant increase in MDA levels only in the duodenum, p <0.05. We conclude that dietary intervention differentially affects the oxidative markers in obese rats. It appears that purified casein diets were more effective than grain-based diet in reduction of oxidative stress in obese rats.

The Effect of Compliance on the Impact of Mass Drug Administration for Elimination of Lymphatic Filariasis in Egypt

PubMed Central

El-Setouhy, Maged; Abd Elaziz, Khaled M.; Helmy, Hanan; Farid, Hoda A.; Kamal, Hussein A.; Ramzy, Reda M. R.; Shannon, William D.; Weil, Gary J.

2008-01-01

We studied effects of compliance on the impact of mass drug administration (MDA) with diethylcarbamazine and albendazole for lymphatic filariasis (LF) in an Egyptian village. Baseline microfilaremia (mf) and filarial antigenemia rates were 11.5% and 19.0%, respectively. The MDA compliance rates were excellent (> 85%). However, individual compliance was highly variable; 7.4% of those surveyed after five rounds of MDA denied having ever taken the medications and 52.4% reported that they had taken all five doses. The mf and antigenemia rates were 0.2% and 2.7% in those who reported five doses of MDA and 8.3% and 13.8% in those who reported zero doses. There was no significant difference in residual infection rates among those who had taken two or more doses. These results underscore the importance of compliance for LF elimination programs based on MDA and suggest that two ingested doses of MDA are as effective as five doses for reducing filariasis infection rates. PMID:18165524

Measurement by reversed-phase high-performance liquid chromatography of malondialdehyde in normal human urine following derivatisation with 2,4-dinitrophenylhydrazine.

PubMed

Korchazhkina, Olga; Exley, Christopher; Andrew Spencer, Stephen

2003-09-05

A selective and sensitive method based on derivatisation with 2,4-dinitrophenylhydrazine (DNPH) and consecutive HPLC gradient separation is described for the determination of malondialdehyde (MDA) in urine. Preparation of urine samples involved a one-step derivatisation/extraction procedure. Separation was achieved using a Waters SymmetryC(18) column (3.9 x 150 mm) and linear gradient of acetonitrile in water (from 30% to 70% in 30 min). The overall detection limit of the method was 56 nM of MDA in urine. The recovery of MDA was 94.3+/-8.6%. MDA in urine of healthy volunteers, measured using the method of standard additions, was 0.019+/-0.012 microM/mmol creatinine. MDA in the same samples measured using the 2-thiobarbituric acid (TBA) assay was 0.181+/-0.063 microM/mmol creatinine. We demonstrate that the commonly used TBA assay in conjunction with HPLC may overestimate the MDA concentration in human urine by almost 10-fold.

Chemoprevention gene therapy (CGT) of pancreatic cancer using perillyl alcohol and a novel chimeric serotype cancer terminator virus.

PubMed

Sarkar, S; Azab, B; Quinn, B A; Shen, X; Dent, P; Klibanov, A L; Emdad, L; Das, S K; Sarkar, D; Fisher, P B

2014-01-01

Conditionally replication competent adenoviruses (Ads) that selectively replicate in cancer cells and simultaneously express a therapeutic cytokine, such as melanoma differentiation associated gene- 7/Interleukin-24 (mda-7/IL-24), a Cancer Terminator Virus (CTV-M7), hold potential for treating human cancers. To enhance the efficacy of the CTV-M7, we generated a chimeric Ad.5 and Ad.3 modified fiber bipartite CTV (Ad.5/3-CTV-M7) that can infect tumor cells in a Coxsackie Adenovirus receptor (CAR) independent manner, while retaining high infectivity in cancer cells containing high CAR. Although mda-7/IL-24 displays broad-spectrum anticancer properties, pancreatic ductal adenocarcinoma (PDAC) cells display an intrinsic resistance to mda-7/IL-24-mediated killing due to an mda-7/IL-24 mRNA translational block. However, using a chemoprevention gene therapy (CGT) approach with perillyl alcohol (POH) and a replication incompetent Ad to deliver mda-7/IL-24 (Ad.mda-7) there is enhanced conversion of mda-7/IL-24 mRNA into protein resulting in pancreatic cancer cell death in vitro and in vivo in nude mice containing human PDAC xenografts. This combination synergistically induces mda-7/IL-24-mediated cancer-specific apoptosis by inhibiting anti-apoptotic Bcl-xL and Bcl-2 protein expression and inducing an endoplasmic reticulum (ER) stress response through induction of BiP/GRP-78, which is most evident in chimeric-modified non-replicating Ad.5/3- mda-7- and CTV-M7-infected PDAC cells. Moreover, Ad.5/3-CTV-M7 in combination with POH sensitizes therapy-resistant MIA PaCa-2 cell lines over-expressing either Bcl-2 or Bcl-xL to mda-7/IL-24-mediated apoptosis. Ad.5/3-CTV-M7 plus POH also exerts a significant antitumor 'bystander' effect in vivo suppressing both primary and distant site tumor growth, confirming therapeutic utility of Ad.5/3-CTV-M7 plus POH in PDAC treatment, where all other current treatment strategies in clinical settings show minimal efficacy.

miR-429 mediates δ-tocotrienol-induced apoptosis in triple-negative breast cancer cells by targeting XIAP

PubMed Central

Wang, Chen; Ju, Hong; Shen, Chunyan; Tong, Zhongsheng

2015-01-01

Vitamin E δ-tocotrienol has been reported to possess anticancer activity both in vitro and in vivo. However, the underlying molecular mechanisms of δ-tocotrienol induced apoptosis in triple-negative breast cancer are not fully understood. Here, we reported that microRNA-429 (miR-429) is up-regulated in two TNBC cell lines (MDA-MB-231 and MDA-MB-468), treated with δ-tocotrienol. Inhibition of miR-429 may partially rescue the apoptosis induced by δ-tocotrienol in MDA-MB-231 cells. We also showed that the forced expression of miR-429 was sufficient to lead to apoptosis in MDA-MB-231 cells. Furthermore, we identified X-linked inhibitor of apoptosis protein (XIAP) as one of miR-429’s target genes. These results suggest that the activation of miR-429 by δ-tocotrienol may be an effective approach for the prevention and treatment of triple-negative breast cancer. PMID:26629059

Pilot assessment of soil-transmitted helminthiasis in the context of transmission assessment surveys for lymphatic filariasis in Benin and Tonga.

PubMed

Chu, Brian K; Gass, Katherine; Batcho, Wilfrid; 'Ake, Malakai; Dorkenoo, Améyo M; Adjinacou, Elvire; Mafi, 'Eva; Addiss, David G

2014-02-01

Mass drug administration (MDA) for lymphatic filariasis (LF) programs has delivered more than 2 billion treatments of albendazole, in combination with either ivermectin or diethylcarbamazine, to communities co-endemic for soil-transmitted helminthiasis (STH), reducing the prevalence of both diseases. A transmission assessment survey (TAS) is recommended to determine if MDA for LF can be stopped within an evaluation unit (EU) after at least five rounds of annual treatment. The TAS also provides an opportunity to simultaneously assess the impact of these MDAs on STH and to determine the frequency of school-based MDA for STH after community-wide MDA is no longer needed for LF. Pilot studies conducted in Benin and Tonga assessed the feasibility of a coordinated approach. Of the schools (clusters) selected for a TAS in each EU, a subset of 5 schools per STH ecological zone was randomly selected, according to World Health Organization (WHO) guidelines, for the coordinated survey. In Benin, 519 children were sampled in 5 schools and 22 (4.2%) had STH infection (A. lumbricoides, T. trichiura, or hookworm) detected using the Kato-Katz method. All infections were classified as light intensity under WHO criteria. In Tonga, 10 schools were chosen for the coordinated TAS and STH survey covering two ecological zones; 32 of 232 (13.8%) children were infected in Tongatapu and 82 of 320 (25.6%) in Vava'u and Ha'apai. All infections were light-intensity with the exception of one with moderate-intensity T. trichiura. Synchronous assessment of STH with TAS is feasible and provides a well-timed evaluation of infection prevalence to guide ongoing treatment decisions at a time when MDA for LF may be stopped. The coordinated field experiences in both countries also suggest potential time and cost savings. Refinement of a coordinated TAS and STH sampling methodology should be pursued, along with further validation of alternative quantitative diagnostic tests for STH that can be used with preserved stool specimens.

Advanced space-based InSAR risk analysis of planned and existing transportation infrastructure.

DOT National Transportation Integrated Search

2017-03-21

The purpose of this document is to summarize activities by Stanford University and : MDA Geospatial Services Inc. (MDA) to estimate surface deformation and associated : risk to transportation infrastructure using SAR Interferometric methods for the :...

Maritime domain awareness community of interest net centric information sharing

NASA Astrophysics Data System (ADS)

Andress, Mark; Freeman, Brian; Rhiddlehover, Trey; Shea, John

2007-04-01

This paper highlights the approach taken by the Maritime Domain Awareness (MDA) Community of Interest (COI) in establishing an approach to data sharing that seeks to overcome many of the obstacles to sharing both within the federal government and with international and private sector partners. The approach uses the DOD Net Centric Data Strategy employed through Net Centric Enterprise Services (NCES) Service Oriented Architecture (SOA) foundation provided by Defense Information Systems Agency (DISA), but is unique in that the community is made up of more than just Defense agencies. For the first pilot project, the MDA COI demonstrated how four agencies from DOD, the Intelligence Community, Department of Homeland Security (DHS), and Department of Transportation (DOT) could share Automatic Identification System (AIS) data in a common format using shared enterprise service components.

Assessment of a Novel Approach to Identify Trichiasis Cases Using Community Treatment Assistants in Tanzania.

PubMed

Greene, Gregory S; West, Sheila K; Mkocha, Harran; Munoz, Beatriz; Merbs, Shannath L

2015-12-01

Simple surgical intervention advocated by the World Health Organization can alleviate trachomatous trichiasis (TT) and prevent subsequent blindness. A large backlog of TT cases remain unidentified and untreated. To increase identification and referral of TT cases, a novel approach using standard screening questions, a card, and simple training for Community Treatment Assistants (CTAs) to use during Mass Drug Administration (MDA) was developed and evaluated in Kongwa District, a trachoma-endemic area of central Tanzania. A community randomized trial was conducted in 36 communities during MDA. CTAs in intervention villages received an additional half-day of training and a TT screening card in addition to the training received by CTAs in villages assigned to usual care. All MDA participants 15 years and older were screened for TT, and senior TT graders confirmed case status by evaluating all screened-positive cases. A random sample of those screened negative for TT and those who did not present at MDA were also evaluated by the master graders. Intervention CTAs identified 5.6 times as many cases (n = 50) as those assigned to usual care (n = 9, p < 0.05). While specificity was above 90% for both groups, the sensitivity for the novel screening tool was 31.2% compared to 5.6% for the usual care group (p < 0.05). CTAs appear to be viable resources for the identification of TT cases. Additional training and use of a TT screening card significantly increased the ability of CTAs to recognize and refer TT cases during MDA; however, further efforts are needed to improve case detection and reduce the number of false positive cases.

Anti-MDA5 autoantibodies in juvenile dermatomyositis identify a distinct clinical phenotype: a prospective cohort study

PubMed Central

2014-01-01

Introduction The aim of this study was to define the frequency and associated clinical phenotype of anti-MDA5 autoantibodies in a large UK based, predominantly Caucasian, cohort of patients with juvenile dermatomyositis (JDM). Methods Serum samples and clinical data were obtained from 285 patients with JDM recruited to the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-MDA5 antibodies was determined by immunoprecipitation and confirmed by ELISA using recombinant MDA5 protein. Results were compared with matched clinical data, muscle biopsies (scored by an experienced paediatric neuropathologist) and chest imaging (reviewed by an experienced paediatric radiologist). Results Anti-MDA5 antibodies were identified in 7.4% of JDM patients and were associated with a distinct clinical phenotype including skin ulceration (P = 0.03) oral ulceration (P = 0.01), arthritis (P <0.01) and milder muscle disease both clinically (as determined by Childhood Myositis Assessment Score (P = 0.03)) and histologically (as determined by a lower JDM muscle biopsy score (P <0.01)) than patients who did not have anti-MDA5 antibodies. A greater proportion of children with anti-MDA5 autoantibodies achieved disease inactivity at two years post-diagnosis according to PRINTO criteria (P = 0.02). A total of 4 out of 21 children with anti-MDA5 had interstitial lung disease; none had rapidly progressive interstitial lung disease. Conclusions Anti-MDA5 antibodies can be identified in a small but significant proportion of patients with JDM and identify a distinctive clinical sub-group. Screening for anti-MDA5 autoantibodies at diagnosis would be useful to guide further investigation for lung disease, inform on prognosis and potentially confirm the diagnosis, as subtle biopsy changes could otherwise be missed. PMID:24989778

Metabolic Study of Cancer Cells Using a pH Sensitive Hydrogel Nanofiber Light Addressable Potentiometric Sensor.

PubMed

Shaibani, Parmiss Mojir; Etayash, Hashem; Naicker, Selvaraj; Kaur, Kamaljit; Thundat, Thomas

2017-01-27

We report a simple, fast, and cost-effective approach that measures cancer cell metabolism and their response to anticancer drugs in real time. Using a Light Addressable Potentiometric Sensor integrated with pH sensitive hydrogel nanofibers (NF-LAPS), we detect localized changes in pH of the media as cancer cells consume glucose and release lactate. NF-LAPS shows a sensitivity response of 74 mV/pH for cancer cells. Cancer cells (MDA MB231) showed a response of ∼0.4 unit change in pH compared to virtually no change observed for normal cells (MCF10A). We also observed a drop in pH for the multidrug-resistant cancer cells (MDA-MB-435MDR) in the presence of doxorubicin. However, inhibition of the metabolic enzymes such as hexokinase and lactate dehydrogenase-A suggested an improvement in the efficacy of doxorubicin by decreasing the level of acidification. This approach, based on extracellular acidification, enhances our understanding of cancer cell metabolic modes and their response to chemotherapies, which will help in the development of better treatments, including choice of drugs and dosages.

Systematic evaluation of bias in microbial community profiles induced by whole genome amplification.

PubMed

Direito, Susana O L; Zaura, Egija; Little, Miranda; Ehrenfreund, Pascale; Röling, Wilfred F M

2014-03-01

Whole genome amplification methods facilitate the detection and characterization of microbial communities in low biomass environments. We examined the extent to which the actual community structure is reliably revealed and factors contributing to bias. One widely used [multiple displacement amplification (MDA)] and one new primer-free method [primase-based whole genome amplification (pWGA)] were compared using a polymerase chain reaction (PCR)-based method as control. Pyrosequencing of an environmental sample and principal component analysis revealed that MDA impacted community profiles more strongly than pWGA and indicated that this related to species GC content, although an influence of DNA integrity could not be excluded. Subsequently, biases by species GC content, DNA integrity and fragment size were separately analysed using defined mixtures of DNA from various species. We found significantly less amplification of species with the highest GC content for MDA-based templates and, to a lesser extent, for pWGA. DNA fragmentation also interfered severely: species with more fragmented DNA were less amplified with MDA and pWGA. pWGA was unable to amplify low molecular weight DNA (< 1.5 kb), whereas MDA was inefficient. We conclude that pWGA is the most promising method for characterization of microbial communities in low-biomass environments and for currently planned astrobiological missions to Mars. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

Assessing the feasibility of interrupting the transmission of soil-transmitted helminths through mass drug administration: The DeWorm3 cluster randomized trial protocol.

PubMed

Ásbjörnsdóttir, Kristjana Hrönn; Ajjampur, Sitara S Rao; Anderson, Roy M; Bailey, Robin; Gardiner, Iain; Halliday, Katherine E; Ibikounle, Moudachirou; Kalua, Khumbo; Kang, Gagandeep; Littlewood, D Timothy J; Luty, Adrian J F; Means, Arianna Rubin; Oswald, William; Pullan, Rachel L; Sarkar, Rajiv; Schär, Fabian; Szpiro, Adam; Truscott, James E; Werkman, Marleen; Yard, Elodie; Walson, Judd L

2018-01-01

Current control strategies for soil-transmitted helminths (STH) emphasize morbidity control through mass drug administration (MDA) targeting preschool- and school-age children, women of childbearing age and adults in certain high-risk occupations such as agricultural laborers or miners. This strategy is effective at reducing morbidity in those treated but, without massive economic development, it is unlikely it will interrupt transmission. MDA will therefore need to continue indefinitely to maintain benefit. Mathematical models suggest that transmission interruption may be achievable through MDA alone, provided that all age groups are targeted with high coverage. The DeWorm3 Project will test the feasibility of interrupting STH transmission using biannual MDA targeting all age groups. Study sites (population ≥80,000) have been identified in Benin, Malawi and India. Each site will be divided into 40 clusters, to be randomized 1:1 to three years of twice-annual community-wide MDA or standard-of-care MDA, typically annual school-based deworming. Community-wide MDA will be delivered door-to-door, while standard-of-care MDA will be delivered according to national guidelines. The primary outcome is transmission interruption of the STH species present at each site, defined as weighted cluster-level prevalence ≤2% by quantitative polymerase chain reaction (qPCR), 24 months after the final round of MDA. Secondary outcomes include the endline prevalence of STH, overall and by species, and the endline prevalence of STH among children under five as an indicator of incident infections. Secondary analyses will identify cluster-level factors associated with transmission interruption. Prevalence will be assessed using qPCR of stool samples collected from a random sample of cluster residents at baseline, six months after the final round of MDA and 24 months post-MDA. A smaller number of individuals in each cluster will be followed with annual sampling to monitor trends in prevalence and reinfection throughout the trial. ClinicalTrials.gov NCT03014167.

Costs of testing for ocular Chlamydia trachomatis infection compared to mass drug administration for trachoma in the Gambia: application of results from the PRET study.

PubMed

Harding-Esch, Emma; Jofre-Bonet, Mireia; Dhanjal, Jaskiran K; Burr, Sarah; Edwards, Tansy; Holland, Martin; Sillah, Ansumana; West, Sheila; Lietman, Tom; Keenan, Jeremy; Mabey, David; Bailey, Robin

2015-04-01

Mass drug administration (MDA) treatment of active trachoma with antibiotic is recommended to be initiated in any district where the prevalence of trachoma inflammation, follicular (TF) is ≥ 10% in children aged 1-9 years, and then to continue for at least three annual rounds before resurvey. In The Gambia the PRET study found that discontinuing MDA based on testing a sample of children for ocular Chlamydia trachomatis(Ct) infection after one MDA round had similar effects to continuing MDA for three rounds. Moreover, one round of MDA reduced disease below the 5% TF threshold. We compared the costs of examining a sample of children for TF, and of testing them for Ct, with those of MDA rounds. The implementation unit in PRET The Gambia was a census enumeration area (EA) of 600-800 people. Personnel, fuel, equipment, consumables, data entry and supervision costs were collected for census and treatment of a sample of EAs and for the examination, sampling and testing for Ct infection of 100 individuals within them. Programme costs and resource savings from testing and treatment strategies were inferred for the 102 EAs in the study area, and compared. Census costs were $103.24 per EA plus initial costs of $108.79. MDA with donated azithromycin cost $227.23 per EA. The mean cost of examining and testing 100 children was $796.90 per EA, with Ct testing kits costing $4.80 per result. A strategy of testing each EA for infection is more expensive than two annual rounds of MDA unless the kit cost is less than $1.38 per result. However stopping or deciding not to initiate treatment in the study area based on testing a sample of EAs for Ct infection (or examining children in a sample of EAs) creates savings relative to further unnecessary treatments. Resources may be saved by using tests for chlamydial infection or clinical examination to determine that initial or subsequent rounds of MDA for trachoma are unnecessary.

Costs of Testing for Ocular Chlamydia trachomatis Infection Compared to Mass Drug Administration for Trachoma in The Gambia: Application of Results from the PRET Study

PubMed Central

Harding-Esch, Emma; Jofre-Bonet, Mireia; Dhanjal, Jaskiran K.; Burr, Sarah; Edwards, Tansy; Holland, Martin; Sillah, Ansumana; West, Sheila; Lietman, Tom; Keenan, Jeremy; Mabey, David; Bailey, Robin

2015-01-01

Background Mass drug administration (MDA) treatment of active trachoma with antibiotic is recommended to be initiated in any district where the prevalence of trachoma inflammation, follicular (TF) is ≥10% in children aged 1–9 years, and then to continue for at least three annual rounds before resurvey. In The Gambia the PRET study found that discontinuing MDA based on testing a sample of children for ocular Chlamydia trachomatis(Ct) infection after one MDA round had similar effects to continuing MDA for three rounds. Moreover, one round of MDA reduced disease below the 5% TF threshold. We compared the costs of examining a sample of children for TF, and of testing them for Ct, with those of MDA rounds. Methods The implementation unit in PRET The Gambia was a census enumeration area (EA) of 600–800 people. Personnel, fuel, equipment, consumables, data entry and supervision costs were collected for census and treatment of a sample of EAs and for the examination, sampling and testing for Ct infection of 100 individuals within them. Programme costs and resource savings from testing and treatment strategies were inferred for the 102 EAs in the study area, and compared. Results Census costs were $103.24 per EA plus initial costs of $108.79. MDA with donated azithromycin cost $227.23 per EA. The mean cost of examining and testing 100 children was $796.90 per EA, with Ct testing kits costing $4.80 per result. A strategy of testing each EA for infection is more expensive than two annual rounds of MDA unless the kit cost is less than $1.38 per result. However stopping or deciding not to initiate treatment in the study area based on testing a sample of EAs for Ct infection (or examining children in a sample of EAs) creates savings relative to further unnecessary treatments. Conclusion Resources may be saved by using tests for chlamydial infection or clinical examination to determine that initial or subsequent rounds of MDA for trachoma are unnecessary. PMID:25901349

Systematic assessment of the performance of whole-genome amplification for SNP/CNV detection and β-thalassemia genotyping.

PubMed

He, Fei; Zhou, Wanjun; Cai, Ren; Yan, Tizhen; Xu, Xiangmin

2018-04-01

In this study, we aimed to assess the performance of two whole-genome amplification methods, multiple displacement amplification (MDA), and multiple annealing and looping-based amplification cycle (MALBAC), for β-thalassemia genotyping and single-nucleotide polymorphism (SNP)/copy-number variant (CNV) detection using two DNA sequencing assays. We collected peripheral blood, cell lines, and discarded embryos, and carried out MALBAC and MDA on single-cell and five-cell samples. We detected and statistically analyzed differences in the amplification efficiency, positive predictive value, sensitivity, allele dropout (ADO) rate, SNPs, and CV values between the two methods. Through Sanger sequencing at the single-cell and five-cell levels, we showed that both the amplification rate and ADO rate of MDA were better than those using MALBAC, and the sensitivity and positive predictive value obtained from MDA were higher than those from MALBAC for β-thalassemia genotyping. Using next-generation sequencing (NGS) at the single-cell level, we confirmed that MDA has better properties than MALBAC for SNP detection. However, MALBAC was more stable and homogeneous than MDA using low-depth NGS at the single-cell level for CNV detection. We conclude that MALBAC is the better option for CNV detection, while MDA is better suited for SNV detection.

Effects of human arylamine N-acetyltransferase I knockdown in triple-negative breast cancer cell lines

PubMed Central

Tiang, Jacky M; Butcher, Neville J; Minchin, Rodney F

2015-01-01

Expression of human arylamine N-acetyltransferase I (NAT1) has been associated with various cancer subtypes and inhibition of this enzyme with small molecule inhibitors or siRNA affects cell growth and survival. Here, we have investigated the role of NAT1 in the invasiveness of breast cancer cells both in vitro and in vivo. We knocked down NAT1 using a lentivirus-based shRNA approach and observed marked changes in cell morphology in the triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-436, and BT-549. Most notable was a reduction in the number and size of the filopodia protrusions on the surface of the cells. The loss of filopodia could be rescued by the reintroduction of NAT1 into the knockdown cells. NAT1 expression was localized to the lamellipodia and extended into the filopodia protrusions. In vitro invasion through Geltrex was significantly inhibited in both the MDA cell lines but not in the BT-549 cells. The expression of Snail increased when NAT1 was knocked down, while other genes associated with mesenchymal to epithelial transition (vimentin, cytokeratin-18, and Twist) did not show any changes. By contrast, both N-cadherin and β-catenin were significantly reduced. When MDA-MB-231 cells expressing shRNA were injected in vivo into BALB/c nu/nu nude mice, a significant reduction in the number of colonies that formed in the lungs was observed. Taken together, the results show that NAT1 can alter the invasion and metastatic properties of some triple-negative breast cancer cells but not all. The study suggests that NAT1 may be a novel therapeutic target in a subset of breast cancers. PMID:25627111

Effects of human arylamine N-acetyltransferase I knockdown in triple-negative breast cancer cell lines.

PubMed

Tiang, Jacky M; Butcher, Neville J; Minchin, Rodney F

2015-04-01

Expression of human arylamine N-acetyltransferase I (NAT1) has been associated with various cancer subtypes and inhibition of this enzyme with small molecule inhibitors or siRNA affects cell growth and survival. Here, we have investigated the role of NAT1 in the invasiveness of breast cancer cells both in vitro and in vivo. We knocked down NAT1 using a lentivirus-based shRNA approach and observed marked changes in cell morphology in the triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-436, and BT-549. Most notable was a reduction in the number and size of the filopodia protrusions on the surface of the cells. The loss of filopodia could be rescued by the reintroduction of NAT1 into the knockdown cells. NAT1 expression was localized to the lamellipodia and extended into the filopodia protrusions. In vitro invasion through Geltrex was significantly inhibited in both the MDA cell lines but not in the BT-549 cells. The expression of Snail increased when NAT1 was knocked down, while other genes associated with mesenchymal to epithelial transition (vimentin, cytokeratin-18, and Twist) did not show any changes. By contrast, both N-cadherin and β-catenin were significantly reduced. When MDA-MB-231 cells expressing shRNA were injected in vivo into BALB/c nu/nu nude mice, a significant reduction in the number of colonies that formed in the lungs was observed. Taken together, the results show that NAT1 can alter the invasion and metastatic properties of some triple-negative breast cancer cells but not all. The study suggests that NAT1 may be a novel therapeutic target in a subset of breast cancers. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Novel targets for sensitizing breast cancer cells to TRAIL-induced apoptosis with siRNA delivery.

PubMed

Thapa, Bindu; Bahadur Kc, Remant; Uludağ, Hasan

2018-02-01

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in variety of cancer cells without affecting most normal cells, which makes it a promising agent for cancer therapy. However, TRAIL therapy is clinically not effective due to resistance induction. To identify novel regulators of TRAIL that can aid in therapy, protein targets whose silencing sensitized breast cancer cells against TRAIL were screened with an siRNA library against 446 human apoptosis-related proteins in MDA-231 cells. Using a cationic lipopolymer (PEI-αLA) for delivery of library members, 16 siRNAs were identified that sensitized the TRAIL-induced death in MDA-231 cells. The siRNAs targeting BCL2L12 and SOD1 were further evaluated based on the novelty and their ability to sensitize TRAIL induced cell death. Silencing both targets sensitized TRAIL-mediated cell death in MDA-231 cells as well as TRAIL resistant breast cancer cells, MCF-7. Combination of TRAIL and siRNA silencing BCL2L12 had no effect in normal human umbilical vein cells and human bone marrow stromal cell. The silencing of BCL2L12 and SOD1 enhanced TRAIL-mediated apoptosis in MDA-231 cells via synergistically activating capsase-3 activity. Hence, here we report siRNAs targeting BCL2L12 and SOD1 as a novel regulator of TRAIL-induced cell death in breast cancer cells, providing a new approach for enhancing TRAIL therapy for breast cancer. The combination of siRNA targeting BCL2L12 and TRAIL can be a highly effective synergistic pair in breast cancer cells with minimal effect on the non-transformed cells. © 2017 UICC.

Inhibition of SIRT1 by a small molecule induces apoptosis in breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalle, Arunasree M., E-mail: arunasreemk@ilsresearch.org; Mallika, A.; Badiger, Jayasree

2010-10-08

Research highlights: {yields} Novel small molecule SIRT1 inhibitor better than sirtinol. {yields} IC{sub 50} 500 nM. {yields} Specific tumor cytotoxicity towards breast cancer cells. {yields} Restoration of H3K9 acetylation levels to baseline when co-treated with SIRT1 activator (Activator X) and inhibitor (ILS-JGB-1741). -- Abstract: Overexpression of SIRT1, a NAD{sup +}-dependent class III histone deacetylases (HDACs), is implicated in many cancers and therefore could become a promising antitumor target. Here we demonstrate a small molecule SIRT1 inhibitor, ILS-JGB-1741(JGB1741) with potent inhibitory effects on the proliferation of human metastatic breast cancer cells, MDA-MB 231. The molecule has been designed using medicinal chemistrymore » approach based on known SIRT1 inhibitor, sirtinol. The molecule showed a significant inhibition of SIRT1 activity compared to sirtinol. Studies on the antitumor effects of JGB on three different cancer cell lines, K562, HepG2 and MDA-MB 231 showed an IC{sub 50} of 1, 10 and 0.5 {mu}M, respectively. Further studies on MDA-MB 231 cells showed a dose-dependent increase in K9 and K382 acetylation of H3 and p53, respectively. Results also demonstrated that JGB1741-induced apoptosis is associated with increase in cytochrome c release, modulation in Bax/Bcl2 ratio and cleavage of PARP. Flowcytometric analysis showed increased percentage of apoptotic cells, decrease in mitochondrial membrane potential and increase in multicaspase activation. In conclusion, the present study indicates the potent apoptotic effects of JGB1741 in MDA-MB 231 cells.« less

Antitumour effects of PLC-gamma1-(SH2)2-TAT fusion proteins on EGFR/c-erbB-2-positive breast cancer cells.

PubMed

Katterle, Y; Brandt, B H; Dowdy, S F; Niggemann, B; Zänker, K S; Dittmar, T

2004-01-12

Due to its pivotal role in the growth factor-mediated tumour cell migration, the adaptor protein phospholipase C-gamma1 (PLC-gamma1) is an appropriate target to block ultimately the spreading of EGFR/c-erbB-2-positive tumour cells, thereby minimising metastasis formation. Here, we present an approach to block PLC-gamma1 activity by using protein-based PLC-gamma1 inhibitors consisting of PLC-gamma1 SH2 domains, which were fused to the TAT-transduction domain to ensure a high protein transduction efficiency. Two proteins were generated containing one PLC-gamma1-SH2-domain (PS1-TAT) or two PLC-gamma1-SH2 domains (PS2-TAT). PS2-TAT treatment of the EGFR/c-erbB-2-positive cell line MDA-HER2 resulted in a reduction of the EGF-mediated PLC-gamma1 tyrosine phosphorylation of about 30%, concomitant with a complete abrogation of the EGF-driven calcium influx. In addition to this, long-term PS2-TAT treatment both reduces the EGF-mediated migration of about 75% combined with a markedly decreased time locomotion of single MDA-HER2 cells as well as decreases the proliferation of MDA-HER2 cells by about 50%. Due to its antitumoral capacity on EGFR/c-erbB-2-positive breast cancer cells, we conclude from our results that the protein-based PLC-gamma1 inhibitor PS2-TAT may be a means for novel adjuvant antitumour strategies to minimise metastasis formation because of the blockade of cell migration and proliferation.

Investigating the Effectiveness of Current and Modified World Health Organization Guidelines for the Control of Soil-Transmitted Helminth Infections.

PubMed

Farrell, Sam H; Coffeng, Luc E; Truscott, James E; Werkman, Marleen; Toor, Jaspreet; de Vlas, Sake J; Anderson, Roy M

2018-06-01

Considerable efforts have been made to better understand the effectiveness of large-scale preventive chemotherapy therapy for the control of morbidity caused by infection with soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura, and the 2 hookworm species, Necator americanus and Ancylostoma duodenale. Current World Health Organization (WHO) guidelines for STH control include mass drug administration (MDA) programs based on prevalence measurements, aiming at reducing morbidity in pre-school-aged children (pre-SAC) and school-aged children (SAC) by lowering the prevalence of moderate- to heavy-intensity infections to <1%. We project the likely impact of following the current WHO guidelines and assess whether the WHO morbidity goals will be achieved across a range of transmission settings. We also investigate modifications that could be made to the current WHO treatment guidelines, and project their potential impacts in achieving morbidity and transmission control. While the standard guidelines are sufficient at low transmission levels, community-wide treatment (ie, involving pre-SAC, SAC, and adults) is essential if WHO morbidity goals are to be met in moderate- to high-transmission settings. Moreover, removing the recommendation of decreasing the treatment frequency at midline (5-6 years after the start of MDA) further improves the likelihood of achieving morbidity control in SAC. We meld analyses based on 2 mathematical models of parasite transmission and control by MDA for the dominant STH species, to generate a unified treatment approach applicable across all settings, regardless of which STH infection is most common. We recommend clearly defined changes to the current WHO guidelines.

The Mediterranean diet adherence by pregnant women delivering prematurely: association with size at birth and complications of prematurity.

PubMed

Parlapani, Elisavet; Agakidis, Charalampos; Karagiozoglou-Lampoudi, Thomais; Sarafidis, Kosmas; Agakidou, Eleni; Athanasiadis, Apostolos; Diamanti, Elisavet

2017-11-13

The Mediterranean diet (MD) is associated with decreased risk of metabolic syndrome and gestational diabetes due to the anti-inflammatory and antioxidative properties of its components. The aim was to investigate the potential association of MD adherence (MDA) during pregnancy by mothers delivering prematurely, with intrauterine growth as expressed by neonates' anthropometry at birth and complications of prematurity. This is a single-center, prospective, observational cohort study of 82 women who delivered preterm singletons at post conceptional age (PCA) ≤ 34 weeks and their live-born neonates. Maternal and neonatal demographic and clinical data were recorded. All mothers filled in a food frequency questionnaire, and the MDA score was calculated. Based on 50th centile of MD score, participants were classified into high-MDA and low-MDA groups. The low-MDA mothers had significantly higher pregestational BMI and rates of overweight/obesity (odd ratios (OR) 3.5) and gestational hypertension/preeclampsia (OR 3.8). Neonates in the low-MDA group had significantly higher incidence of intrauterine growth restriction (IUGR) (OR 3.3) and lower z-scores of birth weight and BMI. Regarding prematurity-related complications, the low MDA-group was more likely to develop necrotizing enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity (OR 3.2, 1.3, and 1.6, respectively), while they were less likely to develop respiratory distress syndrome (OR 0.49), although the differences were not statistically significant. However, adjustment for confounders revealed MDA as a significant independent predictor of hypertension/preeclampsia, IUGR, birth weight z-score, necrotizing enterocolitis, and bronchopulmonary dysplasia. High MDA during pregnancy may favorably affect intrauterine growth and certain acute and chronic complications of prematurity as well as maternal hypertension/preeclampsia.

A well-refined in vitro model derived from human embryonic stem cell for screening phytochemicals with midbrain dopaminergic differentiation-boosting potential for improving Parkinson's disease.

PubMed

Hsieh, Wen-Ting; Chiang, Been-Huang

2014-07-09

Stimulation of endogenous neurogenesis is a potential approach to compensate for loss of dopaminergic neurons of substantia nigra compacta nigra (SNpc) in patients with Parkinson's disease (PD). This objective was to establish an in vitro model by differentiating pluripotent human embryonic stem cells (hESCs) into midbrain dopaminergic (mDA) neurons for screening phytochemicals with mDA neurogenesis-boosting potentials. Consequently, a five-stage differentiation process was developed. The derived cells expressed many mDA markers including tyrosine hydroxylase (TH), β-III tubulin, and dopamine transporter (DAT). The voltage-gated ion channels and dopamine release were also examined for verifying neuron function, and the dopamine receptor agonists bromocriptine and 7-hydroxy-2-(dipropylamino)tetralin (7-OH-DPAT) were used to validate our model. Then, several potential phytochemicals including green tea catechins and ginsenosides were tested using the model. Finally, ginsenoside Rb1 was identified as the most potent phytochemical which is capable of upregulating neurotrophin expression and inducing mDA differentiation.

Enhanced situational awareness in the maritime domain: an agent-based approach for situation management

NASA Astrophysics Data System (ADS)

Brax, Christoffer; Niklasson, Lars

2009-05-01

Maritime Domain Awareness is important for both civilian and military applications. An important part of MDA is detection of unusual vessel activities such as piracy, smuggling, poaching, collisions, etc. Today's interconnected sensorsystems provide us with huge amounts of information over large geographical areas which can make the operators reach their cognitive capacity and start to miss important events. We propose and agent-based situation management system that automatically analyse sensor information to detect unusual activity and anomalies. The system combines knowledge-based detection with data-driven anomaly detection. The system is evaluated using information from both radar and AIS sensors.

Effects of maternally-derived antibodies on serologic responses to vaccination in kittens.

PubMed

Digangi, Brian A; Levy, Julie K; Griffin, Brenda; Reese, Michael J; Dingman, Patricia A; Tucker, Sylvia J; Dubovi, Edward J

2012-02-01

The optimal vaccination protocol to induce immunity in kittens with maternal antibodies is unknown. The objective of this study was to determine the effects of maternally-derived antibody (MDA) on serologic responses to vaccination in kittens. Vaccination with a modified live virus (MLV) product was more effective than an inactivated (IA) product at inducing protective antibody titers (PAT) against feline panleukopenia virus (FPV). IA vaccination against feline herpesvirus-1 (FHV) and feline calicivirus (FCV) was more effective in the presence of low MDA than high MDA. Among kittens with low MDA, MLV vaccination against FCV was more effective than IA vaccination. A total of 15%, 44% and 4% of kittens had insufficient titers against FPV, FHV and FCV, respectively, at 17 weeks of age. Serologic response to vaccination of kittens varies based on vaccination type and MDA level. In most situations, MLV vaccination should be utilized and protocols continued beyond 14 weeks of age to optimize response by all kittens.

RGD Peptide Cell-Surface Display Enhances the Targeting and Therapeutic Efficacy of Attenuated Salmonella-mediated Cancer Therapy.

PubMed

Park, Seung-Hwan; Zheng, Jin Hai; Nguyen, Vu Hong; Jiang, Sheng-Nan; Kim, Dong-Yeon; Szardenings, Michael; Min, Jung Hyun; Hong, Yeongjin; Choy, Hyon E; Min, Jung-Joon

2016-01-01

Bacteria-based anticancer therapies aim to overcome the limitations of current cancer therapy by actively targeting and efficiently removing cancer. To achieve this goal, new approaches that target and maintain bacterial drugs at sufficient concentrations during the therapeutic window are essential. Here, we examined the tumor tropism of attenuated Salmonella typhimurium displaying the RGD peptide sequence (ACDCRGDCFCG) on the external loop of outer membrane protein A (OmpA). RGD-displaying Salmonella strongly bound to cancer cells overexpressing αvβ3, but weakly bound to αvβ3-negative cancer cells, suggesting the feasibility of displaying a preferential homing peptide on the bacterial surface. In vivo studies revealed that RGD-displaying Salmonellae showed strong targeting efficiency, resulting in the regression in αvβ3-overexpressing cancer xenografts, and prolonged survival of mouse models of human breast cancer (MDA-MB-231) and human melanoma (MDA-MB-435). Thus, surface engineering of Salmonellae to display RGD peptides increases both their targeting efficiency and therapeutic effect.

Selenium Nanoparticles Induce the Chemo-Sensitivity of Fluorouracil Nanoparticles in Breast and Colon Cancer Cells.

PubMed

Abd-Rabou, Ahmed A; Shalby, Aziza B; Ahmed, Hanaa H

2018-05-11

Drug resistance is a major challenge of breast and colon cancer therapies leading to treatment failure. The main objective of the current study is to investigate whether selenium nanoparticles (nano-Se) can induce the chemo-sensitivity of 5-fluorouracil (FU)-encapsulated poly (D, L-lactide-co-glycolide) nanoparticles (nano-FU) in breast and colon cancer cell lines. Nano-Se and nano-FU were synthesized and characterized, then applied individually or in combination upon MCF7, MDA-MB-231, HCT 116, and Caco-2 cancerous cell lines. Cytotoxicity, cellular glucose uptake, and apoptosis, as well as malondialdehyde (MDA), nitric oxide (NO), and zinc (Zn) levels, were investigated upon the different treatments. We have resulted that nano-FU induced cell death in MCF7 and Caco-2 more effectively than MDA-MB-231 and HCT 116 cell lines. Moreover, nano-FU plus nano-Se potentiate MCF7 and Caco-2 chemo-sensitivity were higher than MDA-MB-231 and HCT 116 cancerous cell lines. It is relevant to note that Se and FU nano-formulations inhibited cancer cell bioenergetics via glucose uptake slight blockage. Furthermore, nano-FU increased the levels of NO and MDA in media over cancer cells, while their combinations with nano-Se rebalance the redox status with Zn increment. We noticed that MCF7 cell line is sensitive, while MDA-MB-231 cell line is resistant to Se and nano-Se. This novel approach could be of great potential to enhance the chemo-sensitivity in breast and colon cancer cells.

Pentameric procyanidin from Theobroma cacao selectively inhibits growth of human breast cancer cells.

PubMed

Ramljak, Danica; Romanczyk, Leo J; Metheny-Barlow, Linda J; Thompson, Nicole; Knezevic, Vladimir; Galperin, Mikhail; Ramesh, Arun; Dickson, Robert B

2005-04-01

A naturally occurring, cocoa-derived pentameric procyanidin (pentamer) was previously shown to cause G0/G1 cell cycle arrest in human breast cancer cells by an unknown molecular mechanism. Here, we show that pentamer selectively inhibits the proliferation of human breast cancer cells (MDA MB-231, MDA MB-436, MDA MB-468, SKBR-3, and MCF-7) and benzo(a)pyrene-immortalized 184A1N4 and 184B5 cells. In contrast, normal human mammary epithelial cells in primary culture and spontaneously immortalized MCF-10A cells were significantly resistant. We evaluated whether this differential response to pentamer may involve depolarization of the mitochondrial membrane. Pentamer caused significant depolarization of mitochondrial membrane in MDA MB231 cells but not the more normal MCF-10A cells, whereas other normal and tumor cell lines tested gave variable results. Further investigations, using a proteomics approach with pentamer-treated MDA MB-231, revealed a specific dephosphorylation, without changes in protein expression, of several G1-modulatory proteins: Cdc2 (at Tyr15), forkhead transcription factor (at Ser256, the Akt phosphorylation site) and p53 (Ser392). Dephosphorylation of p53 (at Ser392) by pentamer was confirmed in MDA MB-468 cells. However, both expression and phosphorylation of retinoblastoma protein were decreased after pentamer treatment. Our results show that breast cancer cells are selectively susceptible to the cytotoxic effects of pentameric procyanidin, and suggest that inhibition of cellular proliferation by this compound is associated with the site-specific dephosphorylation or down-regulation of several cell cycle regulatory proteins.

Are Alternative Strategies Required to Accelerate the Global Elimination of Lymphatic Filariasis? Insights From Mathematical Models

PubMed Central

Stolk, Wilma A; Prada, Joaquin M; Smith, Morgan E; Kontoroupis, Periklis; de Vos, Anneke S; Touloupou, Panayiota; Irvine, Michael A; Brown, Paul; Subramanian, Swaminathan; Kloek, Marielle; Michael, E; Hollingsworth, T Deirdre; de Vlas, Sake J

2018-01-01

Abstract Background With the 2020 target year for elimination of lymphatic filariasis (LF) approaching, there is an urgent need to assess how long mass drug administration (MDA) programs with annual ivermectin + albendazole (IA) or diethylcarbamazine + albendazole (DA) would still have to be continued, and how elimination can be accelerated. We addressed this using mathematical modeling. Methods We used 3 structurally different mathematical models for LF transmission (EPIFIL, LYMFASIM, TRANSFIL) to simulate trends in microfilariae (mf) prevalence for a range of endemic settings, both for the current annual MDA strategy and alternative strategies, assessing the required duration to bring mf prevalence below the critical threshold of 1%. Results Three annual MDA rounds with IA or DA and good coverage (≥65%) are sufficient to reach the threshold in settings that are currently at mf prevalence <4%, but the required duration increases with increasing mf prevalence. Switching to biannual MDA or employing triple-drug therapy (ivermectin, diethylcarbamazine, and albendazole [IDA]) could reduce program duration by about one-third. Optimization of coverage reduces the time to elimination and is particularly important for settings with a history of poorly implemented MDA (low coverage, high systematic noncompliance). Conclusions Modeling suggests that, in several settings, current annual MDA strategies will be insufficient to achieve the 2020 LF elimination targets, and programs could consider policy adjustment to accelerate, guided by recent monitoring and evaluation data. Biannual treatment and IDA hold promise in reducing program duration, provided that coverage is good, but their efficacy remains to be confirmed by more extensive field studies. PMID:29860286

Are Alternative Strategies Required to Accelerate the Global Elimination of Lymphatic Filariasis? Insights From Mathematical Models.

PubMed

Stolk, Wilma A; Prada, Joaquin M; Smith, Morgan E; Kontoroupis, Periklis; de Vos, Anneke S; Touloupou, Panayiota; Irvine, Michael A; Brown, Paul; Subramanian, Swaminathan; Kloek, Marielle; Michael, E; Hollingsworth, T Deirdre; de Vlas, Sake J

2018-06-01

With the 2020 target year for elimination of lymphatic filariasis (LF) approaching, there is an urgent need to assess how long mass drug administration (MDA) programs with annual ivermectin + albendazole (IA) or diethylcarbamazine + albendazole (DA) would still have to be continued, and how elimination can be accelerated. We addressed this using mathematical modeling. We used 3 structurally different mathematical models for LF transmission (EPIFIL, LYMFASIM, TRANSFIL) to simulate trends in microfilariae (mf) prevalence for a range of endemic settings, both for the current annual MDA strategy and alternative strategies, assessing the required duration to bring mf prevalence below the critical threshold of 1%. Three annual MDA rounds with IA or DA and good coverage (≥65%) are sufficient to reach the threshold in settings that are currently at mf prevalence <4%, but the required duration increases with increasing mf prevalence. Switching to biannual MDA or employing triple-drug therapy (ivermectin, diethylcarbamazine, and albendazole [IDA]) could reduce program duration by about one-third. Optimization of coverage reduces the time to elimination and is particularly important for settings with a history of poorly implemented MDA (low coverage, high systematic noncompliance). Modeling suggests that, in several settings, current annual MDA strategies will be insufficient to achieve the 2020 LF elimination targets, and programs could consider policy adjustment to accelerate, guided by recent monitoring and evaluation data. Biannual treatment and IDA hold promise in reducing program duration, provided that coverage is good, but their efficacy remains to be confirmed by more extensive field studies.

Small molecule inhibition of arylamine N-acetyltransferase Type I inhibits proliferation and invasiveness of MDA-MB-231 breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tiang, Jacky M.; Butcher, Neville J., E-mail: n.butcher@uq.edu.au; Minchin, Rodney F.

2010-02-26

Arylamine N-acetyltransferase 1 is a phase II metabolizing enzyme that has been associated with certain breast cancer subtypes. While it has been linked to breast cancer risk because of its role in the metabolic activation and detoxification of carcinogens, recent studies have suggested it may be important in cell growth and survival. To address the possible importance of NAT1 in breast cancer, we have used a novel small molecule inhibitor (Rhod-o-hp) of the enzyme to examine growth and invasion of the breast adenocarcinoma line MDA-MB-231. The inhibitor significantly reduced cell growth by increasing the percent of cells in G2/M phasemore » of the cell cycle. Rhod-o-hp also reduced the ability of the MDA-MB-231 cells to grow in soft agar. Using an in vitro invasion assay, the inhibitor significantly reduced the invasiveness of the cells. To test whether this effect was due to inhibition of NAT1, the enzyme was knocked down using a lentivirus-based shRNA approach and invasion potential was significantly reduced. Taken together, the results of this study demonstrate that NAT1 activity may be important in breast cancer growth and metastasis. The study suggests that NAT1 is a novel target for breast cancer treatment.« less

[Development of POCT and medical digital assistant for primary medical healthcare].

PubMed

Shi, Jun; Yan, Zhuang-Zhi; Pan, Zhi-Hao

2008-01-01

In this paper, we discuss the meaning, advantages and methods of applying the point of care testing (POCT) and medical digital assistant (MDA) to primary healthcare services. We also introduce the development of the POCT and MDA based on the electronic health record(EHR) system.

Assessing the feasibility of interrupting the transmission of soil-transmitted helminths through mass drug administration: The DeWorm3 cluster randomized trial protocol

PubMed Central

Ajjampur, Sitara S. Rao; Anderson, Roy M.; Bailey, Robin; Gardiner, Iain; Halliday, Katherine E.; Ibikounle, Moudachirou; Kalua, Khumbo; Kang, Gagandeep; Littlewood, D. Timothy J.; Luty, Adrian J. F.; Means, Arianna Rubin; Oswald, William; Pullan, Rachel L.; Sarkar, Rajiv; Schär, Fabian; Szpiro, Adam; Truscott, James E.; Werkman, Marleen; Yard, Elodie; Walson, Judd L.

2018-01-01

Current control strategies for soil-transmitted helminths (STH) emphasize morbidity control through mass drug administration (MDA) targeting preschool- and school-age children, women of childbearing age and adults in certain high-risk occupations such as agricultural laborers or miners. This strategy is effective at reducing morbidity in those treated but, without massive economic development, it is unlikely it will interrupt transmission. MDA will therefore need to continue indefinitely to maintain benefit. Mathematical models suggest that transmission interruption may be achievable through MDA alone, provided that all age groups are targeted with high coverage. The DeWorm3 Project will test the feasibility of interrupting STH transmission using biannual MDA targeting all age groups. Study sites (population ≥80,000) have been identified in Benin, Malawi and India. Each site will be divided into 40 clusters, to be randomized 1:1 to three years of twice-annual community-wide MDA or standard-of-care MDA, typically annual school-based deworming. Community-wide MDA will be delivered door-to-door, while standard-of-care MDA will be delivered according to national guidelines. The primary outcome is transmission interruption of the STH species present at each site, defined as weighted cluster-level prevalence ≤2% by quantitative polymerase chain reaction (qPCR), 24 months after the final round of MDA. Secondary outcomes include the endline prevalence of STH, overall and by species, and the endline prevalence of STH among children under five as an indicator of incident infections. Secondary analyses will identify cluster-level factors associated with transmission interruption. Prevalence will be assessed using qPCR of stool samples collected from a random sample of cluster residents at baseline, six months after the final round of MDA and 24 months post-MDA. A smaller number of individuals in each cluster will be followed with annual sampling to monitor trends in prevalence and reinfection throughout the trial. Trial registration ClinicalTrials.gov NCT03014167 PMID:29346377

Pilot Assessment of Soil-Transmitted Helminthiasis in the Context of Transmission Assessment Surveys for Lymphatic Filariasis in Benin and Tonga

PubMed Central

Chu, Brian K.; Gass, Katherine; Batcho, Wilfrid; 'Ake, Malakai; Dorkenoo, Améyo M.; Adjinacou, Elvire; Mafi, 'Eva; Addiss, David G.

2014-01-01

Background Mass drug administration (MDA) for lymphatic filariasis (LF) programs has delivered more than 2 billion treatments of albendazole, in combination with either ivermectin or diethylcarbamazine, to communities co-endemic for soil-transmitted helminthiasis (STH), reducing the prevalence of both diseases. A transmission assessment survey (TAS) is recommended to determine if MDA for LF can be stopped within an evaluation unit (EU) after at least five rounds of annual treatment. The TAS also provides an opportunity to simultaneously assess the impact of these MDAs on STH and to determine the frequency of school-based MDA for STH after community-wide MDA is no longer needed for LF. Methodology/Principal Findings Pilot studies conducted in Benin and Tonga assessed the feasibility of a coordinated approach. Of the schools (clusters) selected for a TAS in each EU, a subset of 5 schools per STH ecological zone was randomly selected, according to World Health Organization (WHO) guidelines, for the coordinated survey. In Benin, 519 children were sampled in 5 schools and 22 (4.2%) had STH infection (A. lumbricoides, T. trichiura, or hookworm) detected using the Kato-Katz method. All infections were classified as light intensity under WHO criteria. In Tonga, 10 schools were chosen for the coordinated TAS and STH survey covering two ecological zones; 32 of 232 (13.8%) children were infected in Tongatapu and 82 of 320 (25.6%) in Vava'u and Ha'apai. All infections were light-intensity with the exception of one with moderate-intensity T. trichiura. Conclusions Synchronous assessment of STH with TAS is feasible and provides a well-timed evaluation of infection prevalence to guide ongoing treatment decisions at a time when MDA for LF may be stopped. The coordinated field experiences in both countries also suggest potential time and cost savings. Refinement of a coordinated TAS and STH sampling methodology should be pursued, along with further validation of alternative quantitative diagnostic tests for STH that can be used with preserved stool specimens. PMID:24551267

Characterization and optimization of the magnetron directional amplifier

NASA Astrophysics Data System (ADS)

Hatfield, Michael Craig

Many applications of microwave wireless power transmission (WPT) are dependent upon a high-powered electronically-steerable phased array composed of many radiating modules. The phase output from the high-gain amplifier in each module must be accurately controlled if the beam is to be properly steered. A highly reliable, rugged, and inexpensive design is essential for making WPT applications practical. A conventional microwave oven magnetron may be combined with a ferrite circulator and other external circuitry to create such a system. By converting it into a two-port amplifier, the magnetron is capable of delivering at least 30 dB of power gain while remaining phase-locked to the input signal over a wide frequency range. The use of the magnetron in this manner is referred to as a MDA (Magnetron Directional Amplifier). The MDA may be integrated with an inexpensive slotted waveguide array (SWA) antenna to form the Electronically-Steerable Phased Array Module (ESPAM). The ESPAM provides a building block approach to creating phased arrays for WPT. The size and shape of the phased array may be tailored to satisfy a diverse range of applications. This study provided an in depth examination into the capabilities of the MDA/ESPAM. The basic behavior of the MDA was already understood, as well as its potential applicability to WPT. The primary objective of this effort was to quantify how well the MDA could perform in this capacity. Subordinate tasks included characterizing the MDA behavior in terms of its system inputs, optimizing its performance, performing sensitivity analyses, and identifying operating limitations. A secondary portion of this study examined the suitability of the ESPAM in satisfying system requirements for the solar power satellite (SPS). Supporting tasks included an analysis of SPS requirements, modeling of the SWA antenna, and the demonstration of a simplified phased array constructed of ESPAM elements. The MDA/ESPAM is well suited for use as an amplifier or an element in a WPT phased array, providing over 75% efficiency and a fractional bandwidth exceeding 1.7% at 2.45 GHz. The results of this effort provide the WPT design engineer with tools to predict the MDA's optimum performance and limitations.

The cost of antibiotic mass drug administration for trachoma control in a remote area of South Sudan.

PubMed

Kolaczinski, Jan H; Robinson, Emily; Finn, Timothy P

2011-10-01

Mass drug administration (MDA) of antibiotics is a key component of the so-called "SAFE" strategy for trachoma control, while MDA of anthelminthics provides the cornerstone for control of a number of other neglected tropical diseases (NTDs). Simultaneous delivery of two or more of these drugs, renowned as "integrated NTD control," is being promoted to reduce costs and expand intervention coverage. A cost analysis was conducted alongside an MDA campaign in a remote trachoma endemic area, to inform budgeting for NTD control in South Sudan. A first round of antibiotic MDA was conducted in the highly trachoma endemic county of Mayom, Unity state, from June to August 2010. A core team of seven staff delivered the intervention, including recruitment and training of 44 supervisors and 542 community drug distributors. Using an ingredients approach, financial and economic costs were captured from the provider perspective in a detailed costing database. Overall, 123,760 individuals were treated for trachoma, resulting in an estimated treatment coverage of 94%. The economic cost per person treated was USD 1.53, excluding the cost of the antibiotic azithromycin. Ninety four per cent of the delivery costs were recurrent costs, with personnel and travel/transport costs taking up the largest share. In a remote setting and for the initial round, MDA of antibiotics was considerably more expensive than USD 0.5 per person treated, an estimate frequently quoted to advocate for integrated NTD control. Drug delivery costs in South Sudan are unlikely to decrease substantially during subsequent MDA rounds, as the major cost drivers were recurrent costs. MDA campaigns for delivery of one or more drugs in South Sudan should thus be budgeted at around USD 1.5 per person treated, at least until further costing data for delivery of other NTD drugs, singly or in combination, are available.

A simple graphene-based pipette tip solid-phase extraction of malondialdehyde from human plasma and its determination by spectrofluorometry.

PubMed

Kaykhaii, Massoud; Yahyavi, Hossain; Hashemi, Mohammad; Khoshroo, Mohammad Reza

2016-07-01

Determination of malondialdehyde (MDA) in human blood plasma is important because of its role as a biomarker of lipid peroxidation in biological and medical sciences. In this work, a miniaturized graphene-based pipette tip solid-phase extraction technique was developed for very efficient extraction of MDA as its dithiobarbituric acid (TBA) adduct from human plasma. Two milligrams of graphene as sorbent were placed into a pipette tip and MDA-TBA compound was extracted and preconcentrated by it, after 4 repeated aspirating/dispensing cycles, then the column was eluted with 80 μL of dimethyl sulfoxide by 4 repeated aspirating/dispensing cycles and elusion was measured spectrofluorimetrically. Various effective parameters such as type and volume of eluent solvent, temperature, sample volume, number of cycles of extraction and desorption, derivatization reaction time, and pH of the sample solution were investigated and optimized. Under optimum conditions, a linear calibration curve was obtained in the range of 0.5-90 μg L(-1) (r (2) = 0.991) with a detection limit of 0.3 μg L(-1). The relative standard deviations for 8 replicate measurements of 10 and 40 μg L(-1) of MDA were found to be 4.51 and 3.78 % respectively. The developed protocol was successfully applied to the determination of MDA in a human blood plasma sample. Graphical Abstract A simple graphene-based pipette tip solid-phase extraction of malondialdehyde from human plasma and its determination by spectrofluorometry.

Unique methods for on-orbit structural repair, maintenance, and assembly

NASA Technical Reports Server (NTRS)

Anderson, Ray; Fuson, Phil

1994-01-01

This paper reviews the MDA independent research and development (IRAD) efforts since 1986 in the development of two distinctly different approaches to on-orbit tube repair: (1) one-piece mechanical tube fittings that are forced, under pressure, onto the tube outer surface to effect the repair; and (2) electron beam weldings as demonstrated with the Paton-developed universal hand tool (UHT) space welding system for the repair of fluid lines and tubular components. Other areas of potential on-orbit repair using the UHT include damage to the flat or curved surfaces of habitation modules and truss assemblies. This paper will also address MDA evaluation of the Paton UHT system for on-orbit coating, cleaning, brazing, and cutting of metals. MDA development of an on-orbit compatible nondestructive evaluation (NDE) system for the inspection of tube welds is an important part of this complete space welding capability and will be discussed in a separate paper.

Malondialdehyde epitopes as targets of immunity and the implications for atherosclerosis

PubMed Central

Binder, Christoph J.

2018-01-01

Accumulating evidence suggests that oxidation-specific epitopes (OSEs) constitute a novel class of damage-associated molecular patterns (DAMPs) generated during high oxidative stress but also in the physiological process of apoptosis. To deal with the potentially harmful consequences of such epitopes, the immune system has developed several mechanisms to protect from OSEs and to orchestrate their clearance, including IgM natural antibodies and both cellular and membrane-bound receptors. Here, we focus on malondialdehyde (MDA) epitopes as prominent examples of OSEs that trigger both innate and adaptive immune responses. First, we review the mechanism of MDA generation, the different types of adducts on various biomolecules and provide relevant examples for physiological carriers of MDA such as apoptotic cells, microvesicles (MV) or oxidized low-density lipoproteins (LDL). Based on recent insights, we argue that MDA epitopes contribute to the maintenance of homeostatic functions by acting as markers of elevated oxidative stress and tissue damage. We discuss multiple lines of evidence that MDA epitopes are pro-inflammatory and thus important targets of innate and adaptive immune responses. Finally, we illustrate the relevance of MDA epitopes in human pathologies by describing their capacity to drive inflammatory processes in atherosclerosis and highlighting protective mechanisms of immunity that could be exploited for therapeutic purposes. PMID:27235680

Mechanism of chimera formation during the Multiple Displacement Amplification reaction.

PubMed

Lasken, Roger S; Stockwell, Timothy B

2007-04-12

Multiple Displacement Amplification (MDA) is a method used for amplifying limiting DNA sources. The high molecular weight amplified DNA is ideal for DNA library construction. While this has enabled genomic sequencing from one or a few cells of unculturable microorganisms, the process is complicated by the tendency of MDA to generate chimeric DNA rearrangements in the amplified DNA. Determining the source of the DNA rearrangements would be an important step towards reducing or eliminating them. Here, we characterize the major types of chimeras formed by carrying out an MDA whole genome amplification from a single E. coli cell and sequencing by the 454 Life Sciences method. Analysis of 475 chimeras revealed the predominant reaction mechanisms that create the DNA rearrangements. The highly branched DNA synthesized in MDA can assume many alternative secondary structures. DNA strands extended on an initial template can be displaced becoming available to prime on a second template creating the chimeras. Evidence supports a model in which branch migration can displace 3'-ends freeing them to prime on the new templates. More than 85% of the resulting DNA rearrangements were inverted sequences with intervening deletions that the model predicts. Intramolecular rearrangements were favored, with displaced 3'-ends reannealing to single stranded 5'-strands contained within the same branched DNA molecule. In over 70% of the chimeric junctions, the 3' termini had initiated priming at complimentary sequences of 2-21 nucleotides (nts) in the new templates. Formation of chimeras is an important limitation to the MDA method, particularly for whole genome sequencing. Identification of the mechanism for chimera formation provides new insight into the MDA reaction and suggests methods to reduce chimeras. The 454 sequencing approach used here will provide a rapid method to assess the utility of reaction modifications.

Mechanism of chimera formation during the Multiple Displacement Amplification reaction

PubMed Central

Lasken, Roger S; Stockwell, Timothy B

2007-01-01

Background Multiple Displacement Amplification (MDA) is a method used for amplifying limiting DNA sources. The high molecular weight amplified DNA is ideal for DNA library construction. While this has enabled genomic sequencing from one or a few cells of unculturable microorganisms, the process is complicated by the tendency of MDA to generate chimeric DNA rearrangements in the amplified DNA. Determining the source of the DNA rearrangements would be an important step towards reducing or eliminating them. Results Here, we characterize the major types of chimeras formed by carrying out an MDA whole genome amplification from a single E. coli cell and sequencing by the 454 Life Sciences method. Analysis of 475 chimeras revealed the predominant reaction mechanisms that create the DNA rearrangements. The highly branched DNA synthesized in MDA can assume many alternative secondary structures. DNA strands extended on an initial template can be displaced becoming available to prime on a second template creating the chimeras. Evidence supports a model in which branch migration can displace 3'-ends freeing them to prime on the new templates. More than 85% of the resulting DNA rearrangements were inverted sequences with intervening deletions that the model predicts. Intramolecular rearrangements were favored, with displaced 3'-ends reannealing to single stranded 5'-strands contained within the same branched DNA molecule. In over 70% of the chimeric junctions, the 3' termini had initiated priming at complimentary sequences of 2–21 nucleotides (nts) in the new templates. Conclusion Formation of chimeras is an important limitation to the MDA method, particularly for whole genome sequencing. Identification of the mechanism for chimera formation provides new insight into the MDA reaction and suggests methods to reduce chimeras. The 454 sequencing approach used here will provide a rapid method to assess the utility of reaction modifications. PMID:17430586

Formation of malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE) and 4-hydroxy-2-nonenal (HNE) in fish and fish oil during dynamic gastrointestinal in vitro digestion.

PubMed

Larsson, Karin; Harrysson, Hanna; Havenaar, Robert; Alminger, Marie; Undeland, Ingrid

2016-02-01

Marine lipids contain a high proportion of polyunsaturated fatty acids (PUFA), including the characteristic long chain (LC) n-3 PUFA. Upon peroxidation these lipids generate reactive products, such as malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE) and 4-hydroxy-2-nonenal (HNE), which can form covalent adducts with biomolecules and thus are regarded as genotoxic and cytotoxic. PUFA peroxidation can occur both before and after ingestion. The aim of this study was to determine what levels of MDA, HHE and HNE can evolve in the gastric and intestinal lumen after ingesting meals containing fish or fish oil using a dynamic gastrointestinal (GI) model (TIM). The impact of the fish muscle matrix, lipid content, fish species, and oven baking on GI oxidation was evaluated. MDA and HHE concentrations in gastric lumen increased for all meals during digestion, with the highest level found with herring mince; ∼ 25 μM MDA and ∼ 850 nM HHE. Aldehyde concentrations reached in intestinal lumen during digestion of fish containing meals were generally lower than in gastric lumen, while isolated herring oils (bulk and emulsified) generated higher MDA and HHE values in intestinal lumen compared to gastric lumen. Based on aldehyde levels in gastric lumen, meals containing herring lipids were ranked: raw herring (17% lipid) = baked herring (4% lipid) > raw herring (4% lipid) ≫ herring oil emulsion > herring oil. Herring developed higher concentrations of MDA and HHE during gastric digestion compared to salmon, which initially contained lower levels of oxidation products. Cooked salmon generated higher MDA concentrations during digestion than raw salmon. Low levels of HNE were observed during digestion of all test meals, in accordance with the low content of n-6 PUFA in fish lipids.

Quantification of malondialdehyde and 4-hydroxynonenal adducts to lysine residues in native and oxidized human low-density lipoprotein.

PubMed Central

Requena, J R; Fu, M X; Ahmed, M U; Jenkins, A J; Lyons, T J; Baynes, J W; Thorpe, S R

1997-01-01

Malondialdehyde (MDA) and 4-hydroxynonenal (HNE) are major end-products of oxidation of polyunsaturated fatty acids, and are frequently measured as indicators of lipid peroxidation and oxidative stress in vivo. MDA forms Schiff-base adducts with lysine residues and cross-links proteins in vitro; HNE also reacts with lysines, primarily via a Michael addition reaction. We have developed methods using NaBH4 reduction to stabilize these adducts to conditions used for acid hydrolysis of protein, and have prepared reduced forms of lysine-MDA [3-(N epsilon-lysino)propan-1-ol (LM)], the lysine-MDA-lysine iminopropene cross-link [1,3-di(N epsilon-lysino)propane (LML)] and lysine-HNE [3-(N epsilon-lysino)-4-hydroxynonan-l-ol (LHNE)]. Gas chromatography/MS assays have been developed for quantification of the reduced compounds in protein. RNase incubated with MDA or HNE was used as a model for quantification of the adducts by gas chromatography/MS. There was excellent agreement between measurement of MDA bound to RNase as LM and LML, and as thiobarbituric acid-MDA adducts measured by HPLC; these adducts accounted for 70-80% of total lysine loss during the reaction with MDA. LM and LML (0.002-0.12 mmol/ mol of lysine) were also found in freshly isolated low-density lipoprotein (LDL) from healthy subjects. LHNE was measured in RNase treated with HNE, but was not detectable in native LDL. LM, LML and LHNE increased in concert with the formation of conjugated dienes during the copper-catalysed oxidation of LDL, but accounted for modification of < 1% of lysine residues in oxidized LDL. These results are the first report of direct chemical measurement of MDA and HNE adducts to lysine residues in LDL. LM, LML and LHNE should be useful as biomarkers of lipid peroxidative modification of protein and of oxidative stress in vitro and in vivo. PMID:9078279

A new bioluminescent reporter system to study the biodistribution of systematically injected tumor-derived bioluminescent extracellular vesicles in mice

PubMed Central

Gangadaran, Prakash; Li, Xiu Juan; Lee, Ho Won; Oh, Ji Min; Kalimuthu, Senthilkumar; Rajendran, Ramya Lakshmi; Son, Seung Hyun; Baek, Se Hwan; Singh, Thoudam Debraj; Zhu, Liya; Jeong, Shin Young; Lee, Sang-Woo; Lee, Jaetae; Ahn, Byeong-Cheol

2017-01-01

In vivo biodistribution and fate of extracellular vesicles (EVs) are still largely unknown and require reliable in vivo tracking techniques. In this study, in vivo bioluminescence imaging (BLI) using Renilla luciferase (Rluc) was developed and applied to monitoring of EVs derived from thyroid cancer (CAL-62 cells) and breast cancer (MDA-MB-231) in nude mice after intravenous administration and was compared with a dye-based labeling method for EV derived from CAL-62 cells. The EVs were successfully labeled with Rluc and visualized by BLI in mice. In vivo distribution of the EVs, as measured by BLI, was consistent with the results of ex vivo organ analysis. EV-CAL-62/Rluc showed strong signals at lung followed by liver, spleen & kidney (P < 0.05). EV-MDA-MB-231/Rluc showed strong signals at liver followed by lung, spleen & kidney (P < 0.05). EV-CAL-62/Rluc and EV-MDA-MB-231/Rluc stayed in animal till day 9 and 3, respectively; showed a differential distribution. Spontaneous EV-CAL-62/Rluc shown distributed mostly to lung followed by liver, spleen & kidney. The new BLI system used to show spontaneous distribution of EV-CAL-62/Rluc in subcutaneous CAL-62/Rluc bearing mice. Dye (DiR)-labeled EV-CAL-62/Rluc showed a different distribution in vivo & ex vivo compared to EV-CAL-62/Rluc. Fluorescent signals were predominately detected in the liver (P < 0.05) and spleen (P < 0.05) regions. The bioluminescent EVs developed in this study may be used for monitoring of EVs in vivo. This novel reporter-imaging approach to visualization of EVs in real time is expected to pave the way for monitoring of EVs in EV-based treatments. PMID:29299117

Investigating the Effectiveness of Current and Modified World Health Organization Guidelines for the Control of Soil-Transmitted Helminth Infections

PubMed Central

Farrell, Sam H; Coffeng, Luc E; Truscott, James E; Werkman, Marleen; Toor, Jaspreet; de Vlas, Sake J; Anderson, Roy M

2018-01-01

Abstract Background Considerable efforts have been made to better understand the effectiveness of large-scale preventive chemotherapy therapy for the control of morbidity caused by infection with soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura, and the 2 hookworm species, Necator americanus and Ancylostoma duodenale. Current World Health Organization (WHO) guidelines for STH control include mass drug administration (MDA) programs based on prevalence measurements, aiming at reducing morbidity in pre–school-aged children (pre-SAC) and school-aged children (SAC) by lowering the prevalence of moderate- to heavy-intensity infections to <1%. Methods We project the likely impact of following the current WHO guidelines and assess whether the WHO morbidity goals will be achieved across a range of transmission settings. We also investigate modifications that could be made to the current WHO treatment guidelines, and project their potential impacts in achieving morbidity and transmission control. Results While the standard guidelines are sufficient at low transmission levels, community-wide treatment (ie, involving pre-SAC, SAC, and adults) is essential if WHO morbidity goals are to be met in moderate- to high-transmission settings. Moreover, removing the recommendation of decreasing the treatment frequency at midline (5–6 years after the start of MDA) further improves the likelihood of achieving morbidity control in SAC. Conclusions We meld analyses based on 2 mathematical models of parasite transmission and control by MDA for the dominant STH species, to generate a unified treatment approach applicable across all settings, regardless of which STH infection is most common. We recommend clearly defined changes to the current WHO guidelines. PMID:29860285

The past matters: estimating intrinsic hookworm transmission intensity in areas with past mass drug administration to control lymphatic filariasis.

PubMed

Werkman, Marleen; Truscott, James E; Toor, Jaspreet; Wright, James E; Anderson, Roy M

2017-05-23

Current WHO guidelines for soil-transmitted helminth (STH) control focus on mass drug administration (MDA) targeting preschool-aged (pre-SAC) and school-aged children (SAC), with the goal of eliminating STH as a public health problem amongst children. Recently, attention and funding has turned towards the question whether MDA alone can result in the interruption of transmission for STH. The lymphatic filariasis (LF) elimination programme, have been successful in reaching whole communities. There is the possibility of building upon the infrastructure created for these LF-programmes to enhance the control of STH. Using hookworm as an example, we explore what further MDA coverage might be required to induce interruption of transmission for hookworm in the wake of a successful LF programme. Analyses based on the model of STH transmission and MDA impact predict the effects of previous LF control by MDA over five years, on a defined baseline prevalence of STH in an area with a defined transmission intensity (the basic reproductive number R 0 ). If the LF MDA programme achieved a high coverage (70, 70 and 60% for pre-SAC, SAC and adults, respectively) we expect that in communities with a hookworm prevalence of 15%, after 5 years of LF control, the intrinsic R 0 value in that setting is 2.47. By contrast, if lower LF coverages were achieved (40, 40 and 30% for pre-SAC, SAC and adults, respectively), with the same prevalence of 15% at baseline (after 5 years of LF MDA), the intrinsic hookworm R 0 value is predicted to be 1.67. The intrinsic R 0 value has a large effect on the expected successes of follow-up STH programmes post LF MDA. Consequently, the outcomes of identical programmes may differ between these communities. To design the optimal MDA intervention to eliminate STH infections, it is vital to have information on historical MDA programmes and baseline prevalence to estimate the intrinsic transmission intensity for the defined setting (R 0 ). The baseline prevalence alone is not sufficient to inform policy for the control of STH, post cessation of LF MDA, since this will be highly dependent on the intensity and effectiveness of past programmes and the intrinsic transmission intensity of the dominant STH species in any given setting.

Mass drug administration for malaria

PubMed Central

Poirot, Eugenie; Skarbinski, Jacek; Sinclair, David; Kachur, S Patrick; Slutsker, Laurence; Hwang, Jimee

2013-01-01

Background Mass drug administration (MDA), defined as the empiric administration of a therapeutic antimalarial regimen to an entire population at the same time, has been a historic component of many malaria control and elimination programmes, but is not currently recommended. With renewed interest in MDA and its role in malaria elimination, this review aims to summarize the findings from existing research studies and program experiences of MDA strategies for reducing malaria burden and transmission. Objectives To assess the impact of antimalarial MDA on population asexual parasitaemia prevalence, parasitaemia incidence, gametocytaemia prevalence, anaemia prevalence, mortality and MDA-associated adverse events. Search methods We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE+, EMBASE, to February 2013. We also searched CABS Abstracts, LILACS, reference lists, and recent conference proceedings. Selection criteria Cluster-randomized trials and non-randomized controlled studies comparing therapeutic MDA versus placebo or no MDA, and uncontrolled before-and-after studies comparing post-MDA to baseline data were selected. Studies administering intermittent preventive treatment (IPT) to sub-populations (for example, pregnant women, children or infants) were excluded. Data collection and analysis Two authors independently reviewed studies for inclusion, extracted data and assessed risk of bias. Studies were stratified by study design and then subgrouped by endemicity, by co-administration of 8-aminoquinoline plus schizonticide drugs and by plasmodium species. The quality of evidence was assessed using the GRADE approach. Main results Two cluster-randomized trials, eight non-randomized controlled studies and 22 uncontrolled before-and-after studies are included in this review. Twenty-two studies (29 comparisons) compared MDA to placebo or no intervention of which two comparisons were conducted in areas of low endemicity (≤5%), 12 in areas of moderate endemicity (6-39%) and 15 in areas of high endemicity (≥ 40%). Ten studies evaluated MDA plus other vector control measures. The studies used a wide variety of MDA regimens incorporating different drugs, dosages, timings and numbers of MDA rounds. Many of the studies are now more than 30 years old. Areas of low endemicity (≤5%) Within the first month post-MDA, a single uncontrolled before-and-after study conducted in 1955 on a small Taiwanese island reported a much lower prevalence of parasitaemia following a single course of chloroquine compared to baseline (1 study, very low quality evidence). This lower parasite prevalence was still present after more than 12 months (one study, very low quality evidence). In addition, one cluster-randomized trial evaluating MDA in a low endemic setting reported zero episodes of parasitaemia at baseline, and throughout five months of follow-up in both the control and intervention arms (one study, very low quality evidence). Areas of moderate endemicity (6-39%) Within the first month post-MDA, the prevalence of parasitaemia was much lower in three non-randomized controlled studies from Kenya and India in the 1950s (RR 0.03, 95% CI 0.01 to 0.08, three studies, moderate quality evidence), and in three uncontrolled before-and-after studies conducted between 1954 and 1961 (RR 0.29, 95% CI 0.17 to 0.48, three studies,low quality evidence). The longest follow-up in these settings was four to six months. At this time point, the prevalence of parasitaemia remained substantially lower than controls in the two non-randomized controlled studies (RR 0.18, 95% CI 0.10 to 0.33, two studies, low quality evidence). In contrast, the two uncontrolled before-and-after studies found mixed results: one found no difference and one found a substantially higher prevalence compared to baseline (not pooled, two studies, very low quality evidence). Areas of high endemicity (≥40%) Within the first month post-MDA, the single cluster-randomized trial from the Gambia in 1999 found no significant difference in parasite prevalence (one study, low quality evidence). However, prevalence was much lower during the MDA programmes in three non-randomized controlled studies conducted in the 1960s and 1970s (RR 0.17, 95% CI 0.11 to 0.27, three studies, moderate quality evidence), and within one month of MDA in four uncontrolled before-and-after studies (RR 0.37, 95% CI 0.28 to 0.49, four studies,low quality evidence). Four trials reported changes in prevalence beyond three months. In the Gambia, the single cluster-randomized trial found no difference at five months (one trial, moderate quality evidence). The three uncontrolled before-and-after studies had mixed findings with large studies from Palestine and Cambodia showing sustained reductions at four months and 12 months, respectively, and a small study from Malaysia showing no difference after four to six months of follow-up (three studies,low quality evidence). 8-aminoquinolines We found no studies directly comparing MDA regimens that included 8-aminoquinolines with regimens that did not. In a crude subgroup analysis with a limited number of studies, we were unable to detect any evidence of additional benefit of primaquine in moderate- and high-transmission settings. Plasmodium species In studies that reported species-specific outcomes, the same interventions resulted in a larger impact on Plasmodium falciparum compared to P. vivax. Authors' conclusions MDA appears to reduce substantially the initial risk of malaria parasitaemia. However, few studies showed sustained impact beyond six months post-MDA, and those that did were conducted on small islands or in highland settings. To assess whether there is an impact of MDA on malaria transmission in the longer term requires more quasi experimental studies with the intention of elimination, especially in low- and moderate-transmission settings. These studies need to address any long-term outcomes, any potential barriers for community uptake, and contribution to the development of drug resistance. PLAIN LANGUAGE SUMMARY Administration of antimalarial drugs to whole populations Malaria is the most important mosquito-borne disease caused by a parasite, accounting for an estimated 660,000 deaths annually. Fortunately, malaria is both preventable and treatable. Several malaria control tools currently exist, and new and innovative approaches are continually under development. The administration of drugs against malaria to whole populations, termed mass drug administration (MDA), was a component of many malaria elimination programmes in the 1950s, and is once again attracting interest as a malaria elimination tool. As a consequence, it is important to review the currently available literature in order to assess the potential for this strategy to reduce malaria burden and transmission, and to identify gaps in our understanding. This review assessed the impact of MDA on several malaria-specific outcome measures. Thirty-two studies were included in this review, from sites in Asia, Africa, Europe and the Americas. The review found that although MDA can reduce the initial risk of malaria-specific outcomes, these reductions are often not sustained. However, a few studies conducted on small islands or in highland areas did show sustained impact more than six months after MDA. Adverse events were inadequately addressed in most studies. Notable severe drug reactions, including haemolysis, haemoglobinuria, severe anaemia and death, were reported with 8-aminoquinoline plus schizonticide drug co-administration, while severe skin reactions were reported with sulphadoxine-pyrimethamine plus artesunate plus primaquine. Assessing the true impact of MDA programmes can be a challenge due to the heterogeneity of the study methods employed. Nonetheless, this review can help guide future antimalarial MDA interventions and their evaluation. PMID:24318836

Assay to detect lipid peroxidation upon exposure to nanoparticles.

PubMed

Potter, Timothy M; Neun, Barry W; Stern, Stephan T

2011-01-01

This chapter describes a method for the analysis of human hepatocarcinoma cells (HEP G2) for lipid peroxidation products, such as malondialdehyde (MDA), following treatment with nanoparticle formulations. Oxidative stress has been identified as a likely mechanism of nanoparticle toxicity, and cell-based in vitro systems for evaluation of nanoparticle-induced oxidative stress are widely considered to be an important component of biocompatibility screens. The products of lipid peroxidation, lipid hydroperoxides, and aldehydes, such as MDA, can be measured via a thiobarbituric acid reactive substances (TBARS) assay. In this assay, which can be performed in cell culture or in cell lysate, MDA combines with thiobarbituric acid (TBA) to form a fluorescent adduct that can be detected at an excitation wavelength of 530 nm and an emission wavelength of 550 nm. The results are then expressed as MDA equivalents, normalized to total cellular protein (determined by Bradford assay).

Whole-genome multiple displacement amplification from single cells.

PubMed

Spits, Claudia; Le Caignec, Cédric; De Rycke, Martine; Van Haute, Lindsey; Van Steirteghem, André; Liebaers, Inge; Sermon, Karen

2006-01-01

Multiple displacement amplification (MDA) is a recently described method of whole-genome amplification (WGA) that has proven efficient in the amplification of small amounts of DNA, including DNA from single cells. Compared with PCR-based WGA methods, MDA generates DNA with a higher molecular weight and shows better genome coverage. This protocol was developed for preimplantation genetic diagnosis, and details a method for performing single-cell MDA using the phi29 DNA polymerase. It can also be useful for the amplification of other minute quantities of DNA, such as from forensic material or microdissected tissue. The protocol includes the collection and lysis of single cells, and all materials and steps involved in the MDA reaction. The whole procedure takes 3 h and generates 1-2 microg of DNA from a single cell, which is suitable for multiple downstream applications, such as sequencing, short tandem repeat analysis or array comparative genomic hybridization.

Duration of detection of anti-BmR1 IgG4 antibodies after mass-drug administration (MDA) in Sarawak, Malaysia.

PubMed

Noordin, R; Muhi, J; Md Idris, Z; Arifin, N; Kiyu, A

2012-03-01

The detection rates of brugian filariasis in three regions of Sarawak namely Central, North and South after three courses of mass drug administration (MDA) from year 2004 to 2006 was investigated. A recombinant BmR1 antigen-based IgG4 detection test, named Brugia Rapid and night blood smear for microfilaria (mf) detection were used. All three regions recorded a sharp fall in mf positive rates after a year post-MDA. Meanwhile Brugia Rapid positive rates declined more gradually to 3.8% and 5.6% of the pre-MDA levels in the Central and North regions, respectively. This study showed that in filariasis endemic areas in Sarawak, anti-filarial IgG4 antibodies to BmR1, as detected by the Brugia Rapid test, were positive for one to two years after mf disappearance.

Monitoring the impact of a mebendazole mass drug administration initiative for soil-transmitted helminthiasis (STH) control in the Western Visayas Region of the Philippines from 2007 through 2011.

PubMed

Sanza, Megan; Totanes, Francis Isidore; Chua, Paul Lester; Belizario, Vicente Y

2013-08-01

School-aged children in tropical developing countries carry the highest burden of soil-transmitted helminth (STH) infections in the world. The Western Visayas region of the Philippines continues to struggle with this as a major public health issue in both private and public schools. The War on Worms-Western Visayas approach was launched in 2007 with school-based mass drug administration (MDA) as one of the strategies to control morbidity from STH in support of the Department of Health - Integrated Helminth Control Program. This study aimed to determine trends in prevalence and intensity of STH infections as well as to assess related morbidity and program sustainability through 2011. A cross-sectional parasitologic survey was conducted on three independent samples of Grade 3 students in 2007, 2009, and 2011. Supporting aggregate data were obtained for MDA coverage, National Achievement Test mean percentage scores, and nutritional status. Tests for trend were utilized to detect changes in prevalence over time, with a particular emphasis on trends seen between 2009 and 2011. The initial impact of the program was robust as cumulative prevalence, infection intensities, and parasite densities were all reduced four years following the launch. However, subsequent and significant increases in each were found from 2009 until 2011. These results implicate issues with program sustainability, despite consistent MDA, and existing frameworks for environmental sanitation, hygiene, and education. Copyright © 2013 Elsevier B.V. All rights reserved.

Knowledge sifters in MDA technologies

NASA Astrophysics Data System (ADS)

Kravchenko, Yuri; Kursitys, Ilona; Bova, Victoria

2018-05-01

The article considers a new approach to efficient management of information processes on the basis of object models. With the help of special design tools, a generic and application-independent application model is created, and then the program is implemented in a specific development environment. At the same time, the development process is completely based on a model that must contain all the information necessary for programming. The presence of a detailed model provides the automatic creation of typical parts of the application, the development of which is amenable to automation.

Identification of Novel Human Breast Carcinoma (MDA-MB-231) Cell Growth Modulators from a Carbohydrate-Based Diversity Oriented Synthesis Library.

PubMed

Lenci, Elena; Innocenti, Riccardo; Biagioni, Alessio; Menchi, Gloria; Bianchini, Francesca; Trabocchi, Andrea

2016-10-20

The application of a cell-based growth inhibition on a library of skeletally different glycomimetics allowed for the selection of a hexahydro-2 H -furo[3,2- b ][1,4]oxazine compound as candidate inhibitors of MDA-MB-231 cell growth. Subsequent synthesis of analogue compounds and preliminary biological studies validated the selection of a valuable hit compound with a novel polyhydroxylated structure for the modulation of the breast carcinoma cell cycle mechanism.

Characterization of the canine mda-7 gene, transcripts and expression patterns

PubMed Central

Sandey, Maninder; Bird, R. Curtis; Das, Swadesh K.; Sarkar, Devanand; Curiel, David T.; Fisher, Paul B.; Smith, Bruce F.

2014-01-01

Human melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) displays potent growth suppressing and cell killing activity against a wide variety of human and rodent cancer cells. In this study, we identified a canine ortholog of the human mda-7/IL-24 gene located within a cluster of IL-10 family members on chromosome 7. The full-length mRNA sequence of canine mda-7 was determined, which encodes a 186-amino acid protein that has 66% similarity to human MDA-7/IL-24. Canine MDA-7 is constitutively expressed in cultured normal canine epidermal keratinocytes (NCEKs), and its expression levels are increased after lipopolysaccharide stimulation. In cultured NCEKs, the canine mda-7 pre-mRNA is differentially spliced, via exon skipping and alternate 5′-splice donor sites, to yield five splice variants (canine mda-7sv1, canine mda-7sv2, canine mda-7sv3, canine mda-7sv4 and canine mda-7sv5) that encode four protein isoforms of the canine MDA-7 protein. These protein isoforms have a conserved N-terminus (signal peptide sequence) and are dissimilar in amino acid sequences at their C-terminus. Canine MDA-7 is not expressed in primary canine tumor samples, and most tumor derived cancer cell lines tested, like its human counterpart. Unlike human MDA-7/IL-24, canine mda-7 mRNA is not expressed in unstimulated or lipopolysaccharide (LPS), concanavalin A (ConA) or phytohemagglutinin (PHA) stimulated canine peripheral blood mononuclear cells (PBMCs). Furthermore, in-silico analysis revealed that canonical canine MDA-7 has a potential 28 amino acid signal peptide sequence that can target it for active secretion. This data suggests that canine mda-7 is indeed an ortholog of human mda-7/IL-24, its protein product has high amino acid similarity to human MDA-7/IL-24 protein and it may possess similar biological properties to human MDA-7/IL-24, but its expression pattern is more restricted than its human ortholog. PMID:24865935

Diagnostic Tests to Support Late-Stage Control Programs for Schistosomiasis and Soil-Transmitted Helminthiases.

PubMed

Hawkins, Kenneth R; Cantera, Jason L; Storey, Helen L; Leader, Brandon T; de Los Santos, Tala

2016-12-01

Global efforts to address schistosomiasis and soil-transmitted helminthiases (STH) include deworming programs for school-aged children that are made possible by large-scale drug donations. Decisions on these mass drug administration (MDA) programs currently rely on microscopic examination of clinical specimens to determine the presence of parasite eggs. However, microscopy-based methods are not sensitive to the low-intensity infections that characterize populations that have undergone MDA. Thus, there has been increasing recognition within the schistosomiasis and STH communities of the need for improved diagnostic tools to support late-stage control program decisions, such as when to stop or reduce MDA. Failure to adequately address the need for new diagnostics could jeopardize achievement of the 2020 London Declaration goals. In this report, we assess diagnostic needs and landscape potential solutions and determine appropriate strategies to improve diagnostic testing to support control and elimination programs. Based upon literature reviews and previous input from experts in the schistosomiasis and STH communities, we prioritized two diagnostic use cases for further exploration: to inform MDA-stopping decisions and post-MDA surveillance. To this end, PATH has refined target product profiles (TPPs) for schistosomiasis and STH diagnostics that are applicable to these use cases. We evaluated the limitations of current diagnostic methods with regards to these use cases and identified candidate biomarkers and diagnostics with potential application as new tools. Based on this analysis, there is a need to develop antigen-detecting rapid diagnostic tests (RDTs) with simplified, field-deployable sample preparation for schistosomiasis. Additionally, there is a need for diagnostic tests that are more sensitive than the current methods for STH, which may include either a field-deployable molecular test or a simple, low-cost, rapid antigen-detecting test.

[Disasters and emergency situations: what have we learned from the past to prepare for the future?].

PubMed

Peleg, Kobi

2010-07-01

Israel has gained extensive experience in the mass casuaLty field, especially from dealing with terrorism events. This special issue of "Harefuah" includes articles that describe and analyze several aspects and approaches related to mass casualty event (MCE) preparedness and response strategies, based on Israel's experience. Feigenberg reports that Magen David Adom (MDA) was able to evacuate all urgent injuries during an MCE from the site to a hospital in 28 minutes, on average. Of the MCE casualties, 71% were evacuated directly to level 1 trauma centers. Rafalowski notes that the ability of MDA to implement organizational and operational Learning processes close to the time of the incident, as well as their modular operational approach, which allows flexibility in responding to simultaneous events, are probably among the reasons that have helped MDA reach a high Level of success in dealing with MCEs. Analysis of terrorism injury data demonstrates that these injuries, suffered by both children and adults, are characterized by increased complexity, with higher severity, higher in-patient mortality rates, and significantly greater use of precious hospital resources such as intensive care, operating rooms, CT, and days of hospitalization. Extensive experience dealing with MCEs has brought managerial insights to the entire health system, for instance in the hospitalization system and clinical management of injuries. In her article, Adini defines five major components for assessing the Israeli health system in emergencies. Shasha's article discusses the principles of hospital preparedness while working under fire. The importance of this subject has in recent years helped bring a more academic approach to emergency and disaster management in the world and in Israel, as enacted at Tel Aviv University's Multidisciplinary Master's Program in Emergency and Disaster Management, and also in other universities that focus on specific disciplines. In summary, achieving improvement requires continuous focus on preparedness, integration of new technologies, routine debriefings, and developing new coping strategies, education, training, and drills. These should all be part of daily preparedness routines. Only in this way can a high quality level of preparedness be maintained over time.

Duchenne and Becker Muscular Dystrophies

MedlinePlus

... trial in boys with the disease. In another approach, MDA-supported researchers at a biotechnology company are ... respira- tory or speech therapy consultations • annual flu shots • support groups for those affected, spouses, parents or ...

Selective imaging of cathepsin L in breast cancer by fluorescent activity-based probes† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc04303a

PubMed Central

Rut, Wioletta; Vizovisek, Matej; Groborz, Katarzyna; Kasperkiewicz, Paulina; Finlay, Darren; Vuori, Kristiina; Turk, Dusan; Turk, Boris; Salvesen, Guy S.

2018-01-01

Cysteine cathepsins normally function in the lysosomal degradation system where they are critical for the maintenance of cellular homeostasis and the MHC II immune response, and have been found to have major roles in several diseases and in tumor progression. Selective visualization of individual protease activity within a complex proteome is of major importance to establish their roles in both normal and tumor cells, thereby facilitating our understanding of the regulation of proteolytic networks. A generally accepted means to monitor protease activity is the use of small molecule substrates and activity-based probes. However, there are eleven human cysteine cathepsins, with a few of them displaying overlapping substrate specificity, making the development of small molecules that selectively target a single cathepsin very challenging. Here, we utilized HyCoSuL, a positional scanning substrate approach, to develop a highly-selective fluorogenic substrate and activity-based probe for monitoring cathepsin L activity in the breast cancer cell line MDA-MB-231. Use of this probe enabled us to distinguish the activity of cathepsin L from that of other cathepsins, particularly cathepsin B, which is abundant and ubiquitously expressed in normal and transformed cell types. We found that cathepsin L localization in MDA-MB-231 cells greatly overlaps with that of cathepsin B, however, several cathepsin L-rich lysosomes lacked cathepsin B activity. Overall, these studies demonstrate that HyCoSuL-derived small molecule probes are valuable tools to image cathepsin L activity in living cells. This approach thus enables evaluation of cathepsin L function in tumorigenesis and is applicable to other cysteine cathepsins. PMID:29719685

Myotonic Muscular Dystrophy

MedlinePlus

... MDA History Fact Sheet Annual Report FAQs Our Team MDA Leadership Meet Our Partners National Ambassadors Advisory ... MDA Services Your MDA Care Center Meet Your Team Your Visit Support & Programs Request Services MDA Summer ...

MPS Li-Ion Batteries Qualified to Fly on Canadian Sapphire Spacecraft

NASA Astrophysics Data System (ADS)

Remy, S.; Carre, A.; Kimber, R.; Alcindor, P.; Krabel, E.

2014-08-01

Saft Li-ion 8S3P MPS (Medium Prismatic cell for Space Battery) autonomous battery has been designed and qualified primarily to meet LEO power requirements. It has been available for more than 8 years, the original battery concept qualification program being successfully carried-out with CNES support in year 2005. This module has been selected for the first time by the UK satellite manufacturer SSTL for the Sapphire spacecraft platform, on behalf of the spacecraft prime MDA Systems Ltd (MDA) and customer the Canadian DND. Due to the high mechanical load demand in the specifications, a delta qualification campaign was launched to make sure that the MPS battery was able to cope with this requirement. A partner approach between Saft and SSTL led Saft to build some dedicated representative 5S packs, which have been step by step tested by SSTL shaker. Based on the results, the battery was made and finally installed inside the Sapphire spacecraft which was successfully launched on February 25th 2013 after battery storage of about 3.5 years.

A Prospective Study of Bone Tumor Response Assessment in Metastatic Breast Cancer

PubMed Central

Hayashi, Naoki; Costelloe, Colleen M.; Hamaoka, Tsuyoshi; Wei, Caimiao; Niikura, Naoki; Theriault, Richard L.; Hortobagyi, Gabriel N.; Madewell, John E.; Ueno, Naoto T.

2013-01-01

In this pilot study, we prospectively compared the response of bone metastasis assessed by our MD Anderson (MDA) bone tumor response criteria (computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) with the response assessed by the World Health Organization (WHO) criteria (XR and SS). Both MDA and WHO criteria predicted progression-free survival (PFS) of patients at 6 months but not at an earlier time point. Background In our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases. Methods We prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions. Results The median follow-up period was 26.7 months (range, 6.1–53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases. Conclusion MDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA criteria in predicting bone tumor response by incorporating 18-fluorodeoxyglucose (18F) positron emission tomography (FDG-PET)/CT to see if findings using this modality are earlier than those with WHO criteria. PMID:23098575

Detection of malondialdehyde in processed meat products without interference from the ingredients.

PubMed

Jung, Samooel; Nam, Ki Chang; Jo, Cheorun

2016-10-15

Our aim was to develop a method for accurate quantification of malondialdehyde (MDA) in meat products. MDA content of uncured ground pork (Control); ground pork cured with sodium nitrite (Nitrite); and ground pork cured with sodium nitrite, sodium chloride, sodium pyrophosphate, maltodextrin, and a sausage seasoning (Mix) was measured by the 2-thiobarbituric acid (TBA) assay with MDA extraction by trichloroacetic acid (method A) and two high-performance liquid chromatography (HPLC) methods: i) HPLC separation of the MDA-dinitrophenyl hydrazine adduct (method B) and ii) HPLC separation of MDA (method C) after MDA extraction with acetonitrile. Methods A and B could not quantify MDA accurately in groups Nitrite and Mix. Nevertheless, MDA in groups Control, Nitrite, and Mix was accurately quantified by method C with good recovery. Therefore, direct MDA quantification by HPLC after MDA extraction with acetonitrile (method C) is useful for accurate measurement of MDA content in processed meat products. Copyright © 2016 Elsevier Ltd. All rights reserved.

Quantifying O3 Impacts in Urban Areas Due to Wildfires Using a Generalized Additive Model.

PubMed

Gong, Xi; Kaulfus, Aaron; Nair, Udaysankar; Jaffe, Daniel A

2017-11-21

Wildfires emit O 3 precursors but there are large variations in emissions, plume heights, and photochemical processing. These factors make it challenging to model O 3 production from wildfires using Eulerian models. Here we describe a statistical approach to characterize the maximum daily 8-h average O 3 (MDA8) for 8 cities in the U.S. for typical, nonfire, conditions. The statistical model represents between 35% and 81% of the variance in MDA8 for each city. We then examine the residual from the model under conditions with elevated particulate matter (PM) and satellite observed smoke ("smoke days"). For these days, the residuals are elevated by an average of 3-8 ppb (MDA8) compared to nonsmoke days. We found that while smoke days are only 4.1% of all days (May-Sept) they are 19% of days with an MDA8 greater than 75 ppb. We also show that a published method that does not account for transport patterns gives rise to large overestimates in the amount of O 3 from fires, particularly for coastal cities. Finally, we apply this method to a case study from August 2015, and show that the method gives results that are directly applicable to the EPA guidance on excluding data due to an uncontrollable source.

UV Decontamination of MDA Reagents for Single Cell Genomics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Janey; Tighe, Damon; Sczyrba, Alexander

2011-03-18

Single cell genomics, the amplification and sequencing of genomes from single cells, can provide a glimpse into the genetic make-up and thus life style of the vast majority of uncultured microbial cells, making it an immensely powerful and increasingly popular tool. This is accomplished by use of multiple displacement amplification (MDA), which can generate billions of copies of a single bacterial genome producing microgram-range DNA required for shotgun sequencing. Here, we address a key challenge inherent to this approach and propose a solution for the improved recovery of single cell genomes. While DNA-free reagents for the amplification of a singlemore » cell genome are a prerequisite for successful single cell sequencing and analysis, DNA contamination has been detected in various reagents, which poses a considerable challenge. Our study demonstrates the effect of UV irradiation in efficient elimination of exogenous contaminant DNA found in MDA reagents, while maintaining Phi29 activity. Consequently, we also find that increased UV exposure to Phi29 does not adversely affect genome coverage of MDA amplified single cells. While additional challenges in single cell genomics remain to be resolved, the proposed methodology is relatively quick and simple and we believe that its application will be of high value for future single cell sequencing projects.« less

Proanthocyanidins from Uncaria rhynchophylla induced apoptosis in MDA-MB-231 breast cancer cells while enhancing cytotoxic effects of 5-fluorouracil.

PubMed

Chen, Xiao-Xin; Leung, George Pak-Heng; Zhang, Zhang-Jin; Xiao, Jian-Bo; Lao, Li-Xing; Feng, Feng; Mak, Judith Choi-Wo; Wang, Ying; Sze, Stephen Cho-Wing; Zhang, Kalin Yan-Bo

2017-09-01

Breast cancer is the most frequently diagnosed cancer and cause of cancer death in women worldwide. Current treatments often result in systematic toxicity and drug resistance. Combinational use of non-toxic phytochemicals with chemotherapeutic agents to enhance the efficacy and reduce toxicity would be one promising approach. In this study, bioactive proanthocyanidins from Uncaria rhynchophylla (UPAs) were isolated and their anti-breast cancer effects alone and in combination with 5- fluorouracil (5-FU) were investigated in MDA-MB-231 breast cancer cells. The results showed that UPAs significantly inhibited cell viability and migration ability in a dose-dependent manner. Moreover, UPAs induced apoptosis in a dose-dependent manner which was associated with increased cellular reactive oxygen species production, loss of mitochondrial membrane potential, increases of Bax/Bcl-2 ratio and levels of cleaved caspase 3. Treatments of the cells with UPAs resulted in an increase in G2/M cell cycle arrest. Cytotoxic effects of 5-FU against MDA-MB-231 cells were enhanced by UPAs. The combination treatment of UPAs and 5-FU for 48 h elicited a synergistic cytotoxic effect on MDA-MB-231 cells. Altogether, these data suggest that UPAs are potential therapeutic agents for breast cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

The 6th Meeting of the Global Alliance to Eliminate Lymphatic Filariasis: A half-time review of lymphatic filariasis elimination and its integration with the control of other neglected tropical diseases

PubMed Central

2010-01-01

The 6th Meeting of the Global Alliance to Eliminate Lymphatic Filariasis (GAELF6) was held 1-3 June, 2010 in Seoul, Korea, with 150 participants from 38 countries. The year 2010 marks the midpoint between the first GAELF meeting, in 2000, and the World Health Organization (WHO) 2020 goal of global elimination of lymphatic filariasis (LF) as a public health problem. The theme of the meeting, "Half-time in LF Elimination: Teaming Up with Neglected Tropical Diseases (NTDs)," reflected significant integration of LF elimination programmes into a comprehensive initiative to control NTDs. Presentations on LF epidemiology, treatment, research, and programmes highlighted both accomplishments and remaining challenges. The WHO strategy to interrupt LF transmission is based on annual mass drug administration (MDA) using two-drug combinations. After mapping the geographic distribution of LF, MDA is implemented for ≥ 5 years, followed by a period of post-MDA surveillance, and, ultimately, verification of LF elimination. Morbidity management further reduces disease burden. Of 81 countries considered LF-endemic in 2000, 52 (64.2%) have begun MDA; 10 (12.3%) others with low-level transmission are unlikely to require MDA. In 2008, ~695 million people were offered treatment (51.7% of the at-risk population); ~496 million participated. Approximately 22 million people have been protected from LF infection and disease, with savings of ~US $24.2 billion. Morbidity management programmes have been implemented in 27 (33.3%) countries. Significant challenges to LF elimination remain. These include: initiating MDA in the remaining 19 countries that require it; achieving full geographic coverage in countries where MDA has started; finding alternative strategies to address the problem of Loa loa co-endemicity in Central Africa; developing strategies to treat urban populations; initiating and sustaining MDA in settings of armed conflict; developing refined guidelines and procedures for stopping MDA, for post-MDA surveillance, and for verifying the elimination of LF; and integrating morbidity management into all LF elimination programmes. Scientific research and enhanced advocacy for NTDs remain critical for addressing these challenges. GAELF6 was characterized by enthusiasm and recognition that "teaming up with NTDs" offers opportunities for new partnerships, fresh perspectives, enhanced advocacy, and greater programmatic integration in a rapidly changing global health environment. PMID:20961435

Biological measure of compliance to Artesunate plus Amodiaquine association: interest in a Mono-Desethyl-Amodiaquine blood assay?

PubMed

Sarrassat, Sophie; Sakho, Madiagne; Le Hesran, Jean Yves

2009-04-01

The deployment of Artemisinin-based Combination Therapy for treating uncomplicated malaria poses problems in the patient compliance to these new treatments. The aim of our study was to investigate the relationship between compliance to 3 days treatment with Artesunate plus Amodiaquine (AS+AQ) and the Mono-Desethyl-Amodiaquine (MDA) blood concentration on the fourth day. A reference scale of mean MDA blood concentrations was constructed in 40 healthy adults. Each concentration corresponded to the MDA level on day 3 in a subject having one of the seven compliance degrees defined by the number and sequence of drug intakes from day 0 to day 2: one single dose on day 0, day 1 or day 2; two single doses separated by 24h, on day 0 and day 1 or on day 1 and day 2; two single doses separated by 48 h, on day 0 and day 2; three single doses, on day 0, day 1 and day 2. MDA was assayed in whole blood samples by HPLC. Non-parametric Mann and Whitney U tests were used for the comparison of two means. Our results demonstrated no clear relationship between the mean MDA blood concentrations on day 3 and compliance degrees, according to neither the number nor the sequence of doses taken. In particular, even though the differences were not significant, the mean concentration after three doses, expected to be the maximum, was unexpectedly lower than after two doses, on day 0 and day 1 or on day 1 and day 2. The high inter-individual variability of MDA concentrations attributed to the different rates of hepatic metabolism of each individual appears to have a greater effect on MDA levels than the number or timing of doses. Therefore, it seems that the role of a MDA blood assay is limited in use to discerning if none or one or more doses have been taken. A MDA assay do not allow to measure the compliance degree of one patient to AS+AQ association. Presently, interview and pill count following treatment seem to be the only tools available that may permit differentiation between degrees of compliance.

A systematic review of factors that shape implementation of mass drug administration for lymphatic filariasis in sub-Saharan Africa.

PubMed

Silumbwe, Adam; Zulu, Joseph Mumba; Halwindi, Hikabasa; Jacobs, Choolwe; Zgambo, Jessy; Dambe, Rosalia; Chola, Mumbi; Chongwe, Gershom; Michelo, Charles

2017-05-22

Understanding factors surrounding the implementation process of mass drug administration for lymphatic filariasis (MDA for LF) elimination programmes is critical for successful implementation of similar interventions. The sub-Saharan Africa (SSA) region records the second highest prevalence of the disease and subsequently several countries have initiated and implemented MDA for LF. Systematic reviews have largely focused on factors that affect coverage and compliance, with less attention on the implementation of MDA for LF activities. This review therefore seeks to document facilitators and barriers to implementation of MDA for LF in sub-Saharan Africa. A systematic search of databases PubMed, Science Direct and Google Scholar was conducted. English peer-reviewed publications focusing on implementation of MDA for LF from 2000 to 2016 were considered for analysis. Using thematic analysis, we synthesized the final 18 articles to identify key facilitators and barriers to MDA for LF programme implementation. The main factors facilitating implementation of MDA for LF programmes were awareness creation through innovative community health education programmes, creation of partnerships and collaborations, integration with existing programmes, creation of morbidity management programmes, motivation of community drug distributors (CDDs) through incentives and training, and management of adverse effects. Barriers to implementation included the lack of geographical demarcations and unregistered migrations into rapidly urbanizing areas, major disease outbreaks like the Ebola virus disease in West Africa, delayed drug deliveries at both country and community levels, inappropriate drug delivery strategies, limited number of drug distributors and the large number of households allocated for drug distribution. Mass drug administration for lymphatic filariasis elimination programmes should design their implementation strategies differently based on specific contextual factors to improve implementation outcomes. Successfully achieving this requires undertaking formative research on the possible constraining and inhibiting factors, and incorporating the findings in the design and implementation of MDA for LF.

Progress and Impact of 13 Years of the Global Programme to Eliminate Lymphatic Filariasis on Reducing the Burden of Filarial Disease

PubMed Central

Ramaiah, K. D.; Ottesen, Eric A.

2014-01-01

Background A Global Programme to Eliminate Lymphatic Filariasis was launched in 2000, with mass drug administration (MDA) as the core strategy of the programme. After completing 13 years of operations through 2012 and with MDA in place in 55 of 73 endemic countries, the impact of the MDA programme on microfilaraemia, hydrocele and lymphedema is in need of being assessed. Methodology/Principal findings During 2000–2012, the MDA programme made remarkable achievements – a total of 6.37 billion treatments were offered and an estimated 4.45 billion treatments were consumed by the population living in endemic areas. Using a model based on empirical observations of the effects of treatment on clinical manifestations, it is estimated that 96.71 million LF cases, including 79.20 million microfilaria carriers, 18.73 million hydrocele cases and a minimum of 5.49 million lymphedema cases have been prevented or cured during this period. Consequently, the global prevalence of LF is calculated to have fallen by 59%, from 3.55% to 1.47%. The fall was highest for microfilaraemia prevalence (68%), followed by 49% in hydrocele prevalence and 25% in lymphedema prevalence. It is estimated that, currently, i.e. after 13 years of the MDA programme, there are still an estimated 67.88 million LF cases that include 36.45 million microfilaria carriers, 19.43 million hydrocele cases and 16.68 million lymphedema cases. Conclusions/Significance The MDA programme has resulted in significant reduction of the LF burden. Extension of MDA to all at-risk countries and to all regions within those countries where MDA has not yet reached 100% geographic coverage is imperative to further reduce the number of microfilaraemia and chronic disease cases and to reach the global target of interrupting transmission of LF by 2020. PMID:25412180

Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic.

PubMed

Sarkar, Siddik; Quinn, Bridget A; Shen, Xue-Ning; Dash, Rupesh; Das, Swadesh K; Emdad, Luni; Klibanov, Alexander L; Wang, Xiang-Yang; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B

2015-05-10

Despite recent advances, treatment options for advanced prostate cancer (CaP) remain limited. We are pioneering approaches to treat advanced CaP that employ conditionally replication-competent oncolytic adenoviruses that simultaneously produce a systemically active cancer-specific therapeutic cytokine, mda-7/IL-24, Cancer Terminator Viruses (CTV). A truncated version of the CCN1/CYR61 gene promoter, tCCN1-Prom, was more active than progression elevated gene-3 promoter (PEG-Prom) in regulating transformation-selective transgene expression in CaP and oncogene-transformed rat embryo cells. Accordingly, we developed a new CTV, Ad.tCCN1-CTV-m7, which displayed dose-dependent killing of CaP without harming normal prostate epithelial cells in vitro with significant anti-cancer activity in vivo in both nude mouse CaP xenograft and transgenic Hi-Myc mice (using ultrasound-targeted microbubble (MB)-destruction, UTMD, with decorated MBs). Resistance to mda-7/IL-24-induced cell death correlated with overexpression of Bcl-2 family proteins. Inhibiting Mcl-1 using an enhanced BH3 mimetic, BI-97D6, sensitized CaP cell lines to mda-7/IL-24-induced apoptosis. Combining BI-97D6 with Ads expressing mda-7/IL-24 promoted ER stress, decreased anti-apoptotic Mcl-1 expression and enhanced mda-7/IL-24 expression through mRNA stabilization selectively in CaP cells. In Hi-myc mice, the combination induced enhanced apoptosis and tumor growth suppression. These studies highlight therapeutic efficacy of combining a BH3 mimetic with a novel CTV, supporting potential clinical applications for treating advanced CaP.

A novel tumor-activated ALA fusion protein for specific inhibition on the growth and invasion of breast cancer cells MDA-MB-231.

PubMed

Liu, Xiufeng; Liu, Xintong; Sunchen, Suwen; Liu, Meixia; Shen, Chen; Wu, Juanjuan; Zhao, Wanli; Yu, Boyang; Liu, Jihua

2017-11-01

The aim of this research was to develop a novel ALA fusion protein for target to the malignant cells surface with high uPAR expression and locally release of the scorpion toxin AGAP in an uPA-cleavable manner. It will provide an effective approach for controlled release of the peptide toxins to treat cancerous cells. The ALA fusion proteins were expressed in pichia pastoris, and the recombinant proteins were purified by Ni-NTA affinity chromatography. The proteins were added to human breast cancer cells (MDA-MB-231) and human embryonic kidney cells (HEK-293) in order to investigate the characteristic of selective targeting and releasing of scorpion toxin AGAP in cancer cells with high uPAR expression. The inhibitory effect of ALA on MDA-MB-231, MCF7, LO2 and HEK-293 was evaluated by MTT assay. Moreover, the antiproliferation mechanism of ALA was determined by flow cytometric and western blot analysis. The results showed that ALA could target MDA-MB-231 cells and the scorpion toxin AGAP could be released with high efficiency and selectivity. ALA inhibited the growth and invasion of breast cancer cells MDA-MB231. Also, cell apoptosis pathway was found to be associated with the inhibition mechanism of ALA according to the data of flow cytometric and western blot analysis. Therefore, ALA could be a novel antitumor candidate for targeting treatment of malignant cell. This study successfully demonstrated that fusion of biotoxins with tumor target domain could provide a simple yet effective way to delivery of peptide or protein drugs.

Electrochemical and spectroscopic characterisation of amphetamine-like drugs: application to the screening of 3,4-methylenedioxymethamphetamine (MDMA) and its synthetic precursors.

PubMed

Milhazes, Nuno; Martins, Pedro; Uriarte, Eugenio; Garrido, Jorge; Calheiros, Rita; Marques, M Paula M; Borges, Fernanda

2007-07-23

A complete physicochemical characterisation of MDMA and its synthetic precursors MDA, 3,4-methylenedioxybenzaldehyde (piperonal) and 3,4-methylenedioxy-beta-methyl-beta-nitrostyrene was carried out through voltammetric assays and Raman spectroscopy combined with theoretical (DFT) calculations. The former provided important analytical redox data, concluding that the oxidative mechanism of the N-demethylation of MDMA involves the removal of an electron from the amino-nitrogen atom, leading to the formation of a primary amine and an aldehyde. The vibrational spectroscopic experiments enable to afford a rapid and reliable detection of this type of compounds, since they yield characteristic spectral patterns that lead to an unequivocal identification. Moreover, the rational synthesis of the drug of abuse 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") from one of its most relevant precursors 3,4-methylene-dioxyamphetamine (MDA), is reported. In addition, several approaches for the N-methylation of MDA, a limiting synthetic step, were attempted and the overall yields compared.

Multidimensional assessment of severe asthma: A systematic review and meta-analysis.

PubMed

Clark, Vanessa L; Gibson, Peter G; Genn, Grayson; Hiles, Sarah A; Pavord, Ian D; McDonald, Vanessa M

2017-10-01

The management of severe asthma is complex. Multidimensional assessment (MDA) of specific traits has been proposed as an effective strategy to manage severe asthma, although it is supported by few prospective studies. We aimed to systematically review the literature published on MDA in severe asthma, to identify the traits included in MDA and to determine the effect of MDA on asthma-related outcomes. We identified 26 studies and classified these based on study type (cohort/cross-sectional studies; experimental/outcome studies; and severe asthma disease registries). Study type determined the comprehensiveness of the assessment. Assessed traits were classified into three domains (airways, co-morbidities and risk factors). The airway domain had the largest number of traits assessed (mean ± SD = 4.2 ± 1.7) compared with co-morbidities (3.6 ± 2.2) and risk factors (3.9 ± 2.1). Bronchodilator reversibility and airflow limitation were assessed in 92% of studies, whereas airway inflammation was only assessed in 50%. Commonly assessed co-morbidities were psychological dysfunction, sinusitis (both 73%) and gastro-oesophageal reflux disease (GORD; 69%). Atopic and smoking statuses were the most commonly assessed risk factors (85% and 86%, respectively). There were six outcome studies, of which five concluded that MDA is effective at improving asthma-related outcomes. Among these studies, significantly more traits were assessed than treated. MDA studies have assessed a variety of different traits and have shown evidence of improved outcomes. This promising model of care requires more research to inform which traits should be assessed, which traits should be treated and what effect MDA has on patient outcomes. © 2017 Asian Pacific Society of Respirology.

Evaluation of drug incorporation into hair segments and nails by enantiomeric analysis following controlled single MDMA intakes.

PubMed

Madry, Milena M; Steuer, Andrea E; Hysek, Cédric M; Liechti, Matthias E; Baumgartner, Markus R; Kraemer, Thomas

2016-01-01

Incorporation rates of the enantiomers of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) into hair and nails were investigated after controlled administration. Fifteen subjects without MDMA use received two doses of 125 mg of MDMA. Hair, nail scrapings, and nail clippings were collected 9-77 days after the last administration (median 20 days). Hair samples were analyzed in segments of 1- to 2-cm length. After chiral derivatization with N-(2,4-dinitro-5-fluorophenyl)-L-valinamide, MDMA and MDA diastereomers were analyzed by liquid chromatography-tandem mass spectrometry. Highest concentrations in hair segments corresponded to the time of MDMA intake. They ranged from 101 to 3200 pg/mg and 71 to 860 pg/mg for R- and S-MDMA, and from 3.2 to 116 pg/mg and 4.4 to 108 pg/mg for R- and S-MDA, respectively. MDMA and MDA concentrations in nail scrapings and clippings were significantly lower than in hair samples. There was no significant difference between enantiomeric ratios of R/S-MDMA and R/S-MDA in hair and nail samples (medians 2.2-2.4 for MDMA and 0.85-0.95 for MDA). Metabolite ratios of MDA to MDMA were in the same range in hair and nail samples (medians 0.044-0.055). Our study demonstrates that administration of two representative doses of MDMA was detected in the hair segments corresponding to the time of intake based on average hair growth rates. MDMA was detected in all nail samples regardless of time passed after intake. Comparable R/S ratios in hair and nail samples may indicate that incorporation mechanisms into both matrices are comparable.

COMMUNITY MEMBERS' PERCEPTIONS OF MASS DRUG ADMINISTRATION FOR CONTROL OF LYMPHATIC FILARIASIS IN RURAL AND URBAN TANZANIA.

PubMed

Kisoka, William J; Tersbøl, Britt Pinkowsky; Meyrowitsch, Dan W; Simonsen, Paul E; Mushi, Declare L

2016-01-01

Lymphatic filariasis is one of several neglected tropical diseases with severely disabling and stigmatizing manifestations that are referred to as 'neglected diseases of poverty'. It is a mosquito-borne disease found endemically and exclusively in low-income contexts where, concomitantly, general public health care is often deeply troubled and fails to meet the basic health needs of impoverished populations. This presents particular challenges for the implementation of mass drug administration (MDA), which currently is the principal means of control and eventual elimination. Several MDA programmes face the dilemma that they are unable to attain and maintain the required drug coverage across target groups. In recognition of this, a qualitative study was conducted in the Morogoro and Lindi regions of Tanzania to gain an understanding of community experiences with, and perceptions of, the MDA campaign implemented in 2011 by the National Lymphatic Filariasis Elimination Programme. The study revealed a wide variation of perceptions and experiences regarding the aim, rationale and justification of MDA. There were positive sentiments about the usefulness of the drugs, but many study participants were sceptical about the manner in which MDA is implemented. People were particularly disappointed with the limited attempts by implementers to share information and mobilize residents. In addition, negative sentiments towards MDA for lymphatic filariasis reflected a general feeling of desertion and marginalization by the health care system and political authorities. However, the results suggest that if the communities are brought on board with genuine respect for their integrity and informed self-determination, there is scope for major improvements in community support for MDA-based control activities.

A DN-mda5 transgenic zebrafish model demonstrates that Mda5 plays an important role in snakehead rhabdovirus resistance.

PubMed

Gabor, K A; Charette, J R; Pietraszewski, M J; Wingfield, D J; Shim, J S; Millard, P J; Kim, C H

2015-08-01

Melanoma Differentiation-Associated protein 5 (MDA5) is a member of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family, which is a cytosolic pattern recognition receptor that detects viral nucleic acids. Here we show an Mda5-dependent response to rhabdovirus infection in vivo using a dominant-negative mda5 transgenic zebrafish. Dominant-negative mda5 zebrafish embryos displayed an impaired antiviral immune response compared to wild-type counterparts that can be rescued by recombinant full-length Mda5. To our knowledge, we have generated the first dominant-negative mda5 transgenic zebrafish and demonstrated a critical role for Mda5 in the antiviral response to rhabdovirus. Copyright © 2015 Elsevier Ltd. All rights reserved.

The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5-RNA interaction and filament assembly

PubMed Central

Bruns, Annie M.; Leser, George P.; Lamb, Robert A.; Horvath, Curt M.

2014-01-01

SUMMARY Cytoplasmic pattern recognition receptors detect non-self RNAs during virus infections and initiate antiviral signaling. One receptor, MDA5, possesses essential signaling domains, but weak RNA binding. A second receptor, LGP2, rapidly detects diverse dsRNA species, but lacks signaling domains. Accumulating evidence suggests LGP2 and MDA5 work together to detect viral RNA and generate a complete antiviral response, but the basis for their cooperation has been elusive. Experiments presented here address this gap in antiviral signaling, revealing that LGP2 assists MDA5-RNA interactions leading to enhanced MDA5-mediated antiviral signaling. LGP2 increases the initial rate of MDA5-RNA interaction and regulates MDA5 filament assembly, resulting in the formation of more numerous, shorter MDA5 filaments that are shown to generate equivalent or greater signaling activity in vivo than the longer filaments containing only MDA5. These findings provide a mechanism for LGP2 co-activation of MDA5 and a biological context for MDA5-RNA filaments in antiviral responses. PMID:25127512

The contribution of mass drug administration to global health: past, present and future.

PubMed

Webster, Joanne P; Molyneux, David H; Hotez, Peter J; Fenwick, Alan

2014-01-01

Mass drug administration (MDA) is a means of delivering safe and inexpensive essential medicines based on the principles of preventive chemotherapy, where populations or sub-populations are offered treatment without individual diagnosis. High-coverage MDA in endemic areas aims to prevent and alleviate symptoms and morbidity on the one hand and can reduce transmission on the other, together improving global health. MDA is the recommended strategy of the World Health Organisation to control or eliminate several neglected tropical diseases (NTDs). More than 700 million people now receive these essential NTD medicines annually. The combined cost of integrated NTD MDA has been calculated to be in the order of $0.50 per person per year. Activities have recently been expanded due, in part, to the proposed attempt to eliminate certain NTDs in the coming two decades. More than 1.9 billion people need to receive MDA annually across several years if these targets are to be met. Such extensive coverage will require additional avenues of financial support, expanded monitoring and evaluation focusing on impact and drug efficacy, as well as new diagnostic tools and social science strategies to encourage adherence. MDA is a means to help reduce the burden of disease, and hence poverty, among the poorest sector of populations. It has already made significant improvements to global health and productivity and has the potential for further successes, particularly where incorporated into sanitation and education programmes. However logistical, financial and biological challenges remain.

The effect of copper, MDA, and accelerated aging on jet fuel thermal stability as measured by the gravimetric JFTOT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pande, S.G.; Hardy, D.R.

1995-05-01

Thermally unstable jet fuels pose operational problems. In order to adequately identify such fuels, factors that realistically impact on thermal stability were examined. Evaluation was based on a quantitative method of measuring thermal stability, viz., NRL`s recently developed gravimetric JFTOT. This method gives a quantitative measurement of both the strip deposit and filterables formed. The pertinent factors examined, included the individual and interactive effects of: soluble copper, MDA (metal deactivator), and aging. The latter was accelerated to simulate field conditions of approximately six months aging at ambient temperature and pressure. The results indicate that the individual and interactive effects ofmore » copper, MDA, and accelerated aging appear to be fuel dependent. Based on the results, the three test fuels examined (one JP-8 and two JP-5s) were categorized as exhibiting very good, typical, and poor thermal stabilities, respectively. For both the very good and poor thermal stability fuels, the effect of copper in conjunction with accelerated aging did not significantly increase the total thermal deposits of the neat fuels. In contrast, for the typical thermal stability fuel, the combined effects of copper and accelerated aging, did. Furthermore, the addition of MDA prior to aging of the copper-doped, typical stability fuel significantly counteracted the adverse effect of copper and aging. A similar beneficial effect of MDA was not observed for the poor stability fuel. These results focus on the compositional differences among fuels and the need to elucidate these differences (physical and chemical) for a better understanding and prediction of their performance.« less

MDA5 cooperatively forms dimers and ATP-sensitive filaments upon binding double-stranded RNA

PubMed Central

Berke, Ian C; Modis, Yorgo

2012-01-01

Melanoma differentiation-associated gene-5 (MDA5) detects viral double-stranded RNA in the cytoplasm. RNA binding induces MDA5 to activate the signalling adaptor MAVS through interactions between the caspase recruitment domains (CARDs) of the two proteins. The molecular mechanism of MDA5 signalling is not well understood. Here, we show that MDA5 cooperatively binds short RNA ligands as a dimer with a 16–18-basepair footprint. A crystal structure of the MDA5 helicase-insert domain demonstrates an evolutionary relationship with the archaeal Hef helicases. In X-ray solution structures, the CARDs in unliganded MDA5 are flexible, and RNA binds on one side of an asymmetric MDA5 dimer, bridging the two subunits. On longer RNA, full-length and CARD-deleted MDA5 constructs assemble into ATP-sensitive filaments. We propose a signalling model in which the CARDs on MDA5–RNA filaments nucleate the assembly of MAVS filaments with the same polymeric geometry. PMID:22314235

MDA5 assembles into a polar helical filament on dsRNA

PubMed Central

Berke, Ian C.; Yu, Xiong; Modis, Yorgo; Egelman, Edward H.

2012-01-01

Melanoma differentiation-associated protein 5 (MDA5) detects viral dsRNA in the cytoplasm. On binding of RNA, MDA5 forms polymers, which trigger assembly of the signaling adaptor mitochondrial antiviral-signaling protein (MAVS) into its active fibril form. The molecular mechanism of MDA5 signaling is not well understood, however. Here we show that MDA5 forms helical filaments on dsRNA and report the 3D structure of the filaments using electron microscopy (EM) and image reconstruction. MDA5 assembles into a polar, single-start helix around the RNA. Fitting of an MDA5 homology model into the structure suggests a key role for the MDA5 C-terminal domain in cooperative filament assembly. Our study supports a signal transduction mechanism in which the helical array of MDA5 within filaments nucleates the assembly of MAVS fibrils. We conclude that MDA5 is a polymerization-dependent signaling platform that uses the amyloid-like self-propagating properties of MAVS to amplify signaling. PMID:23090998

Quantitative assessment of the impact of partially protective anti-schistosomiasis vaccines

PubMed Central

Ndeffo Mbah, Martial; Galvani, Alison

2017-01-01

Background Mass drug administration (MDA) of praziquantel has been the intervention of choice against schistosomiasis but with limited success in interrupting the transmission. The development of anti-Schistosoma vaccines is underway. Our objective is to quantify the population-level impact of anti-Schistosoma vaccines when administered alone and in combination with mass drug administration (MDA) and determine factors in vaccine design and public health implementation that optimize vaccination role in schistosomiasis control and elimination. Methods and findings We developed a deterministic compartmental model simulation of schistosomiasis transmission in a high-risk Kenyan community, including stratification by age, parasite burden, and vaccination status. The modeled schistosomiasis vaccines differed in terms of vaccine duration of protection (durability) and three biological efficacies. These are vaccine susceptibility effect (SE) of reducing person’s susceptibility to Schistosoma acquisition, vaccine mortality effect (ME) of reducing established worm burden and vaccine fecundity effect (FE) of reducing egg release by mature worms. We quantified the population-level impact of vaccination over two decades under diverse vaccination schemes (childhood vs. mass campaigns), with different age-targeting scenarios, different risk settings, and with combined intervention with MDA. We also assessed the sensitivity of our predictions to uncertainties in model parameters. Over two decades, our base case vaccine with 80% SE, FE, and ME efficacies, 10 years’ durability, provided by mass vaccination every 10 years, reduced host prevalence, mean intensity, incidence, and patent snail prevalence to 31%, 20 eggs/10-ml sample/person, 0.87 worm/person-year, and 0.74%, from endemic-state values of 71%, 152, 3.3, and 0.98%, respectively. Lower impact was found when coverage did not encompass all potential contaminators, and childhood-only vaccination schemes showed delayed and lower impact. In lower prevalence settings, the base case vaccine generated a proportionately smaller impact. A substantially larger vaccine program effect was generated when MDA + mass vaccination was provided every 5 years, which could be achieved by an MDA-only program only if drug was offered annually. Vaccine impact on schistosomiasis transmission was sensitive to a number of parameters including vaccine efficacies, human contact rates with water, human density, patent snails’ rate of patency and lifespan, and force of infection to snails. Conclusions To be successful a vaccine-based control strategy will need a moderately to highly effective formulation combined with early vaccination of potential contaminators and aggressive coverage in repeated rounds of mass vaccination. Compared to MDA-only program, vaccination combined with MDA accelerates and prolongs the impact by reducing the acquisition of new worms and reducing egg release from residual worms. PMID:28410369

Quantitative assessment of the impact of partially protective anti-schistosomiasis vaccines.

PubMed

Alsallaq, Ramzi A; Gurarie, David; Ndeffo Mbah, Martial; Galvani, Alison; King, Charles

2017-04-01

Mass drug administration (MDA) of praziquantel has been the intervention of choice against schistosomiasis but with limited success in interrupting the transmission. The development of anti-Schistosoma vaccines is underway. Our objective is to quantify the population-level impact of anti-Schistosoma vaccines when administered alone and in combination with mass drug administration (MDA) and determine factors in vaccine design and public health implementation that optimize vaccination role in schistosomiasis control and elimination. We developed a deterministic compartmental model simulation of schistosomiasis transmission in a high-risk Kenyan community, including stratification by age, parasite burden, and vaccination status. The modeled schistosomiasis vaccines differed in terms of vaccine duration of protection (durability) and three biological efficacies. These are vaccine susceptibility effect (SE) of reducing person's susceptibility to Schistosoma acquisition, vaccine mortality effect (ME) of reducing established worm burden and vaccine fecundity effect (FE) of reducing egg release by mature worms. We quantified the population-level impact of vaccination over two decades under diverse vaccination schemes (childhood vs. mass campaigns), with different age-targeting scenarios, different risk settings, and with combined intervention with MDA. We also assessed the sensitivity of our predictions to uncertainties in model parameters. Over two decades, our base case vaccine with 80% SE, FE, and ME efficacies, 10 years' durability, provided by mass vaccination every 10 years, reduced host prevalence, mean intensity, incidence, and patent snail prevalence to 31%, 20 eggs/10-ml sample/person, 0.87 worm/person-year, and 0.74%, from endemic-state values of 71%, 152, 3.3, and 0.98%, respectively. Lower impact was found when coverage did not encompass all potential contaminators, and childhood-only vaccination schemes showed delayed and lower impact. In lower prevalence settings, the base case vaccine generated a proportionately smaller impact. A substantially larger vaccine program effect was generated when MDA + mass vaccination was provided every 5 years, which could be achieved by an MDA-only program only if drug was offered annually. Vaccine impact on schistosomiasis transmission was sensitive to a number of parameters including vaccine efficacies, human contact rates with water, human density, patent snails' rate of patency and lifespan, and force of infection to snails. To be successful a vaccine-based control strategy will need a moderately to highly effective formulation combined with early vaccination of potential contaminators and aggressive coverage in repeated rounds of mass vaccination. Compared to MDA-only program, vaccination combined with MDA accelerates and prolongs the impact by reducing the acquisition of new worms and reducing egg release from residual worms.

Novel Simvastatin-Loaded Nanoparticles Based on Cholic Acid-Core Star-Shaped PLGA for Breast Cancer Treatment.

PubMed

Wu, Yanping; Wang, Zhongyuan; Liu, Gan; Zeng, Xiaowei; Wang, Xusheng; Gao, Yongfeng; Jiang, Lijuan; Shi, Xiaojun; Tao, Wei; Huang, Laiqiang; Mei, Lin

2015-07-01

A novel nanocarrier system of cholic acid (CA) core, star-shaped polymer consisting of poly(D,L-lactide-co-glycolide) (PLGA) was developed for sustained and controlled delivery of simvastatin for chemotherapy of breast adenocarcinoma. The star-shaped polymer CA-PLGA with three branch arms was synthesized successfully through the core-first approach. The simvastatin-loaded star-shaped CA-PLGA nanoparticles were prepared through a modified nanoprecipitation method. The data showed that the fluorescence star-shaped CA-PLGA nanoparticles could be internalized into MDA-MB-231 and MDA-MB-468 human breast cancer cells. The simvastatin-loaded star-shaped CA-PLGA nanoparticles achieved significantly higher level of cytotoxicity than pristine simvastatin and simvastatin-loaded linear PLGA nanoparticles. Moreover, the expression of the cell cycle protein cyclin D1 was dramatically inhibited by simvastatin in both cells, with simvastatin-loaded star-shaped CA-PLGA nanoparticles having the greatest effect. MDA-MB-231 xenograft tumor model on BALB/c nude mice showed that simvastatin-loaded star-shaped CA-PLGA nanoformulations could effectively inhibit the growth of tumor over a longer period of time than pristine simvastatin and simvastatin-loaded linear PLGA nanoformulations at the same dose. In agreement with these, the nuclear expression of proliferation marker Ki-67 in simvastatin-loaded star-shaped CA-PLGA nanoparticles group was reduced to a most extent among four groups through tumor frozen section immunohistochemistry. In conclusion, the star-shaped CA-PLGA polymers could serve as a novel polymeric nanocarrier for breast cancer chemotherapy.

Analysis of the Antiproliferative Effects of Curcumin and Nanocurcumin in MDA-MB231 as a Breast Cancer Cell Line.

PubMed

Khosropanah, Mohammad Hossein; Dinarvand, Amin; Nezhadhosseini, Afsaneh; Haghighi, Alireza; Hashemi, Sima; Nirouzad, Fereidon; Khatamsaz, Sepideh; Entezari, Maliheh; Hashemi, Mehrdad; Dehghani, Hossein

2016-01-01

Cancer is one of the main causes of mortality in the world which appears by the effect of enviromental physico-chemical mutagen and carcinogen agents. The identification of new cytotoxic drug with low sid effects on immune system has developed as important area in new studies of immunopharmacology. Curcumin is a natural polyphenol with anti-oxidative, anti-inflammatory and anti-cancer properties. Its therapeutic potential is substantially hindered by the rather low water solubility and bioavailability, hence the need for suitable carriers. In this report we employed nanogel-based nanoparticle approach to improve upon its effectiveness. Myristic acid-chitosan (MA-chitosan) nanogels were prepared by the technique of self-assembly. Curcumin was loaded into the nanogels. The surface morphology of the prepared nanoparticles was determined using SEM and TEM. The other objective of this study was to examine the in vitro cytotoxic activity of cell death of curcumin and nanocurcumin on human breast adenocarcinoma cell line (MDA-MB231). Cytotoxicity and viability of curcumin and nanocurcumin were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and dye exclusion assay. Transmission electron microscopy confirmed the particle diameter was between 150 to 200 nm. Proliferation of MDA-MB231 cells was significantly inhibited by curcumin and nanocurcumin in a concentration-dependent manner in defined times. There were significant differences in IC50 curcumin and nanocurcumin. curcumin -loaded nanoparticles proved more effective compared to TQ solution. The high drug-targeting potential and efficiency demonstrates the significant role of the anticancer properties of curcumin -loaded nanoparticles.

Manufacturing of Smart Structures Using Fiber Placement Manufacturing Processes

NASA Technical Reports Server (NTRS)

Thomas, Matthew M.; Glowasky, Robert A.; McIlroy, Bruce E.; Story, Todd A.

1996-01-01

Smart structures research and development, with the ultimate aim of rapid commercial and military production of these structures, are at the forefront of the Synthesis and Processing of Intelligent Cost-Effective Structures (SPICES) program. As part of this ARPA-sponsored program, MDA-E is using fiber placement processes to manufacture integrated smart structure systems. These systems comprise advanced composite structures with embedded fiber optic sensors, shape memory alloys, piezoelectric actuators, and miniature accelerometers. Cost-effective approaches and solutions to smart material synthesis in the fiber-placement process, based upon integrated product development, are discussed herein.

A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young

2013-01-25

Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24{sup −}/CD44{sup +}) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies.more » This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.« less

Missing the Mark? A Two Time Point Cohort Study Estimating Intestinal Parasite Prevalence in Informal Settlements in Lima, Peru.

PubMed

Cooper, Michael Townsend; Searing, Rapha A; Thompson, David M; Bard, David; Carabin, Hélène; Gonzales, Carlos; Zavala, Carmen; Woodson, Kyle; Naifeh, Monique

2017-01-01

Objectives: The World Health Organization's (WHO) recommendations list Peru as potentially needing prevention of soil-transmitted helminthiasis (STH). Prevalence of STH varies regionally and remains understudied in the newest informal settlements of the capital city, Lima. The purpose of this study was to evaluate the need for Mass Drug Administration (MDA) of antiparasitic drugs in the newest informal settlements of Lima. The aim of this study was to estimate the season-specific prevalence of STH to determine if these prevalence estimates met the WHO threshold for MDA in 3 informal settlements. Methods : A 2 time point cohort study was conducted among a sample of 140 children aged 1 to 10 years living in 3 purposively sampled informal settlements of Lima, Peru. Children were asked to provide 2 stool samples that were analyzed with the spontaneous sedimentation in tube technique. The season-specific prevalence proportions of MDA-targeted STH were estimated using a hidden (latent) Markov modeling approach to adjust for repeated measurements over the 2 seasons and the imperfect validity of the screening tests. Results : The prevalence of MDA targeted STH was low at 2.2% (95% confidence interval = 0.3% to 6%) and 3.8% (95% confidence interval = 0.7% to 9.3%) among children sampled in the summer and winter months, respectively, when using the most conservative estimate of test sensitivity. These estimates were below the WHO threshold for MDA (20%). Conclusions : Empiric treatment for STH by organizations active in the newest informal settlements is not supported by the data and could contribute to unnecessary medication exposures and poor allocation of resources.

Missing the Mark? A Two Time Point Cohort Study Estimating Intestinal Parasite Prevalence in Informal Settlements in Lima, Peru

PubMed Central

Cooper, Michael Townsend; Searing, Rapha A.; Thompson, David M.; Bard, David; Carabin, Hélène; Gonzales, Carlos; Zavala, Carmen; Woodson, Kyle; Naifeh, Monique

2017-01-01

Objectives: The World Health Organization’s (WHO) recommendations list Peru as potentially needing prevention of soil-transmitted helminthiasis (STH). Prevalence of STH varies regionally and remains understudied in the newest informal settlements of the capital city, Lima. The purpose of this study was to evaluate the need for Mass Drug Administration (MDA) of antiparasitic drugs in the newest informal settlements of Lima. The aim of this study was to estimate the season-specific prevalence of STH to determine if these prevalence estimates met the WHO threshold for MDA in 3 informal settlements. Methods: A 2 time point cohort study was conducted among a sample of 140 children aged 1 to 10 years living in 3 purposively sampled informal settlements of Lima, Peru. Children were asked to provide 2 stool samples that were analyzed with the spontaneous sedimentation in tube technique. The season-specific prevalence proportions of MDA-targeted STH were estimated using a hidden (latent) Markov modeling approach to adjust for repeated measurements over the 2 seasons and the imperfect validity of the screening tests. Results: The prevalence of MDA targeted STH was low at 2.2% (95% confidence interval = 0.3% to 6%) and 3.8% (95% confidence interval = 0.7% to 9.3%) among children sampled in the summer and winter months, respectively, when using the most conservative estimate of test sensitivity. These estimates were below the WHO threshold for MDA (20%). Conclusions: Empiric treatment for STH by organizations active in the newest informal settlements is not supported by the data and could contribute to unnecessary medication exposures and poor allocation of resources. PMID:29152541

Advancing bioluminescence imaging technology for the evaluation of anticancer agents in the MDA-MB-435-HAL-Luc mammary fat pad and subrenal capsule tumor models.

PubMed

Zhang, Cathy; Yan, Zhengming; Arango, Maria E; Painter, Cory L; Anderes, Kenna

2009-01-01

Tumors grafted s.c. or under the mammary fat pad (MFP) rarely develop efficient metastasis. By applying bioluminescence imaging (BLI) technology, the MDA-MB-435-HAL-Luc subrenal capsule (SRC) model was compared with the MFP model for disease progression, metastatic potential, and response to therapy. The luciferase-expressing MDA-MB-435-HAL-Luc cell line was used in both MFP and SRC models. BLI technology allowed longitudinal assessment of disease progression and the therapeutic response to PD-0332991, Avastin, and docetaxel. Immunohistochemical analysis of Ki67 and CD31 staining in the primary tumors was compared in these models. Caliper measurement was used in the MFP model to validate the BLI quantification of primary tumors. The primary tumors in MDA-MB-435-HAL-Luc MFP and SRC models displayed comparable growth rates and vascularity. However, tumor-bearing mice in the SRC model developed lung metastases much earlier (4 weeks) than in the MFP model (>7 weeks), and the metastatic progression contributed significantly to the survival time. In the MFP model, BLI and caliper measurements were comparable for quantifying palpable tumors, but BLI offered an advantage for detecting the primary tumors that fell below a palpable threshold and for visualizing metastases. In the SRC model, BLI allowed longitudinal assessment of the antitumor and antimetastatic effects of PD-0332991, Avastin, and docetaxel, and the results correlated with the survival benefits of these agents. The MDA-MB-435-HAL-Luc SRC model and the MFP model displayed differences in disease progression. BLI is an innovative approach for developing animal models and creates opportunities for improving preclinical evaluations of anticancer agents.

Selective androgen receptor modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

PubMed

Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D; Yepuru, Muralimohan; Miller, Duane D; Steiner, Mitchell S; Dalton, James T

2014-01-01

The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action. Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

Selective Androgen Receptor Modulators (SARMs) Negatively Regulate Triple-Negative Breast Cancer Growth and Epithelial:Mesenchymal Stem Cell Signaling

PubMed Central

Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D.; Yepuru, Muralimohan; Miller, Duane D.; Steiner, Mitchell S.; Dalton, James T.

2014-01-01

Abstract Introduction The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75–95% of estrogen receptor (ER)-positive and 40–70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Materials and Methods Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action. Results Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. Conclusion 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer. PMID:25072326

Strong fascin expression promotes metastasis independent of its F-actin bundling activity.

PubMed

Heinz, Lisa S; Muhs, Stefanie; Schiewek, Johanna; Grüb, Saskia; Nalaskowski, Marcus; Lin, Yuan-Na; Wikman, Harriet; Oliveira-Ferrer, Leticia; Lange, Tobias; Wellbrock, Jasmin; Konietzny, Anja; Mikhaylova, Marina; Windhorst, Sabine

2017-12-15

High expression of the actin bundling protein Fascin increases the malignancy of tumor cells. Here we show that fascin expression is up-regulated in more malignant sub-cell lines of MDA-MB-231 cells as compared to parental cells. Since also parental MDA-MB-231 cells exhibit high fascin levels, increased fascin expression was termed as "hyperexpression". To examine the effect of fascin hyperexpression, fascin was hyperexpressed in parental MDA-MB-231 cells and metastasis was analyzed in NOD scid gamma (NSG) mice. In addition, the effect of fascin mutants with inactive or constitutively active actin bundling activity was examined. Unexpectedly, we found that hyperexpression of both, wildtype (wt) and mutant fascin strongly increased metastasis in vivo , showing that the effect of fascin hyperexpression did not depend on its actin bundling activity. Cellular assays revealed that hyperexpression of wt and mutant fascin increased adhesion of MDA-MB-231 cells while transmigration and proliferation were not affected. Since it has been shown that fascin controls adhesion by directly interacting with microtubules ( MTs), we analyzed if fascin hyperexpression affects MT dynamics. We found that at high concentrations fascin significantly increased MT dynamics in cells and in cell-free approaches. In summary our data show that strong expression of fascin in breast cancer cells increases metastasis independent of its actin bundling activity. Thus, it seems that the mechanism of fascin-stimulated metastasis depends on its concentration.

Relationship between the degree of antioxidant protection and the level of malondialdehyde in high-performance Polish Holstein-Friesian cows in peak of lactation

PubMed Central

2018-01-01

Lipid peroxidation can be described as a process under which free radicals attack carbon double bonds of omega-3 and omega-6 fatty acids. Whereas the end products of this process are reactive aldehydes, such as malondialdehyde (MDA). Lipid peroxidation leads to adverse changes in the nutritional value of milk; therefore, higher degree of antioxidant protection (DAP) ensures higher stability of dairy products by effecting their high antioxidative potential. Therefore, the purpose of this study was to demonstrate the relationship between the DAP and the level of MDA in high-performance Polish Holstein-Friesian cows in peak of lactation. Sixty-three Polish Holstein-Friesian cows were selected to the experiment according to: parity (all in the 2nd lactation), phase of lactation (peak of lactation), cytological quality of milk (somatic cell count < 150 thousand/ml) and without diagnosed metabolic diseases. The data obtained were analyzed statistically by two–way ANOVA, and Tukey’s post-hoc test. After analysis of performance the cows were divided into 3 groups (twenty one cows in each group) based on milk yield and MDA concentration. The study revealed a significant effect of the lactation performance of cows on MDA levels in milk (P ≤ 0.01). The highest concentration of MDA (61.137 nM/mL) was shown in milk of cows yielding between 50.00 and 55.80 kg/day. The highest concentration of fat was found in milk in which the MDA level ranged from 48 to 86 nM/mL. Whereas, the inverse relationship was demonstrated in case of protein concentration. The highest level of protein was found in cows with MDA levels in the range of 18–28 nM/mL (P ≤ 0.01). The lowest MDA level (in the range of 18–28 nM/mL) was associated with the highest concentration of vitamin E, β-carotene, total antioxidant status (TAS) and DAP, measured in both milk and plasma. The obtained results show that lipid peroxidation leads to adverse changes in the nutritional value of milk; the highest DAP (7.89 x 10−3) was found in the cows with the lowest MDA concentration in milk. PMID:29494660

Impact of Four Years of Annual Mass Drug Administration on Prevalence and Intensity of Schistosomiasis among Primary and High School Children in Western Kenya: A Repeated Cross-Sectional Study

PubMed Central

Abudho, Bernard O.; Ndombi, Eric M.; Guya, Bernard; Carter, Jennifer M.; Riner, Diana K.; Kittur, Nupur; Karanja, Diana M. S.; Secor, W. Evan; Colley, Daniel G.

2018-01-01

Abstract. Schistosomiasis remains a major public health problem in Kenya. The World Health Organization recommends preventive chemotherapy with praziquantel (PZQ) to control morbidity due to schistosomiasis. Morbidity is considered linked to intensity of infection, which along with prevalence is used to determine the frequency of mass drug administration (MDA) to school-age children. We determined the impact of annual school-based MDA on children across all primary and high school years using a repeated cross-sectional study design in five schools near Lake Victoria in western Kenya, an area endemic for Schistosoma mansoni. At baseline and for the following four consecutive years, between 897 and 1,440 school children in Grades 1–12 were enrolled and evaluated by Kato-Katz for S. mansoni and soil-transmitted helminths (STH), followed by annual MDA with PZQ and albendazole. Four annual rounds of MDA with PZQ were associated with reduced S. mansoni prevalence in all school children (44.7–14.0%; P < 0.001) and mean intensity of infection by 91% (90.4 to 8.1 eggs per gram [epg] of stool; P < 0.001). Prevalence of high-intensity infection (≥ 400 epg) decreased from 6.8% at baseline to 0.3% by the end of the study. Soil-transmitted helminth infections, already low at baseline, also decreased significantly over the years. In this high prevalence area, annual school-based MDA with high coverage across all Grades (1–12) resulted in rapid and progressive declines in overall prevalence and intensity of infection. This decrease was dramatic in regard to heavy infections in older school-attending children. PMID:29532768

Impact of Four Years of Annual Mass Drug Administration on Prevalence and Intensity of Schistosomiasis among Primary and High School Children in Western Kenya: A Repeated Cross-Sectional Study.

PubMed

Abudho, Bernard O; Ndombi, Eric M; Guya, Bernard; Carter, Jennifer M; Riner, Diana K; Kittur, Nupur; Karanja, Diana M S; Secor, W Evan; Colley, Daniel G

2018-05-01

Schistosomiasis remains a major public health problem in Kenya. The World Health Organization recommends preventive chemotherapy with praziquantel (PZQ) to control morbidity due to schistosomiasis. Morbidity is considered linked to intensity of infection, which along with prevalence is used to determine the frequency of mass drug administration (MDA) to school-age children. We determined the impact of annual school-based MDA on children across all primary and high school years using a repeated cross-sectional study design in five schools near Lake Victoria in western Kenya, an area endemic for Schistosoma mansoni . At baseline and for the following four consecutive years, between 897 and 1,440 school children in Grades 1-12 were enrolled and evaluated by Kato-Katz for S. mansoni and soil-transmitted helminths (STH), followed by annual MDA with PZQ and albendazole. Four annual rounds of MDA with PZQ were associated with reduced S. mansoni prevalence in all school children (44.7-14.0%; P < 0.001) and mean intensity of infection by 91% (90.4 to 8.1 eggs per gram [epg] of stool; P < 0.001). Prevalence of high-intensity infection (≥ 400 epg) decreased from 6.8% at baseline to 0.3% by the end of the study. Soil-transmitted helminth infections, already low at baseline, also decreased significantly over the years. In this high prevalence area, annual school-based MDA with high coverage across all Grades (1-12) resulted in rapid and progressive declines in overall prevalence and intensity of infection. This decrease was dramatic in regard to heavy infections in older school-attending children.

Quantitative Characterization of Cell Behaviors through Cell Cycle Progression via Automated Cell Tracking

PubMed Central

Wang, Yuliang; Jeong, Younkoo; Jhiang, Sissy M.; Yu, Lianbo; Menq, Chia-Hsiang

2014-01-01

Cell behaviors are reflections of intracellular tension dynamics and play important roles in many cellular processes. In this study, temporal variations in cell geometry and cell motion through cell cycle progression were quantitatively characterized via automated cell tracking for MCF-10A non-transformed breast cells, MCF-7 non-invasive breast cancer cells, and MDA-MB-231 highly metastatic breast cancer cells. A new cell segmentation method, which combines the threshold method and our modified edge based active contour method, was applied to optimize cell boundary detection for all cells in the field-of-view. An automated cell-tracking program was implemented to conduct live cell tracking over 40 hours for the three cell lines. The cell boundary and location information was measured and aligned with cell cycle progression with constructed cell lineage trees. Cell behaviors were studied in terms of cell geometry and cell motion. For cell geometry, cell area and cell axis ratio were investigated. For cell motion, instantaneous migration speed, cell motion type, as well as cell motion range were analyzed. We applied a cell-based approach that allows us to examine and compare temporal variations of cell behavior along with cell cycle progression at a single cell level. Cell body geometry along with distribution of peripheral protrusion structures appears to be associated with cell motion features. Migration speed together with motion type and motion ranges are required to distinguish the three cell-lines examined. We found that cells dividing or overlapping vertically are unique features of cell malignancy for both MCF-7 and MDA-MB-231 cells, whereas abrupt changes in cell body geometry and cell motion during mitosis are unique to highly metastatic MDA-MB-231 cells. Taken together, our live cell tracking system serves as an invaluable tool to identify cell behaviors that are unique to malignant and/or highly metastatic breast cancer cells. PMID:24911281

Development of modified MDA (M-MDA), PWR fuel cladding tube for high duty operation in future

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watanabe, Seiichi; Kido, Toshiya; Arakawa, Yasushi

2007-07-01

A new cladding material of M-MDA has been developed in order to prepare for a strong growing demand for advanced fuel which can maintain its integrity even under high duties due to more efficient operation such as higher burnup, higher LHR, and longer operation cycle which will contribute the suppression of environmental burdens like CO{sub 2} emission. The main aim of M-MDA is to have excellent corrosion resistance while the other properties are inherited from MDA, which has been adopted to the step 2 fuel, instead of Zry-4, of Japanese PWR plant whose upper limit of assembly discharged burnup ismore » 55 MWd/kgU. And we could confirm that the main aim of M-MDA was achieved by means of out-of-pile tests. In order to confirm improvement of corrosion resistance of M-MDA in the actual operation, irradiation test of M-MDA in the commercial reactor of Vandellos II is ongoing. The latest results of on-site examination after every end of cycle showed that oxide thickness of M-MDA-SR was much smaller than that of MDA at rod discharged burnup of approximately 60 MWd/kgU. The final irradiation cycle was completed on April 2007 and then we will obtain corrosion data of M-MDA over 70 MWd/kgU. M-MDA is a candidate alloy for advanced fuel under higher duty usage. (authors)« less

Community Attitudes toward Mass Drug Administration for Control and Elimination of Neglected Tropical Diseases after the 2014 Outbreak of Ebola Virus Disease in Lofa County, Liberia

PubMed Central

Bogus, Joshua; Gankpala, Lincoln; Fischer, Kerstin; Krentel, Alison; Weil, Gary J.; Fischer, Peter U.; Kollie, Karsor; Bolay, Fatorma K.

2016-01-01

The recent outbreak of Ebola virus disease (EVD) interrupted mass drug administration (MDA) programs to control and eliminate neglected tropical diseases in Liberia. MDA programs treat entire communities with medication regardless of infection status to interrupt transmission and eliminate lymphatic filariasis and onchocerciasis. Following reports of hostilities toward health workers and fear that they might be spreading EVD, it was important to determine whether attitudes toward MDA might have changed after the outbreak. We surveyed 140 community leaders from 32 villages in Lofa County, Liberia, that had previously participated in MDA and are located in an area that was an early epicenter of the EVD outbreak. Survey respondents reported a high degree of community trust in the MDA program, and 97% thought their communities were ready to resume MDA. However, respondents predicted that fewer people would comply with MDA after the EVD epidemic than before. The survey also uncovered fears in the community that EVD and MDA might be linked. Respondents suggested that MDA programs emphasize to people that the medications are identical to those previously distributed and that MDA programs have nothing to do with EVD. PMID:26666700

Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

PubMed Central

Lamborn, Ian T.; Jing, Huie; Zhang, Yu; Munir, Shirin; Bade, Sangeeta; Murdock, Heardley M.; Santos, Celia P.; Brock, Linda G.; Masutani, Evan; Matthews, Helen F.; Collins, Peter L.; Subbarao, Kanta; Gelfand, Erwin W.

2017-01-01

MDA5 is a cytosolic sensor of double-stranded RNA (ds)RNA including viral byproducts and intermediates. We studied a child with life-threatening, recurrent respiratory tract infections, caused by viruses including human rhinovirus (HRV), influenza virus, and respiratory syncytial virus (RSV). We identified in her a homozygous missense mutation in IFIH1 that encodes MDA5. Mutant MDA5 was expressed but did not recognize the synthetic MDA5 agonist/(ds)RNA mimic polyinosinic-polycytidylic acid. When overexpressed, mutant MDA5 failed to drive luciferase activity from the IFNB1 promoter or promoters containing ISRE or NF-κB sequence motifs. In respiratory epithelial cells or fibroblasts, wild-type but not knockdown of MDA5 restricted HRV infection while increasing IFN-stimulated gene expression and IFN-β/λ. However, wild-type MDA5 did not restrict influenza virus or RSV replication. Moreover, nasal epithelial cells from the patient, or fibroblasts gene-edited to express mutant MDA5, showed increased replication of HRV but not influenza or RSV. Thus, human MDA5 deficiency is a novel inborn error of innate and/or intrinsic immunity that causes impaired (ds)RNA sensing, reduced IFN induction, and susceptibility to the common cold virus. PMID:28606988

Cancer Terminator Viruses and Approaches for Enhancing Therapeutic Outcomes

PubMed Central

Das, Swadesh K.; Sarkar, Siddik; Dash, Rupesh; Dent, Paul; Wang, Xiang-Yang; Sarkar, Devanand; Fisher, Paul B.

2015-01-01

No single or combinatorial therapeutic approach has proven effective in decreasing morbidity or engendering a cure of metastatic cancer. In principle, conditionally replication-competent adenoviruses that induce tumor oncolysis through cancer-specific replication hold promise for cancer therapy. However, a single-agent approach may not be adequate to completely eradicate cancer in a patient because most cancers arise from abnormalities in multiple genetic and signal transduction pathways and targeting disseminated metastases is difficult to achieve. Based on these considerations, a novel class of cancer destroying adenoviruses have been produced, cancer terminator viruses (CTVs), in which cancer-specific replication is controlled by the progression-elevated gene-3 promoter and replicating viruses produce a second transgene encoding an apoptosis-inducing and immunomodulatory cytokine, either melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) or interferon-γ. This review focuses on these viruses and ways to improve their delivery systemically and enhance their therapeutic efficacy. PMID:23021240

Effects of oxidative modification on thermal aggregation and gel properties of soy protein by malondialdehyde.

PubMed

Wu, Wei; Hua, Yufei; Lin, Qinlu

2014-03-01

Malondialdehyde (MDA) was selected as a representative of lipid peroxidation products to investigate the effects of oxidative modification on thermal aggregation and gel properties of soy protein by lipid peroxidation products. Incubation of soy protein with increasing concentration of MDA resulted in gradual decrease of particle size and content of thermal aggregates during heat denaturation. Oxidative modification by MDA resulted in a decrease in water holding capacity, gel hardness, and gel strength of soy protein gel. An increase in coarseness and interstice of MDA modified protein gel network was accompanied by uneven distribution of interstice as MDA concentration increased. The results showed that degree of thermal aggregation of MDA-modified soy protein gradually decreased as MDA concentration increased, which contributed to a decrease in water holding capacity, gel hardness, and gel strength of MDA-modified soy protein gel.

Antiviral function of grouper MDA5 against iridovirus and nodavirus.

PubMed

Huang, Youhua; Yu, Yepin; Yang, Ying; Yang, Min; Zhou, Linli; Huang, Xiaohong; Qin, Qiwei

2016-07-01

Melanoma differentiation-associated gene 5 (MDA5) is a critical member of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family which can recognize viral RNA and enhances antiviral response in host cells. In this study, a MDA5 homolog from orange spotted grouper (Epinephelus coioides) (EcMDA5) was cloned, and its roles on grouper virus infection were characterized. The full-length EcMDA5 cDNA encoded a polypeptide of 982 amino acids with 74% identity with MDA5 homolog from rock bream (Oplegnathus fasciatus). Amino acid alignment analysis indicated that EcMDA5 contained three functional domains: two caspase activation and recruitment domain (CARDs), a DEAD box helicase-like (DExDc) domain, a helicase superfamily C-terminal domain (HELICc), and a C-terminal regulatory domain (RD). Upon challenge with Singapore grouper iridovirus (SGIV) or polyinosin-polycytidylic acid (poly I:C), the transcript of EcMDA5 was significantly up-regulated especially at the early stage post-injection. Under fluorescence microscopy, we observed that EcMDA5 mostly localized in the cytoplasm of grouper spleen (GS) cells. Interestingly, during virus infection, the distribution pattern of EcMDA5 was significantly altered in SGIV infected cells, but not in red spotted grouper nervous necrosis virus (RGNNV) infected cells, suggested that EcMDA5 might interact with viral proteins during SGIV infection. The ectopic expression of EcMDA5 in vitro obviously delayed virus infection induced cytopathic effect (CPE) progression and significantly inhibited viral gene transcription of RGNNV and SGIV. Moreover, overexpression of EcMDA5 not only significantly increased interferon (IFN) and IFN-stimulated response element (ISRE) promoter activities in a dose dependent manner, but also enhanced the expression of IRF3, IRF7 and TRAF6. In addition, the transcription level of the proinflammatory factors, including TNF-α, IL-6 and IL-8 were differently altered by EcMDA5 overexpression during SGIV or RGNNV infection, suggesting that the regulation on proinflammatory cytokines by EcMDA5 were also important for RGNNV infection. Together, our results demonstrated for the first time that the inhibitory effect of fish MDA5 on iridovirus replication might be mainly through the regulation of proinflammatory cytokines. Copyright © 2016 Elsevier Ltd. All rights reserved.

Feasibility of Biological Effective Monitoring of Chrome Electroplaters to Chromium through Analysis of Serum Malondialdehyde.

PubMed

Mozafari, P; Rezazadeh Azari, M; Shokoohi, Y; Sayadi, M

2016-10-01

Great concern about occupational exposure to chromium (Cr [VI]) has been reported due to escalated risk of lung cancer in exposed workers. Consequences of occupational exposure to Cr (VI) have been reported as oxidative stress and lung tissue damage. To investigate the feasibility of biological effect monitoring of chrome electroplaters through analysis of serum malondialdehyde (MDA). 90 workers directly involved in chrome electroplating---categorized into three equal groups based on their job as near bath workers, degreaser, and washers---and 30 workers without exposure to Cr (VI), served as the control group, were studied. Personal samples were collected and analyzed according to NIOSH method 7600. Serum MDA level was measured by HPLC using a UV detector. Median Cr (VI) exposure level was 0.38 mg/m(3) in near bath workers, 0.20 mg/m(3) in degreasers, and 0.05 mg/m(3) in washers. The median serum MDA level of three exposed groups (2.76 μmol/L) was significantly (p<0.001) higher than that in the control group (2.00 μmol/L). There was a positive correlation between electroplaters' level of exposure to Cr (VI) and their serum MDA level (Spearman's ρ 0.806, p<0.001). Serum MDA level is a good biomarker for the level of occupational exposure to Cr (VI) in electroplaters.

The Impact of Two Semiannual Treatments with Albendazole Alone on Lymphatic Filariasis and Soil-Transmitted Helminth Infections: A Community-Based Study in the Republic of Congo

PubMed Central

Pion, Sébastien D. S.; Chesnais, Cédric B.; Bopda, Jean; Louya, Frédéric; Fischer, Peter U.; Majewski, Andrew C.; Weil, Gary J.; Boussinesq, Michel; Missamou, François

2015-01-01

Implementation of mass drug administration (MDA) with ivermectin plus albendazole (ALB) for lymphatic filariasis (LF) has been delayed in central Africa because of the risk of serious adverse events in subjects with high Loa loa microfilaremia. We conducted a community trial to assess the impact of semiannual MDA with ALB (400 mg) alone on LF and soil-transmitted helminth (STH) infections in the Republic of Congo. Evaluation at 12 months showed that ALB MDA had not significantly reduced Wuchereria bancrofti antigenemia or microfilaria (mf) rates in the community (from 17.3% to 16.6% and from 5.3% to 4.2%, respectively). However, the geometric mean mf count in mf-positive subjects was reduced from 202.2 to 80.9 mf/mL (60% reduction, P = 0.01). The effect of ALB was impressive in 38 subjects who were mf-positive at baseline and retested at 12 months: 37% had total mf clearance, and individual mf densities were reduced by 73.0%. MDA also dramatically reduced the hookworm infection rate in the community from 6.5% to 0.6% (91% reduction), with less impressive effects on Ascaris and Trichuris. These preliminary results suggest that semiannual community MDA with ALB is a promising strategy for controlling LF and STH in areas with coendemic loiasis. PMID:25758650

Strength Enhancement and Application Development of Carbon Foam for Thermal Protection Systems

DTIC Science & Technology

2004-09-01

to implementation was the inherent weakness and friability of the carbon foams. Under a MDA funded SBIR program, Ceramic Composites Inc . has...there are two approaches under consideration for utilizing carbon foams. Allcomp Inc.iii, Materials and Electrochemical Researchiv, Touchstonev...Ceramic Composites Inc . (CCI) elected to take an alternative approach to enhancing the strength of carbon foam. For our evaluation, two polymeric pre

Effect of National Schistosomiasis Control Programme on Taenia solium taeniosis and porcine cysticercosis in rural communities of Tanzania.

PubMed

Braae, Uffe Christian; Magnussen, Pascal; Harrison, Wendy; Ndawi, Benedict; Lekule, Faustin; Johansen, Maria Vang

2016-09-01

Taenia solium is found throughout sub-Saharan Africa and co-endemic with schistosomiasis in many regions. Taenia solium leads to taeniosis and neurocysticercosis - the leading cause of preventable epilepsy globally. This study aimed to assess the effects of the National Schistosomiasis Control Programme on prevalence of taeniosis and porcine cysticercosis over a four year period in Tanzania. School-based mass drug administration (MDA) of praziquantel was carried out based on schistosomiasis endemicity. Four human and five porcine cross-sectional surveys were carried out from 2012 to 2015 in Mbozi and Mbeya district in Tanzania. Three rounds of school-based MDA of praziquantel were delivered in Mbozi and two in Mbeya. The prevalence of taeniosis and porcine cysticercosis was estimated annually. Stool samples were collected from humans and prevalence of taeniosis estimated by copro-Ag-ELISA. Blood samples from pigs were collected to estimate cysticercosis prevalence by Ag-ELISA. "Track-and-treat" of taeniosis cases was carried out after each survey. In total 12082 stool samples and 4579 porcine serum samples were collected. Significantly fewer children (≤ 15) from Mbozi were infected throughout the study than children from Mbeya who showed a significant decrease in copro-Ag prevalence after the first treatment only. During the final survey in Mbozi the prevalence of taeniosis in adults (1.8%) was significantly lower (p = 0.031, OR 0.40, CI: 0.17-0.89), compared to baseline (4.1%). The prevalence of porcine cysticercosis (8%) had also dropped significantly (p = 0.002, OR 0.49, CI: 0.32-0.76) in this district compared to baseline (13%), whereas no significant difference was seen in Mbeya compared to baseline. The study suggests that three rounds of MDA targeting schistosomiasis in school-aged children combined with 'track-and-treat' contributed to a reduction in prevalence of T. solium in this population, and also had a spillover effect on adults in treated areas as well as reducing the prevalence of T. solium in the intermediate pig host population. Elimination of T. solium in this area would require a One Health approach.

Community Attitudes Toward Mass Drug Administration for Control and Elimination of Neglected Tropical Diseases After the 2014 Outbreak of Ebola Virus Disease in Lofa County, Liberia.

PubMed

Bogus, Joshua; Gankpala, Lincoln; Fischer, Kerstin; Krentel, Alison; Weil, Gary J; Fischer, Peter U; Kollie, Karsor; Bolay, Fatorma K

2016-03-01

The recent outbreak of Ebola virus disease (EVD) interrupted mass drug administration (MDA) programs to control and eliminate neglected tropical diseases in Liberia. MDA programs treat entire communities with medication regardless of infection status to interrupt transmission and eliminate lymphatic filariasis and onchocerciasis. Following reports of hostilities toward health workers and fear that they might be spreading EVD, it was important to determine whether attitudes toward MDA might have changed after the outbreak. We surveyed 140 community leaders from 32 villages in Lofa County, Liberia, that had previously participated in MDA and are located in an area that was an early epicenter of the EVD outbreak. Survey respondents reported a high degree of community trust in the MDA program, and 97% thought their communities were ready to resume MDA. However, respondents predicted that fewer people would comply with MDA after the EVD epidemic than before. The survey also uncovered fears in the community that EVD and MDA might be linked. Respondents suggested that MDA programs emphasize to people that the medications are identical to those previously distributed and that MDA programs have nothing to do with EVD. © The American Society of Tropical Medicine and Hygiene.

Minimum Detectable Activity for Tomographic Gamma Scanning System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Venkataraman, Ram; Smith, Susan; Kirkpatrick, J. M.

2015-01-01

For any radiation measurement system, it is useful to explore and establish the detection limits and a minimum detectable activity (MDA) for the radionuclides of interest, even if the system is to be used at far higher values. The MDA serves as an important figure of merit, and often a system is optimized and configured so that it can meet the MDA requirements of a measurement campaign. The non-destructive assay (NDA) systems based on gamma ray analysis are no exception and well established conventions, such the Currie method, exist for estimating the detection limits and the MDA. However, the Tomographicmore » Gamma Scanning (TGS) technique poses some challenges for the estimation of detection limits and MDAs. The TGS combines high resolution gamma ray spectrometry (HRGS) with low spatial resolution image reconstruction techniques. In non-imaging gamma ray based NDA techniques measured counts in a full energy peak can be used to estimate the activity of a radionuclide, independently of other counting trials. However, in the case of the TGS each “view” is a full spectral grab (each a counting trial), and each scan consists of 150 spectral grabs in the transmission and emission scans per vertical layer of the item. The set of views in a complete scan are then used to solve for the radionuclide activities on a voxel by voxel basis, over 16 layers of a 10x10 voxel grid. Thus, the raw count data are not independent trials any more, but rather constitute input to a matrix solution for the emission image values at the various locations inside the item volume used in the reconstruction. So, the validity of the methods used to estimate MDA for an imaging technique such as TGS warrant a close scrutiny, because the pair-counting concept of Currie is not directly applicable. One can also raise questions as to whether the TGS, along with other image reconstruction techniques which heavily intertwine data, is a suitable method if one expects to measure samples whose activities are at or just above MDA levels. The paper examines methods used to estimate MDAs for a TGS system, and explores possible solutions that can be rigorously defended.« less

Persistent 'hotspots' of lymphatic filariasis microfilaraemia despite 14 years of mass drug administration in Ghana.

PubMed

Biritwum, Nana-Kwadwo; Yikpotey, Paul; Marfo, Benjamin K; Odoom, Samuel; Mensah, Ernest O; Asiedu, Odame; Alomatu, Bright; Hervie, Edward T; Yeboah, Abednego; Ade, Serge; Hinderaker, Sven G; Reid, Anthony; Takarinda, Kudakwashe C; Koudou, Benjamin; Koroma, Joseph B

2016-12-01

Among the 216 districts in Ghana, 98 were declared endemic for lymphatic filariasis in 1999 after mapping. Pursuing the goal of elimination, WHO recommends annual treatment using mass drugs administration (MDA) for at least 5 years. MDA was started in the country in 2001 and reached national coverage in 2006. By 2014, 69 districts had 'stopped-MDA' (after passing the transmission assessment survey) while 29 others remained with persistent microfilaraemia (mf) prevalence (≥1%) despite more than 11 years of MDA and were classified as 'hotspots'. An ecological study was carried out to compare baseline mf prevalence and anti-microfilaria interventions between hotspot and stopped-MDA districts. Baseline mf prevalence was significantly higher in hotspots than stopped-MDA districts (p<0.001). After three years of MDA, there was a significant decrease in mf prevalence in hotspot districts, but it was still higher than in stopped-MDA districts. The number of MDA rounds was slightly higher in hotspot districts (p<0.001), but there were no differences in coverage of MDA or long-lasting-insecticide-treated nets. The main difference in hotspots and stopped-MDA districts was a high baseline mf prevalence. This finding indicates that the recommended 5-6 rounds annual treatment may not achieve interruption of transmission. © The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Synthesis markers in illegally manufactured 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine.

PubMed

Bohn, M; Bohn, G; Blaschke, G

1993-01-01

In this paper the isolation and identification of 12 compounds as impurities in illicit 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) is reported. Isolation of these substances is performed by preparative TLC, while identification is performed by using mass spectrometry and 1H-NMR spectroscopy. A simple and rapid method for detection of these impurities in seized MDA and MDMA samples is described. The identification of the impurities can provide numerous points on which to base comparative analysis of different exhibits.

Preparation, characterization, and banking of clinical-grade cells for neural transplantation: Scale up, fingerprinting, and genomic stability of stem cell lines.

PubMed

Natalwala, Ammar; Kunath, Tilo

2017-01-01

Parkinson's disease is a complex and progressive neurodegenerative condition that is characterized by the severe loss of midbrain dopaminergic (mDA) neurons, which innervate the striatum. Cell transplantation therapies to rebuild this dopaminergic network have been attempted for over 30 years. The most promising outcomes were observed when human fetal mesencephalic tissue was used as the source of cells for transplantation. However, reliance on terminations for a Parkinson's therapy presents significant logistical and ethical hurdles. An alternative source of transplantable mDA neurons is urgently needed, and the solution may come from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). Protocols to differentiate hESCs/iPSCs toward mDA neurons are now robust and efficient, and upon grafting the cells rescue preclinical animal models of Parkinson's disease. The challenge now is to apply Good Manufacturing Practice (GMP) to the academic discoveries and protocols to produce clinical-grade transplantable mDA cells. Major technical and logistical considerations include (i) source of hESC or iPSC line, (ii) GMP compliance of the differentiation protocol and all reagents, (iii) characterization of the cell product in terms of identity, safety, and efficacy, (iv) characterization of genomic state and stability, and (v) banking of a transplantation-ready cell product. Approaches and solutions to these challenges are reviewed here. © 2017 Elsevier B.V. All rights reserved.

Pomegranate peel extract decreases small intestine lipid peroxidation by enhancing activities of major antioxidant enzymes.

PubMed

Al-Gubory, Kaïs H; Blachier, François; Faure, Patrice; Garrel, Catherine

2016-08-01

Pomegranate peel extract (PPE) contains several compounds with antioxidative properties. PPE added to foods may interact with endogenous antioxidants and promote health. However, little is known about the biochemical mechanisms by which PPE exerts their actions on tissues of biological systems in vivo. The purpose of this study was to determine the effects of PPE on activities of antioxidant enzymes. Mice were used to investigate the effects of PPE on plasma levels of malondialdehyde (MDA), tissue MDA content and activities of superoxide dismutase 1 (SOD1), SOD2 and glutathione peroxidase (GPX) in the small intestine, liver and skeletal muscle - different tissues involved in the digestion, absorption and metabolism of dietary nutrients. Control mice were fed a standard diet, whereas treated mice were fed for 40 days with the standard diet containing 5% or 10% PPE. Mice fed the 10% PPE diet exhibited lower plasma MDA concentrations, reduced content of MDA in the small intestine and liver and higher levels of SOD1 and GPX activities in the small intestine compared to mice fed the control diet. These findings demonstrate that intake of PPE in diet attenuates small intestine lipid peroxidation and strengthens the first line of small intestine antioxidant defense by enhancing enzymatic antioxidative pathways. PPE is worthy of further study as a therapeutic approach to prevent peroxidative stress-induced gut pathogenesis. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

How Can Onchocerciasis Elimination in Africa Be Accelerated? Modeling the Impact of Increased Ivermectin Treatment Frequency and Complementary Vector Control.

PubMed

Verver, Suzanne; Walker, Martin; Kim, Young Eun; Fobi, Grace; Tekle, Afework H; Zouré, Honorat G M; Wanji, Samuel; Boakye, Daniel A; Kuesel, Annette C; de Vlas, Sake J; Boussinesq, Michel; Basáñez, Maria-Gloria; Stolk, Wilma A

2018-06-01

Great strides have been made toward onchocerciasis elimination by mass drug administration (MDA) of ivermectin. Focusing on MDA-eligible areas, we investigated where the elimination goal can be achieved by 2025 by continuation of current practice (annual MDA with ivermectin) and where intensification or additional vector control is required. We did not consider areas hypoendemic for onchocerciasis with loiasis coendemicity where MDA is contraindicated. We used 2 previously published mathematical models, ONCHOSIM and EPIONCHO, to simulate future trends in microfilarial prevalence for 80 different settings (defined by precontrol endemicity and past MDA frequency and coverage) under different future treatment scenarios (annual, biannual, or quarterly MDA with different treatment coverage through 2025, with or without vector control strategies), assessing for each strategy whether it eventually leads to elimination. Areas with 40%-50% precontrol microfilarial prevalence and ≥10 years of annual MDA may achieve elimination with a further 7 years of annual MDA, if not achieved already, according to both models. For most areas with 70%-80% precontrol prevalence, ONCHOSIM predicts that either annual or biannual MDA is sufficient to achieve elimination by 2025, whereas EPIONCHO predicts that elimination will not be achieved even with complementary vector control. Whether elimination will be reached by 2025 depends on precontrol endemicity, control history, and strategies chosen from now until 2025. Biannual or quarterly MDA will accelerate progress toward elimination but cannot guarantee it by 2025 in high-endemicity areas. Long-term concomitant MDA and vector control for high-endemicity areas might be useful.

MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma.

PubMed

Oyesanya, Regina A; Bhatia, Shilpa; Menezes, Mitchell E; Dumur, Catherine I; Singh, Karan P; Bae, Sejong; Troyer, Dean A; Wells, Robert B; Sauter, Edward R; Sidransky, David; Fisher, Paul B; Semmes, Oliver J; Dasgupta, Santanu

2014-01-01

Little is known about the molecular pathways regulating poor differentiation and invasion of head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to determine the role of MDA-9/Syntenin, a metastasis associated molecule in HNSCC tumorigenesis. Elevated MDA-9/Syntenin expression was evident in 67% (54/81) primary HNSCC tumors (p=0.001-0.002) and 69% (9/13) pre-neoplastic tissues (p=0.02-0.03). MDA-9/Syntenin overexpression was associated with the stage (p=0.001), grade (p=0.001) and lymph node metastasis (p=0.0001). Silencing of MDA-9/Syntenin in 3 poorly differentiated HNSCC cell lines induced squamous epithelial cell differentiation, disrupted angiogenesis and reduced tumor growth in vitro and in vivo. We confirmed SPRR1B and VEGFR1 as the key molecular targets of MDA-9/Syntenin on influencing HNSCC differentiation and angiogenesis respectively. MDA-9/Syntenin disrupted SPRR1B expression interacting through its PDZ1 domain and altered VEGFR1 expression in vitro and in vivo. VEGFR1 co-localized with MDA-9/Syntenin in HNSCC cell lines and primary tumor. Downregulation of growth regulatory molecules CyclinD1, CDK4, STAT3, PI3K and CTNNB1 was also evident in the MDA-9/Syntenin depleted cells, which was reversed following over-expression of MDA-9/Syntenin in immortalized oral epithelial cells. Our results suggest that early induction of MDA-9/Syntenin expression influences HNSCC progression and should be further evaluated for potential biomarker development.

MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma

PubMed Central

Dumur, Catherine I.; Singh, Karan P; Bae, Sejong; Troyer, Dean A.; Wells, Robert B.; Sauter, Edward R.; Sidransky, David; Fisher, Paul B.; Semmes, Oliver J.; Dasgupta, Santanu

2014-01-01

Little is known about the molecular pathways regulating poor differentiation and invasion of head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to determine the role of MDA-9/Syntenin, a metastasis associated molecule in HNSCC tumorigenesis. Elevated MDA-9/Syntenin expression was evident in 67% (54/81) primary HNSCC tumors (p=0.001-0.002) and 69% (9/13) pre-neoplastic tissues (p=0.02-0.03). MDA-9/Syntenin overexpression was associated with the stage (p=0.001), grade (p=0.001) and lymph node metastasis (p=0.0001). Silencing of MDA-9/Syntenin in 3 poorly differentiated HNSCC cell lines induced squamous epithelial cell differentiation, disrupted angiogenesis and reduced tumor growth in vitro and in vivo. We confirmed SPRR1B and VEGFR1 as the key molecular targets of MDA-9/Syntenin on influencing HNSCC differentiation and angiogenesis respectively. MDA-9/Syntenin disrupted SPRR1B expression interacting through its PDZ1 domain and altered VEGFR1 expression in vitro and in vivo. VEGFR1 co-localized with MDA-9/Syntenin in HNSCC cell lines and primary tumor. Downregulation of growth regulatory molecules CyclinD1, CDK4, STAT3, PI3K and CTNNB1 was also evident in the MDA-9/Syntenin depleted cells, which was reversed following over-expression of MDA-9/Syntenin in immortalized oral epithelial cells. Our results suggest that early induction of MDA-9/Syntenin expression influences HNSCC progression and should be further evaluated for potential biomarker development. PMID:25593999

School-based control of soil-transmitted helminthiasis in western Visayas, Philippines.

PubMed

Belizario, V Y; Totañes, F I G; de Leon, W U; Matias, K M H

2014-05-01

We evaluated the effect of a local government unit-led, school-based, teacher-assisted mass drug administration (MDA) treatment of soil-transmitted helminthiasis (STH) on the morbidity of school children in selected provinces of western Visayas, the Philippines. Parasitological assessment was done on stool samples using the Kato-Katz technique. Nutritional status and school performance were also evaluated using secondary data from the Department of Education. The overall prevalence of STH decreased from 71.1% to 44.3% (p < 0.0001) and the prevalence of heavy infection with STH decreased from 40.5% to 14.5% (p < 0.0001), after two years of biannual MDA. The prevalence of underweight children decreased from 26.2% to 17.8% (p < 0.0001) and the prevalence of stunted children decreased from 20.9% to 16.6% (p < 0.0001) after two years of biannual MDA. School performance improved on standardized testing from a mean percentage of 53.8% to 64.6%. Advocacy, social mobilization, strong local government support and intersectoral collaboration with other agencies probably contributed to the success of the program.

Spatiotemporal prediction of daily ambient ozone levels across China using random forest for human exposure assessment.

PubMed

Zhan, Yu; Luo, Yuzhou; Deng, Xunfei; Grieneisen, Michael L; Zhang, Minghua; Di, Baofeng

2018-02-01

In China, ozone pollution shows an increasing trend and becomes the primary air pollutant in warm seasons. Leveraging the air quality monitoring network, a random forest model is developed to predict the daily maximum 8-h average ozone concentrations ([O 3 ] MDA8 ) across China in 2015 for human exposure assessment. This model captures the observed spatiotemporal variations of [O 3 ] MDA8 by using the data of meteorology, elevation, and recent-year emission inventories (cross-validation R 2  = 0.69 and RMSE = 26 μg/m 3 ). Compared with chemical transport models that require a plenty of variables and expensive computation, the random forest model shows comparable or higher predictive performance based on only a handful of readily-available variables at much lower computational cost. The nationwide population-weighted [O 3 ] MDA8 is predicted to be 84 ± 23 μg/m 3 annually, with the highest seasonal mean in the summer (103 ± 8 μg/m 3 ). The summer [O 3 ] MDA8 is predicted to be the highest in North China (125 ± 17 μg/m 3 ). Approximately 58% of the population lives in areas with more than 100 nonattainment days ([O 3 ] MDA8 >100 μg/m 3 ), and 12% of the population are exposed to [O 3 ] MDA8 >160 μg/m 3 (WHO Interim Target 1) for more than 30 days. As the most populous zones in China, the Beijing-Tianjin Metro, Yangtze River Delta, Pearl River Delta, and Sichuan Basin are predicted to be at 154, 141, 124, and 98 nonattainment days, respectively. Effective controls of O 3 pollution are urgently needed for the highly-populated zones, especially the Beijing-Tianjin Metro with seasonal [O 3 ] MDA8 of 140 ± 29 μg/m 3 in summer. To the best of the authors' knowledge, this study is the first statistical modeling work of ambient O 3 for China at the national level. This timely and extensively validated [O 3 ] MDA8 dataset is valuable for refining epidemiological analyses on O 3 pollution in China. Copyright © 2017 Elsevier Ltd. All rights reserved.

A methodology for the validated design space exploration of fuel cell powered unmanned aerial vehicles

NASA Astrophysics Data System (ADS)

Moffitt, Blake Almy

Unmanned Aerial Vehicles (UAVs) are the most dynamic growth sector of the aerospace industry today. The need to provide persistent intelligence, surveillance, and reconnaissance for military operations is driving the planned acquisition of over 5,000 UAVs over the next five years. The most pressing need is for quiet, small UAVs with endurance beyond what is capable with advanced batteries or small internal combustion propulsion systems. Fuel cell systems demonstrate high efficiency, high specific energy, low noise, low temperature operation, modularity, and rapid refuelability making them a promising enabler of the small, quiet, and persistent UAVs that military planners are seeking. Despite the perceived benefits, the actual near-term performance of fuel cell powered UAVs is unknown. Until the auto industry began spending billions of dollars in research, fuel cell systems were too heavy for useful flight applications. However, the last decade has seen rapid development with fuel cell gravimetric and volumetric power density nearly doubling every 2--3 years. As a result, a few design studies and demonstrator aircraft have appeared, but overall the design methodology and vehicles are still in their infancy. The design of fuel cell aircraft poses many challenges. Fuel cells differ fundamentally from combustion based propulsion in how they generate power and interact with other aircraft subsystems. As a result, traditional multidisciplinary analysis (MDA) codes are inappropriate. Building new MDAs is difficult since fuel cells are rapidly changing in design, and various competitive architectures exist for balance of plant, hydrogen storage, and all electric aircraft subsystems. In addition, fuel cell design and performance data is closely protected which makes validation difficult and uncertainty significant. Finally, low specific power and high volumes compared to traditional combustion based propulsion result in more highly constrained design spaces that are problematic for design space exploration. To begin addressing the current gaps in fuel cell aircraft development, a methodology has been developed to explore and characterize the near-term performance of fuel cell powered UAVs. The first step of the methodology is the development of a valid MDA. This is accomplished by using propagated uncertainty estimates to guide the decomposition of a MDA into key contributing analyses (CAs) that can be individually refined and validated to increase the overall accuracy of the MDA. To assist in MDA development, a flexible framework for simultaneously solving the CAs is specified. This enables the MDA to be easily adapted to changes in technology and the changes in data that occur throughout a design process. Various CAs that model a polymer electrolyte membrane fuel cell (PEMFC) UAV are developed, validated, and shown to be in agreement with hardware-in-the-loop simulations of a fully developed fuel cell propulsion system. After creating a valid MDA, the final step of the methodology is the synthesis of the MDA with an uncertainty propagation analysis, an optimization routine, and a chance constrained problem formulation. This synthesis allows an efficient calculation of the probabilistic constraint boundaries and Pareto frontiers that will govern the design space and influence design decisions relating to optimization and uncertainty mitigation. A key element of the methodology is uncertainty propagation. The methodology uses Systems Sensitivity Analysis (SSA) to estimate the uncertainty of key performance metrics due to uncertainties in design variables and uncertainties in the accuracy of the CAs. A summary of SSA is provided and key rules for properly decomposing a MDA for use with SSA are provided. Verification of SSA uncertainty estimates via Monte Carlo simulations is provided for both an example problem as well as a detailed MDA of a fuel cell UAV. Implementation of the methodology was performed on a small fuel cell UAV designed to carry a 2.2 kg payload with 24 hours of endurance. Uncertainty distributions for both design variables and the CAs were estimated based on experimental results and were found to dominate the design space. To reduce uncertainty and test the flexibility of the MDA framework, CAs were replaced with either empirical, or semi-empirical relationships during the optimization process. The final design was validated via a hardware-in-the loop simulation. Finally, the fuel cell UAV probabilistic design space was studied. A graphical representation of the design space was generated and the optima due to deterministic and probabilistic constraints were identified. The methodology was used to identify Pareto frontiers of the design space which were shown on contour plots of the design space. Unanticipated discontinuities of the Pareto fronts were observed as different constraints became active providing useful information on which to base design and development decisions.

Vitamin C protects rat cerebellum and encephalon from oxidative stress following exposure to radiofrequency wave generated by a BTS antenna model.

PubMed

Akbari, Abolfazl; Jelodar, Gholamali; Nazifi, Saeed

2014-06-01

Radio frequency wave (RFW) generated by base transceiver station has been reported to produce deleterious effects on the central nervous system function, possibly through oxidative stress. This study was conducted to evaluate the effect of RFW-induced oxidative stress in the cerebellum and encephalon and the prophylactic effect of vitamin C on theses tissues by measuring the antioxidant enzymes activity, including: glutathione peroxidase, superoxide dismutase, catalase, and malondialdehyde (MDA). Thirty-two adult male Sprague-Dawley rats were randomly divided into four equal groups. The control group; the control-vitamin C group received L-ascorbic acid (200 mg/kg of body weight/day by gavage) for 45 days. The RFW group was exposed to RFW and the RFW+ vitamin C group was exposed to RFW and received vitamin C. At the end of the experiment, all groups were killed and encephalon and cerebellum of all rats were removed and stored at -70 °C for measurement of antioxidant enzymes activity and MDA. The results indicate that exposure to RFW in the test group decreased antioxidant enzymes activity and increased MDA compared with the control groups (p < 0.05). The protective role of vitamin C in the treated group improved antioxidant enzymes activity and reduced MDA compared with the test group (p < 0.05). It can be concluded that RFW causes oxidative stress in the brain and vitamin C improves the antioxidant enzymes activity and decreases MDA.

The impact of two semiannual treatments with albendazole alone on lymphatic filariasis and soil-transmitted helminth infections: a community-based study in the Republic of Congo.

PubMed

Pion, Sébastien D S; Chesnais, Cédric B; Bopda, Jean; Louya, Frédéric; Fischer, Peter U; Majewski, Andrew C; Weil, Gary J; Boussinesq, Michel; Missamou, François

2015-05-01

Implementation of mass drug administration (MDA) with ivermectin plus albendazole (ALB) for lymphatic filariasis (LF) has been delayed in central Africa because of the risk of serious adverse events in subjects with high Loa loa microfilaremia. We conducted a community trial to assess the impact of semiannual MDA with ALB (400 mg) alone on LF and soil-transmitted helminth (STH) infections in the Republic of Congo. Evaluation at 12 months showed that ALB MDA had not significantly reduced Wuchereria bancrofti antigenemia or microfilaria (mf) rates in the community (from 17.3% to 16.6% and from 5.3% to 4.2%, respectively). However, the geometric mean mf count in mf-positive subjects was reduced from 202.2 to 80.9 mf/mL (60% reduction, P = 0.01). The effect of ALB was impressive in 38 subjects who were mf-positive at baseline and retested at 12 months: 37% had total mf clearance, and individual mf densities were reduced by 73.0%. MDA also dramatically reduced the hookworm infection rate in the community from 6.5% to 0.6% (91% reduction), with less impressive effects on Ascaris and Trichuris. These preliminary results suggest that semiannual community MDA with ALB is a promising strategy for controlling LF and STH in areas with coendemic loiasis. © The American Society of Tropical Medicine and Hygiene.

MDA-9/Syntenin-Slug transcriptional complex promote epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma

PubMed Central

Wang, Lu-Kai; Pan, Szu-Hua; Chang, Yih-Leong; Hung, Pei-Fang; Kao, Shih-Han; Wang, Wen-Lung; Lin, Ching-Wen; Yang, Shuenn-Chen; Liang, Chen-Hsien; Wu, Chen-Tu; Hsiao, Tzu-Hung

2016-01-01

Melanoma differentiation-associated gene-9 (MDA-9)/Syntenin is a novel therapeutic target because it plays critical roles in cancer progression and exosome biogenesis. Here we show that Slug, a key epithelial-mesenchymal-transition (EMT) regulator, is a MDA-9/Syntenin downstream target. Mitogen EGF stimulation increases Slug expression and MDA-9/Syntenin nuclear translocation. MDA-9/Syntenin uses its PDZ1 domain to bind with Slug, and this interaction further leads to HDAC1 recruitment, up-regulation of Slug transcriptional repressor activity, enhanced Slug-mediated EMT, and promotion of cancer invasion and metastasis. The PDZ domains and nuclear localization of MDA-9/Syntenin are both required for promoting Slug-mediated cancer invasion. Clinically, patients with high MDA-9/Syntenin and high Slug expressions were associated with poor overall survival compared to those with low expression in lung adenocarcinomas. Our findings provide evidence that MDA-9/Syntenin acts as a pivotal adaptor of Slug and it transcriptionally enhances Slug-mediated EMT to promote cancer invasion and metastasis. PMID:26561205

A Mediated Discourse Analysis (MDA) Approach to Multimodal Data

ERIC Educational Resources Information Center

Dooly, Melinda

2017-01-01

Just as research in language learning is moving beyond the four walls of the classroom, there is a growing awareness that language use (and simultaneous learning) takes place in increasingly complex and interconnected ways, in particular through the use of technology. This chapter summarizes an investigation into multimodal communicative…

MiR-34b-5p Suppresses Melanoma Differentiation-Associated Gene 5 (MDA5) Signaling Pathway to Promote Avian Leukosis Virus Subgroup J (ALV-J)-Infected Cells Proliferaction and ALV-J Replication

PubMed Central

Li, Zhenhui; Luo, Qingbin; Xu, Haiping; Zheng, Ming; Abdalla, Bahareldin Ali; Feng, Min; Cai, Bolin; Zhang, Xiaocui; Nie, Qinghua; Zhang, Xiquan

2017-01-01

Avian leukosis virus subgroup J (ALV-J) is an oncogenic retrovirus that has a similar replication cycle to multiple viruses and therefore can be used as a model system for viral entry into host cells. However, there are few reports on the genes or microRNAs (miRNAs) that are responsible for the replication of ALV-J. Our previous miRNA and RNA sequencing data showed that the expression of miR-34b-5p was significantly upregulated in ALV-J-infected chicken spleens compared to non-infected chicken spleens, but melanoma differentiation-associated gene 5 (MDA5) had the opposite expression pattern. In this study, a dual-luciferase reporter assay showed that MDA5 is a direct target of miR-34b-5p. In vitro, overexpression of miR-34b-5p accelerated the proliferation of ALV-J-infected cells by inducing the progression from G2 to S phase and it promoted cell migration. Ectopic expression of MDA5 inhibited ALV-J-infected cell proliferation, the cell cycle and cell migration, and knockdown of MDA5 promoted proliferation, the cell cycle and migration. In addition, during ALV-J infections, MDA5 can detect virus invasion and it triggers the MDA5 signaling pathway. MDA5 overexpression can activate the MDA5 signaling pathway, and thus it can inhibit the mRNA and protein expression of the ALV-J env gene and it can suppress virion secretion. In contrast, in response to the knockdown of MDA5 by small interfering RNA (siRNA) or an miR-34b-5p mimic, genes in the MDA5 signaling pathway were significantly downregulated (P < 0.05), but the mRNA and protein expression of ALV-J env and the sample-to-positive ratio of virion in the supernatants were increased. This indicates that miR-34b-5p is able to trigger the MDA5 signaling pathway and affect ALV-J infections. Together, these results suggest that miR-34b-5p targets MDA5 to accelerate the proliferation and migration of ALV-J-infected cells, and it promotes ALV-J replication, via the MDA5 signaling pathway. PMID:28194372

LncITPRIP-1 Positively Regulates Innate Immune Response through Promoting Oligomerization and Activation of MDA5.

PubMed

Xie, Qinya; Chen, Shengwen; Tian, Renyun; Huang, Xiang; Deng, Rilin; Xue, Binbin; Qin, Yuwen; Xu, Yan; Wang, Jingjing; Guo, Mengmeng; Chen, Jinwen; Tang, Songqing; Li, Guangdi; Zhu, Haizhen

2018-06-13

Emerging evidence indicates that long non-coding RNAs (lncRNAs) regulate various biological processes, especially innate and adaptive immunity. However, the relationship between lncRNAs and interferon (IFN) pathway remains largely unknown. Here, we report that lncRNA ITPRIP-1 (lncITPRIP-1) is involved in viral infection and plays a crucial role in virus-triggered IFN signaling pathway through targeting MDA5. LncITPRIP-1 can be induced by viral infection, which is not entirely dependent on IFN signal. Besides, there is no coding potential found in lncITPRIP-1 transcript. LncITPRIP-1 binds to the C-terminal of MDA5 and it possesses the ability to boost oligomerization of both full length and 2CARD domains of MDA5 in a K63-linked-polyubiquitination-independent manner. Amazingly, we also find that MDA5 could suppress HCV replication independent of IFN signaling through its C-terminal deficient domain bound to viral RNA, in which lncITPRIP-1 plays as an assistant. In addition, the expression of lncITPRIP-1 is highly consistent with MDA5 expression, indicating that lncITPRIP-1 may function as a cofactor of MDA5. All the data suggest that lncITPRIP-1 enhances innate immune response to viral infection through promoting oligomerization and activation of MDA5. Our study discovers the first lncRNA ITPRIP-1 involved in MDA5 activation. SIGNIFICANCE Hepatitis C virus infection causes a global health issue and there is still no available vaccine, which makes it urgent to reveal the underlying mechanisms of HCV and host factors. Although RIG-I has been recognized as the leading cytoplasmic sensor against HCV for a long time, recent findings of MDA5 regulating IFN response to HCV have emerged. Our work validates the significant role of MDA5 in IFN signaling and HCV infection, and proposes the first lncRNA inhibiting HCV replication by promoting the activation of MDA5 and mediating the association between MDA5 and HCV RNA, which may shed light on MDA5 function study and the treatment for hepatitis C patients. Our suggested model of how lncITPRIP-1 can orchestrate signal transduction for IFN production illustrates the essential role of lncRNAs in virus elimination. Copyright © 2018 American Society for Microbiology.

MiR-34b-5p Suppresses Melanoma Differentiation-Associated Gene 5 (MDA5) Signaling Pathway to Promote Avian Leukosis Virus Subgroup J (ALV-J)-Infected Cells Proliferaction and ALV-J Replication.

PubMed

Li, Zhenhui; Luo, Qingbin; Xu, Haiping; Zheng, Ming; Abdalla, Bahareldin Ali; Feng, Min; Cai, Bolin; Zhang, Xiaocui; Nie, Qinghua; Zhang, Xiquan

2017-01-01

Avian leukosis virus subgroup J (ALV-J) is an oncogenic retrovirus that has a similar replication cycle to multiple viruses and therefore can be used as a model system for viral entry into host cells. However, there are few reports on the genes or microRNAs (miRNAs) that are responsible for the replication of ALV-J. Our previous miRNA and RNA sequencing data showed that the expression of miR-34b-5p was significantly upregulated in ALV-J-infected chicken spleens compared to non-infected chicken spleens, but melanoma differentiation-associated gene 5 ( MDA5 ) had the opposite expression pattern. In this study, a dual-luciferase reporter assay showed that MDA5 is a direct target of miR-34b-5p. In vitro , overexpression of miR-34b-5p accelerated the proliferation of ALV-J-infected cells by inducing the progression from G2 to S phase and it promoted cell migration. Ectopic expression of MDA5 inhibited ALV-J-infected cell proliferation, the cell cycle and cell migration, and knockdown of MDA5 promoted proliferation, the cell cycle and migration. In addition, during ALV-J infections, MDA5 can detect virus invasion and it triggers the MDA5 signaling pathway. MDA5 overexpression can activate the MDA5 signaling pathway, and thus it can inhibit the mRNA and protein expression of the ALV-J env gene and it can suppress virion secretion. In contrast, in response to the knockdown of MDA5 by small interfering RNA (siRNA) or an miR-34b-5p mimic, genes in the MDA5 signaling pathway were significantly downregulated ( P < 0.05), but the mRNA and protein expression of ALV-J env and the sample-to-positive ratio of virion in the supernatants were increased. This indicates that miR-34b-5p is able to trigger the MDA5 signaling pathway and affect ALV-J infections. Together, these results suggest that miR-34b-5p targets MDA5 to accelerate the proliferation and migration of ALV-J-infected cells, and it promotes ALV-J replication, via the MDA5 signaling pathway.

Study protocol for a cluster randomised controlled factorial design trial to assess the effectiveness and feasibility of reactive focal mass drug administration and vector control to reduce malaria transmission in the low endemic setting of Namibia

PubMed Central

Medzihradsky, Oliver F; Kleinschmidt, Immo; Mumbengegwi, Davis; Roberts, Kathryn W; McCreesh, Patrick; Dufour, Mi-Suk Kang; Uusiku, Petrina; Katokele, Stark; Bennett, Adam; Smith, Jennifer; Sturrock, Hugh; Prach, Lisa M; Ntuku, Henry; Tambo, Munyaradzi; Didier, Bradley; Greenhouse, Bryan; Gani, Zaahira; Aerts, Ann; Gosling, Roly; Hsiang, Michelle S

2018-01-01

Introduction To interrupt malaria transmission, strategies must target the parasite reservoir in both humans and mosquitos. Testing of community members linked to an index case, termed reactive case detection (RACD), is commonly implemented in low transmission areas, though its impact may be limited by the sensitivity of current diagnostics. Indoor residual spraying (IRS) before malaria season is a cornerstone of vector control efforts. Despite their implementation in Namibia, a country approaching elimination, these methods have been met with recent plateaus in transmission reduction. This study evaluates the effectiveness and feasibility of two new targeted strategies, reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in Namibia. Methods and analysis This is an open-label cluster randomised controlled trial with 2×2 factorial design. The interventions include: rfMDA (presumptive treatment with artemether-lumefantrine (AL)) versus RACD (rapid diagnostic testing and treatment using AL) and RAVC (IRS with Acellic 300CS) versus no RAVC. Factorial design also enables comparison of the combined rfMDA+RAVC intervention to RACD. Participants living in 56 enumeration areas will be randomised to one of four arms: rfMDA, rfMDA+RAVC, RACD or RACD+RAVC. These interventions, triggered by index cases detected at health facilities, will be targeted to individuals residing within 500 m of an index. The primary outcome is cumulative incidence of locally acquired malaria detected at health facilities over 1 year. Secondary outcomes include seroprevalence, infection prevalence, intervention coverage, safety, acceptability, adherence, cost and cost-effectiveness. Ethics and dissemination Findings will be reported on clinicaltrials.gov, in peer-reviewed publications and through stakeholder meetings with MoHSS and community leaders in Namibia. Trial registration number NCT02610400; Pre-results. PMID:29374672

Vasodilator-Stimulated Phosphoprotein (VASP) depletion from breast cancer MDA-MB-231 cells inhibits tumor spheroid invasion through downregulation of Migfilin, β-catenin and urokinase-plasminogen activator (uPA)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gkretsi, Vasiliki; Stylianou, Andreas; Stylianopoulos, Triantafyllos, E-mail: tstylian@ucy.ac.cy

A hallmark of cancer cells is their ability to invade surrounding tissues and form metastases. Cell-extracellular matrix (ECM)-adhesion proteins are crucial in metastasis, connecting tumor ECM with actin cytoskeleton thus enabling cells to respond to mechanical cues. Vasodilator-stimulated phosphoprotein (VASP) is an actin-polymerization regulator which interacts with cell-ECM adhesion protein Migfilin, and regulates cell migration. We compared VASP expression in MCF-7 and MDA-MB-231 breast cancer (BC) cells and found that more invasive MDA-MB-231 cells overexpress VASP. We then utilized a 3-dimensional (3D) approach to study metastasis in MDA-MB-231 cells using a system that considers mechanical forces exerted by the ECM.more » We prepared 3D collagen I gels of increasing concentration, imaged them by atomic force microscopy, and used them to either embed cells or tumor spheroids, in the presence or absence of VASP. We show, for the first time, that VASP silencing downregulated Migfilin, β-catenin and urokinase plasminogen activator both in 2D and 3D, suggesting a matrix-independent mechanism. Tumor spheroids lacking VASP demonstrated impaired invasion, indicating VASP’s involvement in metastasis, which was corroborated by Kaplan-Meier plotter showing high VASP expression to be associated with poor remission-free survival in lymph node-positive BC patients. Hence, VASP may be a novel BC metastasis biomarker. - Highlights: • More invasive MDA-MB-231 overexpress VASP compared to MCF-7 breast cancer cells. • We prepared 3D collagen I gels of increasing concentration and characterized them. • VASP silencing downregulated Migfilin, β-catenin and uPA both in 2D and 3D culture. • Tumor spheroids lacking VASP demonstrated impaired invasion. • Kaplan-Meier plotter shows association of high VASP expression with poor survival.« less

Study protocol for a cluster randomised controlled factorial design trial to assess the effectiveness and feasibility of reactive focal mass drug administration and vector control to reduce malaria transmission in the low endemic setting of Namibia.

PubMed

Medzihradsky, Oliver F; Kleinschmidt, Immo; Mumbengegwi, Davis; Roberts, Kathryn W; McCreesh, Patrick; Dufour, Mi-Suk Kang; Uusiku, Petrina; Katokele, Stark; Bennett, Adam; Smith, Jennifer; Sturrock, Hugh; Prach, Lisa M; Ntuku, Henry; Tambo, Munyaradzi; Didier, Bradley; Greenhouse, Bryan; Gani, Zaahira; Aerts, Ann; Gosling, Roly; Hsiang, Michelle S

2018-01-27

To interrupt malaria transmission, strategies must target the parasite reservoir in both humans and mosquitos. Testing of community members linked to an index case, termed reactive case detection (RACD), is commonly implemented in low transmission areas, though its impact may be limited by the sensitivity of current diagnostics. Indoor residual spraying (IRS) before malaria season is a cornerstone of vector control efforts. Despite their implementation in Namibia, a country approaching elimination, these methods have been met with recent plateaus in transmission reduction. This study evaluates the effectiveness and feasibility of two new targeted strategies, reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in Namibia. This is an open-label cluster randomised controlled trial with 2×2 factorial design. The interventions include: rfMDA (presumptive treatment with artemether-lumefantrine (AL)) versus RACD (rapid diagnostic testing and treatment using AL) and RAVC (IRS with Acellic 300CS) versus no RAVC. Factorial design also enables comparison of the combined rfMDA+RAVC intervention to RACD. Participants living in 56 enumeration areas will be randomised to one of four arms: rfMDA, rfMDA+RAVC, RACD or RACD+RAVC. These interventions, triggered by index cases detected at health facilities, will be targeted to individuals residing within 500 m of an index. The primary outcome is cumulative incidence of locally acquired malaria detected at health facilities over 1 year. Secondary outcomes include seroprevalence, infection prevalence, intervention coverage, safety, acceptability, adherence, cost and cost-effectiveness. Findings will be reported on clinicaltrials.gov, in peer-reviewed publications and through stakeholder meetings with MoHSS and community leaders in Namibia. NCT02610400; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Establishment of a novel HLA genotyping method for preimplantation genetic diagnonis using multiple displacement amplification-polymerase chain reaction-sequencing based technique].

PubMed

Zhang, Yinfeng; Luo, Haining; Zhang, Yunshan

2015-12-01

To establish a novel HLA genotyping method for preimplantation genetic diagnonis (PGD) using multiple displacement amplification-polymerase chain reaction-sequencing based technique (MDA-PCR-SBT). Peripheral blood samples and 76 1PN, 2PN, 3PN discarded embryos from 9 couples were collected. The alleles of HLA-A, B, DR loci were detected from the MDA product with the PCR-SBT method. The HLA genotypes of the parental peripheral blood samples were analyzed with the same protocol. The genotypes of specific HLA region were evaluated for distinguishing the segregation of haplotypes among the family members, and primary HLA matching was performed between the embryos. The 76 embryos were subjected to MDA and 74 (97.4%) were successfully amplified. For the 34 embryos from the single blastomere group, the amplification rate was 94.1%, and for the 40 embryos in the two blastomeres group, the rate was 100%. The dropout rates for DQ allele and DR allele were 1.3% and 0, respectively. The positive rate for MDA in the single blastomere group was 100%, with the dropout rates for DQ allele and DR allele being 1.5% and 0, respectively. The positive rate of MDA for the two blastomere group was 100%, with the dropout rates for both DQ and DR alleles being 0. The recombination rate of fetal HLA was 20.2% (30/148). Due to the improper classification and abnormal fertilized embryos, the proportion of matched embryos HLA was 20.3% (15/74),which was lower than the theoretical value of 25%. PGD with HLA matching can facilitate creation of a HLA-identical donor (saviour child) for umbilical cord blood or bone marrow stem cells for its affected sibling with a genetic disease. Therefore, preimplantation HLA matching may provide a tool for couples desiring to conceive a potential donor progeny for transplantation for its sibling with a life-threatening disorder.

Integrated Array/Metadata Analytics

NASA Astrophysics Data System (ADS)

Misev, Dimitar; Baumann, Peter

2015-04-01

Data comes in various forms and types, and integration usually presents a problem that is often simply ignored and solved with ad-hoc solutions. Multidimensional arrays are an ubiquitous data type, that we find at the core of virtually all science and engineering domains, as sensor, model, image, statistics data. Naturally, arrays are richly described by and intertwined with additional metadata (alphanumeric relational data, XML, JSON, etc). Database systems, however, a fundamental building block of what we call "Big Data", lack adequate support for modelling and expressing these array data/metadata relationships. Array analytics is hence quite primitive or non-existent at all in modern relational DBMS. Recognizing this, we extended SQL with a new SQL/MDA part seamlessly integrating multidimensional array analytics into the standard database query language. We demonstrate the benefits of SQL/MDA with real-world examples executed in ASQLDB, an open-source mediator system based on HSQLDB and rasdaman, that already implements SQL/MDA.

Effect of Cell Phone Use on Salivary Total Protein, Enzymes and Oxidative Stress Markers in Young Adults: A Pilot Study

PubMed Central

Joy, Jasmi; Sunitha, Venkatesh; Rai, Manoj P.; Rao, Suresh; Nambranathayil, Shafeeque; Baliga, Manjeshwar Shrinath

2015-01-01

Introduction: The present study aimed to assess the levels of salivary enzymes, protein and oxidant-antioxidant system in young college-going cell phone users. Materials and Methods: The cell users (students) were categorized in to two groups – less mobile users and high mobile users, based on the duration and frequency of cell use. Unstimulated whole saliva samples of the volunteers were analysed for amylase, lactate dehydrogenase (LDH), malondialdehdye (MDA) and glutathione (GSH). Results: High mobile users had significantly higher levels of amylase (p = 0.001), LDH (p = 0.002) and MDA (p = 0.002) in saliva, when compared to less mobile users. The marginal decrease in salivary total proteins, GSH and flow rate were statistically not significant (p >0.05). Conclusion: Significant changes in salivary enzymes and MDA suggest adverse effect of high use of cell phones on cell health. PMID:25859446

Digital antimicrobial susceptibility testing using the MilliDrop technology.

PubMed

Jiang, L; Boitard, L; Broyer, P; Chareire, A-C; Bourne-Branchu, P; Mahé, P; Tournoud, M; Franceschi, C; Zambardi, G; Baudry, J; Bibette, J

2016-03-01

We present the MilliDrop Analyzer (MDA), a droplet-based millifluidic system for digital antimicrobial susceptibility testing (D-AST), which enables us to determine minimum inhibitory concentrations (MICs) precisely and accurately. The MilliDrop technology was validated by using resazurin for fluorescence readout, for comparison with standard methodology, and for conducting reproducibility studies. In this first assessment, the susceptibility of a reference Gram-negative strain Escherichia coli ATCC 25922 to gentamicin, chloramphenicol, and nalidixic acid were tested by the MDA, VITEK®2, and broth microdilution as a reference standard. We measured the susceptibility of clinically relevant Gram-positive strains of Staphylococcus aureus to vancomycin, including vancomycin-intermediate S. aureus (VISA), heterogeneous vancomycin-intermediate S. aureus (hVISA), and vancomycin-susceptible S. aureus (VSSA) strains. The MDA provided results which were much more accurate than those of VITEK®2 and standard broth microdilution. The enhanced accuracy enabled us to reliably discriminate between VSSA and hVISA strains.

The diverse roles of glutathione-associated cell resistance against hypericin photodynamic therapy.

PubMed

Theodossiou, Theodossis A; Olsen, Cathrine E; Jonsson, Marte; Kubin, Andreas; Hothersall, John S; Berg, Kristian

2017-08-01

The diverse responses of different cancers to treatments such as photodynamic therapy of cancer (PDT) have fueled a growing need for reliable predictive markers for treatment outcome. In the present work we have studied the differential response of two phenotypically and genotypically different breast adenocarcinoma cell lines, MCF7 and MDA-MB-231, to hypericin PDT (HYP-PDT). MDA-MB-231 cells were 70% more sensitive to HYP PDT than MCF7 cells at LD 50 . MCF7 were found to express a substantially higher level of glutathione peroxidase (GPX4) than MDA-MB-231, while MDA-MB-231 differentially expressed glutathione-S-transferase (GSTP1), mainly used for xenobiotic detoxification. Eighty % reduction of intracellular glutathione (GSH) by buthionine sulfoximine (BSO), largely enhanced the sensitivity of the GSTP1 expressing MDA-MB-231 cells to HYP-PDT, but not in MCF7 cells. Further inhibition of the GSH reduction however by carmustine (BCNU) resulted in an enhanced sensitivity of MCF7 to HYP-PDT. HYP loading studies suggested that HYP can be a substrate of GSTP for GSH conjugation as BSO enhanced the cellular HYP accumulation by 20% in MDA-MB-231 cells, but not in MCF7 cells. Studies in solutions showed that L-cysteine can bind the GSTP substrate CDNB in the absence of GSTP. This means that the GSTP-lacking MCF7 may use L-cysteine for xenobiotic detoxification, especially during GSH synthesis inhibition, which leads to L-cysteine build-up. This was confirmed by the lowered accumulation of HYP in both cell lines in the presence of BSO and the L-cysteine source NAC. NAC reduced the sensitivity of MCF7, but not MDA-MB-231, cells to HYP PDT which is in accordance with the antioxidant effects of L-cysteine and its potential as a GSTP substrate. As a conclusion we have herein shown that the different GSH based cell defense mechanisms can be utilized as predictive markers for the outcome of PDT and as a guide for selecting optimal combination strategies. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Oxidative status of human milk and its variations during cold storage.

PubMed

Miranda, María; Muriach, María; Almansa, Inmaculada; Jareño, Enrique; Bosch-Morell, Francisco; Romero, Francisco J; Silvestre, Dolores

2004-01-01

Breastfeeding and human milk are widely accepted as optimal for human infants' nutrition. Nowadays lifestyle often makes it difficult to maintain or even initiate human lactation. This situation is mostly related to the workload of women away from home. New approaches are needed to enable maternal lactation under these circumstances. Human breastmilk storage for differed use is one possibility. The aim of this study was to assess changes in glutathione peroxidase (GPx) activity and in the concentration of the lipid peroxidation marker, malondialdehyde (MDA), when human milk was kept refrigerated or frozen. Thirty-two human milk samples were assayed for GPx activity and MDA concentration. Samples were divided in three aliquot portions, the first to be immediately analysed, the second to be refrigerated at 4 degrees C and analysed 24 h thereafter, and the third to be frozen at -20 degrees C and assayed after 10 days. GPx activity was significantly decreased in refrigerated and in frozen milk, when compared to their control samples. MDA was increased only in refrigerated milk but not in frozen samples. Thus, freezing seems better than refrigeration in order to prevent lipid peroxidation in stored human milk samples.

Malondialdehyde-Derived Epitopes In Human Skin Result From Acute Exposure To Solar UV And Occur In Nonmelanoma Skin Cancer Tissue

PubMed Central

Williams, Joshua D.; Bermudez, Yira; Park, Sophia L.; Stratton, Steven P.; Uchida, Koji; Hurst, Craig A.; Wondrak, Georg T.

2014-01-01

Cutaneous exposure to solar ultraviolet radiation (UVR) is a causative factor in photoaging and photocarcinogenesis. In human skin, oxidative stress is widely considered a key mechanism underlying the detrimental effects of acute and chronic UVR exposure. The lipid peroxidation product malondialdehyde (MDA) accumulates in tissue under conditions of increased oxidative stress, and the occurrence of MDA-derived protein epitopes, including dihydropyridine-lysine (DHP), has recently been substantiated in human skin. Here we demonstrate for the first time that acute exposure to sub-apoptogenic doses of solar simulated UV light (SSL) causes the formation of free MDA and protein-bound MDA-derived epitopes in cultured human HaCaT keratinocytes and healthy human skin. Immunohistochemical staining revealed that acute exposure to SSL is sufficient to cause an almost twenty-fold increase in general MDA- and specific DHP-epitope content in human skin. When compared to dose-matched solar simulated UVA, complete SSL was more efficient generating both free MDA and MDA-derived epitopes. Subsequent tissue microarray (TMA) analysis revealed the prevalence of MDA- and DHP-epitopes in nonmelanoma skin cancer (NMSC). In squamous cell carcinoma tissue, both MDA- and DHP-epitopes were increased more than three-fold as compared to adjacent normal tissue. Taken together, these date demonstrate the occurrence of MDA-derived epitopes in both solar UVR-exposed healthy human skin and NMSC TMA tissue; however, the potential utility of these epitopes as novel biomarkers of cutaneous photodamage and a functional role in the process of skin photocarcinogenesis remain to be explored. PMID:24584085

MDA-9/Syntenin (SDCBP) modulates small GTPases RhoA and Cdc42 via transforming growth factor β1 to enhance epithelial-mesenchymal transition in breast cancer.

PubMed

Menezes, Mitchell E; Shen, Xue-Ning; Das, Swadesh K; Emdad, Luni; Sarkar, Devanand; Fisher, Paul B

2016-12-06

Epithelial-mesenchymal transition (EMT) is one of the decisive steps regulating cancer invasion and metastasis. However, the molecular mechanisms underlying this transition require further clarification. MDA-9/syntenin (SDCBP) expression is elevated in breast cancer patient samples as well as cultured breast cancer cells. Silencing expression of MDA-9 in mesenchymal metastatic breast cancer cells triggered a change in cell morphology in both 2D- and 3D-cultures to a more epithelial-like phenotype, along with changes in EMT markers, cytoskeletal rearrangement and decreased invasion. Conversely, over expressing MDA-9 in epithelial non-metastatic breast cancer cells instigated a change in morphology to a more mesenchymal phenotype with corresponding changes in EMT markers, cytoskeletal rearrangement and an increase in invasion. We also found that MDA-9 upregulated active levels of known modulators of EMT, the small GTPases RhoA and Cdc42, via TGFβ1. Reintroducing TGFβ1 in MDA-9 silenced cells restored active RhoA and cdc42 levels, modulated cytoskeletal rearrangement and increased invasion. We further determined that MDA-9 interacts with TGFβ1 via its PDZ1 domain. Finally, in vivo studies demonstrated that silencing the expression of MDA-9 resulted in decreased lung metastasis and TGFβ1 re-expression partially restored lung metastases. Our findings provide evidence for the relevance of MDA-9 in mediating EMT in breast cancer and support the potential of MDA-9 as a therapeutic target against metastatic disease.

Duck MDA5 functions in innate immunity against H5N1 highly pathogenic avian influenza virus infections

PubMed Central

2014-01-01

Melanoma differentiation-associated gene 5 (MDA5) is an important intracellular receptor that recognizes long molecules of viral double-stranded RNA in innate immunity. To understand the mechanism of duck MDA5-mediated innate immunity, we cloned the MDA5 cDNA from the Muscovy duck (Cairina moschata). Quantitative real-time PCR analysis indicates that duck MDA5 mRNA was constitutively expressed in all sampled tissues. A significant increase of MDA5 mRNA was detected in the brain, spleen and lungs of ducks after infection with an H5N1 highly pathogenic avian influenza virus (HPAIV). We investigated the role of the predicted functional domains of MDA5. The results indicate the caspase activation and recruitment domain (CARD) of duck MDA5 had a signal transmission function through IRF-7-dependent signaling pathway. Overexpression of the CARD strongly activated the chicken IFN-β promoter and upregulated the mRNA expression of antiviral molecules (such as OAS, PKR and Mx), proinflammatory cytokines (such as IL-2, IL-6, IFN-α and IFN-γ, but not IL-1β and IL-8) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) (RIG-I and LGP2) without exogenous stimulation. We also demonstrate the NS1 of the H5N1 HPAIV inhibited the duck MDA5-mediated signaling pathway in vitro. These results suggest that duck MDA5 is an important receptor for inducing antiviral activity in the host immune response of ducks. PMID:24939427

Analysis of malondialdehyde in human plasma samples through derivatization with 2,4-dinitrophenylhydrazine by ultrasound-assisted dispersive liquid-liquid microextraction-GC-FID approach.

PubMed

Malaei, Reyhane; Ramezani, Amir M; Absalan, Ghodratollah

2018-05-04

A sensitive and reliable ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) procedure was developed and validated for extraction and analysis of malondialdehyde (MDA) as an important lipids-peroxidation biomarker in human plasma. In this methodology, to achieve an applicable extraction procedure, the whole optimization processes were performed in human plasma. To convert MDA into readily extractable species, it was derivatized to hydrazone structure-base by 2,4-dinitrophenylhydrazine (DNPH) at 40 °C within 60 min. Influences of experimental variables on the extraction process including type and volume of extraction and disperser solvents, amount of derivatization agent, temperature, pH, ionic strength, sonication and centrifugation times were evaluated. Under the optimal experimental conditions, the enhancement factor and extraction recovery were 79.8 and 95.8%, respectively. The analytical signal linearly (R 2  = 0.9988) responded over a concentration range of 5.00-4000 ng mL -1 with a limit of detection of 0.75 ng mL -1 (S/N = 3) in the plasma sample. To validate the developed procedure, the recommend guidelines of Food and Drug Administration for bioanalytical analysis have been employed. Copyright © 2018. Published by Elsevier B.V.

Sensitive and selective quantification of free and total malondialdehyde in plasma using UHPLC-HRMS.

PubMed

Mendonça, Rute; Gning, Ophélie; Di Cesaré, Claudia; Lachat, Laurence; Bennett, Nigel C; Helfenstein, Fabrice; Glauser, Gaétan

2017-09-01

Quantification of malondialdehyde (MDA) as a marker of lipid peroxidation is relevant for many research fields. We describe a new sensitive and selective method to measure free and total plasmatic MDA using derivatization with 2,4-dinitrophenylhydrazine (DNPH) and ultra-HPLC-high-resolution MS. Free and total MDA were extracted from minute sample amounts (10 μl) using acidic precipitation and alkaline hydrolysis followed by acidic precipitation, respectively. Derivatization was completed within 10 min at room temperature, and the excess DNPH discarded by liquid-liquid extraction. Quantification was achieved by internal standardization using dideuterated MDA as internal standard. The method's lowest limit of quantification was 100 nM and linearity spanned greater than three orders of magnitude. Intra- and inter-day precisions for total MDA were 2.9% and 3.0%, respectively, and those for free MDA were 12.8% and 24.9%, respectively. Accuracy was 101% and 107% at low and high concentrations, respectively. In human plasma, free MDA levels were 120 nM (SD 36.26) and total MDA levels were 6.7 μM (SD 0.46). In addition, we show the applicability of this method to measure MDA plasma levels from a variety of animal species, making it invaluable to scientists in various fields. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Improved quantification of a commercial enzyme-linked immunosorbent assay kit for measuring anti-MDA5 antibody.

PubMed

Gono, Takahisa; Okazaki, Yuka; Murakami, Akihiro; Kuwana, Masataka

2018-04-09

To compare the quantitative performance for measuring anti-MDA5 antibody titer of two enzyme-linked immunosorbent assay (ELISA) systems: an in-house ELISA and the commercial MESACUP TM anti-MDA5 test. Anti-MDA5 antibody titer was measured in sera from 70 patients with dermatomyositis using an in-house ELISA and the MESACUP TM anti-MDA5 test side-by-side. For the commercial ELISA kit, serum samples diluted 1:101 were used according to the manufacturer's protocol, but serial dilutions of sera were also examined to identify the optimal serum dilution for quantification. The anti-MDA5 antibody titers measured by the in-house and commercial ELISAs were positively correlated with each other (r = 0.53, p = .0001), but the antibody titer measured by the commercial ELISA was less sensitive to change after medical treatment, and 37 (80%) of 46 anti-MDA5-positive sera had antibody titer exceeding the quantification range specified by the manufacturer (≥150 index). Experiments using diluted serum samples revealed that diluting the sera 1:5050 improved the quantitative performance of the MESACUP TM anti-MDA5 test, including a better correlation with the in-house ELISA results and an increased sensitivity to change. We improved the ability of the commercial ELISA kit to quantify anti-MDA5 antibody titer by altering its protocol.

Impregnating magnetic components with MDA free epoxy

NASA Astrophysics Data System (ADS)

Sanchez, R. O.; Domeier, L.; Gunewardena, S.

1995-08-01

This paper describes the use of 'Formula 456' an aliphatic amine cured epoxy for impregnating coils. Methylene dianiline (MDA) has been used for more than 20 years as the curing agent for various epoxy formulations throughout the Department of Energy. Sandia National Laboratories began the process of replacing MDA with other formulations because of regulations imposed by OSHA on the use of MDA.

Paramyxovirus V protein interaction with the antiviral sensor LGP2 disrupts MDA5 signaling enhancement but is not relevant to LGP2-mediated RLR signaling inhibition.

PubMed

Rodriguez, Kenny R; Horvath, Curt M

2014-07-01

The interferon antiviral system is a primary barrier to virus replication triggered upon recognition of nonself RNAs by the cytoplasmic sensors encoded by retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology gene 2 (LGP2). Paramyxovirus V proteins are interferon antagonists that can selectively interact with MDA5 and LGP2 through contact with a discrete helicase domain region. Interaction with MDA5, an activator of antiviral signaling, disrupts interferon gene expression and antiviral responses. LGP2 has more diverse reported roles as both a coactivator of MDA5 and a negative regulator of both RIG-I and MDA5. This functional dichotomy, along with the concurrent interference with both cellular targets, has made it difficult to assess the unique consequences of V protein interaction with LGP2. To directly evaluate the impact of LGP2 interference, MDA5 and LGP2 variants unable to be recognized by measles virus and parainfluenza virus 5 (PIV5) V proteins were tested in signaling assays. Results indicate that interaction with LGP2 specifically prevents coactivation of MDA5 signaling and that LGP2's negative regulatory capacity was not affected. V proteins only partially antagonize RIG-I at high concentrations, and their expression had no additive effects on LGP2-mediated negative regulation. However, conversion of RIG-I to a direct V protein target was accomplished by only two amino acid substitutions that allowed both V protein interaction and efficient interference. These results clarify the unique consequences of MDA5 and LGP2 interference by paramyxovirus V proteins and help resolve the distinct roles of LGP2 in both activation and inhibition of antiviral signal transduction. Importance: Paramyxovirus V proteins interact with two innate immune receptors, MDA5 and LGP2, but not RIG-I. V proteins prevent MDA5 from signaling to the beta interferon promoter, but the consequences of LGP2 targeting are poorly understood. As the V protein targets MDA5 and LGP2 simultaneously, and LGP2 is both a positive and negative regulator of both MDA5 and RIG-I, it has been difficult to evaluate the specific advantages conferred by LGP2 targeting. Experiments with V-insensitive proteins revealed that the primary outcome of LGP2 interference is suppression of its ability to synergize with MDA5. LGP2's negative regulation of MDA5 and RIG-I remains intact irrespective of V protein interaction. Complementary experiments demonstrate that RIG-I can be converted to V protein sensitivity by two amino acid substitutions. These findings clarify the functions of LGP2 as a positive regulator of MDA5 signaling, demonstrate the basis for V-mediated LGP2 targeting, and broaden our understanding of paramyxovirus-host interactions. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Paramyxovirus V Protein Interaction with the Antiviral Sensor LGP2 Disrupts MDA5 Signaling Enhancement but Is Not Relevant to LGP2-Mediated RLR Signaling Inhibition

PubMed Central

Rodriguez, Kenny R.

2014-01-01

ABSTRACT The interferon antiviral system is a primary barrier to virus replication triggered upon recognition of nonself RNAs by the cytoplasmic sensors encoded by retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology gene 2 (LGP2). Paramyxovirus V proteins are interferon antagonists that can selectively interact with MDA5 and LGP2 through contact with a discrete helicase domain region. Interaction with MDA5, an activator of antiviral signaling, disrupts interferon gene expression and antiviral responses. LGP2 has more diverse reported roles as both a coactivator of MDA5 and a negative regulator of both RIG-I and MDA5. This functional dichotomy, along with the concurrent interference with both cellular targets, has made it difficult to assess the unique consequences of V protein interaction with LGP2. To directly evaluate the impact of LGP2 interference, MDA5 and LGP2 variants unable to be recognized by measles virus and parainfluenza virus 5 (PIV5) V proteins were tested in signaling assays. Results indicate that interaction with LGP2 specifically prevents coactivation of MDA5 signaling and that LGP2's negative regulatory capacity was not affected. V proteins only partially antagonize RIG-I at high concentrations, and their expression had no additive effects on LGP2-mediated negative regulation. However, conversion of RIG-I to a direct V protein target was accomplished by only two amino acid substitutions that allowed both V protein interaction and efficient interference. These results clarify the unique consequences of MDA5 and LGP2 interference by paramyxovirus V proteins and help resolve the distinct roles of LGP2 in both activation and inhibition of antiviral signal transduction. IMPORTANCE Paramyxovirus V proteins interact with two innate immune receptors, MDA5 and LGP2, but not RIG-I. V proteins prevent MDA5 from signaling to the beta interferon promoter, but the consequences of LGP2 targeting are poorly understood. As the V protein targets MDA5 and LGP2 simultaneously, and LGP2 is both a positive and negative regulator of both MDA5 and RIG-I, it has been difficult to evaluate the specific advantages conferred by LGP2 targeting. Experiments with V-insensitive proteins revealed that the primary outcome of LGP2 interference is suppression of its ability to synergize with MDA5. LGP2's negative regulation of MDA5 and RIG-I remains intact irrespective of V protein interaction. Complementary experiments demonstrate that RIG-I can be converted to V protein sensitivity by two amino acid substitutions. These findings clarify the functions of LGP2 as a positive regulator of MDA5 signaling, demonstrate the basis for V-mediated LGP2 targeting, and broaden our understanding of paramyxovirus-host interactions. PMID:24829334

Chapter One---Cancer terminator viruses and approaches for enhancing therapeutic outcomes.

PubMed

Das, Swadesh K; Sarkar, Siddik; Dash, Rupesh; Dent, Paul; Wang, Xiang-Yang; Sarkar, Devanand; Fisher, Paul B

2012-01-01

No single or combinatorial therapeutic approach has proven effective in decreasing morbidity or engendering a cure of metastatic cancer. In principle, conditionally replication-competent adenoviruses that induce tumor oncolysis through cancer-specific replication hold promise for cancer therapy. However, a single-agent approach may not be adequate to completely eradicate cancer in a patient because most cancers arise from abnormalities in multiple genetic and signal transduction pathways and targeting disseminated metastases is difficult to achieve. Based on these considerations, a novel class of cancer destroying adenoviruses have been produced, cancer terminator viruses (CTVs), in which cancer-specific replication is controlled by the progression-elevated gene-3 promoter and replicating viruses produce a second transgene encoding an apoptosis-inducing and immunomodulatory cytokine, either melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) or interferon-γ. This review focuses on these viruses and ways to improve their delivery systemically and enhance their therapeutic efficacy. Copyright © 2012 Elsevier Inc. All rights reserved.

Autophagic Cell Death, Polyploidy and Senescence Induced in Breast Tumor Cells by the Substituted Pyrrole JG-03-14, a Novel Microtubule Poison

PubMed Central

Arthur, Christopher R.; Gupton, John T.; Kellogg, Glen E.; Yeudall, W. Andrew; Cabot, Myles C.; Newsham, Irene; Gewirtz, David A.

2007-01-01

JG-03-14, a substituted pyrrole that inhibits microtubule polymerization, was screened against MCF-7 (p53 wild type), MDA-MB 231 (p53 mutant), MCF-7/caspase 3 and MCF-7/ADR (multidrug resistant) breast tumor cell lines. Cell viability and growth inhibition were assessed by the crystal violet dye assay. Apoptosis was evaluated by the TUNEL assay, cell cycle distribution by flow cytometry, autophagy by acridine orange staining of vesicle formation, and senescence based on β-galactosidase staining and cell morphology. Our studies indicate that exposure to JG-03-14, at a concentration of 500 nM, induces time dependent cell death in the MCF-7 and MDA-MB 231 cell lines. In MCF-7 cells, a residual surviving cell population was found to be senescent; in contrast, there was no surviving senescent population in treated MDA-MB 231 cells. No proliferative recovery was detected over a period of 15 days post-treatment in either cell line. Both the TUNEL assay and FLOW cytometry indicated a relatively limited degree of apoptosis (< 10%) in response to drug treatment in MCF-7 cells with more extensive apoptosis (but < 20%) in MDA-MB231 cells; acidic vacuole formation indicative of autophagic cell death was relatively extensive in both MCF-7 and MDA-MB231 cells. In addition, JG-03-14 induced the formation of a large hyperdiploid cell population in MDA-MB231 cells. JG-03-14 also demonstrated pronounced anti-proliferative activity in MCF-7/caspase 3 cells and in the MCF-7/ADR cell line. The observation that JG-03-14 promotes autophagic cell death and also retains activity in tumor cells expressing the multidrug resistance pump indicates that novel microtubule poisons of the substituted pyrroles class may hold promise in the treatment of breast cancer. PMID:17692290

Adverse event management in mass drug administration for neglected tropical diseases.

PubMed

Caplan, Arthur; Zink, Amanda

2014-03-01

The ethical challenges of reporting and managing adverse events (AEs) and serious AEs (SAEs) in the context of mass drug administration (MDA) for the treatment of neglected tropical diseases (NTDs) require reassessment of domestic and international policies on a global scale. Although the World Health Organization has set forth AE/SAE guidelines specifically for NTD MDA that incorporate suspected causality, and recommends that only SAEs get reported in this setting, most regulatory agencies continue to require the reporting of all SAEs exhibiting even a merely temporal relationship to activities associated with an MDA program. This greatly increases the potential for excess "noise" and undue risk aversion and is not only impractical but arguably unethical where huge proportions of populations are being treated for devastating diseases, and no good baseline exists against which to compare possible AE/SAE reports. Other population-specific variables that might change the way drug safety ought to be assessed include differing efficacy rates of a drug, background morbidity/mortality rates of the target disease in question, the growth rate of the incidence of disease, the availability of rescue or salvage therapies, and the willingness of local populations to take risks that other populations might not. The fact that NTDs are controllable and potentially eradicable with well-tolerated, effective, existing drugs might further alter our assessment of MDA safety and AE/SAE tolerability. At the same time, diffuseness of population, communication barriers, lack of resources, and other difficult surveillance challenges may present in NTD-affected settings. These limitations could impair the ability to monitor an MDA program's success, as well as hinder efforts to obtain informed consent or provide rescue therapy. Denying beneficial research interventions and MDA programs intended to benefit millions requires sound ethical justification based on more than the identification of and rote response to AEs and SAEs. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

A multi-center field study of two point-of-care tests for circulating Wuchereria bancrofti antigenemia in Africa

PubMed Central

Chesnais, Cédric B.; Awaca-Uvon, Naomi-Pitchouna; Bolay, Fatoma K.; Boussinesq, Michel; Fischer, Peter U.; Gankpala, Lincoln; Meite, Aboulaye; Missamou, François; Pion, Sébastien D.

2017-01-01

Background The Global Programme to Eliminate Lymphatic Filariasis uses point-of-care tests for circulating filarial antigenemia (CFA) to map endemic areas and for monitoring and evaluating the success of mass drug administration (MDA) programs. We compared the performance of the reference BinaxNOW Filariasis card test (ICT, introduced in 1997) with the Alere Filariasis Test Strip (FTS, introduced in 2013) in 5 endemic study sites in Africa. Methodology The tests were compared prior to MDA in two study sites (Congo and Côte d'Ivoire) and in three sites that had received MDA (DRC and 2 sites in Liberia). Data were analyzed with regard to % positivity, % agreement, and heterogeneity. Models evaluated potential effects of age, gender, and blood microfilaria (Mf) counts in individuals and effects of endemicity and history of MDA at the village level as potential factors linked to higher sensitivity of the FTS. Lastly, we assessed relationships between CFA scores and Mf in pre- and post-MDA settings. Principal findings Paired test results were available for 3,682 individuals. Antigenemia rates were 8% and 22% higher by FTS than by ICT in pre-MDA and in post-MDA sites, respectively. FTS/ICT ratios were higher in areas with low infection rates. The probability of having microfilaremia was much higher in persons with CFA scores >1 in untreated areas. However, this was not true in post-MDA settings. Conclusions/Significance This study has provided extensive new information on the performance of the FTS compared to ICT in Africa and it has confirmed the increased sensitivity of FTS reported in prior studies. Variability in FTS/ICT was related in part to endemicity level, history of MDA, and perhaps to the medications used for MDA. These results suggest that FTS should be superior to ICT for mapping, for transmission assessment surveys, and for post-MDA surveillance. PMID:28892473

Novel Role of MDA-9/Syntenin in Regulating Urothelial Cell Proliferation by Modulating EGFR Signaling

PubMed Central

Dasgupta, Santanu; Menezes, Mitchell E.; Das, Swadesh K.; Emdad, Luni; Janjic, Aleksandar; Bhatia, Shilpa; Mukhopadhyay, Nitai D; Shao, Chunbo; Sarkar, Devanand; Fisher, Paul B.

2013-01-01

Purpose Urothelial cell carcinoma (UCC) rapidly progresses from superficial to muscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of the metastasis-associated gene MDA-9/Syntenin in UCC progression. Experimental Design Expression pattern of MDA-9/Syntenin was examined in 44 primary UCC and the impact of its overexpression and knock down was examined in multiple cells lines and key findings were validated in primary tumors. Results Significantly higher (p= 0.002–0.003) expression of MDA-9/Syntenin was observed in 64% (28/44) of primary tumors and an association was evident with stage (p=0.01), grade (p=0.03) and invasion status (p=0.02). MDA-9/Syntenin overexpression in non-tumorigenic HUC-1 cells increased proliferation (p=0.0012), invasion (p=0.0001) and EGFR, AKT, PI3K and c-Src expression. Alteration of Beta-catenin, E-Cadherin, Vimentin, Claudin-1, ZO-1 and TCF4 expression were also observed. MDA-9/Syntenin knock down in 3 UCC cell lines reversed phenotypic and molecular changes observed in the HUC-1 cells and reduced in vivo metastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and co-localization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin: AKT expressions with stage (p=0.04, EGFR), (p=0.01, AKT). A correlation between MDA-9/Syntenin: β-catenin co-expression with stage (p=0.03) and invasion (p=0.04) was also evident. Conclusions Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring and therapeutic strategies for managing UCC. PMID:23873690

Novel role of MDA-9/syntenin in regulating urothelial cell proliferation by modulating EGFR signaling.

PubMed

Dasgupta, Santanu; Menezes, Mitchell E; Das, Swadesh K; Emdad, Luni; Janjic, Aleksandar; Bhatia, Shilpa; Mukhopadhyay, Nitai D; Shao, Chunbo; Sarkar, Devanand; Fisher, Paul B

2013-09-01

Urothelial cell carcinoma (UCC) rapidly progresses from superficial to muscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of the metastasis-associated gene MDA-9/Syntenin in UCC progression. Expression pattern of MDA-9/Syntenin was examined in 44 primary UCC and the impact of its overexpression and knockdown was examined in multiple cells lines and key findings were validated in primary tumors. Significantly higher (P=0.002-0.003) expression of MDA-9/Syntenin was observed in 64% (28 of 44) of primary tumors and an association was evident with stage (P=0.01), grade (P=0.03), and invasion status (P=0.02). MDA-9/Syntenin overexpression in nontumorigenic HUC-1 cells increased proliferation (P=0.0012), invasion (P=0.0001), and EGF receptor (EGFR), AKT, phosphoinositide 3-kinase (PI3K), and c-Src expression. Alteration of β-catenin, E-cadherin, vimentin, claudin-1, ZO-1, and T-cell factor-4 (TCF4) expression was also observed. MDA-9/Syntenin knockdown in three UCC cell lines reversed phenotypic and molecular changes observed in the HUC-1 cells and reduced in vivo metastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and colocalization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin:AKT expressions with stage (P=0.04, EGFR; P=0.01, AKT). A correlation between MDA-9/Syntenin:β-catenin coexpression with stage (P=0.03) and invasion (P=0.04) was also evident. Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring, and therapeutic strategies for managing UCC. ©2013 AACR.

A multi-center field study of two point-of-care tests for circulating Wuchereria bancrofti antigenemia in Africa.

PubMed

Chesnais, Cédric B; Awaca-Uvon, Naomi-Pitchouna; Bolay, Fatoma K; Boussinesq, Michel; Fischer, Peter U; Gankpala, Lincoln; Meite, Aboulaye; Missamou, François; Pion, Sébastien D; Weil, Gary J

2017-09-01

The Global Programme to Eliminate Lymphatic Filariasis uses point-of-care tests for circulating filarial antigenemia (CFA) to map endemic areas and for monitoring and evaluating the success of mass drug administration (MDA) programs. We compared the performance of the reference BinaxNOW Filariasis card test (ICT, introduced in 1997) with the Alere Filariasis Test Strip (FTS, introduced in 2013) in 5 endemic study sites in Africa. The tests were compared prior to MDA in two study sites (Congo and Côte d'Ivoire) and in three sites that had received MDA (DRC and 2 sites in Liberia). Data were analyzed with regard to % positivity, % agreement, and heterogeneity. Models evaluated potential effects of age, gender, and blood microfilaria (Mf) counts in individuals and effects of endemicity and history of MDA at the village level as potential factors linked to higher sensitivity of the FTS. Lastly, we assessed relationships between CFA scores and Mf in pre- and post-MDA settings. Paired test results were available for 3,682 individuals. Antigenemia rates were 8% and 22% higher by FTS than by ICT in pre-MDA and in post-MDA sites, respectively. FTS/ICT ratios were higher in areas with low infection rates. The probability of having microfilaremia was much higher in persons with CFA scores >1 in untreated areas. However, this was not true in post-MDA settings. This study has provided extensive new information on the performance of the FTS compared to ICT in Africa and it has confirmed the increased sensitivity of FTS reported in prior studies. Variability in FTS/ICT was related in part to endemicity level, history of MDA, and perhaps to the medications used for MDA. These results suggest that FTS should be superior to ICT for mapping, for transmission assessment surveys, and for post-MDA surveillance.

The prophylactic effect of vitamin C on induced oxidative stress in rat testis following exposure to 900 MHz radio frequency wave generated by a BTS antenna model.

PubMed

Jelodar, Gholamali; Nazifi, Saeed; Akbari, Abolfazl

2013-09-01

Radio frequency wave (RFW) generated by base transceiver station (BTS) has been reported to make deleterious effects on reproduction, possibly through oxidative stress. This study was conducted to evaluate the effect of RFW generated by BTS on oxidative stress in testis and the prophylactic effect of vitamin C by measuring the antioxidant enzymes activity, including glutathione peroxidase, superoxide dismutase (SOD) and catalase, and malondialdehyde (MDA). Thirty-two adult male Sprague-Dawley rats were randomly divided into four experimental groups and treated daily for 45 days as follows: sham, sham+vitamin C (l-ascorbic acid 200 mg/kg of body weight/day by gavage), RFW (exposed to 900 MHz RFW) 'sham' and 'RFW' animals were given the vehicle, i.e., distilled water and the RFW+vitamin C group (received vitamin C in addition to exposure to RFW). At the end of the experiment, all the rats were sacrificed and their testes were removed and used for measurement of antioxidant enzymes and MDA activity. The results indicate that exposure to RFW in the test group decreased antioxidant enzymes activity and increased MDA compared with the control groups (p < 0.05). In the treated group, vitamin C improved antioxidant enzymes activity and reduced MDA compared with the test group (p < 0.05). It can be concluded that RFW causes oxidative stress in testis and vitamin C improves the antioxidant enzymes activity and decreases MDA.

The Environmental Behavior of Methylene-4,4'-dianiline.

PubMed

Schupp, Thomas; Allmendinger, Hans; Boegi, Christian; Bossuyt, Bart T A; Hidding, Bjoern; Shen, Summer; Tury, Bernard; West, Robert J

2018-06-24

Methylene-4,4'-dianiline (MDA, CAS-No. 101-77-9) is a high production volume intermediate that is mainly processed to diisocyanates and finally polyurethanes. This review summarizes available data concerning the environmental behavior. When released into the environment, MDA distributes into water and subsequently sediment and soil compartments; the air is of little relevance, owed to the low vapor pressure and short atmospheric half-life, which renders MDA non-critical for long-range transport. Biodegradation data present a diverged picture; in some tests, MDA is not readily biodegradable or even not inherent biodegradable; in other tests, MDA turned out to be readily biodegradable (but failing the 10-d window). The history and composition of the inoculum used for testing seem to play an important role, which is underlined by good test results with adapted inoculum. In soil, initially a rapid mineralization is observed, which slows down within the first days due to competitive chemical absorption. The latter results in degradation rates comparable to that of natural organic matter. Under anaerobic conditions, mineralization is poor. Irreversible chemisorption occurs unless soils/sediments are highly reduced. Half-lives due to primary decay do not indicate MDA to be persistent according to the regulatory guidance used in then EU, Canada, or the USA; in Japan, however, due to test results in MITI degradation tests, MDA would be regarded as persistent. The identification of microbial MDA metabolites deserves further research. MDA is not bioaccumulative, but it is toxic to aquatic organisms and mammals. MDA in pore water of soils is rapidly adsorbed on the surface of plant roots. Test runs were too short to draw a final conclusion with regards to transport to stem, leaves, and fruits. Data from structurally similar compounds indicate that such transport would account for less than 1% of the root-adsorbed material.

A comparative study of biodegradability of a carcinogenic aromatic amine (4,4'-diaminodiphenylmethane) with OECD 301 test methods.

PubMed

Mei, Cheng-Fang; Liu, Yan-Zhen; Long, Wei-Nian; Sun, Guo-Ping; Zeng, Guo-Qu; Xu, Mei-Ying; Luan, Tian-Gang

2015-01-01

4,4'-Diaminodiphenylmethane (MDA) is a widely used compound in industries. Studies on the biodegradability of MDA are necessary for environmental hazard identification and risk assessment. Previous studies have suggested that MDA was not readily biodegradable. In the present study, three batches of biodegradation tests (OECD 301A, B, D and F tests) were performed on MDA in June, August and December of 2012. MDA was found to be readily biodegradable and produced colored intermediates in the 301A, B and F test systems. MDA biodegradation measurements were consistent among the three batches of tests. Differences in the extent of biodegradation determined in different methods originated from different test conditions and assessment endpoints. The 301D test has stringent test conditions and is usually performed on chemicals that are toxic to microorganisms, so the test results obtained from 301D tests are less meaningful for evaluating the biodegradability of MDA. The low MDA biodegradation measurements in the 301B tests compared to the 301A and F tests were due to the assessment method, which did not account for MDA incorporation into biomass in its calculation of CO2 formation rate. The differences in the biodegradation rates, as measured by the different OECD 301 test systems, could also be related to the structure and properties of the chemical. For test substances that can be assessed by all OECD 301 test methods, the highest biodegradation values may be obtained from the 301A and F test methods. This study provides new information to assess the environmental fate in the risk assessment of MDA. Copyright © 2014 Elsevier Inc. All rights reserved.

Malondialdehyde-derived epitopes in human skin result from acute exposure to solar UV and occur in nonmelanoma skin cancer tissue.

PubMed

Williams, Joshua D; Bermudez, Yira; Park, Sophia L; Stratton, Steven P; Uchida, Koji; Hurst, Craig A; Wondrak, Georg T

2014-03-05

Cutaneous exposure to solar ultraviolet radiation (UVR) is a causative factor in photoaging and photocarcinogenesis. In human skin, oxidative stress is widely considered a key mechanism underlying the detrimental effects of acute and chronic UVR exposure. The lipid peroxidation product malondialdehyde (MDA) accumulates in tissue under conditions of increased oxidative stress, and the occurrence of MDA-derived protein epitopes, including dihydropyridine-lysine (DHP), has recently been substantiated in human skin. Here we demonstrate for the first time that acute exposure to sub-apoptogenic doses of solar simulated UV light (SSL) causes the formation of free MDA and protein-bound MDA-derived epitopes in cultured human HaCaT keratinocytes and healthy human skin. Immunohistochemical staining revealed that acute exposure to SSL is sufficient to cause an almost twenty-fold increase in general MDA- and specific DHP-epitope content in human skin. When compared to dose-matched solar simulated UVA, complete SSL was more efficient generating both free MDA and MDA-derived epitopes. Subsequent tissue microarray (TMA) analysis revealed the prevalence of MDA- and DHP-epitopes in nonmelanoma skin cancer (NMSC). In squamous cell carcinoma tissue, both MDA- and DHP-epitopes were increased more than threefold as compared to adjacent normal tissue. Taken together, these date demonstrate the occurrence of MDA-derived epitopes in both solar UVR-exposed healthy human skin and NMSC TMA tissue; however, the potential utility of these epitopes as novel biomarkers of cutaneous photodamage and a functional role in the process of skin photocarcinogenesis remain to be explored. Copyright © 2014 Elsevier B.V. All rights reserved.

Modeling the Impact and Costs of Semiannual Mass Drug Administration for Accelerated Elimination of Lymphatic Filariasis

PubMed Central

de Vlas, Sake J.; Fischer, Peter U.; Weil, Gary J.; Goldman, Ann S.

2013-01-01

The Global Program to Eliminate Lymphatic Filariasis (LF) has a target date of 2020. This program is progressing well in many countries. However, progress has been slow in some countries, and others have not yet started their mass drug administration (MDA) programs. Acceleration is needed. We studied how increasing MDA frequency from once to twice per year would affect program duration and costs by using computer simulation modeling and cost projections. We used the LYMFASIM simulation model to estimate how many annual or semiannual MDA rounds would be required to eliminate LF for Indian and West African scenarios with varied pre-control endemicity and coverage levels. Results were used to estimate total program costs assuming a target population of 100,000 eligibles, a 3% discount rate, and not counting the costs of donated drugs. A sensitivity analysis was done to investigate the robustness of these results with varied assumptions for key parameters. Model predictions suggested that semiannual MDA will require the same number of MDA rounds to achieve LF elimination as annual MDA in most scenarios. Thus semiannual MDA programs should achieve this goal in half of the time required for annual programs. Due to efficiency gains, total program costs for semiannual MDA programs are projected to be lower than those for annual MDA programs in most scenarios. A sensitivity analysis showed that this conclusion is robust. Semiannual MDA is likely to shorten the time and lower the cost required for LF elimination in countries where it can be implemented. This strategy may improve prospects for global elimination of LF by the target year 2020. PMID:23301115

Review of the Ecotoxicological Properties of the Methylenedianiline Substances.

PubMed

Schupp, T; Allmendinger, H; Bossuyt, B T A; Hidding, B; Tury, B; West, R J

Concerning chronic toxicity, D. magna is the most sensitive species tested against MDA aquatic exposures, with a 21 days-NOEC of 0.00525 mg/L. Exposure of daphnids takes place via the aquatic phase. Other species of the same phylum (Arthropoda) appear to be less sensitive albeit with exposures via soil or sediment, with a 28 days-NOEC of 562 mg/kg d. w. soil (F. candida) and 41.3 mg/kg d. w. sediment (Hyalella azteca), for reproductive and survival endpoints, respectively. Also for acute toxicity, D. magna is more sensitive than the other species, with an 48 h-EC50 that spreads over two orders of magnitude, ranging from 0.019 to 2.7 mg/L. Fish show a more uniform reaction to MDA, with 96 h-LC50 ranging from about 20 to 60 mg/L; chronic data for fish are not available. Acute toxicity data for algae and cyanobacteria are in the range of 1-10 mg/L; based on growth rate, the 72 h-NOEC r or E r C 10 of MDA to algae is 0.3-9.3 mg/L.For sediment organisms, the black worm L. variegatus shows the highest sensitivity against MDA with a NOEC between ≤3.75 mg/kg and 30 mg/kg d. w., followed by the amphipod H. azteca. The lower sensitivity of L. variegatus in the second study compared to the first study is obviously attributable to the different feeding regimes (semi-continuous feeding against pre-spiked sediment). One argument might be that semi-continuous feeding allows the organisms to avoid the contaminated food. However, a change from semi-continuous feeding to sediment pre-spiked with nettle powder (Urtica sp.) results in an earlier and much stronger increase in ammonia concentration in the system. This became apparent after both studies on the blackworm were finalized. The ammonia 96 h-EC50 for the blackworm is 0.69 mg/L at pH = 8.2, and the 96 h-EC10 at pH = 8.2 is 0.33 mg/L (Hickey and Vickers, Arch Environ Contam Toxicol 26:292-298, 1994). As a result, the lower NOEC and LOEC in the second study with L. variegatus are probably attributable to interference by ammonia.MDA binds irreversibly to soil and sediment which may explain the general, but not uniform lower sensitivity of soil and sediment organisms against aquatic organisms. However, species with intense soil or sediment contact (L. variegatus and E. fetida) show in general lower NOEC values than those organisms with less direct contact (3.75 and 11.2 mg/kg d. w., respectively). On the one hand it may be hypothesized that this intense contact to soil bound MDA is one reason for the higher sensitivity; on the other hand, metabolic capacity against MDA of the organisms tested is unknown at this point in time and might as well explain differences in species sensitivity. For plants there are only acute data available, and in respect to acute toxicity L. sativa is more sensitive to MDA than E. fetida.Limited aquatic data available so far do not indicate that the toxicity of pMDA is different to MDA. In addition, the limited set of data generated with the marine M. macrocopa (crustacean), N. fustulum (diatom) and V. fisheri (bacteria) do not indicate that sea water organisms are more sensitive to MDA than fresh water organisms.In mammals, MDA is unlikely to interact with the endocrine sexual system; interaction with the adrenergic system cannot be ruled out, and effects of MDA on the thyroid hormone system have been demonstrated. MDA inhibits the thyroid peroxidase which might contribute to the thyroid gland tumors observed in chronic studies with rats and mice. Some anti-androgenic activity in in vitro studies with yeast cell did not prevail in in vivo studies with rats and mice.

A physical sciences network characterization of non-tumorigenic and metastatic cells

PubMed Central

Agus, David B.; Alexander, Jenolyn F.; Arap, Wadih; Ashili, Shashanka; Aslan, Joseph E.; Austin, Robert H.; Backman, Vadim; Bethel, Kelly J.; Bonneau, Richard; Chen, Wei-Chiang; Chen-Tanyolac, Chira; Choi, Nathan C.; Curley, Steven A.; Dallas, Matthew; Damania, Dhwanil; Davies, Paul C. W.; Decuzzi, Paolo; Dickinson, Laura; Estevez-Salmeron, Luis; Estrella, Veronica; Ferrari, Mauro; Fischbach, Claudia; Foo, Jasmine; Fraley, Stephanie I.; Frantz, Christian; Fuhrmann, Alexander; Gascard, Philippe; Gatenby, Robert A.; Geng, Yue; Gerecht, Sharon; Gillies, Robert J.; Godin, Biana; Grady, William M.; Greenfield, Alex; Hemphill, Courtney; Hempstead, Barbara L.; Hielscher, Abigail; Hillis, W. Daniel; Holland, Eric C.; Ibrahim-Hashim, Arig; Jacks, Tyler; Johnson, Roger H.; Joo, Ahyoung; Katz, Jonathan E.; Kelbauskas, Laimonas; Kesselman, Carl; King, Michael R.; Konstantopoulos, Konstantinos; Kraning-Rush, Casey M.; Kuhn, Peter; Kung, Kevin; Kwee, Brian; Lakins, Johnathon N.; Lambert, Guillaume; Liao, David; Licht, Jonathan D.; Liphardt, Jan T.; Liu, Liyu; Lloyd, Mark C.; Lyubimova, Anna; Mallick, Parag; Marko, John; McCarty, Owen J. T.; Meldrum, Deirdre R.; Michor, Franziska; Mumenthaler, Shannon M.; Nandakumar, Vivek; O’Halloran, Thomas V.; Oh, Steve; Pasqualini, Renata; Paszek, Matthew J.; Philips, Kevin G.; Poultney, Christopher S.; Rana, Kuldeepsinh; Reinhart-King, Cynthia A.; Ros, Robert; Semenza, Gregg L.; Senechal, Patti; Shuler, Michael L.; Srinivasan, Srimeenakshi; Staunton, Jack R.; Stypula, Yolanda; Subramanian, Hariharan; Tlsty, Thea D.; Tormoen, Garth W.; Tseng, Yiider; van Oudenaarden, Alexander; Verbridge, Scott S.; Wan, Jenny C.; Weaver, Valerie M.; Widom, Jonathan; Will, Christine; Wirtz, Denis; Wojtkowiak, Jonathan; Wu, Pei-Hsun

2013-01-01

To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells' regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis. PMID:23618955

A physical sciences network characterization of non-tumorigenic and metastatic cells.

PubMed

Agus, David B; Alexander, Jenolyn F; Arap, Wadih; Ashili, Shashanka; Aslan, Joseph E; Austin, Robert H; Backman, Vadim; Bethel, Kelly J; Bonneau, Richard; Chen, Wei-Chiang; Chen-Tanyolac, Chira; Choi, Nathan C; Curley, Steven A; Dallas, Matthew; Damania, Dhwanil; Davies, Paul C W; Decuzzi, Paolo; Dickinson, Laura; Estevez-Salmeron, Luis; Estrella, Veronica; Ferrari, Mauro; Fischbach, Claudia; Foo, Jasmine; Fraley, Stephanie I; Frantz, Christian; Fuhrmann, Alexander; Gascard, Philippe; Gatenby, Robert A; Geng, Yue; Gerecht, Sharon; Gillies, Robert J; Godin, Biana; Grady, William M; Greenfield, Alex; Hemphill, Courtney; Hempstead, Barbara L; Hielscher, Abigail; Hillis, W Daniel; Holland, Eric C; Ibrahim-Hashim, Arig; Jacks, Tyler; Johnson, Roger H; Joo, Ahyoung; Katz, Jonathan E; Kelbauskas, Laimonas; Kesselman, Carl; King, Michael R; Konstantopoulos, Konstantinos; Kraning-Rush, Casey M; Kuhn, Peter; Kung, Kevin; Kwee, Brian; Lakins, Johnathon N; Lambert, Guillaume; Liao, David; Licht, Jonathan D; Liphardt, Jan T; Liu, Liyu; Lloyd, Mark C; Lyubimova, Anna; Mallick, Parag; Marko, John; McCarty, Owen J T; Meldrum, Deirdre R; Michor, Franziska; Mumenthaler, Shannon M; Nandakumar, Vivek; O'Halloran, Thomas V; Oh, Steve; Pasqualini, Renata; Paszek, Matthew J; Philips, Kevin G; Poultney, Christopher S; Rana, Kuldeepsinh; Reinhart-King, Cynthia A; Ros, Robert; Semenza, Gregg L; Senechal, Patti; Shuler, Michael L; Srinivasan, Srimeenakshi; Staunton, Jack R; Stypula, Yolanda; Subramanian, Hariharan; Tlsty, Thea D; Tormoen, Garth W; Tseng, Yiider; van Oudenaarden, Alexander; Verbridge, Scott S; Wan, Jenny C; Weaver, Valerie M; Widom, Jonathan; Will, Christine; Wirtz, Denis; Wojtkowiak, Jonathan; Wu, Pei-Hsun

2013-01-01

To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences-Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells' regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.

A physical sciences network characterization of non-tumorigenic and metastatic cells

NASA Astrophysics Data System (ADS)

Physical Sciences-Oncology Centers Network; Agus, David B.; Alexander, Jenolyn F.; Arap, Wadih; Ashili, Shashanka; Aslan, Joseph E.; Austin, Robert H.; Backman, Vadim; Bethel, Kelly J.; Bonneau, Richard; Chen, Wei-Chiang; Chen-Tanyolac, Chira; Choi, Nathan C.; Curley, Steven A.; Dallas, Matthew; Damania, Dhwanil; Davies, Paul C. W.; Decuzzi, Paolo; Dickinson, Laura; Estevez-Salmeron, Luis; Estrella, Veronica; Ferrari, Mauro; Fischbach, Claudia; Foo, Jasmine; Fraley, Stephanie I.; Frantz, Christian; Fuhrmann, Alexander; Gascard, Philippe; Gatenby, Robert A.; Geng, Yue; Gerecht, Sharon; Gillies, Robert J.; Godin, Biana; Grady, William M.; Greenfield, Alex; Hemphill, Courtney; Hempstead, Barbara L.; Hielscher, Abigail; Hillis, W. Daniel; Holland, Eric C.; Ibrahim-Hashim, Arig; Jacks, Tyler; Johnson, Roger H.; Joo, Ahyoung; Katz, Jonathan E.; Kelbauskas, Laimonas; Kesselman, Carl; King, Michael R.; Konstantopoulos, Konstantinos; Kraning-Rush, Casey M.; Kuhn, Peter; Kung, Kevin; Kwee, Brian; Lakins, Johnathon N.; Lambert, Guillaume; Liao, David; Licht, Jonathan D.; Liphardt, Jan T.; Liu, Liyu; Lloyd, Mark C.; Lyubimova, Anna; Mallick, Parag; Marko, John; McCarty, Owen J. T.; Meldrum, Deirdre R.; Michor, Franziska; Mumenthaler, Shannon M.; Nandakumar, Vivek; O'Halloran, Thomas V.; Oh, Steve; Pasqualini, Renata; Paszek, Matthew J.; Philips, Kevin G.; Poultney, Christopher S.; Rana, Kuldeepsinh; Reinhart-King, Cynthia A.; Ros, Robert; Semenza, Gregg L.; Senechal, Patti; Shuler, Michael L.; Srinivasan, Srimeenakshi; Staunton, Jack R.; Stypula, Yolanda; Subramanian, Hariharan; Tlsty, Thea D.; Tormoen, Garth W.; Tseng, Yiider; van Oudenaarden, Alexander; Verbridge, Scott S.; Wan, Jenny C.; Weaver, Valerie M.; Widom, Jonathan; Will, Christine; Wirtz, Denis; Wojtkowiak, Jonathan; Wu, Pei-Hsun

2013-04-01

To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences-Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells' regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.

Oxidants and anti-oxidants status in acne vulgaris patients with varying severity.

PubMed

Al-Shobaili, Hani A

2014-01-01

Acne vulgaris is a common dermatological disorder with a multifactorial pathogenesis. Oxidative status has been implicated in the pathogenesis of several skin diseases, including acne. This study was aimed to investigate the levels of oxidative stress biomarkers in acne vulgaris patients with varying severities. The study involved 156 patients with acne and 46 healthy human controls. Based on clinical examination, patients were grouped into 3 subgroups as follows: mild, moderate, and severe acne. Oxidative stress was examined by measuring plasma levels of catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (TAC), and malondialdehyde (MDA). Plasma levels of MDA in acne patients were significantly higher as compared with that of the controls, whereas activities of the antioxidant enzymes SOD and CAT were lower. Moreover, TAC was also low in acne patients as compared with that of the controls. Higher MDA levels in the severe acne subgroup as compared with that of the mild and moderate subgroups were also observed. Furthermore, in the severe acne subgroup, a significant negative correlation was observed between MDA and CAT levels. The data suggests that oxidative stress plays a key role in acne progress and may be employed as a biomarker index to assess the disease's activity and to monitor its treatment.

MARSAME Radiological Release Report for Archaeological Artifacts Excavated from Area L

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ruedig, Elizabeth; Whicker, Jeffrey Jay; Gillis, Jessica Mcdonnel

In 1991 Los Alamos National Laboratory’s (LANL’s) cultural resources team excavated archaeological site LA 4618 located at Technical Area 54, within Material Disposal Area L (MDA L). MDA L received non-radioactive chemical waste from the early 1960s until 1985. Further development of the MDA required excavation of several cultural sites under National Historic Preservation Act requirements; artifacts from these sites have been subsequently stored at LANL. The LANL cultural resources group would now like to release these artifacts to the Museum of Indian Arts and Culture in Santa Fe for curation. The history of disposal at Area L suggests thatmore » the artifact pool is unlikely to be chemically contaminated and LANL staff washed each artifact at least once following excavation. Thus, it is unlikely that the artifacts present a chemical hazard. LANL’s Environmental Stewardship group (EPC-ES) has evaluated the radiological survey results for the Area L artifact pool and found that the items described in this report meet the criteria for unrestricted radiological release under Department of Energy (DOE) Order 458.1 Radiation Protection of the Public and the Environment and are candidates for release without restriction from LANL control. This conclusion is based on the known history of MDA L and on radiation survey data.« less

One Hundred Years After Its Discovery in Guatemala by Rodolfo Robles, Onchocerca volvulus Transmission Has Been Eliminated from the Central Endemic Zone

PubMed Central

Richards, Frank; Rizzo, Nidia; Espinoza, Carlos Enrique Diaz; Monroy, Zoraida Morales; Valdez, Carol Guillermina Crovella; de Cabrera, Renata Mendizabal; de Leon, Oscar; Zea-Flores, Guillermo; Sauerbrey, Mauricio; Morales, Alba Lucia; Rios, Dalila; Unnasch, Thomas R.; Hassan, Hassan K.; Klein, Robert; Eberhard, Mark; Cupp, Ed; Domínguez, Alfredo

2015-01-01

We report the elimination of Onchocerca volvulus transmission from the Central Endemic Zone (CEZ) of onchocerciasis in Guatemala, the largest focus of this disease in the Americas and the first to be discovered in this hemisphere by Rodolfo Robles Valverde in 1915. Mass drug administration (MDA) with ivermectin was launched in 1988, with semiannual MDA coverage reaching at least 85% of the eligible population in > 95% of treatment rounds during the 12-year period, 2000–2011. Serial parasitological testing to monitor MDA impact in sentinel villages showed a decrease in microfilaria skin prevalence from 70% to 0%, and polymerase chain reaction (PCR)-based entomological assessments of the principal vector Simulium ochraceum s.l. showed transmission interruption by 2007. These assessments, together with a 2010 serological survey in children 9–69 months of age that showed Ov16 IgG4 antibody prevalence to be < 0.1%, meeting World Health Organization (WHO) guidelines for stopping MDA, and treatment was halted after 2011. After 3 years an entomological assessment showed no evidence of vector infection or recrudescence of transmission. In 2015, 100 years after the discovery of its presence, the Ministry of Health of Guatemala declared onchocerciasis transmission as having been eliminated from the CEZ. PMID:26503275

Skylab

NASA Image and Video Library

1972-09-01

The Multiple Docking Adapter (MDA), designed and constructed under the direction of the Marshall Space Flight Center, was one of four principal sections comprising Skylab. The MDA provided the means by which the Command and Service Modules attached to the Skylab, enabling the crews to enter and work in it. Also included in the MDA was a control and display console for the Apollo Telescope Mount. This image shows an interior view of the MDA.

Degree of neutrophil, atrophy, and metaplasia intestinal were associate with malondialdehyde level in gastritis patients

NASA Astrophysics Data System (ADS)

Siregar, G. A.; Sari, D. K.; Sungkar, T.

2018-03-01

The main pathogenesis of gastritis is inflammation that closely related to free radicals. Malondialdehyde (MDA) is a free radical biomarker and is found to increase in gastritis patients. However, these studies are generally performed on experimental animals as well as MDA examination in gastric mucosa. This study aim was to determine the association of degrees of gastritis (degree of lymphocyte infiltration, neutrophil activity, atrophy, and intestinal metaplasia) with plasma MDA level. A cross-sectional study of 80 consecutive gastritis patients who came to an endoscopic unit of Adam Malik General Hospital in Medan, Indonesia, from May–September 2017. Assessed for severity of chronic inflammatory, neutrophil activity, atrophy, and intestinal metaplasia refers to Updated Sydney System. Plasma MDA levels were examined using an HPLC MDA kit. Univariate analysis, bivariate (chi-square and Fisher exact test), and multivariate (binary logistic regression test) were programmed with SPSS version 22. There was no significant association between degree of lymphocyte infiltration with MDA level. There were significant associations between degree of neutrophil activity, atrophy, and intestinal metaplasia with MDA level (p=0.039, 0.003, 0.021; respectively). The moderate+severe degree of neutrophil activity, atrophy, and intestinal metaplasia were associated with high level of MDA.

Dissociation of Paramyxovirus Interferon Evasion Activities: Universal and Virus-Specific Requirements for Conserved V Protein Amino Acids in MDA5 Interference ▿

PubMed Central

Ramachandran, Aparna; Horvath, Curt M.

2010-01-01

The V protein of the paramyxovirus subfamily Paramyxovirinae is an important virulence factor that can interfere with host innate immunity by inactivating the cytosolic pathogen recognition receptor MDA5. This interference is a result of a protein-protein interaction between the highly conserved carboxyl-terminal domain of the V protein and the helicase domain of MDA5. The V protein C-terminal domain (CTD) is an evolutionarily conserved 49- to 68-amino-acid region that coordinates two zinc atoms per protein chain. Site-directed mutagenesis of conserved residues in the V protein CTD has revealed both universal and virus-specific requirements for zinc coordination in MDA5 engagement and has also identified other conserved residues as critical for MDA5 interaction and interference. Mutation of these residues produces V proteins that are specifically defective for MDA5 interference and not impaired in targeting STAT1 for proteasomal degradation via the VDC ubiquitin ligase complex. Results demonstrate that mutation of conserved charged residues in the V proteins of Nipah virus, measles virus, and mumps virus also abolishes MDA5 interaction. These findings clearly define molecular determinants for MDA5 inhibition by the paramyxovirus V proteins. PMID:20719949

Lateral parapatellar and subvastus approaches are superior to the medial parapatellar approach in terms of soft tissue perfusion.

PubMed

Koçak, Aykut; Özmeriç, Ahmet; Koca, Gökhan; Senes, Mehmet; Yumuşak, Nihat; Iltar, Serkan; Korkmaz, Meliha; Alemdaroğlu, Kadir Bahadır

2017-08-23

The arthrotomy techniques of knee surgery may cause varying degrees of disruption to the tissue blood supply. The aim of this study was to investigate the effects of the medial parapatellar (MPPa), midvastus (MVa), subvastus (SVa) and lateral parapatellar (LPPa) approaches on regional tissue perfusion of the knee. In this experimental study, a total of 28 female rabbits were applied with four different arthrotomy techniques as Group MPPa, Group MVa, Group SVa and Group LPPa. The blood supply of the tissue around the knee was examined by scintigraphic imaging including the perfusion reserve and T max , and biochemical alteration of the oxidative stress parameters including malondialdehyde (MDA), fluorescent oxidation products (FlOPs), and histopathological findings were evaluated on tissue samples after 3 weeks. The perfusion reserve was increased in all four groups compared to the healthy, contralateral knees. In the Group LPPa, the vascularity was significantly increased compared to the Group MPPa (p = 0.006). In the examination of biochemical parameters, the increase in MDA levels was statistically significant in the Group MPPa compared with the Group LPPa (p = 0.004), and in the Group MVa compared with the Group LPPa (p = 0.006). The increase in the value of MDA levels was striking in the Group MPPa and Group MVa compared with the control group (p = 0.004, p = 0.004, respectively). The increase in another oxidative stress parameter, the tissue FlOPs levels, was statistically significant in the Group MPPa compared with the control group (p = 0.035). The LPPa and SVa caused less oxidative stress and less disruption of the muscle blood supply, in biochemical and scintigraphic parameters, compared to the MPPa and MVa. Therefore, in clinical practice, the SVa is preferable to the MPPa and MVa in total knee arthroplasty and the LPPa should be preferred more frequently in selected cases with critical soft tissue viability.

Peroxyoxalate chemiluminescence detection of condensates of malondialdehyde with thiobarbituric acids using a flow system.

PubMed

Nakashima, K; Nagata, M; Takahashi, M; Akiyama, S

1992-01-01

The peroxyoxalate chemiluminescence(CL) detection method for the evaluation of the CL intensity of malondialdehyde(MDA) condensates with seven 2-thiobarbituric acid derivatives is described. The method consists of a flow injection technique together with a CL detection system using bis(2,4,6-trichlorophenyl) oxalate(TCPO) and hydrogen peroxide as chemiluminogenic reagents. Linear correlations between CL intensity and concentration are obtained for pmol levels of condensates. Among the condensates, 1,3-diethyl-2-thiobarbituric acid(DETBA)-MDA shows the largest CL intensity. High performance liquid chromatography (HPLC)/CL detection of DETBA-MDA and 1,3-diphenyl-2-thiobarbituric acid(DPTBA)-MDA using a mixture of TCPO and hydrogen peroxide in acetonitrile as a postcolumn reagent solution is also described. The detection limits for DETBA-MDA and DPTBA-MDA are 20 and 200 fmol, respectively, per 20 microL injection at a signal-to-noise ratio of 2. This HPLC/CL detection system was applied to the determination of MDA in rat brains by using DETBA as a fluorescent derivatizing reagent.

Malondialdehyde Suppresses Cerebral Function by Breaking Homeostasis between Excitation and Inhibition in Turtle Trachemys scripta

PubMed Central

Li, Fangxu; Yang, Zhilai; Lu, Yang; Wei, Yan; Wang, Jinhui; Yin, Dazhong; He, Rongqiao

2010-01-01

The levels of malondialdehyde (MDA) are high in the brain during carbonyl stress, such as following daily activities and sleep deprivation. To examine our hypothesis that MDA is one of the major substances in the brain leading to fatigue, the influences of MDA on brain functions and neuronal encodings in red-eared turtle (Trachemys scripta) were studied. The intrathecal injections of MDA brought about sleep-like EEG and fatigue-like behaviors in a dose-dependent manner. These changes were found associated with the deterioration of encoding action potentials in cortical neurons. In addition, MDA increased the ratio of γ-aminobutyric acid to glutamate in turtle's brain, as well as the sensitivity of GABAergic neurons to inputs compared to excitatory neurons. Therefore, MDA, as a metabolic product in the brain, may weaken cerebral function during carbonyl stress through breaking the homeostasis between excitatory and inhibitory neurons. PMID:21203547

MD-11 PCA - Research flight team photo

NASA Technical Reports Server (NTRS)

1995-01-01

On Aug. 30, 1995, a the McDonnell Douglas MD-11 transport aircraft landed equipped with a computer-assisted engine control system that has the potential to increase flight safety. In landings at NASA Dryden Flight Research Center, Edwards, California, on August 29 and 30, the aircraft demonstrated software used in the aircraft's flight control computer that essentially landed the MD-11 without a need for the pilot to manipulate the flight controls significantly. In partnership with McDonnell Douglas Aerospace (MDA), with Pratt & Whitney and Honeywell helping to design the software, NASA developed this propulsion-controlled aircraft (PCA) system following a series of incidents in which hydraulic failures resulted in the loss of flight controls. This new system enables a pilot to operate and land the aircraft safely when its normal, hydraulically-activated control surfaces are disabled. This August 29, 1995, photo shows the MD-11 team. Back row, left to right: Tim Dingen, MDA pilot; John Miller, MD-11 Chief pilot (MDA); Wayne Anselmo, MD-11 Flight Test Engineer (MDA); Gordon Fullerton, PCA Project pilot; Bill Burcham, PCA Chief Engineer; Rudey Duran, PCA Controls Engineer (MDA); John Feather, PCA Controls Engineer (MDA); Daryl Townsend, Crew Chief; Henry Hernandez, aircraft mechanic; Bob Baron, PCA Project Manager; Don Hermann, aircraft mechanic; Jerry Cousins, aircraft mechanic; Eric Petersen, PCA Manager (Honeywell); Trindel Maine, PCA Data Engineer; Jeff Kahler, PCA Software Engineer (Honeywell); Steve Goldthorpe, PCA Controls Engineer (MDA). Front row, left to right: Teresa Hass, Senior Project Management Analyst; Hollie Allingham (Aguilera), Senior Project Management Analyst; Taher Zeglum, PCA Data Engineer (MDA); Drew Pappas, PCA Project Manager (MDA); John Burken, PCA Control Engineer.

mda-9/Syntenin protein positively regulates the activation of Akt protein by facilitating integrin-linked kinase adaptor function during adhesion to type I collagen.

PubMed

Hwangbo, Cheol; Park, Juhee; Lee, Jeong-Hyung

2011-09-23

The integrin-linked kinase (ILK)-PINCH1-α-parvin (IPP) complex functions as a signaling platform for integrins that modulates various cellular processes. ILK functions as a central adaptor for the assembly of IPP complex. We report here that mda-9/syntenin, a positive regulator of cancer metastasis, regulates the activation of Akt (also known as protein kinase B) by facilitating ILK adaptor function during adhesion to type I collagen (COL-I) in human breast cancer cells. COL-I stimulation induced the phosphorylation and plasma membrane translocation of Akt. Inhibition of mda-9/syntenin or expression of mutant ILK (E359K) significantly blocked the translocation of both ILK and Akt to the plasma membrane. mda-9/syntenin associated with ILK, and this association was increased at the plasma membrane by COL-I stimulation. Knockdown of mda-9/syntenin impaired COL-I-induced association of ILK with Akt and plasma membrane targeting of ILK-Akt complex. These results demonstrated that mda-9/syntenin regulates the activation of Akt by controlling the plasma membrane targeting of Akt via a mechanism that facilitates the association of Akt with ILK at the plasma membrane during adhesion to COL-I. On a striking note, inhibition of mda-9/syntenin impaired COL-I-induced plasma membrane translocation of the IPP complex and assembly of integrin β1-IPP signaling complexes. Thus, our study defines the role of mda-9/syntenin in ILK adaptor function and describes a new mechanism of mda-9/syntenin for regulation of cell migration.

Model-Driven Development for scientific computing. An upgrade of the RHEEDGr program

NASA Astrophysics Data System (ADS)

Daniluk, Andrzej

2009-11-01

Model-Driven Engineering (MDE) is the software engineering discipline, which considers models as the most important element for software development, and for the maintenance and evolution of software, through model transformation. Model-Driven Architecture (MDA) is the approach for software development under the Model-Driven Engineering framework. This paper surveys the core MDA technology that was used to upgrade of the RHEEDGR program to C++0x language standards. New version program summaryProgram title: RHEEDGR-09 Catalogue identifier: ADUY_v3_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADUY_v3_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 21 263 No. of bytes in distributed program, including test data, etc.: 1 266 982 Distribution format: tar.gz Programming language: Code Gear C++ Builder Computer: Intel Core Duo-based PC Operating system: Windows XP, Vista, 7 RAM: more than 1 MB Classification: 4.3, 7.2, 6.2, 8, 14 Does the new version supersede the previous version?: Yes Nature of problem: Reflection High-Energy Electron Diffraction (RHEED) is a very useful technique for studying growth and surface analysis of thin epitaxial structures prepared by the Molecular Beam Epitaxy (MBE). The RHEED technique can reveal, almost instantaneously, changes either in the coverage of the sample surface by adsorbates or in the surface structure of a thin film. Solution method: The calculations are based on the use of a dynamical diffraction theory in which the electrons are taken to be diffracted by a potential, which is periodic in the dimension perpendicular to the surface. Reasons for new version: Responding to the user feedback the graphical version of the RHEED program has been upgraded to C++0x language standards. Also, functionality and documentation of the program have been improved. Summary of revisions: Model-Driven Architecture (MDA) is the approach defined by the Object Management Group (OMG) for software development under the Model-Driven Engineering framework [1]. The MDA approach shifts the focus of software development from writing code to building models. By adapting a model-centric approach, the MDA approach hopes to automate the generation of system implementation artifacts directly from the model. The following three models are the core of the MDA: (i) the Computation Independent Model (CIM), which is focused on basic requirements of the system, (ii) the Platform Independent Model (PIM), which is used by software architects and designers, and is focused on the operational capabilities of a system outside the context of a specific platform, and (iii) the Platform Specific Model (PSM), which is used by software developers and programmers, and includes details relating to the system for a specific platform. Basic requirements for the calculation of the RHEED intensity rocking curves in the one-beam condition have been described in Ref. [2]. Fig. 1 shows the PIM for the present version of the program. Fig. 2 presents the PSM for the program. The TGraph2D.bpk package has been recompiled to Graph2D0x.bpl and upgraded according to C++0x language standards. Fig. 3 shows the PSM of the Graph2D component, which is manifested by the Graph2D0x.bpl package presently. This diagram is a graphic presentation of the static view, which shows a collection of declarative model elements and their relationships. Installation instructions of the Graph2D0x package can be found in the new distribution. The program requires the user to provide the appropriate parameters for the crystal structure under investigation. These parameters are loaded from the parameters.ini file at run-time. Instructions for the preparation of the .ini files can be found in the new distribution. The program enables carrying out one-dimensional dynamical calculations for the fcc lattice, with a two-atoms basis and fcc lattice, with one atom basis but yet the zeroth Fourier component of the scattering potential in the TRHEED1D::crystPotUg() function can be modified according to users' specific application requirements. A graphical user interface (GUI) for the program has been reconstructed. The program has been compiled with English/USA regional and language options. Unusual features: The program is distributed in the form of main projects RHEEDGr_09.cbproj and Graph2D0x.cbproj with associated files, and should be compiled using Code Gear C++ Builder 2009 compilers. Running time: The typical running time is machine and user-parameters dependent. References: OMG, Model Driven Architecture Guide Version 1.0.1, 2003, http://www.omg.org/cgi-bin/doc?omg/03-06-01. A. Daniluk, Comput. Phys. Comm. 166 (2005) 123.

Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells.

PubMed

Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Gendler, Sandra J; Mukherjee, Pinku

2005-01-01

Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G0/G1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and increased necrosis in the tumor mass. The disparate molecular mechanisms of celecoxib-induced growth inhibition in human breast cancer cells depends upon the level of COX-2 expression and the invasive potential of the cell lines examined. Data suggest a role for COX-2 not only in the growth of cancer cells but also in activating the angiogenic pathway through regulating levels of vascular endothelial growth factor.

The impact of a single round of community mass treatment with azithromycin on disease severity and ocular Chlamydia trachomatis load in treatment-naïve trachoma-endemic island communities in West Africa.

PubMed

Last, Anna R; Burr, Sarah E; Harding-Esch, Emma; Cassama, Eunice; Nabicassa, Meno; Roberts, Chrissy H; Mabey, David C W; Holland, Martin J; Bailey, Robin L

2017-12-28

Trachoma, a neglected tropical disease, is caused by ocular infection with Chlamydia trachomatis (Ct). The World Health Organization (WHO) recommends three annual rounds of community mass drug treatment with azithromycin (MDA) if the prevalence of follicular trachoma in 1-9 year olds (TF 1-9 ) exceeds 10% at district level to achieve an elimination target of district-level TF 1-9 below 5% after. To evaluate this strategy in treatment-naïve trachoma-endemic island communities in Guinea Bissau, we conducted a cross-sectional population-based trachoma survey on four islands. The upper tarsal conjunctivae of each participant were clinically assessed for trachoma and conjunctival swabs were obtained (n = 1507). We used a droplet digital PCR assay to detect Ct infection and estimate bacterial load. We visited the same households during a second cross-sectional survey and repeated the ocular examination and obtained conjunctival swabs from these households one year after MDA (n = 1029). Pre-MDA TF 1-9 was 22.0% (136/618). Overall Ct infection prevalence (CtI) was 18.6% (25.4% in 1-9 year olds). Post-MDA (estimated coverage 70%), TF 1-9 and CtI were significantly reduced (7.4% (29/394, P < 0.001) and 3.3% (34/1029, P < 0.001) (6.6% in 1-9 year olds, P < 0.001), respectively. Median ocular Ct load was reduced from 2038 to 384 copies/swab (P < 0.001). Following MDA cases of Ct infection were highly clustered (Moran's I 0.27, P < 0.001), with fewer clusters of Ct infection overall, fewer clusters of cases with high load infections and less severe disease. Despite a significant reduction in the number of clusters of Ct infection, mean Ct load, disease severity and presence of clusters of cases of high load Ct infection suggesting the beginning of trachoma control in isolated island communities, following a single round of MDA we demonstrate that transmission is still ongoing. These detailed data are useful in understanding the epidemiology of ocular Ct infection in the context of MDA and the tools employed may have utility in determining trachoma elimination and surveillance activities in similar settings.

Advanced Teleprocessing Systems

DTIC Science & Technology

1983-09-30

Defenae AdTanced Research Projects Agency DAHC1S.C0368 DARPA rw M n*~ MDA 903.77.C-0272 A ^^ ^ 2490 MDA «)W3-C-0064 COMPUTER NETWORK...i -.% W-V."’ * - \\ ATV.VVV" ir*7 ADVANCED TELEPROCESSING SYSTEMS Semi-Annual Technical Report September 30, 1983 Contract Number: MDA 903-82...83 through 30 SEPT 83 6 PERFORMING ORG. REPORT NUMBER 7. AUTHORC«; Leonard Kleinrock 8 CONTRACT OR GRANT NUMBERr«; MDA 903-82-C-0064 9

Measurement of free and bound malondialdehyde in plasma by high-performance liquid chromatography as the 2,4-dinitrophenylhydrazine derivative.

PubMed

Pilz, J; Meineke, I; Gleiter, C H

2000-06-09

We established a method for the detection of free and total (free and bound) malondialdehyde (MDA) in human plasma samples after derivatisation with 2,4-dinitrophenylhydrazine (DNPH). Free MDA was prepared by perchloric acid deproteinisation whereas an alkaline hydrolysation step for 30 min at 60 degrees C was introduced prior to protein precipitation for the determination of total MDA. Derivatisation was accomplished in 10 min at room temperature subsequently chromatographed by HPLC on a reversed-phase 3 microm C(18) column with UV detection (310 nm). The detection limit was 25 pmol/ml for free and 0.3 nmol/ml for total MDA. The recovery of MDA added to different human plasma samples was 93.6% (n=11; RSD 7.1%) for the hydrolysation procedure. In samples from 12 healthy volunteers who underwent a hypoxic treatment (13% O2 for 6 h) we estimated a baseline value of total MDA of 2.16 nmol/ml (SD 0.29) (ambient air) with a significant increase to 2.92 (nmol/ml, SD 0.57; P=0.01) after the end of this physiological oxidative stress challenge. Plasma values of free MDA in these samples were close to our detection limit. The presented technique can easily performed with an isocratic HPLC apparatus and provides highly specific results for MDA as do sophisticated GC-MS methods.

[Effect of gross saponins of Tribulus terrestris on cardiocytes impaired by adriamycin].

PubMed

Zhang, Shuang; Li, Hong; Xu, Hui; Yang, Shi-Jie

2010-01-01

This study is to observe the protection of gross saponins of Tribulus terrestris (GSTT) on cardiocytes impaired by adriamycin (ADR) and approach its mechanism of action. Cardiocytes of neonate rat were cultivated for 72 hours and divided into normal control group, model (ADR 2 mg x L(-1)) group, and GSTT (100, 30, and 10 mg x L(-1)) groups. MTT colorimetric method was deployed to detect cardiocyte survival rate, activities of CK, LDH, AST, SOD, MDA and NO were detected, and apoptosis was detected with flow cytometry. Effect of GSTT on caspase-3 was detected with Western blotting. Compared with control group, contents of CK, LDH, AST, MDA and NO were increased, and activity of SOD was reduced (P < 0.05, P < 0.01, P < 0.001) by ADR. Numbers of survival cells were increased (P < 0.05, P < 0.001), contents of CK, LDH, AST, MDA and NO were decreased, and activity of SOD was increased (P < 0.05, P < 0.01, P < 0.001) by GSTT (100 and 30 mg x L(-1)). Apoptosis of cardiocytes and concentration of caspase-3 can be reduced by GSTT (100 and 30 mg x L(-1)). GSTT can protect cardiocytes impaired by ADR, which are possible involved with its effect of resisting oxygen free radical.

Identification and structural characterization of a new pro-apoptotic cyclic octapeptide cyclosaplin from somatic seedlings of Santalum album L.

PubMed

Mishra, Abheepsa; Gauri, Samiran S; Mukhopadhyay, Sourav K; Chatterjee, Soumya; Das, Shibendu S; Mandal, Santi M; Dey, Satyahari

2014-04-01

Small cyclic peptides exhibiting potent biological activity have great potential for anticancer therapy. An antiproliferative cyclic octapeptide, cyclosaplin was purified from somatic seedlings of Santalum album L. (sandalwood) using gel filtration and RP-HPLC separation process. The molecular mass of purified peptide was found to be 858 Da and the sequence was determined by MALDI-ToF-PSD-MS as 'RLGDGCTR' (cyclic). The cytotoxic activity of the peptide was tested against human breast cancer (MDA-MB-231) cell line in a dose and time-dependent manner. The purified peptide exhibited significant antiproliferative activity with an IC50 2.06 μg/mL. In a mechanistic approach, apoptosis was observed in differential microscopic studies for peptide treated MDA-MB-231 cells, which was further confirmed by mitochondrial membrane potential, DNA fragmentation assay, cell cycle analysis and caspase 3 activities. The modeling and docking experiments revealed strong affinity (kcal/mol) of peptide toward EGFR and procaspase 3. The co-localization studies revealed that the peptide sensitizes MDA-MB-231 cells by possibly binding to EGFR and induces apoptosis. This unique cyclic octapeptide revealed to be a favorable candidate for development of anticancer agents. Copyright © 2014 Elsevier Inc. All rights reserved.

CpA/CpG methylation of CiMDA5 possesses tight association with the resistance against GCRV and negatively regulates mRNA expression in grass carp, Ctenopharyngodon idella.

PubMed

Shang, Xueying; Su, Jianguo; Wan, Quanyuan; Su, Juanjuan

2015-01-01

Melanoma differentiation-associated gene 5 (MDA5) plays a crucial role in recognizing intracellular viral infection, activating the interferon regulatory factor pathways as well as inducing antiviral response. While the antiviral regulatory mechanism of MDA5 remains unclear. In the present study, CiMDA5 (Ctenopharyngodon idella MDA5) against grass carp reovirus (GCRV) would be initially revealed from the perspective of DNA methylation, a pivotal epigenetic modification. Two CpG islands (CGIs) were predicted located in the first exon of CiMDA5, of which the first CpG island was 427 bp in length possessed 29 candidate CpG loci and 34 CpA loci, and the second one was 130 bp in length involving 7 CpG loci as well as 10 CpA loci. By bisulfite sequencing PCR (BSP), the methylation statuses were detected in spleen of 70 individuals divided into resistant/susceptible groups post challenge experiment, and the resistance-association analysis was performed with Chi-square test. Quantitative real-time RT-PCR (qRT-PCR) was carried out to explore the relationship between DNA methylation and gene expression in CiMDA5. Results indicated that the methylation levels of CpA/CpG sites at +200, +202, +204, +207 nt, which consisted of a putative densely methylated element (DME), were significantly higher in the susceptible group than those in the resistant group. Meanwhile, the average transcription of CiMDA5 was down-regulated in the susceptible individuals compared with the resistant individuals. Evidently, the DNA methylation may be the negative modulator of CiMDA5 antiviral expression. Collectively, the methylation levels of CiMDA5 demonstrated the tight association with the resistance against GCRV and the negative-regulated roles in mRNA expression. This study first discovered the resistance-associated gene modulated by DNA methylation in teleost, preliminary revealed the underlying regulatory mechanism of CiMDA5 transcription against GCRV as well as laid a theoretical foundation on molecular nosogenesis of hemorrhagic diseases in C. idella. Copyright © 2014 Elsevier Ltd. All rights reserved.

Direct plating technique for enumeration of Listeria monocytogenes in foods.

PubMed

Golden, D A; Beuchat, L R; Brackett, R E

1988-01-01

The advantages and disadvantages of various techniques for detecting and enumerating Listeria monocytogenes in foods are reviewed, and results from a study designed to compare 14 direct plating media for their suitability to recover uninjured cells of L. monocytogenes from 4 foods are summarized. McBride Listeria agar (MLA), gum base nalidixic acid tryptone soy agar (GBNTSA), modified Despierres agar (MDA), and modified MLA (MMLA) performed best for recovering all inoculum populations from milk and ice cream mix. For Brie cheese, MLA, MDA, MMLA, and Dominguez Rodriguez isolation agar were superior for recovering L. monocytogenes; GBNTSA, MDA, MMLA, and Donnelly's Listeria enrichment agar were best for recovering the organism from cabbage. Direct plating procedures without prior enrichment can be utilized successfully for recovering L. monocytogenes from foods such as pasteurized milk and ice cream mix, which contain low populations of background microflora. However, recovery of L. monocytogenes from foods such as raw cabbage and Brie cheese, which contain high populations of other microorganisms, was not satisfactory using direct plating procedures.

Evaluation of the antioxidant impact of ginger-based kombucha on the murine breast cancer model.

PubMed

Salafzoon, Samaneh; Mahmoodzadeh Hosseini, Hamideh; Halabian, Raheleh

2017-10-21

Background Abnormal metabolism is a common event in cancerous cells. For example, the increase of reactive oxygen species (ROS) production, particularly due to aerobic respiration during invasive stage, results in cancer progression. Herein, the impact of kombucha tea prepared from ginger on the alteration of antioxidant agents was assessed in the breast cancer animal model. Methods Two types of kombucha tea with or without ginger were administered to BALB/c mice before and after tumor challenge. Superoxide dismutase (SOD), catalase, glutathione (GSH) and malondialdehyde (MDA) were evaluated in tumor, liver and kidney. Results Administration of kombucha ginger tea significantly decreased catalase activity as well as GSH and MDA level in tumor homogenate (p<0.001). A significant decrease in SOD activity and increase in MDA quantity was determined in the kidney which had received kombucha ginger tea (p<0.01). Conclusions The consumption of kombucha prepared from ginger could exert minor antioxidant impacts by balancing multi antioxidant factors in different tissues in the breast cancer models.

Quantitative Silylation Speciations of Primary Phenylalkyl Amines, Including Amphetamine and 3,4-Methylenedioxyamphetamine Prior to Their Analysis by GC/MS.

PubMed

Molnár, Borbála; Fodor, Blanka; Boldizsár, Imre; Molnár-Perl, Ibolya

2015-10-20

A novel, quantitative trimethylsilylation approach derivatizing 11 primary phenylalkyl amines (PPAAs), including amphetamine (A) and 3,4-methylenedioxyamphetamine (MDA), was noted. Triggering the fully derivatized ditrimethylsilyl (diTMS) species with the N-methyl-N-(trimethylsilyl)-trifluoroacetamide (MSTFA) reagent, a new principle was recognized followed by GC/MS. In the course of method optimization, the complementary impact of solvents (acetonitrile, ACN; ethyl acetate, ETAC; pyridine, PYR) and catalysts (trimethylchlorosilane, TMCS; trimethyliodosilane, TMIS) was studied: the role of solvent and catalyst proved to be equally crucial. Optimum, proportional, huge responses were obtained with the MSTFA/PYR = 2/1-9/1 (v/v) reagent applying catalysts; A and MDA needed the TMIS, while the rest of PPAAs provided the diTMS products also with TMCS. Similar to derivatives generated with hexamethyldisilazane and perfluorocarboxylic acid (HMDS and PFCA) ( Molnár et al. Anal. Chem. 2015 , 87 , 848 - 852 ), the fully silylated PPAAs offer several advantages. Both of our methods save time and cost by allowing for direct injection of analytes into the column; this is in stark contrast with the requirement to evaporate acid anhydrides by nitrogen prior to their injection. Efficiences of the novel catalyzed trimethylsilylation (MSTFA) and our recently introduced (now, for A and MDA extended) acylation principle were contrasted. Catalyzed trimethylsilylation led to diTMS derivatives resulting in on average a 1.7 times larger response compared to the corresponding acylated species. Catalyzed trimethylsilylation of PPAAs, A, and MDA were characterized with retention, mass fragmentation, and analytical performance properties (R(2), LOQ values). The practical utility of ditrimethylsilyation was shown by analyzing A in urine and mescaline (MSC) in cactus samples.

Impact of induced levels of specific free radicals and malondialdehyde on chicken semen quality and fertility.

PubMed

Rui, Bruno R; Shibuya, Fábio Y; Kawaoku, Allison J T; Losano, João D A; Angrimani, Daniel S R; Dalmazzo, Andressa; Nichi, Marcilio; Pereira, Ricardo J G

2017-03-01

Over the past decades, scientists endeavored to comprehend oxidative stress in poultry spermatozoa and its relationship with fertilizing ability, lipid peroxidation (LPO), free-radical scavenging systems, and antioxidant therapy. Although considerable progress has been made, further improvement is needed in understanding how specific reactive oxygen species (ROS) and malondialdehyde (MDA, a toxic byproduct of LPO) disrupt organelles in avian spermatozoon. Hence, this study examined functional changes in chicken spermatozoa after incubation with different ROS, and their implications for the fertility. First, semen samples from 14 roosters were individually diluted and aliquoted into five equal parts: control, superoxide anion, hydrogen peroxide (H 2 O 2 ), hydroxyl radicals, and MDA. After incubation with these molecules, aliquots were analyzed for motility, plasma membrane and acrosome integrity, mitochondrial activity, and LPO and DNA damage. Hydrogen peroxide was more detrimental for sperm motility than hydroxyl radicals, whereas the superoxide anion and MDA exhibited no differences compared with controls. In turn, plasma membrane and acrosome integrity, mitochondrial activity, LPO and DNA integrity rates were only affected by hydroxyl radicals. Thereafter, semen aliquots were incubated under the same conditions and used for artificial insemination. In accordance to our in vitro observations, H 2 O 2 and hydroxyl radicals sharply reduced egg fertility, whereas superoxide anion and MDA only induced slight declines. Thus, chicken sperm function was severely impaired by H 2 O 2 and hydroxyl radicals, but their mechanisms of action seemingly comprise different pathways. Further analysis regarding susceptibility of spermatozoon organelles to specific radicals in other poultry will help us to understand the development of interspecific differences in scavenging systems and to outline more oriented antioxidant approaches. Copyright © 2016 Elsevier Inc. All rights reserved.

Combined enzyme/prodrug treatment by genetically engineered AT-MSC exerts synergy and inhibits growth of MDA-MB-231 induced lung metastases.

PubMed

Matuskova, Miroslava; Kozovska, Zuzana; Toro, Lenka; Durinikova, Erika; Tyciakova, Silvia; Cierna, Zuzana; Bohovic, Roman; Kucerova, Lucia

2015-04-09

Metastatic spread of tumor cells remains a serious problem in cancer treatment. Gene-directed enzyme/prodrug therapy mediated by tumor-homing genetically engineered mesenchymal stromal cells (MSC) represents a promising therapeutic modality for elimination of disseminated cells. Efficacy of gene-directed enzyme/prodrug therapy can be improved by combination of individual systems. We aimed to define the combination effect of two systems of gene therapy mediated by MSC, and evaluate the ability of systemically administered genetically engineered mesenchymal stromal cells to inhibit the growth of experimental metastases derived from human breast adenocarcinoma cells MDA-MB-231/EGFP. Human adipose tissue-derived mesenchymal stromal cells (AT-MSC) were retrovirally transduced with fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT) or with Herpes simplex virus thymidine kinase (HSVtk). Engineered MSC were cocultured with tumor cells in the presence of prodrugs 5-fluorocytosin (5-FC) and ganciclovir (GCV). Combination effect of these enzyme/prodrug approaches was calculated. SCID/bg mice bearing experimental lung metastases were treated with CD::UPRT-MSC, HSVtk-MSC or both in combination in the presence of respective prodrug(s). Treatment efficiency was evaluated by EGFP-positive cell detection by flow cytometry combined with real-time PCR quantification of human cells in mouse organs. Results were confirmed by histological and immunohistochemical examination. We demonstrated various extent of synergy depending on tested cell line and experimental setup. The strongest synergism was observed on breast cancer-derived cell line MDA-MB-231/EGFP. Systemic administration of CD::UPRT-MSC and HSVtk-MSC in combination with 5-FC and GCV inhibited growth of MDA-MB-231 induced lung metastases. Combined gene-directed enzyme/prodrug therapy mediated by MSC exerted synergic cytotoxic effect and resulted in high therapeutic efficacy in vivo.

Effect of toll-like receptor 3 agonists on the functionality and metastatic properties of breast cancer cell model.

PubMed

Alizadeh, Nastaran; Amiri, Mohammad Mehdi; Salek Moghadam, Alireza; Zarnani, Amir Hassan; Saadat, Farshid; Safavifar, Farnaz; Berahmeh, Azar; Khorramizadeh, Mohammad Reza

2013-05-15

There exists compelling evidence that Toll-like receptor 3 (TLR3) agonists can directly affect human cancer cells. The aim of this study was to investigate anti-cancer effects of TLR3 agonist in human breast cell line. We assessed potential effects of poly (A:U) on human breast cell line (MDA-MB-231) on a dose-response and time-course basis. Human breast cell line MDA-MB-231 was treated with different concentrations of poly (A:U) and lipopolysaccharide (LPS). Then, the following assays were performed on the treated cells: dose-response and time-course cytotoxicity using colorimetric method; matrix metalloproteinase-2 (MMP-2) activity using gelatin zymography method; apoptosis using annexin-v flowcytometry method; and relative expression of TLR3 and MMP-2 mRNA using reverse transcriptase polymerase chain reaction (RT-PCR) method. Following treatments, dose- response and time-course cytotoxicity using a colorimetric method, (MMP-2) activity (using gelatin zymography), apoptosis (using annexin-v flowcytometry method) assays and expression of TLR3 and MMP-2 genes (using PCR method) were performed. Cytotoxicity and flowcytometry analysis of poly (A:U) showed that poly (A:U) do not have any cytotoxic and apoptotic effects in different concentrations used. MMP-2 activity analysis showed significant decrease in higher concentrations (50 and 100 μg/ ml) between treated and untreated cells. Moreover, poly A:U treated cells demonstrated decreased expression of MMP-2 gene in higher concentrations. Collectively, our data indicated that human breast cancer cell line (MDA-MB-231) was highly responsive to poly (A:U). The antimetastatic effect of direct poly (A:U) and TLR3 interactions in MDA-MB-231 cells could provide new approaches in malignant tumor therapeutic strategy.

Mobile Technology for Empowering Health Workers in Underserved Communities: New Approaches to Facilitate the Elimination of Neglected Tropical Diseases.

PubMed

Stanton, Michelle; Molineux, Andrew; Mackenzie, Charles; Kelly-Hope, Louise

2016-01-01

As global mobile phone penetration increases, direct health information communication from hard-to-reach communities is becoming commonplace. Mobile health (mHealth) tools that enable disease control programs to benefit from this information, while simultaneously empowering community members to take control of their own health, are vital to the goal of universal health care. Our aim was to highlight the development of the Liverpool mHealth Suite (LMS), which has been designed to address this need and improve health services for neglected tropical diseases being targeted for global elimination, such as lymphatic filariasis. The LMS has two main communication approaches-short message service and mobile phone apps-to facilitate real-time mass drug administration (MDA) coverage, reporting patient numbers, managing stock levels of treatment supplies, and exchanging health information to improve the quality of care of those affected. The LMS includes the MeasureSMS-MDA tool to improve drug supplies and MDA coverage rates in real-time (currently being trialed in urban Tanzania); the MeasureSMS-Morbidity tool to map morbidity, including lymphedema and hydrocele cases (initially piloted in rural Malawi and Ghana, then extended to Ethiopia, and scaled up to large urban areas in Bangladesh and Tanzania); the LyMSS-lymphedema management supply system app to improve distribution of treatments (trialed for 6 months in Malawi with positive impacts on health workers and patients); and the HealthFront app to improve education and training (in development with field trials planned). The current success and scale-up of the LMS by many community health workers in rural and urban settings across Africa and Asia highlights the value of this simple and practical suite of tools that empowers local health care workers to contribute to local, national, and global elimination of disease.

The expression of VE-cadherin in breast cancer cells modulates cell dynamics as a function of tumor differentiation and promotes tumor-endothelial cell interactions.

PubMed

Rezaei, Maryam; Cao, Jiahui; Friedrich, Katrin; Kemper, Björn; Brendel, Oliver; Grosser, Marianne; Adrian, Manuela; Baretton, Gustavo; Breier, Georg; Schnittler, Hans-Joachim

2018-01-01

The cadherin switch has profound consequences on cancer invasion and metastasis. The endothelial-specific vascular endothelial cadherin (VE-cadherin) has been demonstrated in diverse cancer types including breast cancer and is supposed to modulate tumor progression and metastasis, but underlying mechanisms need to be better understood. First, we evaluated VE-cadherin expression by tissue microarray in 392 cases of breast cancer tumors and found a diverse expression and distribution of VE-cadherin. Experimental expression of fluorescence-tagged VE-cadherin (VE-EGFP) in undifferentiated, fibroblastoid and E-cadherin-negative MDA-231 (MDA-VE-EGFP) as well as in differentiated E-cadherin-positive MCF-7 human breast cancer cell lines (MCF-VE-EGFP), respectively, displayed differentiation-dependent functional differences. VE-EGFP expression reversed the fibroblastoid MDA-231 cells to an epithelial-like phenotype accompanied by increased β-catenin expression, actin and vimentin remodeling, increased cell spreading and barrier function and a reduced migration ability due to formation of VE-cadherin-mediated cell junctions. The effects were largely absent in both MDA-VE-EGFP and in control MCF-EGFP cell lines. However, MCF-7 cells displayed a VE-cadherin-independent planar cell polarity and directed cell migration that both developed in MDA-231 only after VE-EGFP expression. Furthermore, VE-cadherin expression had no effect on tumor cell proliferation in monocultures while co-culturing with endothelial cells enhanced tumor cell proliferation due to integration of the tumor cells into monolayer where they form VE-cadherin-mediated cell contacts with the endothelium. We propose an interactive VE-cadherin-based crosstalk that might activate proliferation-promoting signals. Together, our study shows a VE-cadherin-mediated cell dynamics and an endothelial-dependent proliferation in a differentiation-dependent manner.

Sprague-Dawley rats display sex-linked differences in the pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fonsart, Julien, E-mail: julien.fonsart@lrb.aphp.f; CNRS, UMR 7157, Paris F-75006; INSERM, U705, Paris F-75006

The use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has increased in recent years; it can lead to life-threatening hyperthermia and serotonin syndrome. Human and rodent males appear to be more sensitive to acute toxicity than are females. MDMA is metabolized to five main metabolites by the enzymes CYP1A2, CYP2D and COMT. Little is presently known about sex-dependent differences in the pharmacokinetics of MDMA and its metabolites. We therefore analyzed MDMA disposition in male and female rats by measuring the plasma and urine concentrations of MDMA and its metabolites using a validated LC-MS method. MDA AUC{sub last} and C{sub max} were 1.6- tomore » 1.7-fold higher in males than in females given MDMA (5 mg/kg sc), while HMMA C{sub max} and AUC{sub last} were 3.2- and 3.5-fold higher, respectively. MDMA renal clearance was 1.26-fold higher in males, and that of MDA was 2.2-fold higher. MDMA AUC{sub last} and t{sub 1/2} were 50% higher in females given MDMA (1 mg/kg iv). MDA C{sub max} and AUC{sub last} were 75-82% higher in males, with a 2.8-fold higher metabolic index. Finally, the AUC{sub last} of MDA was 0.73-fold lower in males given 1 mg/kg iv MDA. The volumes of distribution of MDMA and MDA at steady-state were similar in the two sexes. These data strongly suggest that differences in the N-demethylation of MDMA to MDA are major influences on the MDMA and MDA pharmacokinetics in male and female rats. Hence, males are exposed to significantly more toxic MDA, which could explain previously reported sexual dysmorphism in the acute effects and toxicity of MDMA in rats.« less

Widespread Increases in Malondialdehyde Immunoreactivity in Dopamine-Rich and Dopamine-Poor Regions of Rat Brain Following Multiple, High Doses of Methamphetamine

PubMed Central

Horner, Kristen A.; Gilbert, Yamiece E.; Cline, Susan D.

2011-01-01

Treatment with multiple high doses of methamphetamine (METH) can induce oxidative damage, including dopamine (DA)-mediated reactive oxygen species (ROS) formation, which may contribute to the neurotoxic damage of monoamine neurons and long-term depletion of DA in the caudate putamen (CPu) and substantia nigra pars compacta (SNpc). Malondialdehyde (MDA), a product of lipid peroxidation by ROS, is commonly used as a marker of oxidative damage and treatment with multiple high doses of METH increases MDA reactivity in the CPu of humans and experimental animals. Recent data indicate that MDA itself may contribute to the destruction of DA neurons, as MDA causes the accumulation of toxic intermediates of DA metabolism via its chemical modification of the enzymes necessary for the breakdown of DA. However, it has been shown that in human METH abusers there is also increased MDA reactivity in the frontal cortex, which receives relatively fewer DA afferents than the CPu. These data suggest that METH may induce neuronal damage regardless of the regional density of DA or origin of DA input. The goal of the current study was to examine the modification of proteins by MDA in the DA-rich nigrostriatal and mesoaccumbal systems, as well as the less DA-dense cortex and hippocampus following a neurotoxic regimen of METH treatment. Animals were treated with METH (10 mg/kg) every 2 h for 6 h, sacrificed 1 week later, and examined using immunocytochemistry for changes in MDA-adducted proteins. Multiple, high doses of METH significantly increased MDA immunoreactivity (MDA-ir) in the CPu, SNpc, cortex, and hippocampus. Multiple METH administration also increased MDA-ir in the ventral tegmental area and nucleus accumbens. Our data indicate that multiple METH treatment can induce persistent and widespread neuronal damage that may not necessarily be limited to the nigrostriatal DA system. PMID:21602916

Insight into Buffalo (Bubalus bubalis) RIG1 and MDA5 Receptors: A Comparative Study on dsRNA Recognition and In-Vitro Antiviral Response

PubMed Central

Singh, Manvender; Brahma, Biswajit; Maharana, Jitendra; Patra, Mahesh Chandra; Kumar, Sushil; Mishra, Purusottam; Saini, Megha; De, Bidhan Chandra; Mahanty, Sourav; Datta, Tirtha Kumar; De, Sachinandan

2014-01-01

RIG1 and MDA5 have emerged as important intracellular innate pattern recognition receptors that recognize viral RNA and mediate cellular signals controlling Type I interferon (IFN-I) response. Buffalo RIG1 and MDA5 genes were investigated to understand the mechanism of receptor induced antiviral response. Sequence analysis revealed that RIG1 and MDA5 maintain a domain arrangement that is common in mammals. Critical binding site residues of the receptors are evolutionary conserved among mammals. Molecular dynamics simulations suggested that RIG1 and MDA5 follow a similar, if not identical, dsRNA binding pattern that has been previously reported in human. Moreover, binding free energy calculation revealed that MDA5 had a greater affinity towards dsRNA compared to RIG1. Constitutive expressions of RLR genes were ubiquitous in different tissues without being specific to immune organs. Poly I:C stimulation induced elevated expressions of IFN-β and IFN-stimulated genes (ISGs) through interferon regulatory factors (IRFs) mediated pathway in buffalo foetal fibroblast cells. The present study provides crucial insights into the structure and function of RIG1 and MDA5 receptors in buffalo. PMID:24587036

Association between Pre-Transplant Serum Malondialdehyde Levels and Survival One Year after Liver Transplantation for Hepatocellular Carcinoma

PubMed Central

Lorente, Leonardo; Rodriguez, Sergio T.; Sanz, Pablo; Abreu-González, Pedro; Díaz, Dácil; Moreno, Antonia M.; Borja, Elisa; Martín, María M.; Jiménez, Alejandro; Barrera, Manuel A.

2016-01-01

Previous studies have found higher levels of serum malondialdehyde (MDA) in hepatocellular carcinoma (HCC) patients compared to healthy controls and higher MDA concentrations in tumoral tissue of HCC patients than in non-tumoral tissue. However, the association between pre-transplant serum levels of MDA and survival in HCC patients after liver transplantation (LT) has not been described, and the aim of the present study was to determine whether such an association exists. In this observational study we measured serum MDA levels in 127 patients before LT. We found higher pre-LT serum MDA levels in 15 non-surviving than in 112 surviving patients one year after LT (p = 0.02). Exact binary logistic regression analysis revealed that pre-LT serum levels of MDA over 3.37 nmol/mL were associated with mortality after one year of LT (Odds ratio = 5.38; 95% confidence interval (CI) = from 1.580 to infinite; p = 0.007) adjusting for age of the deceased donor. The main finding of our study was that there is an association between serum MDA levels before LT for HCC and 1-year survival after LT. PMID:27058525

Effect of Red Yeast Rice and Coconut, Rice Bran or Sunflower Oil Combination in Rats on Hypercholesterolemic Diet.

PubMed

Govindarajan, Sumitra; Vellingiri, Kishore

2016-04-01

Dietary supplements provide a novel population based health approach for treating hyperlipidemias. Red yeast rice is known to have lipid lowering effects. Combination of red yeast rice with various oils is taken by different population around the world. In this present work, we aimed to compare the effects of red yeast rice with different oil (coconut, rice bran and sunflower oil) supplementations on lipid levels and oxidative stress in rats fed on hypercholesterolemic diet. A Randomized controlled study was conducted on 28 male Sprague Dawley rats. It included 4 arms-Control arm (hypercholesterolemic diet), Test arm A (hypercholesterolemic diet +Red yeast rice + Rice bran oil), arm B (hypercholesterolemic diet +Red yeast rice + Coconut oil) and arm C (hypercholesterolemic diet +Red yeast rice + Sunflower oil). At the end of one month, serum cholesterol, triglycerides, MDA and paraoxonase was measured. The mean values of analytes between the different groups were compared using student 't-' test. The rats fed with red yeast rice and rice bran oil combination showed significantly lower levels of serum cholesterol, triglycerides and MDA when compared to the controls. The serum paraoxonase levels were significantly higher in this group when compared to the controls. The rats fed with red yeast rice and coconut oil combination showed significantly lower serum cholesterol and MDA levels when compared to the controls. The mean triglyceride and paraoxonase levels did not show any statistically significant difference from the controls. The rats on red yeast rice and sunflower oil combination did not show any statistically significant difference in the lipid levels and oxidative stress parameters. The food combination which had best outcome in preventing the development of hyperlipidemia and oxidative stress in rats fed with hypercholesterolemic diet was red yeast rice and rice bran oil. Combining red yeast rice with coconut oil and sunflower oil gave suboptimal benefits.

The lipid phenotype of breast cancer cells characterized by Raman microspectroscopy: towards a stratification of malignancy.

PubMed

Nieva, Claudia; Marro, Monica; Santana-Codina, Naiara; Rao, Satish; Petrov, Dmitri; Sierra, Angels

2012-01-01

Although molecular classification brings interesting insights into breast cancer taxonomy, its implementation in daily clinical care is questionable because of its expense and the information supplied in a single sample allocation is not sufficiently reliable. New approaches, based on a panel of small molecules derived from the global or targeted analysis of metabolic profiles of cells, have found a correlation between activation of de novo lipogenesis and poorer prognosis and shorter disease-free survival for many tumors. We hypothesized that the lipid content of breast cancer cells might be a useful indirect measure of a variety of functions coupled to breast cancer progression. Raman microspectroscopy was used to characterize metabolism of breast cancer cells with different degrees of malignancy. Raman spectra from MDA-MB-435, MDA-MB-468, MDA-MB-231, SKBR3, MCF7 and MCF10A cells were acquired with an InVia Raman microscope (Renishaw) with a backscattered configuration. We used Principal Component Analysis and Partial Least Squares Discriminant Analyses to assess the different profiling of the lipid composition of breast cancer cells. Characteristic bands related to lipid content were found at 3014, 2935, 2890 and 2845 cm(-1), and related to lipid and protein content at 2940 cm(-1). A classificatory model was generated which segregated metastatic cells and non-metastatic cells without basal-like phenotype with a sensitivity of 90% and a specificity of 82.1%. Moreover, expression of SREBP-1c and ABCA1 genes validated the assignation of the lipid phenotype of breast cancer cells. Indeed, changes in fatty acid unsaturation were related with the epithelial-to-mesenchymal transition phenotype. Raman microspectroscopy is a promising technique for characterizing and classifying the malignant phenotype of breast cancer cells on the basis of their lipid profiling. The algorithm for the discrimination of metastatic ability is a first step towards stratifying breast cancer cells using this rapid and reagent-free tool.

Melamine-based dendrimer amine-modified magnetic nanoparticles as an efficient Pb(II) adsorbent for wastewater treatment: Adsorption optimization by response surface methodology.

PubMed

Jiryaei Sharahi, Fatemeh; Shahbazi, Afsaneh

2017-12-01

Magnetic Fe 3 O 4 nanoparticles with an average diameter of 64 nm was synthesized solvothermically and subsequently modified with melamine-based dendrimer amine (MDA-Fe 3 O 4 ) via grafting method. The synthesized materials were characterized using DLS, SEM, XRD, FTIR, VSM, TGA and elemental analysis techniques. The MDA-Fe 3 O 4 was employed for the efficient removal of Pb(II) ions from an aqueous solution. The adsorption efficiency was investigated in relation to the independent variables of Pb(II) concentration (80-250 mg L -1 ), pH of the solution (3-7), adsorbent dosage (0.1-0.5 g L -1 ) and temperature (10-40 °C) via a central composite design (CCD) using response surface methodology (RSM). The significance of independent variables and their interactions was tested using ANOVA at a 95% confidence limit (α = 0.05). A second-order quadratic model was established to predict the adsorption efficiency. Under the optimum condition (initial Pb(II) concentration = 110 mg L -1 , MDA-Fe 3 O 4 dosage = 0.49 g L -1 , pH = 5 and temperature = 30 °C) a removal percentage of 85.6% was obtained. The isotherm data fitted well to the Freundlich model within the concentration range of the experimental study. A maximum adsorption capacity of 333.3 mg g -1 was predicted by the Langmuir model. The adsorption rate of Pb(II) ions onto MDA-Fe 3 O 4 was in good agreement with the pseudo-second-order model (R 2  = 0.999; k 2  = 4.7 × 10 -4  g mg -1 min -1 ). Thermodynamically, adsorption was spontaneous and endothermic. The MDA-Fe 3 O 4 was successfully regenerated using 0.3 M HCl with little loss of adsorption capacity (≈7%) for five successive adsorption cycles. Copyright © 2017 Elsevier Ltd. All rights reserved.

How much will it cost to eradicate lymphatic filariasis? An analysis of the financial and economic costs of intensified efforts against lymphatic filariasis.

PubMed

Kastner, Randee J; Sicuri, Elisa; Stone, Christopher M; Matwale, Gabriel; Onapa, Ambrose; Tediosi, Fabrizio

2017-09-01

Lymphatic filariasis (LF), a neglected tropical disease (NTD) preventable through mass drug administration (MDA), is one of six diseases deemed possibly eradicable. Previously we developed one LF elimination scenario, which assumes MDA scale-up to continue in all countries that have previously undertaken MDA. In contrast, our three previously developed eradication scenarios assume all LF endemic countries will undertake MDA at an average (eradication I), fast (eradication II), or instantaneous (eradication III) rate of scale-up. In this analysis we use a micro-costing model to project the financial and economic costs of each of these scenarios in order to provide evidence to decision makers about the investment required to eliminate and eradicate LF. Costing was undertaken from a health system perspective, with all results expressed in 2012 US dollars (USD). A discount rate of 3% was applied to calculate the net present value of future costs. Prospective NTD budgets from LF endemic countries were reviewed to preliminarily determine activities and resources necessary to undertake a program to eliminate LF at a country level. In consultation with LF program experts, activities and resources were further reviewed and a refined list of activities and necessary resources, along with their associated quantities and costs, were determined and grouped into the following activities: advocacy and communication, capacity strengthening, coordination and strengthening partnerships, data management, ongoing surveillance, monitoring and supervision, drug delivery, and administration. The costs of mapping and undertaking transmission assessment surveys and the value of donated drugs and volunteer time were also accounted for. Using previously developed scenarios and deterministic estimates of MDA duration, the financial and economic costs of interrupting LF transmission under varying rates of MDA scale-up were then modelled using a micro-costing approach. The elimination scenario, which includes countries that previously undertook MDA, is estimated to cost 929 million USD (95% Credible Interval: 884m-972m). Proceeding to eradication is anticipated to require a higher financial investment, estimated at 1.24 billion USD (1.17bn-1.30bn) in the eradication III scenario (immediate scale-up), with eradication II (intensified scale-up) projected at 1.27 billion USD (1.21bn-1.33bn), and eradication I (slow scale-up) estimated at 1.29 billion USD (1.23bn-1.34bn). The economic costs of the eradication III scenario are estimated at approximately 7.57 billion USD (7.12bn-7.94bn), while the elimination scenario is projected to have an economic cost of 5.21 billion USD (4.91bn-5.45bn). Countries in the AFRO region will require the greatest investment to reach elimination or eradication, but also stand to gain the most in cost savings. Across all scenarios, capacity strengthening and advocacy and communication represent the greatest financial costs, whereas mapping, post-MDA surveillance, and administration comprise the least. Though challenging to implement, our results indicate that financial and economic savings are greatest under the eradication III scenario. Thus, if eradication for LF is the objective, accelerated scale-up is projected to be the best investment.

Evaluating the sustainability, scalability, and replicability of an STH transmission interruption intervention: The DeWorm3 implementation science protocol.

PubMed

Means, Arianna Rubin; Ajjampur, Sitara S R; Bailey, Robin; Galactionova, Katya; Gwayi-Chore, Marie-Claire; Halliday, Katherine; Ibikounle, Moudachirou; Juvekar, Sanjay; Kalua, Khumbo; Kang, Gagandeep; Lele, Pallavi; Luty, Adrian J F; Pullan, Rachel; Sarkar, Rajiv; Schär, Fabian; Tediosi, Fabrizio; Weiner, Bryan J; Yard, Elodie; Walson, Judd

2018-01-01

Hybrid trials that include both clinical and implementation science outcomes are increasingly relevant for public health researchers that aim to rapidly translate study findings into evidence-based practice. The DeWorm3 Project is a series of hybrid trials testing the feasibility of interrupting the transmission of soil transmitted helminths (STH), while conducting implementation science research that contextualizes clinical research findings and provides guidance on opportunities to optimize delivery of STH interventions. The purpose of DeWorm3 implementation science studies is to ensure rapid and efficient translation of evidence into practice. DeWorm3 will use stakeholder mapping to identify individuals who influence or are influenced by school-based or community-wide mass drug administration (MDA) for STH and to evaluate network dynamics that may affect study outcomes and future policy development. Individual interviews and focus groups will generate the qualitative data needed to identify factors that shape, contextualize, and explain DeWorm3 trial outputs and outcomes. Structural readiness surveys will be used to evaluate the factors that drive health system readiness to implement novel interventions, such as community-wide MDA for STH, in order to target change management activities and identify opportunities for sustaining or scaling the intervention. Process mapping will be used to understand what aspects of the intervention are adaptable across heterogeneous implementation settings and to identify contextually-relevant modifiable bottlenecks that may be addressed to improve the intervention delivery process and to achieve intervention outputs. Lastly, intervention costs and incremental cost-effectiveness will be evaluated to compare the efficiency of community-wide MDA to standard-of-care targeted MDA both over the duration of the trial and over a longer elimination time horizon.

Oral fluid and plasma 3,4-methylenedioxymethamphetamine (MDMA) and metabolite correlation after controlled oral MDMA administration.

PubMed

Desrosiers, Nathalie A; Barnes, Allan J; Hartman, Rebecca L; Scheidweiler, Karl B; Kolbrich-Spargo, Erin A; Gorelick, David A; Goodwin, Robert S; Huestis, Marilyn A

2013-05-01

Oral fluid (OF) offers a noninvasive sample collection for drug testing. However, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in OF has not been adequately characterized in comparison to plasma. We administered oral low-dose (1.0 mg/kg) and high-dose (1.6 mg/kg) MDMA to 26 participants and collected simultaneous OF and plasma specimens for up to 143 h after dosing. We compared OF/plasma (OF/P) ratios, time of initial detection (t first), maximal concentrations (C max), time of peak concentrations (t max), time of last detection (t last), clearance, and 3,4-methylenedioxyamphetamine (MDA)-to-MDMA ratios over time. For OF MDMA and MDA, C max was higher, t last was later, and clearance was slower compared to plasma. For OF MDA only, t first was later compared to plasma. Median (range) OF/P ratios were 5.6 (0.1-52.3) for MDMA and 3.7 (0.7-24.3) for MDA. OF and plasma concentrations were weakly but significantly correlated (MDMA: R(2) = 0.438, MDA: R(2) = 0.197, p < 0.0001). Median OF/P ratios were significantly higher following high dose administration: MDMA low = 5.2 (0.1-40.4), high = 6.0 (0.4-52.3, p < 0.05); MDA low = 3.3 (0.7-17.1), high = 4.1 (0.9-24.3, p < 0.001). There was a large inter-subject variation in OF/P ratios. The MDA/MDMA ratios in plasma were higher than those in OF (p < 0.001), and the MDA/MDMA ratios significantly increased over time in OF and plasma. The MDMA and MDA concentrations were higher in OF than in plasma. OF and plasma concentrations were correlated, but large inter-subject variability precludes the estimation of plasma concentrations from OF.

Oral Fluid and Plasma 3,4-Methylenedioxymethamphetamine (MDMA) and Metabolite Correlation after Controlled Oral MDMA Administration

PubMed Central

Desrosiers, Nathalie A.; Barnes, Allan J.; Hartman, Rebecca L.; Scheidweiler, Karl B.; Kolbrich-Spargo, Erin A.; Gorelick, David A.; Goodwin, Robert S.; Huestis, Marilyn A.

2013-01-01

Oral fluid (OF) offers a non-invasive sample collection for drug testing. However, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in OF has not been adequately characterized in comparison to plasma. We administered oral low (1.0 mg/kg) and high (1.6 mg/kg) dose MDMA to 26 participants and collected simultaneous OF and plasma specimens for up to 143 h after dosing. We compared OF/plasma (OF/P) ratios, time of initial detection (tfirst), maximal concentrations (Cmax), time of peak concentrations (tmax), time of last detection (tlast), clearance, and 3,4-methylenedioxyamphetamine (MDA) to MDMA ratios over time. For OF MDMA and MDA, Cmax was higher, tlast was later, and clearance was slower compared to plasma. For OF MDA only, tfirst was later compared to plasma. Median (range) OF/P ratios were 5.6 (0.1-52.3) for MDMA and 3.7 (0.7-24.3) for MDA. OF and plasma concentrations were weakly but significantly correlated (MDMA R2= 0.438, MDA R2= 0.197, p<0.0001). Median OF/P ratios were significantly higher following high dose: MDMA low 5.2 (0.1-40.4) and high 6.0 (0.4-52.3) (p<0.05); MDA low 3.3 (0.7-17.1) and high 4.1 (0.9-24.3) (p<0.001). There was large inter-subject variation in OF/P ratios. MDA/MDMA ratios in plasma were higher than those in OF (p<0.001), and MDA/MDMA ratios significantly increased over time in OF and plasma. MDMA and MDA concentrations were higher in OF than in plasma. OF and plasma concentrations were correlated, but large inter-subject variability precludes estimation of plasma concentrations from OF. PMID:23471370

Low expression of Mda-7/IL-24 and high expression of C-myb in tumour tissues are predictors of poor prognosis for Burkitt lymphoma patients.

PubMed

Ma, Ming; Zhao, Riyang; Yang, Xingxiao; Zhao, Lianmei; Liu, Lihua; Zhang, Cong; Wang, Xuexiao; Shan, Baoen

2018-02-08

Burkitt lymphoma is one of the most common types of haematopoietic malignancy in children and adolescents. Mda-7/IL-24 had been identified as a differentiation inducer of Burkitt lymphoma cells. Previous studies have revealed that knockdown of C-myb can also lead to the terminal differentiation of Burkitt lymphoma cells. The aim of the present study was to investigate the correlation between the expression of Mda-7/IL-24 and C-myb, as well as their prognostic significance, for Burkitt lymphoma patients. The tumour tissues were collected from 59 cases of Burkitt lymphoma patients and detected with Western blotting and immunohistochemistry. The results showed that the expression of Mda-7/IL-24 was lower, whereas the expression of C-myb was higher in Burkitt lymphoma tissues compared to specimens of normal lymph node tissues. Furthermore, C-myb expression was negatively correlated with Mda-7/IL-24 expression at the protein level in Burkitt lymphoma tissues and cell lines. Both the expression of Mda-7/IL-24 and C-myb in Burkitt lymphoma tissues was associated with some clinicopathological parameters, such as clinical stage, infiltration in the bone marrow, Ki67 and overall survival rates. These results indicated that low expression of Mda-7/IL-24 along with high expression of C-myb are predictors for poor prognosis of Burkitt lymphoma patients; this outcome suggests that Mda-7/IL-24 and C-myb might be potential targets for clinical treatment of Burkitt lymphoma. Mda-7/IL-24: melanoma differentiation associated gene7/interleukin 24; FCM: flow cytometry; Ecog: Eastern Cooperative Oncology Group; IPI: International lymphoma prognosis index.

Cancer terminator viruses (CTV): A better solution for viral-based therapy of cancer.

PubMed

Emdad, Luni; Das, Swadesh K; Wang, Xiang-Yang; Sarkar, Devanand; Fisher, Paul B

2018-08-01

In principle, viral gene therapy holds significant potential for the therapy of solid cancers. However, this promise has not been fully realized and systemic administration of viruses has not proven as successful as envisioned in the clinical arena. Our research is focused on developing the next generation of efficacious viruses to specifically treat both primary cancers and a major cause of cancer lethality, metastatic tumors (that have spread from a primary site of origin to other areas in the body and are responsible for an estimated 90% of cancer deaths). We have generated a chimeric tropism-modified type 5 and 3 adenovirus that selectively replicates in cancer cells and simultaneously produces a secreted anti-cancer toxic cytokine, melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24), referred to as a Cancer Terminator Virus (CTV) (Ad.5/3-CTV). In preclinical animal models, injection into a primary tumor causes selective cell death and therapeutic activity is also observed in non-injected distant tumors, that is, "bystander anti-tumor activity." To enhance the impact and therapeutic utility of the CTV, we have pioneered an elegant approach in which viruses are encapsulated in microbubbles allowing "stealth delivery" to tumor cells that when treated with focused ultrasound causes viral release killing tumor cells through viral replication, and producing and secreting MDA-7/IL-24, which stimulates the immune system to attack distant cancers, inhibits tumor angiogenesis and directly promotes apoptosis in distant cancer cells. This strategy is called UTMD (ultrasound-targeted microbubble-destruction). This novel CTV and UTMD approach hold significant promise for the effective therapy of primary and disseminated tumors. © 2017 Wiley Periodicals, Inc.

PSMB5 plays a dual role in cancer development and immunosuppression

PubMed Central

Wang, Chih-Yang; Li, Chung-Yen; Hsu, Hui-Ping; Cho, Chien-Yu; Yen, Meng-Chi; Weng, Tzu-Yang; Chen, Wei-Ching; Hung, Yu-Hsuan; Lee, Kuo-Ting; Hung, Jui-Hsiang; Chen, Yi-Ling; Lai, Ming-Derg

2017-01-01

Tumor progression and metastasis are dependent on the intrinsic properties of tumor cells and the influence of microenvironment including the immune system. It would be important to identify target drug that can inhibit cancer cell and activate immune cells. Proteasome β subunits (PSMB) family, one component of the ubiquitin-proteasome system, has been demonstrated to play an important role in tumor cells and immune cells. Therefore, we used a bioinformatics approach to examine the potential role of PSMB family. Analysis of breast TCGA and METABRIC database revealed that high expression of PSMB5 was observed in breast cancer tissue and that high expression of PSMB5 predicted worse survival. In addition, high expression of PSMB5 was observed in M2 macrophages. Based on our bioinformatics analysis, we hypothesized that PSMB5 contained immunosuppressive and oncogenic characteristics. To study the effects of PSMB5 on the cancer cell and macrophage in vitro, we silenced PSMB5 expression with shRNA in THP-1 monocytes and MDA-MB-231 cells respectively. Knockdown of PSMB5 promoted human THP-1 monocyte differentiation into M1 macrophage. On the other hand, knockdown PSMB5 gene expression inhibited MDA-MB-231 cell growth and migration by colony formation assay and boyden chamber. Collectively, our data demonstrated that delivery of PSMB5 shRNA suppressed cell growth and activated defensive M1 macrophages in vitro. Furthermore, lentiviral delivery of PSMB5 shRNA significantly decreased tumor growth in a subcutaneous mouse model. In conclusion, our bioinformatics study and functional experiments revealed that PSMB5 served as novel cancer therapeutic targets. These results also demonstrated a novel translational approach to improve cancer immunotherapy. PMID:29218236

One Bacterial Cell, One Complete Genome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woyke, Tanja; Tighe, Damon; Mavrommatis, Konstantinos

2010-04-26

While the bulk of the finished microbial genomes sequenced to date are derived from cultured bacterial and archaeal representatives, the vast majority of microorganisms elude current culturing attempts, severely limiting the ability to recover complete or even partial genomes from these environmental species. Single cell genomics is a novel culture-independent approach, which enables access to the genetic material of an individual cell. No single cell genome has to our knowledge been closed and finished to date. Here we report the completed genome from an uncultured single cell of Candidatus Sulcia muelleri DMIN. Digital PCR on single symbiont cells isolated frommore » the bacteriome of the green sharpshooter Draeculacephala minerva bacteriome allowed us to assess that this bacteria is polyploid with genome copies ranging from approximately 200?900 per cell, making it a most suitable target for single cell finishing efforts. For single cell shotgun sequencing, an individual Sulcia cell was isolated and whole genome amplified by multiple displacement amplification (MDA). Sanger-based finishing methods allowed us to close the genome. To verify the correctness of our single cell genome and exclude MDA-derived artifacts, we independently shotgun sequenced and assembled the Sulcia genome from pooled bacteriomes using a metagenomic approach, yielding a nearly identical genome. Four variations we detected appear to be genuine biological differences between the two samples. Comparison of the single cell genome with bacteriome metagenomic sequence data detected two single nucleotide polymorphisms (SNPs), indicating extremely low genetic diversity within a Sulcia population. This study demonstrates the power of single cell genomics to generate a complete, high quality, non-composite reference genome within an environmental sample, which can be used for population genetic analyzes.« less

Amino Acid Requirements for MDA5 and LGP2 Recognition by Paramyxovirus V Proteins: a Single Arginine Distinguishes MDA5 from RIG-I

PubMed Central

Rodriguez, Kenny R.

2013-01-01

Paramyxovirus V proteins bind to MDA5 (melanoma differentiation-associated gene 5) and LGP2 (laboratory of genetics and physiology gene 2) but not RIG-I (retinoic acid-inducible gene I). The results demonstrate MDA5 R806 is essential for inhibition by diverse V proteins. Complementary substitution for the analogous RIG-I L714 confers V protein recognition. The analogous LGP2 R455 is required for recognition by measles V protein, but not other V proteins. These findings indicate that paramyxoviruses use a single amino acid to distinguish MDA5 from RIG-I and have evolved distinct contact sites for LGP2 interference. PMID:23269789

Simultaneous Inhibition of EGFR and PI3K Enhances Radiosensitivity in Human Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Ping; Zhang Qing; Torossian, Artour

2012-07-01

Purpose: Mutations in the epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/Akt signaling transduction pathway are common in cancer. This pathway is imperative to the radiosensitivity of cancer cells. We aimed to investigate the radiosensitizing effects of the simultaneous inhibition of EGFR and PI3K in breast cancer cells. Methods and Materials: MCF-7 cell lines with low expression of EGFR and wild-type PTEN and MDA-MB-468 cell lines with high expression of EGFR and mutant PTEN were used. The radiosensitizing effects by the inhibition of EGFR with AG1478 and/or PI3K with Ly294002 were determined by colony formation assay, Western blot was used tomore » investigate the effects on downstream signaling. Flow cytometry was used for apoptosis and cell cycle analysis. Mice-bearing xenografts of MDA-MB-468 breast cancer cells were also used to observe the radiosensitizing effect. Results: Simultaneous inhibition of EGFR and PI3K greatly enhanced radiosensitizing effect in MDA-MB-468 in terms of apoptosis and mitotic death, either inhibition of EGFR or PI3K alone could enhance radiosensitivity with a dose-modifying factor (DMF{sub SF2}) of 1.311 and 1.437, radiosensitizing effect was further enhanced by simultaneous inhibition of EGFR and PI3K with a DMF{sub SF2} at 2.698. DNA flow cytometric analysis indicated that dual inhibition combined with irradiation significantly induced G0/G1 phase arrest in MDA-MB-468 cells. The expression of phosphor-Akt and phosphor-Erk1/2 (induced by irradiation and PI3K inhibitor) were fully attenuated by simultaneous treatment with both inhibitors in combination with irradiation. In addition, dual inhibition combined with irradiation induced dramatic tumor growth delay in MDA-MB-468 xenografts. Conclusions: Our study indicated that simultaneous inhibition of EGFR and PI3K could further sensitize the cancer cells to irradiation compared to the single inhibitor with irradiation in vitro and in vivo. The approach may have important therapeutic implication in the treatment of a subset of breast cancer patients with high expression of EGFR and deficient function of PTEN.« less

High-throughput autofluorescence flow cytometry of breast cancer metabolism (Conference Presentation)

NASA Astrophysics Data System (ADS)

Shah, Amy T.; Cannon, Taylor M.; Higginbotham, Jim N.; Skala, Melissa C.

2016-02-01

Tumor heterogeneity poses challenges for devising optimal treatment regimens for cancer patients. In particular, subpopulations of cells can escape treatment and cause relapse. There is a need for methods to characterize tumor heterogeneity of treatment response. Cell metabolism is altered in cancer (Warburg effect), and cells use the autofluorescent cofactor NADH in numerous metabolic reactions. Previous studies have shown that microscopy measurements of NADH autofluorescence are sensitive to treatment response in breast cancer, and these techniques typically assess hundreds of cells per group. An alternative approach is flow cytometry, which measures fluorescence on a single-cell level and is attractive for characterizing tumor heterogeneity because it achieves high-throughput analysis and cell sorting in millions of cells per group. Current applications for flow cytometry rely on staining with fluorophores. This study characterizes flow cytometry measurements of NADH autofluorescence in breast cancer cells. Preliminary results indicate flow cytometry of NADH is sensitive to cyanide perturbation, which inhibits oxidative phosphorylation, in nonmalignant MCF10A cells. Additionally, flow cytometry is sensitive to higher NADH intensity for HER2-positive SKBr3 cells compared with triple-negative MDA-MB-231 cells. These results agree with previous microscopy studies. Finally, a mixture of SKBr3 and MDA-MB-231 cells were sorted into each cell type using NADH intensity. Sorted cells were cultured, and microscopy validation showed the expected morphology for each cell type. Ultimately, flow cytometry could be applied to characterize tumor heterogeneity based on treatment response and sort cell subpopulations based on metabolic profile. These achievements could enable individualized treatment strategies and improved patient outcomes.

Critical parameters of hard-core Yukawa fluids within the structural theory

NASA Astrophysics Data System (ADS)

Bahaa Khedr, M.; Osman, S. M.

2012-10-01

A purely statistical mechanical approach is proposed to account for the liquid-vapor critical point based on the mean density approximation (MDA) of the direct correlation function. The application to hard-core Yukawa (HCY) fluids facilitates the use of the series mean spherical approximation (SMSA). The location of the critical parameters for HCY fluid with variable intermolecular range is accurately calculated. Good agreement is observed with computer simulation results and with the inverse temperature expansion (ITE) predictions. The influence of the potential range on the critical parameters is demonstrated and the universality of the critical compressibility ratio is discussed. The behavior of the isochoric and isobaric heat capacities along the equilibrium line and the near vicinity of the critical point is discussed in details.

Lipid peroxidation is increased in tears from the elderly.

PubMed

Benlloch-Navarro, Soledad; Franco, Ilenia; Sánchez-Vallejo, Violeta; Silvestre, Dolores; Romero, Francisco Javier; Miranda, María

2013-10-01

We describe a procedure in which tears, obtained from Schirmer strips, are used to measure a marker of lipid peroxidation, malondialdehyde (MDA). We also compared the levels of proteins and MDA in tears from two groups of people: young adults (18-30 years old) and elderly adults (65-85 years old), because the data related to total protein concentration of human tears vary widely and because the majority of people over the age of 65 experience some symptoms of dry eyes and this condition has been recognized as an oxidative stress-induced disease. Our results show a significant difference in the protein concentration of the tears taken from the two age categories, younger adults (18-30 years old) and older adults (65-85 years old). Herein, we report for the first time an increase in MDA concentrations determined by HPLC in human tears based on age. It is possible that alterations in the tear lipid layer may lead to an increase in lipid peroxidation. Further studies are needed to understand the nature and function of tear film and stability in order to obtain new methods to analyze tears in patients with different diseases. In this sense, it would be interesting to compare MDA concentration in tears from control subjects and from people with meibomian gland dysfunction. Copyright © 2013 Elsevier Ltd. All rights reserved.

One Hundred Years After Its Discovery in Guatemala by Rodolfo Robles, Onchocerca volvulus Transmission Has Been Eliminated from the Central Endemic Zone.

PubMed

Richards, Frank; Rizzo, Nidia; Diaz Espinoza, Carlos Enrique; Monroy, Zoraida Morales; Crovella Valdez, Carol Guillermina; de Cabrera, Renata Mendizabal; de Leon, Oscar; Zea-Flores, Guillermo; Sauerbrey, Mauricio; Morales, Alba Lucia; Rios, Dalila; Unnasch, Thomas R; Hassan, Hassan K; Klein, Robert; Eberhard, Mark; Cupp, Ed; Domínguez, Alfredo

2015-12-01

We report the elimination of Onchocerca volvulus transmission from the Central Endemic Zone (CEZ) of onchocerciasis in Guatemala, the largest focus of this disease in the Americas and the first to be discovered in this hemisphere by Rodolfo Robles Valverde in 1915. Mass drug administration (MDA) with ivermectin was launched in 1988, with semiannual MDA coverage reaching at least 85% of the eligible population in > 95% of treatment rounds during the 12-year period, 2000-2011. Serial parasitological testing to monitor MDA impact in sentinel villages showed a decrease in microfilaria skin prevalence from 70% to 0%, and polymerase chain reaction (PCR)-based entomological assessments of the principal vector Simulium ochraceum s.l. showed transmission interruption by 2007. These assessments, together with a 2010 serological survey in children 9-69 months of age that showed Ov16 IgG4 antibody prevalence to be < 0.1%, meeting World Health Organization (WHO) guidelines for stopping MDA, and treatment was halted after 2011. After 3 years an entomological assessment showed no evidence of vector infection or recrudescence of transmission. In 2015, 100 years after the discovery of its presence, the Ministry of Health of Guatemala declared onchocerciasis transmission as having been eliminated from the CEZ. © The American Society of Tropical Medicine and Hygiene.

Recombinant FIP-gat, a Fungal Immunomodulatory Protein from Ganoderma atrum, Induces Growth Inhibition and Cell Death in Breast Cancer Cells.

PubMed

Xu, Hui; Kong, Ying-Yu; Chen, Xin; Guo, Meng-Yuan; Bai, Xiao-Hui; Lu, Yu-Jia; Li, Wei; Zhou, Xuan-Wei

2016-04-06

FIP-gat, an immunomodulatory protein isolated from Ganoderma atrum, is a new member of the FIP family. Little is known, however, about its expressional properties and antitumor activities. It was availably expressed in Escherichia coli with a total yield of 29.75 mg/L. The migration of recombinant FIP-gat (rFIP-gat) on SDS-PAGE corresponded to the predicted molecular mass, and the band was correctly detected by a specific antibody. To characterize the direct effects of rFIP-gat on MDA-MB-231 breast cancer cells, MDA-MB-231 cells were treated with different concentrations of rFIP-gat in vitro; the results showed that this protein could reduce cell viability dose-dependently with a median inhibitory concentration (IC50) of 9.96 μg/mL and agglutinate the MDA-MB-231 cells at a concentration as low as 5 μg/mL. Furthermore, FIP-gat at a concentration of 10 μg/mL can induce significant growth inhibition and cell death in MDA-MB-231 cells. Notably, FIP-gat treatment triggers significant cell cycle arrest at the G1/S transition and pronounced increase in apoptotic cell population. Molecular assays based on microarray and real-time PCR further revealed the potential mechanisms encompassing growth arrest, apoptosis, and autophagy underlying the phenotypic effects.

Whole genome amplification and real-time PCR in forensic casework

PubMed Central

Giardina, Emiliano; Pietrangeli, Ilenia; Martone, Claudia; Zampatti, Stefania; Marsala, Patrizio; Gabriele, Luciano; Ricci, Omero; Solla, Gianluca; Asili, Paola; Arcudi, Giovanni; Spinella, Aldo; Novelli, Giuseppe

2009-01-01

Background WGA (Whole Genome Amplification) in forensic genetics can eliminate the technical limitations arising from low amounts of genomic DNA (gDNA). However, it has not been used to date because any amplification bias generated may complicate the interpretation of results. Our aim in this paper was to assess the applicability of MDA to forensic SNP genotyping by performing a comparative analysis of genomic and amplified DNA samples. A 26-SNPs TaqMan panel specifically designed for low copy number (LCN) and/or severely degraded genomic DNA was typed on 100 genomic as well as amplified DNA samples. Results Aliquots containing 1, 0.1 and 0.01 ng each of 100 DNA samples were typed for a 26-SNPs panel. Similar aliquots of the same DNA samples underwent multiple displacement amplification (MDA) before being typed for the same panel. Genomic DNA samples showed 0% PCR failure rate for all three dilutions, whilst the PCR failure rate of the amplified DNA samples was 0% for the 1 ng and 0.1 ng dilutions and 0.077% for the 0.01 ng dilution. The genotyping results of both the amplified and genomic DNA samples were also compared with reference genotypes of the same samples obtained by direct sequencing. The genomic DNA samples showed genotype concordance rates of 100% for all three dilutions while the concordance rates of the amplified DNA samples were 100% for the 1 ng and 0.1 ng dilutions and 99.923% for the 0.01 ng dilution. Moreover, ten artificially-degraded DNA samples, which gave no results when analyzed by current forensic methods, were also amplified by MDA and genotyped with 100% concordance. Conclusion We investigated the suitability of MDA material for forensic SNP typing. Comparative analysis of amplified and genomic DNA samples showed that a large number of SNPs could be accurately typed starting from just 0.01 ng of template. We found that the MDA genotyping call and accuracy rates were only slightly lower than those for genomic DNA. Indeed, when 10 pg of input DNA was used in MDA, we obtained 99.923% concordance, indicating a genotyping error rate of 1/1299 (7.7 × 10-4). This is quite similar to the genotyping error rate of STRs used in current forensic analysis. Such efficiency and accuracy of SNP typing of amplified DNA suggest that MDA can also generate large amounts of genome-equivalent DNA from a minimal amount of input DNA. These results show for the first time that MDA material is suitable for SNP-based forensic protocols and in general when samples fail to give interpretable STR results. PMID:19366436

Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells

PubMed Central

Basu, Gargi D; Pathangey, Latha B; Tinder, Teresa L; Gendler, Sandra J; Mukherjee, Pinku

2005-01-01

Introduction Inhibitors of cyclo-oxygenase (COX)-2 are being extensively studied as anticancer agents. In the present study we evaluated the mechanisms by which a highly selective COX-2 inhibitor, celecoxib, affects tumor growth of two differentially invasive human breast cancer cell lines. Methods MDA-MB-231 (highly invasive) and MDA-MB-468 (moderately invasive) cell lines were treated with varying concentrations of celecoxib in vitro, and the effects of this agent on cell growth and angiogenesis were monitored by evaluating cell proliferation, apoptosis, cell cycle arrest, and vasculogenic mimicry. The in vitro results of MDA-MB-231 cell line were further confirmed in vivo in a mouse xenograft model. Results The highly invasive MDA-MB-231 cells express higher levels of COX-2 than do the less invasive MDA-MB-468 cells. Celecoxib treatment inhibited COX-2 activity, indicated by prostaglandin E2 secretion, and caused significant growth arrest in both breast cancer cell lines. In the highly invasive MDA-MB-231 cells, the mechanism of celecoxib-induced growth arrest was by induction of apoptosis, associated with reduced activation of protein kinase B/Akt, and subsequent activation of caspases 3 and 7. In the less invasive MDA-MB-468 cells, growth arrest was a consequence of cell cycle arrest at the G0/G1 checkpoint. Celecoxib-induced growth inhibition was reversed by addition of exogenous prostaglandin E2 in MDA-MB-468 cells but not in MDA-MB-231 cells. Furthermore, MDA-MB-468 cells formed significantly fewer extracellular matrix associated microvascular channels in vitro than did the high COX-2 expressing MDA-MB-231 cells. Celecoxib treatment not only inhibited cell growth and vascular channel formation but also reduced vascular endothelial growth factor levels. The in vitro findings corroborated in vivo data from a mouse xenograft model in which daily administration of celecoxib significantly reduced tumor growth of MDA-MB-231 cells, which was associated with reduced vascularization and increased necrosis in the tumor mass. Conclusion The disparate molecular mechanisms of celecoxib-induced growth inhibition in human breast cancer cells depends upon the level of COX-2 expression and the invasive potential of the cell lines examined. Data suggest a role for COX-2 not only in the growth of cancer cells but also in activating the angiogenic pathway through regulating levels of vascular endothelial growth factor. PMID:15987447

75 FR 60090 - Membership of the Performance Review Board

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-29

...: Missile Defense Agency (MDA), DoD. ACTION: Notice. SUMMARY: This notice announces the appointment of the members of the Performance Review Board (PRB) of the Missile Defense Agency (MDA). The publication of PRB... CONTACT: Jovey Martir, MDA SES Program Management, Missile Defense Agency, Arlington, Virginia, (703) 693...

Relevance of plasma malondialdehyde level and severity of portal hypertension in cirrhotic patients.

PubMed

Wang, Sheng-Lan; Zhu, Xin-Yan; Zhang, Dong-Wei; Zhang, Zhao-Jie; Gao, Heng-Jun; Yang, Chang-Qing

2015-01-01

Portal hypertension is one of the death reasons for the liver cirrhosis patients. The oxidative stress is related to the occurrence and development of portal hypertension in cirrhosis. Malondialdehyde (MDA), one of the lipid peroxides, increases substantially in cirrhotic patients. To evaluate the relevance between the MDA level and portal hypertension in cirrhotic patients. 60 liver cirrhotic patients and 30 healthy controls were enrolled. The plasma MDA level and general blood tests including ALT, AST, ALB, total bilirubin, and platelet were measured. All people enrolled accepted endoscopic examination and B-Ultrasound check to evaluate the severity of portal hypertension. The MDA plasma level of cirrhotic patients was significantly higher than the controls (P<0.001) and increased significantly accompanied by the severity of liver fibrosis and portal hypertension (P<0.01). Further, the plasma MDA level of cirrhotic patients was significantly correlated with Child-Pugh classification of cirrhosis (r=0.820, P<0.001), the degree of esophageal varices (r=0.857, P<0.001) and the width of portal vein (r=0.652, P<0.001). The ROC curve analyses showed that the plasma MDA level is a strong predictor of liver cirrhosis and portal hypertension. Plasma MDA level may correlate with the severity of portal hypertension in cirrhotic patients.

New Approaches for Prostate Cancer Combination Therapy

DTIC Science & Technology

2007-04-01

in DU145 cells. Strong inducers of apoptosis included Sulindac sulfide, Finasteride , Diclofenac, Flufenamic acid, Flurbiprofen, Sulindac sulfone and... Finasteride , a selective 5-alpha-reductase inhibitor, is not known to inhibit COX-2, strongly induces MDA-7/IL-24 expression and apoptosis, whereas the...ibuprofen, aspirin, acet- aminophen, and naproxen were obtained from Sigma-Aldrich (St. Louis, MO). Meloxicam, celecoxib, diclofenac, finasteride , and

Clinical Utility of an Enzyme-Linked Immunosorbent Assay for Detecting Anti-Melanoma Differentiation-Associated Gene 5 Autoantibodies

PubMed Central

Sato, Shinji; Murakami, Akihiro; Kuwajima, Akiko; Takehara, Kazuhiko; Mimori, Tsuneyo; Kawakami, Atsushi; Mishima, Michiaki; Suda, Takafumi; Seishima, Mariko; Fujimoto, Manabu; Kuwana, Masataka

2016-01-01

Objective Autoantibodies to melanoma differentiation-associated gene 5 (MDA5) are specifically expressed in patients with dermatomyositis (DM) and are associated with a subset of DM patients with rapidly progressive interstitial lung disease (RP-ILD). Here, we examined the clinical utility of a newly developed enzyme-linked immunosorbent assay (ELISA) system for detecting these antibodies. Methods Here we developed an improved ELISA for detecting anti-MDA5 antibodies. We then performed a multicenter clinical study involving 8 medical centers and enrolled 242 adult patients with polymyositis (PM)/DM, 190 with non-PM/DM connective tissue disease (CTD), 154 with idiopathic interstitial pneumonia (IIP), and 123 healthy controls. Anti-MDA5 antibodies in the patients’ serum samples were quantified using our newly developed ELISA, and the results were compared to those obtained using the gold-standard immunoprecipitation (IP) assay. In addition, correlations between the ELISA-quantified anti-MDA5 antibodies and clinical characteristics were evaluated. Results In patients with PM/DM, the anti-MDA5 antibody measurements obtained from the ELISA and IP assay were highly concordant; the ELISA exhibited an analytical sensitivity of 98.2%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.5% (compared to the IP assay). Anti-MDA5 antibodies were detected in 22.7% of the DM patients, but not in any of the patients with PM, non-PM/DM CTD, or IIP. Clinically amyopathic DM, RP-ILD, arthritis, and fever were more prevalent in DM patients who were anti-MDA5 antibody-positive than in those who were antibody-negative (P ≤ 0.0002 for all comparisons). In addition, anti-MDA5 antibody-positive patients with RP-ILD exhibited higher antibody levels than those without RP-ILD (P = 0.006). Conclusion Our newly developed ELISA can detect anti-MDA5 antibodies as efficiently as the gold standard IP assay and has the potential to facilitate the routine clinical measurement of anti-MDA5 antibodies in patients who suspected to have DM. PMID:27115353

Clinical Utility of an Enzyme-Linked Immunosorbent Assay for Detecting Anti-Melanoma Differentiation-Associated Gene 5 Autoantibodies.

PubMed

Sato, Shinji; Murakami, Akihiro; Kuwajima, Akiko; Takehara, Kazuhiko; Mimori, Tsuneyo; Kawakami, Atsushi; Mishima, Michiaki; Suda, Takafumi; Seishima, Mariko; Fujimoto, Manabu; Kuwana, Masataka

2016-01-01

Autoantibodies to melanoma differentiation-associated gene 5 (MDA5) are specifically expressed in patients with dermatomyositis (DM) and are associated with a subset of DM patients with rapidly progressive interstitial lung disease (RP-ILD). Here, we examined the clinical utility of a newly developed enzyme-linked immunosorbent assay (ELISA) system for detecting these antibodies. Here we developed an improved ELISA for detecting anti-MDA5 antibodies. We then performed a multicenter clinical study involving 8 medical centers and enrolled 242 adult patients with polymyositis (PM)/DM, 190 with non-PM/DM connective tissue disease (CTD), 154 with idiopathic interstitial pneumonia (IIP), and 123 healthy controls. Anti-MDA5 antibodies in the patients' serum samples were quantified using our newly developed ELISA, and the results were compared to those obtained using the gold-standard immunoprecipitation (IP) assay. In addition, correlations between the ELISA-quantified anti-MDA5 antibodies and clinical characteristics were evaluated. In patients with PM/DM, the anti-MDA5 antibody measurements obtained from the ELISA and IP assay were highly concordant; the ELISA exhibited an analytical sensitivity of 98.2%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.5% (compared to the IP assay). Anti-MDA5 antibodies were detected in 22.7% of the DM patients, but not in any of the patients with PM, non-PM/DM CTD, or IIP. Clinically amyopathic DM, RP-ILD, arthritis, and fever were more prevalent in DM patients who were anti-MDA5 antibody-positive than in those who were antibody-negative (P ≤ 0.0002 for all comparisons). In addition, anti-MDA5 antibody-positive patients with RP-ILD exhibited higher antibody levels than those without RP-ILD (P = 0.006). Our newly developed ELISA can detect anti-MDA5 antibodies as efficiently as the gold standard IP assay and has the potential to facilitate the routine clinical measurement of anti-MDA5 antibodies in patients who suspected to have DM.

In Vivo Ligands of MDA5 and RIG-I in Measles Virus-Infected Cells

PubMed Central

Hembach, Katharina; Baum, Alina; García-Sastre, Adolfo; Söding, Johannes; Conzelmann, Karl-Klaus

2014-01-01

RIG-I-like receptors (RLRs: RIG-I, MDA5 and LGP2) play a major role in the innate immune response against viral infections and detect patterns on viral RNA molecules that are typically absent from host RNA. Upon RNA binding, RLRs trigger a complex downstream signaling cascade resulting in the expression of type I interferons and proinflammatory cytokines. In the past decade extensive efforts were made to elucidate the nature of putative RLR ligands. In vitro and transfection studies identified 5′-triphosphate containing blunt-ended double-strand RNAs as potent RIG-I inducers and these findings were confirmed by next-generation sequencing of RIG-I associated RNAs from virus-infected cells. The nature of RNA ligands of MDA5 is less clear. Several studies suggest that double-stranded RNAs are the preferred agonists for the protein. However, the exact nature of physiological MDA5 ligands from virus-infected cells needs to be elucidated. In this work, we combine a crosslinking technique with next-generation sequencing in order to shed light on MDA5-associated RNAs from human cells infected with measles virus. Our findings suggest that RIG-I and MDA5 associate with AU-rich RNA species originating from the mRNA of the measles virus L gene. Corresponding sequences are poorer activators of ATP-hydrolysis by MDA5 in vitro, suggesting that they result in more stable MDA5 filaments. These data provide a possible model of how AU-rich sequences could activate type I interferon signaling. PMID:24743923

Sensitization and cross-reactivity patterns of contact allergy to diisocyanates and corresponding amines: investigation of diphenylmethane-4,4'-diisocyanate, diphenylmethane-4,4'-diamine, dicyclohexylmethane-4,4'-diisocyanate, and dicylohexylmethane-4,4'-diamine.

PubMed

Hamada, Haneen; Bruze, Magnus; Zimerson, Erik; Isaksson, Marléne; Engfeldt, Malin

2017-10-01

Isocyanates are used in polyurethane production. Dermal exposure to isocyanates can induce contact allergy. The most common isocyanate is diphenylmethane diisocyanate used for industrial purposes. The isomer diphenylmethane-4,4'-diisocyanate (4,4'-MDI) is used in patch testing. Diphenylmethane-4,4'-diamine (4,4'-MDA) is its corresponding amine. Concurrent reactions to 4,4'-MDI and 4,4'-MDA have been reported, as have concurrent reactions to 4,4'-MDI and dicyclohexylmethane-4,4'-diisocyanate (4,4'-DMDI). To investigate the sensitization capacities and the cross-reactivity of 4,4'-MDI, 4,4'-MDA, 4,4'-DMDI, and dicyclohexylmethane-4,4'-diamine (4,4'-DMDA). The guinea-pig maximization test (GPMT) was used. The GPMT showed sensitizing capacities for all investigated substances: 4,4'-MDI, 4,4'-MDA, 4,4'-DMDI, and 4,4'-DMDA (all p < 0.001). 4,4'-MDI-sensitized animals showed cross-reactivity to 4,4'-MDA (p < 0.001) and 4,4'-DMDI (all p < 0.05). 4,4'-MDA-sensitized animals showed cross-reactivity to 4,4'-DMDA (p = 0.008). All of the investigated substances were shown to be strong sensitizers. Animals sensitized to 4,4'-MDI showed cross-reactivity to 4,4'-MDA and 4,4'-DMDI, supporting previous findings in the literature. The aromatic amine 4,4'-MDA showed cross-reactivity to the aliphatic amine 4,4'-DMDA. © 2017 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells

PubMed Central

Besch, Robert; Poeck, Hendrik; Hohenauer, Tobias; Senft, Daniela; Häcker, Georg; Berking, Carola; Hornung, Veit; Endres, Stefan; Ruzicka, Thomas; Rothenfusser, Simon; Hartmann, Gunther

2009-01-01

The retinoic acid–inducible gene I (RIG-I) and melanoma differentiation–associated antigen 5 (MDA-5) helicases sense viral RNA in infected cells and initiate antiviral responses such as the production of type I IFNs. Here we have shown that RIG-I and MDA-5 also initiate a proapoptotic signaling pathway that is independent of type I IFNs. In human melanoma cells, this signaling pathway required the mitochondrial adapter Cardif (also known as IPS-1) and induced the proapoptotic BH3-only proteins Puma and Noxa. RIG-I– and MDA-5–initiated apoptosis required Noxa but was independent of the tumor suppressor p53. Triggering this pathway led to efficient activation of mitochondrial apoptosis, requiring caspase-9 and Apaf-1. Surprisingly, this proapoptotic signaling pathway was also active in nonmalignant cells, but these cells were much less sensitive to apoptosis than melanoma cells. Endogenous Bcl-xL rescued nonmalignant, but not melanoma, cells from RIG-I– and MDA-5–mediated apoptosis. In addition, we confirmed the results of the in vitro studies, demonstrating that RIG-I and MDA-5 ligands both reduced human tumor lung metastasis in immunodeficient NOD/SCID mice. These results identify an IFN-independent antiviral signaling pathway initiated by RIG-I and MDA-5 that activates proapoptotic signaling and, unless blocked by Bcl-xL, results in apoptosis. Due to their immunostimulatory and proapoptotic activity, RIG-I and MDA-5 ligands have therapeutic potential due to their ability to overcome the characteristic resistance of melanoma cells to apoptosis. PMID:19620789

Preimplantation genetic diagnosis for Duchenne muscular dystrophy by multiple displacement amplification.

PubMed

Ren, Zi; Zeng, Hai-tao; Xu, Yan-wen; Zhuang, Guang-lun; Deng, Jie; Zhang, Cheng; Zhou, Can-quan

2009-02-01

To evaluate the use of multiple displacement amplification (MDA) in preimplantation genetic diagnosis (PGD) for female carriers with Duchenne muscular dystrophy (DMD). MDA was used to amplify a whole genome of single cells. Following the setup on single cells, the test was applied in two clinical cases of PGD. One mutant exon, six short tandem repeats (STR) markers within the dystrophin gene, and amelogenin were incorporated into singleplex polymerase chain reaction (PCR) assays on MDA products of single blastomeres. Center for reproductive medicine in First Affiliated Hospital, Sun Yat-sen University, China. Two female carriers with a duplication of exons 3-11 and a deletion of exons 47-50, respectively. The MDA of single cells and fluorescent PCR assays for PGD. The ability to analyze single blastomeres for DMD using MDA. The protocol setup previously allowed for the accurate diagnosis of each embryo. Two clinical cases resulted in a healthy girl, which was the first successful clinical application of MDA in PGD for DMD. We suggest that this protocol is reliable to increase the accuracy of the PGD for DMD.

Investigation of biological effects of some Mannich Bases containing Bis-1,2,4- Triazole.

PubMed

Parlak, A E; Celik, S; Karatepe, M; Turkoglu, S; Alayunt, N O; Dastan, S D; Ulas, M; Sandal, S; Tekin, S; Koparir, M

2016-06-30

In this study, the effects of Mannich bases containing bis-1,2,4-triazole on the levels of in vivo malondialdehyde (MDA) and antioxidant vitamins (A, E, C) were examined in serum, livers and kidneys of rats. DA and vitamin (A, E, C) levels were determined by high performance liquid chromatography (HPLC). Antioxidant effect was investigated by determining the MDA levels in Saccharomyces cerevisiae cells as in vitro. Furthermore, the antitumor effects of compounds were investigated against MCF-7 human breast cancer cells. Interrelations of results among control and compound groups were evaluated using SPSS statistical software package. As a result, some of the compounds showed effective biological activity when compared to control conditions. The test compounds used in this study may be effective for utilization in the selection and design of model compounds for further studies.

Activation of β-catenin signaling in androgen receptor-negative prostate cancer cells.

PubMed

Wan, Xinhai; Liu, Jie; Lu, Jing-Fang; Tzelepi, Vassiliki; Yang, Jun; Starbuck, Michael W; Diao, Lixia; Wang, Jing; Efstathiou, Eleni; Vazquez, Elba S; Troncoso, Patricia; Maity, Sankar N; Navone, Nora M

2012-02-01

To study Wnt/β-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the β-catenin-androgen receptor (AR) interaction. We carried out β-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of β-catenin-mediated transcription), and sequenced the β-catenin gene in MDA prostate cancer 118a, MDA prostate cancer 118b, MDA prostate cancer 2b, and PC-3 prostate cancer cells. We knocked down β-catenin in AR-negative MDA prostate cancer 118b cells and carried out comparative gene-array analysis. We also immunohistochemically analyzed β-catenin and AR in 27 bone metastases of human CRPCs. β-Catenin nuclear accumulation and TOP-flash reporter activity were high in MDA prostate cancer 118b but not in MDA prostate cancer 2b or PC-3 cells. MDA prostate cancer 118a and MDA prostate cancer 118b cells carry a mutated β-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA prostate cancer 118b cells with downregulated β-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant β-catenin. Finally, we found nuclear localization of β-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher's exact test), suggesting that reduced AR expression enables Wnt/β-catenin signaling. We identified a previously unknown downstream target of β-catenin, HAS2, in prostate cancer, and found that high β-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone metastatic prostate cancer. These findings may guide physicians in managing these patients.

Methyl malondialdehyde is not suitable as an internal standard for malondialdehyde detection in urine after derivatisation with 2,4-dinitrophenylhydrazine.

PubMed

Korchazhkina, Olga; Yang, Ying

2004-07-05

A previously described method of measurement of malondialdehyde (MDA) in human urine after derivatisation with 2,4-dinitrophenylhydrazine (DNPH) was tested for a possibility of using methyl malondialdehyde (MeMDA) as an internal standard. Despite structural similarity, those compounds were found to produce different yields of derivatisation under the same conditions depending on urine matrix. We conclude, that MeMDA is not suitable as an internal standard for the measurement of MDA in urine under previously reported conditions when DNPH is used as a deriviatising agent.

How much will it cost to eradicate lymphatic filariasis? An analysis of the financial and economic costs of intensified efforts against lymphatic filariasis

PubMed Central

Kastner, Randee J.; Sicuri, Elisa; Stone, Christopher M.; Matwale, Gabriel; Onapa, Ambrose; Tediosi, Fabrizio

2017-01-01

Introduction Lymphatic filariasis (LF), a neglected tropical disease (NTD) preventable through mass drug administration (MDA), is one of six diseases deemed possibly eradicable. Previously we developed one LF elimination scenario, which assumes MDA scale-up to continue in all countries that have previously undertaken MDA. In contrast, our three previously developed eradication scenarios assume all LF endemic countries will undertake MDA at an average (eradication I), fast (eradication II), or instantaneous (eradication III) rate of scale-up. In this analysis we use a micro-costing model to project the financial and economic costs of each of these scenarios in order to provide evidence to decision makers about the investment required to eliminate and eradicate LF. Methodology/Key findings Costing was undertaken from a health system perspective, with all results expressed in 2012 US dollars (USD). A discount rate of 3% was applied to calculate the net present value of future costs. Prospective NTD budgets from LF endemic countries were reviewed to preliminarily determine activities and resources necessary to undertake a program to eliminate LF at a country level. In consultation with LF program experts, activities and resources were further reviewed and a refined list of activities and necessary resources, along with their associated quantities and costs, were determined and grouped into the following activities: advocacy and communication, capacity strengthening, coordination and strengthening partnerships, data management, ongoing surveillance, monitoring and supervision, drug delivery, and administration. The costs of mapping and undertaking transmission assessment surveys and the value of donated drugs and volunteer time were also accounted for. Using previously developed scenarios and deterministic estimates of MDA duration, the financial and economic costs of interrupting LF transmission under varying rates of MDA scale-up were then modelled using a micro-costing approach. The elimination scenario, which includes countries that previously undertook MDA, is estimated to cost 929 million USD (95% Credible Interval: 884m-972m). Proceeding to eradication is anticipated to require a higher financial investment, estimated at 1.24 billion USD (1.17bn-1.30bn) in the eradication III scenario (immediate scale-up), with eradication II (intensified scale-up) projected at 1.27 billion USD (1.21bn-1.33bn), and eradication I (slow scale-up) estimated at 1.29 billion USD (1.23bn-1.34bn). The economic costs of the eradication III scenario are estimated at approximately 7.57 billion USD (7.12bn-7.94bn), while the elimination scenario is projected to have an economic cost of 5.21 billion USD (4.91bn-5.45bn). Countries in the AFRO region will require the greatest investment to reach elimination or eradication, but also stand to gain the most in cost savings. Across all scenarios, capacity strengthening and advocacy and communication represent the greatest financial costs, whereas mapping, post-MDA surveillance, and administration comprise the least. Conclusions/Significance Though challenging to implement, our results indicate that financial and economic savings are greatest under the eradication III scenario. Thus, if eradication for LF is the objective, accelerated scale-up is projected to be the best investment. PMID:28949987

Controlled formation of emulsion gels stabilized by salted myofibrillar protein under malondialdehyde (MDA)-induced oxidative stress.

PubMed

Zhou, Feibai; Sun, Weizheng; Zhao, Mouming

2015-04-15

This study presented the cold-set gelation of emulsions stabilized by salted myofibrillar protein (MP) under oxidative stress originated from malondialdehyde (MDA). Gel properties were compared over a range of MDA/NaCl concentrations including gel viscoelastic properties, strength, water-holding capacity (WHC), amount of protein entrapped, and microstructure. The oxidative stability of emulsion gels as indicated by lipid hydroperoxide was further determined and compared. Results indicated that emulsion stabilized by MP at swollen state under certain ionic strengths (0.2-0.6 M) was the premise of gel formation under MDA. In the presence of intermediate MDA concentrations (2.5-10 mM), the emulsion gels showed an improved elasticity, strength, WHC, and oxidative stability. This improvement should be mainly attributed to the enhanced protein-protein cross-linkings via MDA, which were homogeneously formed among absorbed and/or unabsorbed proteins, entrapping a greater amount and fractions of protein within network. Therefore, the oil droplets were better adherent to the gel matrix. Nevertheless, addition of high MDA concentrations (25-50 mM) led to the formation of excessive covalent bonds, which might break protein-protein bonds and trigger the desorption of protein from the interface. This ultimately caused "oil leak" phenomena as well as the collapse of gel structure and, thus, overall decreased gel properties and oxidative stability.

Knowledge, attitudes and perceptions regarding lymphatic filariasis: study on systematic noncompliance with mass drug administration

PubMed Central

Cabral, Silvia; Bonfim, Cristine; Oliveira, Rosalira; Oliveira, Paula; Guimarães, Terezinha; Brandão, Eduardo; Aguiar-Santos, Ana Maria; Medeiros, Zulma

2017-01-01

ABSTRACT The aim of this study was to investigate the epidemiological characteristics, antigenic profile, perceptions, attitudes and practices of individuals who have been systematically non-compliant in mass drug administration (MDA) campaigns targeting lymphatic filariasis, in the municipality of Olinda, State of Pernambuco, Northeastern Brazil. A pretested questionnaire was used to obtain information on socioenvironmental demographics, perceptions of lymphatic filariasis and MDA, and reasons for systematic noncompliance with treatment. A rapid immunochromatographic test (ICT) was performed during the survey to screen for filariasis. It was found that the survey subjects knew about filariasis and MDA. Filariasis was identified as a disease (86.2%) and 74.4% associated it with the presence of swelling in the legs. About 80% knew about MDA, and the main source of information was healthcare workers (68.3%). For men the main reasons for systematic noncompliance with MDA were that “the individual had not received the medication” (p=0.03) and for women “the individual either feared experiencing adverse reactions”. According to the ICT, the prevalence of lymphatic filariasis was 2%. The most important causes of systematic noncompliance were not receiving the drug and fear of side-effects. For successful implementation of MDA programs, good planning, educational campaigns promoting the benefits of MDA, adoption of measures to minimize the impact of adverse effects and improvement of drug distribution logistics are needed. PMID:28443941

IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production.

PubMed

Escobar, Pauline; Bouclier, Céline; Serret, Julien; Bièche, Ivan; Brigitte, Madly; Caicedo, Andres; Sanchez, Elodie; Vacher, Sophie; Vignais, Marie-Luce; Bourin, Philippe; Geneviève, David; Molina, Franck; Jorgensen, Christian; Lazennec, Gwendal

2015-10-06

The aim of this work was to understand whether the nature of breast cancer cells could modify the nature of the dialog of mesenchymal stem cells (MSCs) with cancer cells. By treating MSCs with the conditioned medium of metastatic Estrogen-receptor (ER)-negative MDA-MB-231, or non-metastatic ER-positive MCF-7 breast cancer cells, we observed that a number of chemokines were produced at higher levels by MSCs treated with MDA-MB-231 conditioned medium (CM). MDA-MB-231 cells were able to induce NF-κB signaling in MSC cells. This was shown by the use of a NF-kB chemical inhibitor or an IκB dominant negative mutant, nuclear translocation of p65 and induction of NF-κB signature. Our results suggest that MDA-MB-231 cells exert their effects on MSCs through the secretion of IL-1β, that activates MSCs and induces the same chemokines as the MDA-MB-231CM. In addition, inhibition of IL-1β secretion in the MDA-MB-231 cells reduces the induced production of a panel of chemokines by MSCs, as well the motility of MDA-MB-231 cells. Our data suggest that aggressive breast cancer cells secrete IL-1β, which increases the production of chemokines by MSCs.

IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production

PubMed Central

Serret, Julien; Bièche, Ivan; Brigitte, Madly; Caicedo, Andres; Sanchez, Elodie; Vacher, Sophie; Vignais, Marie-Luce; Bourin, Philippe; Geneviève, David; Molina, Franck; Jorgensen, Christian; Lazennec, Gwendal

2015-01-01

The aim of this work was to understand whether the nature of breast cancer cells could modify the nature of the dialog of mesenchymal stem cells (MSCs) with cancer cells. By treating MSCs with the conditioned medium of metastatic Estrogen-receptor (ER)-negative MDA-MB-231, or non-metastatic ER-positive MCF-7 breast cancer cells, we observed that a number of chemokines were produced at higher levels by MSCs treated with MDA-MB-231 conditioned medium (CM). MDA-MB-231 cells were able to induce NF-κB signaling in MSC cells. This was shown by the use of a NF-kB chemical inhibitor or an IκB dominant negative mutant, nuclear translocation of p65 and induction of NF-κB signature. Our results suggest that MDA-MB-231 cells exert their effects on MSCs through the secretion of IL-1β, that activates MSCs and induces the same chemokines as the MDA-MB-231CM. In addition, inhibition of IL-1β secretion in the MDA-MB-231 cells reduces the induced production of a panel of chemokines by MSCs, as well the motility of MDA-MB-231 cells. Our data suggest that aggressive breast cancer cells secrete IL-1β, which increases the production of chemokines by MSCs. PMID:26362269

ELF magnetic therapy and oxidative balance.

PubMed

Raggi, Francesco; Vallesi, Giuseppe; Rufini, Stefano; Gizzi, Stefania; Ercolani, Enrico; Rossi, Ruggero

2008-01-01

Knowledge about the relationship between exposure to extremely low-frequency (ELF) EMF and formation (or neutralization) of free radicals in the living cells is limited. Studies performed on animals and plants have shown conflicting effects on the relation between EMF and oxidative stress. Very few experiments have been performed on humans. The present study reports on the effects of an ELF magnetic therapy device (Seqex) on oxidative scale in humans. This device supplies complex magnetic signals with specific choices of frequency, intensity, and shape that are based on Liboff's ion cyclotron resonance hypothesis. Thirty-two healthy volunteers were treated using the Seqex cycle. A quantitative determination of oxidative stress was obtained at three time points by measuring Malondialdehyde (MDA) concentrations in peripheral blood before and after the cycle and one month following completion of the cycle. A highly significant reduction in mean MDA (53.8%, p = 0.0002) was found at the end of the treatment. One month later the mean MDA had again risen, but there was still a significant overall reduction of 15.6% (p = 0.010) compared to original values.

Markers of Oxidative Status in a Clinical Model of Oxidative Assault: a Pilot Study in Human Blood Following Doxorubicin Administration

PubMed Central

Il'yasova, Dora; Mixon, Gabriel; Wang, Frances; Marcom, P Kelly; Marks, Jeffrey; Spasojevich, Ivan; Craft, Neal; Arredondo, Francisco; DiGiulio, Richard

2009-01-01

We used doxorubicin-based chemotherapy as a clinical model for oxidative assault. Study recruited 23 breast cancer patients and collected blood samples before (T0), at 1 (T1) and 24 hours (T24) after treatment administration. Measurements included protein carbonyl content (PPCC), malondialdehyde (MDA), and α- and γ-tocopherols in plasma and total glutathione content in erythrocytes (erGSHt). In all subjects, PPCC and MDA levels did not change. erGSHt levels increased at T24 by 8% (p=0.03). Levels of α, γ, and total tocopherols progressively decreased by 7%−15% (P<0.05). In subjects with low erGSHt levels (below median), PPCC mean levels progressively increased from 0.35 (T0) to 0.56 (T1) and 0.72 nmol carbonyl/mg protein (T24) (p=0.2). These results indicate that (1) plasma MDA is not a sensitive biomarker in humans; (2) PPCC potentially may be used, if antioxidant reserves are taken into account; (3) antioxidant reserves play an important role in the reaction to oxidative stress. PMID:19476408

UPLC-QTOF/MS-based phenolic profiling of Melastomaceae, their antioxidant activity and cytotoxic effects against human breast cancer cell MDA-MB-231.

PubMed

Hamid, Hazrulrizawati Abd; Ramli, Aizi Nor Mazila; Zamri, Normaiza; Yusoff, Mashitah M

2018-11-01

Eleven compounds were identified during profiling of polyphenols by UPLC-QTOF/MS. In abundance was quercetin-3-O-α-l-arabinofuranoside in M. malabathricum ethanolic leaves extract while 6-hydroxykaempferol-3-O-glucoside was present in the leaves extract of M. decenfidum (its rare variety). TPC and TFC were significantly higher in M. decemfidum extract than M. malabathricum extract. During DPPH, FRAF and β-carotene bleaching assays, M. decemfidum extract exhibited greater antioxidant activity compared to M. malabathricum extract. Effect of M. malabathricum and M. decemfidum extracts on viability of MDA-MB-231 cell at concentrations 6.25-100 μg/mL were evaluated for 24, 48 and 72 h. After 48 and 72 h treatment, M. malabathricum and M. decemfidum leaves extracts exhibited significant activity in inhibiting MDA-MB-231 cancer cell line with M. malabathricum extract being more cytotoxic. M. malabathricum and M. imbricatum serves as potential daily dietary source of natural phenolics and to improve chemotherapeutic effectiveness. Copyright © 2018 Elsevier Ltd. All rights reserved.

Anti and Androgenic Activities in MDA-KB2 Cells: A Comparison of Performance in 96 Well Versus HTS Assays

EPA Science Inventory

We developed the MDA-kb2 cell line to screen androgen agonists/antagonists (Wilson et al., ToxSci 66:69, 2002). MDA-kb2 has been used to quantify anti- and androgenic activities of chemicals, mixtures, combustion by-products, oil dispersants and waste, source and drinking water s...

Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy

PubMed Central

Chen, Haijun; Yang, Zhengduo; Ding, Chunyong; Chu, Lili; Zhang, Yusong; Terry, Kristin; Liu, Huiling; Shen, Qiang; Zhou, Jia

2013-01-01

Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known STAT3 inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (HJC0123) has demonstrated to inhibit STAT3 promoter activity, downregulate phosphorylation of STAT3, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy. PMID:23416191

Metabolic profiling of goldfish (Carassius auratis) after long-term glyphosate-based herbicide exposure.

PubMed

Li, Ming-Hui; Ruan, Ling-Yu; Zhou, Jin-Wei; Fu, Yong-Hong; Jiang, Lei; Zhao, He; Wang, Jun-Song

2017-07-01

Glyphosate is an efficient herbicide widely used worldwide. However, its toxicity to non-targeted organisms has not been fully elucidated. In this study, the toxicity of glyphosate-based herbicide was evaluated on goldfish (Carassius auratus) after long-term exposure. Tissues of brains, kidneys and livers were collected and submitted to NMR-based metabolomics analysis and histopathological inspection. Plasma was collected and the blood biochemical indexes of AST, ALT, BUN, CRE, LDH, SOD, GSH-Px, GR and MDA were measured. Long-term glyphosate exposure caused disorders of blood biochemical indexes and renal tissue injury in goldfish. Metabolomics analysis combined with correlation network analysis uncovered significant perturbations in oxidative stress, energy metabolism, amino acids metabolism and nucleosides metabolism in glyphosate dosed fish, which provide new clues to the toxicity of glyphosate. This integrated metabolomics approach showed its applicability in discovering the toxic mechanisms of pesticides, which provided new strategy for the assessment of the environmental risk of herbicides to non-target organisms. Copyright © 2017 Elsevier B.V. All rights reserved.

Controlling Taenia solium and soil transmitted helminths in a northern Lao PDR village: Impact of a triple dose albendazole regime.

PubMed

Ash, Amanda; Okello, Anna; Khamlome, Boualam; Inthavong, Phouth; Allen, John; Thompson, R C Andrew

2017-10-01

Taenia solium taeniasis-cysticercosis and soil-transmitted helminths (STHs) are parasitic Neglected Tropical Diseases endemic throughout Southeast Asia. Within Lao PDR, a remote northern hill tribe village had previously been identified as a hyper endemic focus for T. solium. To reduce this observed prevalence, a One Health intervention covering both pigs and humans was implemented, which included two Mass drug administrations (MDA1 and MDA2) for village residents using a triple dose albendazole 400mg treatment regime. In addition to the effect on T. solium levels, the dual impact of this anthelmintic regime on STHs within the community was also monitored. Faecal samples were collected pre and post MDA1 and MDA2 and analysed for the presence of Taenia species and the STHs Ascaris lumbricoides, Trichuris trichiura and hookworm species. The McMaster technique was used to measure the changes in both prevalence and intensity of infection. Molecular characterisation of Taenia and hookworm species was conducted to detect zoonotic species. The level of taeniasis within the sampled population decreased by 79.4% after MDA1, remained steady during the five month inter-treatment interval and decreased again by 100% after MDA2. The prevalence of STHs decreased by 65.5% and 62.8% after MDA1 and MDA2 respectively; however an increase to 62.1% of pre MDA1 levels was detected during the inter-treatment interval. Individually, hookworm prevalence decreased by 83.4% (MDA1) and 84.5% (MDA2), A. lumbricoides by 95.6% and 93.5% and T. trichiura by 69.2% and 61%. The intensity of infection within the sampled population also decreased, with egg reduction rates of 94.4% and 97.8% for hookworm, 99.4% and 99.3% for A. lumbricoides and 77.2% and 88.5% for T. trichiura. Molecular characterisation identified a T. solium tapeworm carrier from 21.6% (13/60) of households in the village. T. saginata was identified in 5% (3/60) of households. The zoonotic hookworm A. ceylanicum was detected in the resident dog population. These results suggest that the triple dose albendazole 400mg treatment regime achieved a significant reduction in the level of taeniasis whilst simultaneously reducing the STH burden within the village. The increased STH prevalence detected between MDAs reflects the need for behavioural changes and a sustained chemotherapy programme, which may also need to include the resident dog population. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Iron chelation as a possible mechanism for aspirin-induced malondialdehyde production by mouse liver microsomes and mitochondria.

PubMed Central

Schwarz, K B; Arey, B J; Tolman, K; Mahanty, S

1988-01-01

To investigate the possibility that lipid peroxidation is the mechanism responsible for aspirin-induced liver damage, pure neutralized acetylsalicylic acid (ASA), 0.6-90.9 mM, was added to calcium-aggregated mouse liver microsomes followed by incubation in NADPH buffer at 37 degrees C for 60 min and subsequent measurement of malondialdehyde (MDA). MDA production at ASA concentrations from 1.2 to 4.6 mM was greater than control (P less than 0.004). Peak MDA values were observed with 4.6 mM ASA, 39.58 +/- 6.73 nmol MDA/mg protein vs. 16.16 +/- 2.85 (P less than 0.004). Higher concentrations of ASA were inhibitory compared with the value at 4.6 mM (P less than 0.001). Aspirin had similar effects on MDA production by mouse liver mitochondria. MDA production with either ASA or buffer was completely suppressed by the potent iron-chelating agents desferrioxamine and alpha,alpha' dipyridyl when these were added to the microsomal preparations. Since MDA production in this system is known to be affected by iron-chelating agents (enhanced at low concentration, inhibited at higher concentration), the iron-chelating properties of ASA were investigated. Conductivity titration curves of Fe(OH)3 added to water or ASA suggested that the ASA was complexing with iron. The presence of an iron-ASA complex was established by high pressure liquid chromatographic analysis of the solution from this study. We conclude that aspirin enhances MDA production by hepatic microsomes and mitochondria via an aspirin-iron chelate and that this represents at least one mechanism by which aspirin may produce liver damage. PMID:3335633

All-trans-retinoic acid activates the pro-invasive Src-YAP-Interleukin 6 axis in triple-negative MDA-MB-231 breast cancer cells while cerivastatin reverses this action.

PubMed

Mezquita, Belén; Mezquita, Pau; Pau, Montserrat; Gasa, Laura; Navarro, Lourdes; Samitier, Mireia; Pons, Miquel; Mezquita, Cristóbal

2018-05-04

All-trans-retinoic acid (RA), the active metabolite of vitamin A, can reduce the malignant phenotype in some types of cancer and paradoxically also can promote cancer growth and invasion in others. For instance, it has been reported that RA induces tumor suppression in tumor xenografts of MDA-MB-468 breast cancer cells while increasing tumor growth and metastases in xenografts of MDA-MB-231 breast cancer cells. The signaling pathways involved in the pro-invasive action of retinoic acid remain mostly unknown. We show here that RA activates the pro-invasive axis Src-YAP-Interleukin 6 (Src-YAP-IL6) in triple negative MDA-MB-231 breast cancer cells, yielding to increased invasion of these cells. On the contrary, RA inhibits the Src-YAP-IL6 axis of triple-negative MDA-MB-468 cells, which results in decreased invasion phenotype. In both types of cells, inhibition of the Src-YAP-IL6 axis by the Src inhibitor PP2 drastically reduces migration and invasion. Src inhibition also downregulates the expression of a pro-invasive isoform of VEGFR1 in MDA-MB-231 breast cancer cells. Furthermore, interference of YAP nuclear translocation using the statin cerivastatin reverses the upregulation of Interleukin 6 (IL-6) and the pro-invasive effect of RA on MDA-MB-231 breast cancer cells and also decreases invasion and viability of MDA-MB-468 breast cancer cells. These results altogether suggest that RA induces pro-invasive or anti-invasive actions in two triple-negative breast cancer cell lines due to its ability to activate or inhibit the Src-YAP-IL6 axis in different cancer cells. The pro-invasive effect of RA can be reversed by the statin cerivastatin.

Activation of Beta-Catenin Signaling in Androgen Receptor–Negative Prostate Cancer Cells

PubMed Central

Wan, Xinhai; Liu, Jie; Lu, Jing-Fang; Tzelepi, Vassiliki; Yang, Jun; Starbuck, Michael W.; Diao, Lixia; Wang, Jing; Efstathiou, Eleni; Vazquez, Elba S.; Troncoso, Patricia; Maity, Sankar N.; Navone, Nora M.

2012-01-01

Purpose To study Wnt/beta-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the beta-catenin–androgen receptor (AR) interaction. Experimental Design We performed beta-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of beta-catenin–mediated transcription), and sequenced the beta-catenin gene in MDA PCa 118a, MDA PCa 118b, MDA PCa 2b, and PC-3 prostate cancer (PCa) cells. We knocked down beta-catenin in AR-negative MDA PCa 118b cells and performed comparative gene-array analysis. We also immunohistochemically analyzed beta-catenin and AR in 27 bone metastases of human CRPCs. Results Beta-catenin nuclear accumulation and TOP-flash reporter activity were high in MDA PCa 118b but not in MDA PCa 2b or PC-3 cells. MDA PCa 118a and 118b cells carry a mutated beta-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA PCa 118b cells with downregulated beta-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant beta-catenin. Finally, we found nuclear localization of beta-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher’s exact test), suggesting that reduced AR expression enables Wnt/beta-catenin signaling. Conclusion We identified a previously unknown downstream target of beta-catenin, HAS2, in PCa, and found that high beta-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone-metastatic PCa. These findings may guide physicians in managing these patients. PMID:22298898

Intratumoral injection of INGN 241, a nonreplicating adenovector expressing the melanoma-differentiation associated gene-7 (mda-7/IL24): biologic outcome in advanced cancer patients.

PubMed

Tong, Alex W; Nemunaitis, John; Su, Dan; Zhang, Yuan; Cunningham, Casey; Senzer, Neil; Netto, George; Rich, Dawn; Mhashilkar, Abner; Parker, Karen; Coffee, Keith; Ramesh, Rajagopal; Ekmekcioglu, Suhendan; Grimm, Elizabeth A; van Wart Hood, Jill; Merritt, James; Chada, Sunil

2005-01-01

The mda-7 gene (approved gene symbol IL24) is a novel tumor suppressor gene with tumor-apoptotic and immune-activating properties. We completed a Phase I dose-escalation clinical trial, in which a nonreplicating adenoviral construct expressing the mda-7 transgene (INGN 241; Ad-mda7) was administered intratumorally to 22 patients with advanced cancer. Excised tumors were evaluated for vector-specific DNA and RNA, transgenic MDA-7 expression, and biological effects. Successful gene transfer as assessed by DNA- and RT-PCR was demonstrated in 100% of patients evaluated. DNA analyses demonstrated a dose-dependent penetration of INGN 241 (up to 4 x 10(8) copies/mug DNA at the 2 x 10(12) vp dose). A parallel distribution of vector DNA, vector RNA, MDA-7 protein expression, and apoptosis induction was observed in all tumors, with signals decreasing with distance away from the injection site. Additional evidence for bioactivity of INGN 241 was illustrated via regulation of the MDA-7 target genes beta-catenin, iNOS, and CD31. Transient increases (up to 20-fold) of serum IL-6, IL-10, and TNF-alpha were observed. Significantly higher elevations of IL-6 and TNF-alpha were observed in patients who responded clinically to INGN 241. Patients also showed marked increases of CD3+CD8+ T cells posttreatment, suggesting that INGN 241 increased systemic TH1 cytokine production and mobilized CD8+ T cells. Intratumoral delivery of INGN 241 induced apoptosis in a large volume of tumor and elicited tumor-regulatory and immune-activating events that are consistent with the preclinical features of MDA-7/IL-24.

The effect of Ramadan intermittent fasting on lipid peroxidation in healthy young men while controlling for diet and sleep: A pilot study.

PubMed

BaHammam, Ahmed S; Pandi-Perumal, Seithikurippu R; Alzoghaibi, Mohammed A

2016-01-01

We hypothesized that if we control for lifestyle changes during Ramadan, Ramadan Islamic intermittent fasting (IF) reduces oxidative stress. This study was conducted to examine the effect of Islamic IF during and outside of Ramadan on the circadian changes in lipid peroxidation marker malondialdehyde (MDA) during and outside while controlling for potential confounders. Serum MDA concentration was measured in eight healthy male volunteers at baseline (BL), after fasting for 1 week before Ramadan (BL fasting), and during Ramadan. Blood samples were drawn at 22:00, 02:00, 04:00, 06:00, and 11:00. The participants were admitted to the sleep laboratory and monitored for 24 h on the day of the measurements. In the laboratory, each participant received meals of fixed compositions and caloric contents based on their ideal body weights. Light exposure, physical activity, and total sleep duration were uniformly maintained during the three study periods. The participants had a mean age of 26.6 ± 4.9 years and a mean body mass index of 23.7 ± 3.5 kg/m(2). No significant changes were observed in MDA levels and blood glucose during BL, BL fasting, or Ramadan. In this pilot study, under conditions of fixed sleep-wake schedules and caloric intake, Ramadan IF does not alter serum MDA levels in healthy subjects. Larger studies are needed to confirm these findings.

The effect of Ramadan intermittent fasting on lipid peroxidation in healthy young men while controlling for diet and sleep: A pilot study

PubMed Central

BaHammam, Ahmed S.; Pandi-Perumal, Seithikurippu R.; Alzoghaibi, Mohammed A.

2016-01-01

AIMS: We hypothesized that if we control for lifestyle changes during Ramadan, Ramadan Islamic intermittent fasting (IF) reduces oxidative stress. This study was conducted to examine the effect of Islamic IF during and outside of Ramadan on the circadian changes in lipid peroxidation marker malondialdehyde (MDA) during and outside while controlling for potential confounders. METHODS: Serum MDA concentration was measured in eight healthy male volunteers at baseline (BL), after fasting for 1 week before Ramadan (BL fasting), and during Ramadan. Blood samples were drawn at 22:00, 02:00, 04:00, 06:00, and 11:00. The participants were admitted to the sleep laboratory and monitored for 24 h on the day of the measurements. In the laboratory, each participant received meals of fixed compositions and caloric contents based on their ideal body weights. Light exposure, physical activity, and total sleep duration were uniformly maintained during the three study periods. RESULTS: The participants had a mean age of 26.6 ± 4.9 years and a mean body mass index of 23.7 ± 3.5 kg/m2. No significant changes were observed in MDA levels and blood glucose during BL, BL fasting, or Ramadan. CONCLUSION: In this pilot study, under conditions of fixed sleep-wake schedules and caloric intake, Ramadan IF does not alter serum MDA levels in healthy subjects. Larger studies are needed to confirm these findings. PMID:26933456

Olive leaves (Olea europaea L.) versus α-tocopheryl acetate as dietary supplements for enhancing the oxidative stability of eggs enriched with very-long-chain n-3 fatty acids.

PubMed

Botsoglou, Evropi N; Govaris, Alexandros K; Ambrosiadis, Ioannis A; Fletouris, Dimitrios J

2013-06-01

Ninety-six brown Lohmann laying hens were equally assigned into four groups with six replicates. Hens within the control group were given a corn/soybean-based diet supplemented with 30 g kg(-1) fish oil. Two other groups were given the same diet further supplemented with olive leaves at 5 (OL5) and 10 (OL10) g kg(-1) respectively, while the diet of the fourth group was supplemented with α-tocopheryl acetate (TOC) at 200 mg kg(-1). Eggs were analysed for lipid hydroperoxide and malondialdehyde (MDA) contents, fatty acid profile, α-tocopherol content and susceptibility to iron-induced lipid oxidation. Neither OL nor TOC supplementation affected (P>0.05) the fatty acid composition. Dietary supplementation with OL10 or TOC reduced (P≤0.05) the lipid hydroperoxide content but exerted no (P>0.05) effect on the MDA content of fresh eggs compared with controls. Eggs submitted to iron-induced lipid oxidation from the OL5 group presented higher (P≤0.05) MDA levels than the control but lower (P≤0.05) than the OL10 group. Eggs from the TOC group presented lower (P≤0.05) MDA levels compared with all groups at all incubation time points. The results of this study suggested that dietary supplementation with both OL10 and TOC could protect n-3 fatty acids in eggs from deterioration. © 2012 Society of Chemical Industry.

Role of mp 170 Seprase in Breast Cancer.

DTIC Science & Technology

1999-07-01

endogenous Seprase/FAPa in MDA-436 cells. Previously, three hammerhead ribozyme constructs targeting Seprase/FAPa at nucleotide residues 703, 892...breast cancer cells using the ribozyme approach. In contrast, I also constructed two hammerhead ribozymes targeting FGF-BP2 at nucleotide residues 223 and...molecule for further characterization, however, with little success. Ribozyme constructs targeting Seprase/FAPa were made, and despite their in vitro

A novel coumarin-quinone derivative SV37 inhibits CDC25 phosphatases, impairs proliferation, and induces cell death.

PubMed

Bana, Emilie; Sibille, Estelle; Valente, Sergio; Cerella, Claudia; Chaimbault, Patrick; Kirsch, Gilbert; Dicato, Mario; Diederich, Marc; Bagrel, Denyse

2015-03-01

Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation by regulating CDK/cyclin complexes. Overexpression of these enzymes is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, targeting CDC25 by compounds, able to inhibit their activity, appears a good therapeutic approach. Here, we describe the synthesis of a new inhibitor (SV37) whose structure is based on both coumarin and quinone moieties. An analytical in vitro approach shows that this compound efficiently inhibits all three purified human CDC25 isoforms (IC50 1-9 µM) in a mixed-type mode. Moreover, SV37 inhibits growth of breast cancer cell lines. In MDA-MB-231 cells, reactive oxygen species generation is followed by pCDK accumulation, a mark of CDC25 dysfunction. Eventually, SV37 treatment leads to activation of apoptosis and DNA cleavage, underlining the potential of this new type of coumarin-quinone structure. © 2013 Wiley Periodicals, Inc.

Highly multiplexed targeted DNA sequencing from single nuclei.

PubMed

Leung, Marco L; Wang, Yong; Kim, Charissa; Gao, Ruli; Jiang, Jerry; Sei, Emi; Navin, Nicholas E

2016-02-01

Single-cell DNA sequencing methods are challenged by poor physical coverage, high technical error rates and low throughput. To address these issues, we developed a single-cell DNA sequencing protocol that combines flow-sorting of single nuclei, time-limited multiple-displacement amplification (MDA), low-input library preparation, DNA barcoding, targeted capture and next-generation sequencing (NGS). This approach represents a major improvement over our previous single nucleus sequencing (SNS) Nature Protocols paper in terms of generating higher-coverage data (>90%), thereby enabling the detection of genome-wide variants in single mammalian cells at base-pair resolution. Furthermore, by pooling 48-96 single-cell libraries together for targeted capture, this approach can be used to sequence many single-cell libraries in parallel in a single reaction. This protocol greatly reduces the cost of single-cell DNA sequencing, and it can be completed in 5-6 d by advanced users. This single-cell DNA sequencing protocol has broad applications for studying rare cells and complex populations in diverse fields of biological research and medicine.

Impact of wildfires on ozone exceptional events in the Western u.s.

PubMed

Jaffe, Daniel A; Wigder, Nicole; Downey, Nicole; Pfister, Gabriele; Boynard, Anne; Reid, Stephen B

2013-10-01

Wildfires generate substantial emissions of nitrogen oxides (NOx) and volatile organic compounds (VOCs). As such, wildfires contribute to elevated ozone (O3) in the atmosphere. However, there is a large amount of variability in the emissions of O3 precursors and the amount of O3 produced between fires. There is also significant interannual variability as seen in median O3, organic carbon and satellite derived carbon monoxide mixing ratios in the western U.S. To better understand O3 produced from wildfires, we developed a statistical model that estimates the maximum daily 8 h average (MDA8) O3 as a function of several meteorological and temporal variables for three urban areas in the western U.S.: Salt Lake City, UT; Boise, ID; and Reno, NV. The model is developed using data from June-September 2000-2012. For these three locations, the statistical model can explain 60, 52, and 27% of the variability in daily MDA8. The Statistical Model Residual (SMR) can give information on additional sources of O3 that are not explained by the usual meteorological pattern. Several possible O3 sources can explain high SMR values on any given day. We examine several cases with high SMR that are due to wildfire influence. The first case considered is for Reno in June 2008 when the MDA8 reached 82 ppbv. The wildfire influence for this episode is supported by PM concentrations, the known location of wildfires at the time and simulations with the Weather and Research Forecasting Model with Chemistry (WRF-Chem) which indicates transport to Reno from large fires burning in California. The contribution to the MDA8 in Reno from the California wildfires is estimated to be 26 ppbv, based on the SMR, and 60 ppbv, based on WRF-Chem. The WRF-Chem model also indicates an important role for peroxyacetyl nitrate (PAN) in producing O3 during transport from the California wildfires. We hypothesize that enhancements in PAN due to wildfire emissions may lead to regional enhancements in O3 during high fire years. The second case is for the Salt Lake City (SLC) region for August 2012. During this period the MDA8 reached 83 ppbv and the SMR suggests a wildfire contribution of 19 ppbv to the MDA8. The wildfire influence is supported by PM2.5 data, the known location of wildfires at the time, HYSPLIT dispersion modeling that indicates transport from fires in Idaho, and results from the CMAQ model that confirm the fire impacts. Concentrations of PM2.5 and O3 are enhanced during this period, but overall there is a poor relationship between them, which is consistent with the complexities in the secondary production of O3. A third case looks at high MDA8 in Boise, ID, during July 2012 and reaches similar conclusions. These results support the use of statistical modeling as a tool to quantify the influence from wildfires on urban O3 concentrations.

Astrionics system designers handbook, volume 1

NASA Technical Reports Server (NTRS)

1973-01-01

Hardware elements in new and advanced astrionics system designs are discussed. This cost effective approach has as its goal the reduction of R&D and testing costs through the application of proven and tested astrionics components. The ready availability to the designer of data facts for applicable system components is highly desirable. The astrionics System Designers Handbook has as its objective this documenting of data facts to serve the anticipated requirements of the astrionics system designer. Eleven NASA programs were selected as the reference base for the document. These programs are: ATS-F, ERTS-B, HEAO-A, OSO-I, Viking Orbiter, OAO-C, Skylab AM/MDA, Skylab ATM, Apollo 17 CSM, Apollo 17 LM and Mariner Mars 71. Four subsystems were chosen for documentation: communications, data management, electrical power and guidance, navigation and control.

A fast and validated method for the determination of malondialdehyde in fish liver using high-performance liquid chromatography with a photodiode array detector.

PubMed

Faizan, Mohammad; Esatbeyoglu, Tuba; Bayram, Banu; Rimbach, Gerald

2014-04-01

Malondialdehyde (MDA) is a biomarker of lipid peroxidation and is present in foods and biological samples such as plasma. A high-performance liquid chromatography (HPLC) method was applied to determine MDA in fish liver samples after derivatization with 2,4-dinitrophenylhydrazine (DNPH) using a ODS2 column (10 cm × 4.6 mm, 3 μm) and a photodiode array detector. The mobile phase consisted of 0.2% acetic acid (v/v) in distilled water and acetonitrile (42:58, v/v). The present method was validated in terms of linearity, lower limit of quantification, lower limit of detection, precision, accuracy, recovery, and stability of MDA according to U.S. Food and Drug Administration (FDA) guidelines. The limit of quantification of MDA was 0.39 μmol/L, which is comparable to other methods. The recovery of the spiked MDA liver samples was in the range of 92.4% to 104.2%. This newly modified HPLC method is specific, sensitive, and accurate and allows the analysis of MDA within 4 min in fish liver but also in other tissues and plasma. © 2014 Institute of Food Technologists®

Glomerular malondialdehyde levels in patients with focal and segmental glomerulosclerosis and minimal change disease.

PubMed

Nezhad, Simin Torabi; Momeni, Babak; Basiratnia, Mitra

2010-09-01

Minimal change disease (MCD) and focal and segmental glomerulosclerosis (FSGS) are often studied together, because both present with heavy proteinuria and the nephrotic syndrome. The precise distinction between MCD and FSGS is sometimes difficult because of inadequate number of glomeruli for definite diagnosis. Some evidence suggests that markers of lipid peroxidation, such as malondialdehyde (MDA) is an index of free radical mediated injury and may be involved in the pathogenesis of FSGS. In this study, we assessed the immunoreactivity of MDA, the end product of lipid peroxidation in glomeruli of patients with idiopathic FSGS, MCD as well as normal controls (NC). Our results showed that the immunostaining level of MDA was significantly higher in patients with FSGS (mean = 1.5) than in either patients with MCD (mean = 0.16) or normal controls (mean = 0.11) with P value < 0.001. Glomerular MDA level correlated well with the degree of glomerulosclerosis in patients with idiopathic FSGS. Our data demonstrates that the glomerular level of MDA is higher in idiopathic FSGS than MCD. We suggest that MDA immunostaining can be helpful in differentiating between FSGS and MCD in problematic cases and when we do not have enough glomeruli for definite and correct diagnosis.

Anti-proliferative and apoptosis inducing potential of hydroalcoholic Achillea wilhelmsii C. Koch extract on human breast adenocarcinoma cell lines MCF-7 and MDA-Mb-468.

PubMed

Galavi, Hamid Reza; Saravani, Ramin; Shahraki, Ali; Ashtiani, Mojtaba

2016-11-01

Achillea wilhelmsii C. Koch contains a variety of components such as flavonoid. The previous studies showed that flavonoid has anti-cancer properties. The aim of the present study was to determine the anti-proliferative and apoptosis-inducing potential of hydroalcoholic Achillea wilhelmsii C. Koch extract (HAWE) on MCF-7 and MDA-Mb-468 human breast carcinoma cell lines. The anti-proliferative activity of HAWE was evaluated using MTT, flowcytometry by annexin V/PI double staining, and caspase-3 activity. The results of MTT showed that the ED50 of MCF-7 and MDA-Mb-468 was 25μg/ml of HAWE, 48h after treatment. Flowcytometry by annexin V/PI showed that HAWE induced late apoptosis in MCF-7 and early apoptosis in MDA-Mb-468. In addition, the caspase-3 colorimetric method showed that caspase-3 increased in the MDA-Mb-468 after treatment with HAWE. This study found that the hydroalcoholic extract of Achillea wilhelmsii C. Koch induced apoptosis in both the MCF-7 and MDA-Mb-468 human breast carcinoma cell lines.

The effect of L-thyroxine replacement therapy on ischemia-modified albümin and malondialdehyde levels in patients with overt and subclinical hypothyroidism.

PubMed

Erem, Cihangir; Suleyman, Akile Karacin; Civan, Nadim; Mentese, Ahmet; Nuhoglu, İrfan; Uzun, Aysegul; Coskun, Hulya; Deger, Orhan

2016-11-01

The main objective of this study was to evaluate the levels of ischemia-modified albumin (IMA) and malondialdehyde (MDA) in patients with subclinical (SHypo) and overt hypothyroidism (OHypo), and to assess the effects of levothyroxine (LT 4 ) therapy on the oxidative stress (OS) parameters. We also investigated the relationships among serum thyroid hormones, lipid parameters, and IMA and MDA in these patients. Thirty untreated patients with OHypo, 25 untreated patients with Shypo, and 30 age- and sex-matched healthy controls were prospectively included in the study. Biochemical and hormonal parameters including IMA and MDA were evaluated in all patients just before and one month after the maintenance of euthyroidism. Compared with the control subjects, the levels of MDA and triglycerides (TG) significantly increased in patients with SHypo (p < 0.001 and p < 0.05, respectively), whereas high density lipoprotein cholesterol (HDL-C) levels significantly decreased (p = 0.01). Patients with OHypo showed significantly high MDA, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and TG levels (p = 0.001, p < 0.01, p = 0.01, and p < 0.01, respectively), and significantly low HDL-C levels compared with the controls (p < 0.05). MDA levels and lipid profile were not significantly different in the patients with OHypo when compared with the patients with SHypo. Serum IMA levels did not significantly change in patients with OHypo and SHypo compared with the controls. In the pre-treatment period, MDA levels were inversely correlated with HDL-C levels in patients with OHypo (r: -0.471, p = 0.009). Plasma MDA and LDL-C levels significantly decreased and HDL-C levels significantly increased in the groups of OHypo and SHypo after LT 4 treatment. Serum IMA levels did not significantly change with the therapy in all patient groups. Increased MDA levels in both patient groups represent increased lipid peroxidation which might play an important role in the pathogenesis of the atherosclerosis seen in these patients. Increased OS in patients with SHypo and OHypo could be improved by LT 4 treatment. Also, MDA can be used as a reliable marker of OS and oxidative damage, while IMA is considered to be inappropriate.

Discovery of 1-(3-aryl-4-chlorophenyl)-3-(p-aryl)urea derivatives against breast cancer by inhibiting PI3K/Akt/mTOR and Hedgehog signalings.

PubMed

Li, Wenlu; Sun, Qinsheng; Song, Lu; Gao, Chunmei; Liu, Feng; Chen, Yuzong; Jiang, Yuyang

2017-12-01

PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design. Several compounds displayed excellent antiproliferative activities against several breast cancer cell lines, including triple-negative breast cancer (TNBC) MDA-MB-231 cell. Further mechanistic studies demonstrated that the representative compound 9i could inhibit both PI3K/Akt/mTOR and hedgehog (Hh) signalings by inhibiting the phosphorylation of S6K and Akt as well as decreasing the SAG elevated expression of Gli1. Compound 9i could also induce apoptosis remarkably in T47D and MDA-MB-231 cells. In the transwell assay, 9i showed significant inhibition on the migration of MDA-MB-231. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Alteration of gene expression in MDA-MB-453 breast cancer cell line in response to continuous exposure to Trastuzumab.

PubMed

Sharieh, Elham Abu; Awidi, Abdulla S; Ahram, Mamoun; Zihlif, Malek A

2016-01-10

Development of resistance against cancer therapeutic agents is a common problem in cancer management. Trastuzumab resistance is one of the challenges in management of HER-2-positive breast cancer patients resulting in breast cancer progression, metastasis, and patient poor outcome. The aim of this study is to determine the alteration in gene expression in response to Trastuzumab resistance after long-term exposure to Trastuzumab. The Trastuzumab-resistant MDA-MB-453 (MDA-MB-453/TR) cell line was developed by exposing cells to 10 μM Trastuzumab continuously for 6 months. Sensitivity toward Trastuzumab was tested using cell viability assays. The acquisition of an epithelial-to mesenchymal transition (EMT) phenotype was also observed in parallel with the development of resistance. Based on the real-time-based PCR array technology, several genes were altered affecting multiple networks. The most up-regulated genes were TGF-β1 and EGF, and IGFBP-3. These genes are known to have a critical role in Trastuzumab resistance in breast cancer cell lines and/or in the acquisition of EMT. They are also recognized for their role in cancer progression and metastasis. These alterations indicate that the development of Trastuzumab resistance is multifactorial and involves a development of a mesenchymal like phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

Simultaneous Analysis of Malondialdehyde, 4-Hydroxy-2-hexenal, and 4-Hydroxy-2-nonenal in Vegetable Oil by Reversed-Phase High-Performance Liquid Chromatography.

PubMed

Ma, Lukai; Liu, Guoqin

2017-12-27

A group of toxic aldehydes such as, malondialdehyde (MDA), 4-hydroxy-2-hexenal (HHE), and 4-hydroxy-2-nonenal (HNE) have been found in various vegetable oils and oil-based foods. Then simultaneous determination of them holds a great need in both the oil chemistry field and food field. In the present study, a simple and efficient analytical method was successfully developed for the simultaneous separation and detection of MDA, HHE, and HNE in vegetable oils by reversed-phase-high-performance liquid chromatography (RP-HPLC) coupled with photodiode array detector (PAD) at dual-channel detection mode. The effect of various experimental factors on the extraction performance, such as coextraction solvent system, butylated hydroxytoluene addition, and trichloroacetic acid addition were systematically investigated. Results showed that the linear ranges were 0.02-10.00 μg/mL for MDA, 0.02-4.00 μg/mL for HHE, and 0.03-4.00 μg/mL for HNE with the satisfactory correlation coefficient of >0.999 for all detected aldehydes. The limit of detection (LOD) and limit of quantification (LOQ) of MDA, HHE, and HNE were ∼0.021and 0.020 μg/mL, ∼0.009 and 0.020 μg/mL, and ∼0.014 and 0.030 μg/mL, respectively. Their recoveries were 99.64-102.18%, 102.34-104.61%, and 98.87-103.04% for rapeseed oil and 96.38-98.05%, 96.19-101.34%, and 96.86-99.04% for French fries, separately. Under the selected conditions, the developed methods was successfully applied to the simultaneous determination of MDA, HHE, and HNE in different tested vegetable oils. The results indicated that this method could be employed for the quality assessment of vegetable oils.

29 CFR 1926.60 - Methylenedianiline.

Code of Federal Regulations, 2013 CFR

2013-07-01

... the following: (i) Construction, alteration, repair, maintenance, or renovation of structures... based are scientifically sound and were collected using methods that are sufficiently accurate and... are substantially similar. The data must be scientifically sound, the characteristics of the MDA...

29 CFR 1926.60 - Methylenedianiline.

Code of Federal Regulations, 2014 CFR

2014-07-01

... the following: (i) Construction, alteration, repair, maintenance, or renovation of structures... based are scientifically sound and were collected using methods that are sufficiently accurate and... are substantially similar. The data must be scientifically sound, the characteristics of the MDA...

29 CFR 1926.60 - Methylenedianiline.

Code of Federal Regulations, 2012 CFR

2012-07-01

... the following: (i) Construction, alteration, repair, maintenance, or renovation of structures... based are scientifically sound and were collected using methods that are sufficiently accurate and... are substantially similar. The data must be scientifically sound, the characteristics of the MDA...

Integrating Neglected Tropical Disease and Immunization Programs: The Experiences of the Tanzanian Ministry of Health

PubMed Central

Mwingira, Upendo John; Means, Arianna Rubin; Chikawe, Maria; Kilembe, Bernard; Lyimo, Dafrossa; Crowley, Kathryn; Rusibamayila, Neema; Nshala, Andreas; Mphuru, Alex

2016-01-01

Global health practitioners are increasingly advocating for the integration of community-based health-care platforms as a strategy for increasing the coverage of programs, encouraging program efficiency, and promoting universal health-care goals. To leverage the strengths of compatible programs and avoid geographic and temporal duplications in efforts, the Tanzanian Ministry of Health and Social Welfare coordinated immunization and neglected tropical disease programs for the first time in 2014. Specifically, a measles and rubella supplementary vaccine campaign, mass drug administration (MDA) of ivermectin and albendazole, and Vitamin A were provisionally integrated into a shared community-based delivery platform. Over 21 million people were targeted by the integrated campaign, with the immunization program and MDA program reaching 97% and 93% of targeted individuals, respectively. The purpose of this short report is to share the Tanzanian experience of launching and managing this integrated campaign with key stakeholders. PMID:27246449

Sequencing of the large dsDNA genome of Oryctes rhinoceros nudivirus using multiple displacement amplification of nanogram amounts of virus DNA.

PubMed

Wang, Yongjie; Kleespies, Regina G; Ramle, Moslim B; Jehle, Johannes A

2008-09-01

The genomic sequence analysis of many large dsDNA viruses is hampered by the lack of enough sample materials. Here, we report a whole genome amplification of the Oryctes rhinoceros nudivirus (OrNV) isolate Ma07 starting from as few as about 10 ng of purified viral DNA by application of phi29 DNA polymerase- and exonuclease-resistant random hexamer-based multiple displacement amplification (MDA) method. About 60 microg of high molecular weight DNA with fragment sizes of up to 25 kbp was amplified. A genomic DNA clone library was generated using the product DNA. After 8-fold sequencing coverage, the 127,615 bp of OrNV whole genome was sequenced successfully. The results demonstrate that the MDA-based whole genome amplification enables rapid access to genomic information from exiguous virus samples.

A stochastic model for the probability of malaria extinction by mass drug administration.

PubMed

Pemberton-Ross, Peter; Chitnis, Nakul; Pothin, Emilie; Smith, Thomas A

2017-09-18

Mass drug administration (MDA) has been proposed as an intervention to achieve local extinction of malaria. Although its effect on the reproduction number is short lived, extinction may subsequently occur in a small population due to stochastic fluctuations. This paper examines how the probability of stochastic extinction depends on population size, MDA coverage and the reproduction number under control, R c . A simple compartmental model is developed which is used to compute the probability of extinction using probability generating functions. The expected time to extinction in small populations after MDA for various scenarios in this model is calculated analytically. The results indicate that mass drug administration (Firstly, R c must be sustained at R c  < 1.2 to avoid the rapid re-establishment of infections in the population. Secondly, the MDA must produce effective cure rates of >95% to have a non-negligible probability of successful elimination. Stochastic fluctuations only significantly affect the probability of extinction in populations of about 1000 individuals or less. The expected time to extinction via stochastic fluctuation is less than 10 years only in populations less than about 150 individuals. Clustering of secondary infections and of MDA distribution both contribute positively to the potential probability of success, indicating that MDA would most effectively be administered at the household level. There are very limited circumstances in which MDA will lead to local malaria elimination with a substantial probability.

Characterization and immune response expression of the Rig-I-like receptor mda5 in common carp Cyprinus carpio.

PubMed

Zhu, Y Y; Xing, W X; Shan, S J; Zhang, S Q; Li, Y Q; Li, T; An, L; Yang, G W

2016-06-01

In this study, the full-length complementary (c)DNA of common carp Cyprinus carpio melanoma differentiation-associated gene 5 (mda5) was cloned. The complete open reading frame of C. carpio mda5 contained 2982 bp and encodes 993 amino acids. The deduced amino acids contained six functional domains: two caspase activation and recruitment domains (CARD), a conserved restriction domain of bacterial type III restriction enzyme (ResIII), a DExD/H box-containing domain (DEXDc), a helicase super family C-terminal domain (HELICc) and a C-terminal regulatory domain (RD). The mda5 gene was expressed in all tested tissues, with high levels in the gills and spleen, while lower expressed in gonad and blood. The copy numbers of mda5 were increased in the liver, spleen, head kidney and the mucosal-associated immune tissues such as the foregut, hindgut, gills and skin after stimulation with polyinosinic polycytidylic [poly(I:C)] and Aeromonas hydrophila. The myxovirus resistance gene (mx) messenger (m)RNA levels in the spleen, head kidney, foregut and gills were significantly up-regulated after poly(I:C) injection. When injected with poly(I:C), mda5 and mx transcripts were also significantly induced in vitro. These results implied that mda5 might be involved in both antiviral and antibacterial innate immune processes in C. carpio. © 2016 The Authors. Journal of Fish Biology © 2016 The Fisheries Society of the British Isles. © 2016 The Fisheries Society of the British Isles.

Brain-derived neurotrophic factor (BDNF) -TrKB signaling modulates cancer-endothelial cells interaction and affects the outcomes of triple negative breast cancer

PubMed Central

Tsai, Yi-Fang; Hsu, Chih-Yi; Yang, Muh-Hwa; Shyr, Yi-Ming

2017-01-01

Aims There is good evidence that the tumor microenvironment plays an important role in cancer metastasis and progression. Our previous studies have shown that brain-derived neurotrophic factor (BDNF) participates in the process of metastasis and in the migration of cancer cells. The aim of this study was to investigate the role of BDNF on the tumor cell microenvironment, namely, the cancer cell-endothelial cell interaction of TNBC cells. Methods We conducted oligoneucleotide microarray analysis of potential biomarkers that are able to differentiate recurrent TNBC from non-recurrent TNBC. The MDA-MB-231 and human endothelial HUVEC lines were used for this study and our approaches included functional studies, such as migration assay, as well as Western blot and real-time PCR analysis of migration and angiogenic signaling. In addition, we analyzed the survival outcome of TNBC breast cancer patients according to their expression level of BDNF using clinical samples. Results The results demonstrated that BDNF was able to bring about autocrinal (MDA-MB-231) and paracrinal (HUVECs) regulation of BDNF-TrkB gene expression and this affected cell migratory activity. The BDNF-induced migratory activity was blocked by inhibitors of ERK, PI3K and TrkB when MDA-MB-231 cells were examined, but only an inhibitor of ERK blocked this activity when HUVEC cells were used. Furthermore, decreased migratory activity was found for △BDNF and △TrkB cell lines. Ingenuity pathway analysis (IPA) of MDA-MB-231 cells showed that BDNF is a key factor that is able to regulate a network made up of metalloproteases and calmodulin. Protein expression levels in a tissue array of tumor slices were found to be correlated with patient prognosis and the results showed that there was significant correlation of TrkB expression, but not of BDNF. expressionwith patient DFS and OS. Conclusion Our study demonstrates that up-regulation of the BDNF signaling pathway seems tobe involved in the mechanism associated with early recurrence in triple negative breast cancer cell. In addition, BDNF can function in either an autocrine or a paracrine manner to increase the migration ability of both MDA-MB-231 cells and HUVEC cells. Finally, overexpression of TrkB, but not of BDNF, is significantly associated with a poor survival outcome for TNBC patients. PMID:28604807

Brain-derived neurotrophic factor (BDNF) -TrKB signaling modulates cancer-endothelial cells interaction and affects the outcomes of triple negative breast cancer.

PubMed

Tsai, Yi-Fang; Tseng, Ling-Ming; Hsu, Chih-Yi; Yang, Muh-Hwa; Chiu, Jen-Hwey; Shyr, Yi-Ming

2017-01-01

There is good evidence that the tumor microenvironment plays an important role in cancer metastasis and progression. Our previous studies have shown that brain-derived neurotrophic factor (BDNF) participates in the process of metastasis and in the migration of cancer cells. The aim of this study was to investigate the role of BDNF on the tumor cell microenvironment, namely, the cancer cell-endothelial cell interaction of TNBC cells. We conducted oligoneucleotide microarray analysis of potential biomarkers that are able to differentiate recurrent TNBC from non-recurrent TNBC. The MDA-MB-231 and human endothelial HUVEC lines were used for this study and our approaches included functional studies, such as migration assay, as well as Western blot and real-time PCR analysis of migration and angiogenic signaling. In addition, we analyzed the survival outcome of TNBC breast cancer patients according to their expression level of BDNF using clinical samples. The results demonstrated that BDNF was able to bring about autocrinal (MDA-MB-231) and paracrinal (HUVECs) regulation of BDNF-TrkB gene expression and this affected cell migratory activity. The BDNF-induced migratory activity was blocked by inhibitors of ERK, PI3K and TrkB when MDA-MB-231 cells were examined, but only an inhibitor of ERK blocked this activity when HUVEC cells were used. Furthermore, decreased migratory activity was found for △BDNF and △TrkB cell lines. Ingenuity pathway analysis (IPA) of MDA-MB-231 cells showed that BDNF is a key factor that is able to regulate a network made up of metalloproteases and calmodulin. Protein expression levels in a tissue array of tumor slices were found to be correlated with patient prognosis and the results showed that there was significant correlation of TrkB expression, but not of BDNF. expressionwith patient DFS and OS. Our study demonstrates that up-regulation of the BDNF signaling pathway seems tobe involved in the mechanism associated with early recurrence in triple negative breast cancer cell. In addition, BDNF can function in either an autocrine or a paracrine manner to increase the migration ability of both MDA-MB-231 cells and HUVEC cells. Finally, overexpression of TrkB, but not of BDNF, is significantly associated with a poor survival outcome for TNBC patients.

miR-145-dependent targeting of junctional adhesion molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness.

PubMed

Götte, M; Mohr, C; Koo, C-Y; Stock, C; Vaske, A-K; Viola, M; Ibrahim, S A; Peddibhotla, S; Teng, Y H-F; Low, J-Y; Ebnet, K; Kiesel, L; Yip, G W

2010-12-16

Micro RNAs are small non-coding RNAs, which regulate fundamental cellular and developmental processes at the transcriptional and translational level. In breast cancer, miR-145 expression is downregulated compared with healthy control tissue. As several predicted targets of miR-145 potentially regulate cell motility, we aimed at investigating a potential role for miR-145 in breast cancer cell motility and invasiveness. Assisted by Affymetrix array technology, we demonstrate that overexpression of miR-145 in MDA-MB-231, MCF-7, MDA-MB-468 and SK-BR-3 breast cancer cells and in Ishikawa endometrial carcinoma cells leads to a downregulation of the cell-cell adhesion protein JAM-A and of the actin bundling protein fascin. Moreover, podocalyxin and Serpin E1 mRNA levels were downregulated, and gamma-actin, transgelin and MYL9 were upregulated upon miR-145 overexpression. These miR-145-dependent expression changes drastically decreased cancer cell motility, as revealed by time-lapse video microscopy, scratch wound closure assays and matrigel invasion assays. Immunofluorescence microscopy demonstrated restructuring of the actin cytoskeleton and a change in cell morphology by miR-145 overexpression, resulting in a more cortical actin distribution, and reduced actin stress fiber and filopodia formation. Nuclear rotation was observed in 10% of the pre-miR-145 transfected MDA-MB-231 cells, accompanied by a reduction of perinuclear actin. Luciferase activation assays confirmed direct miR-145-dependent regulation of the 3'UTR of JAM-A, whereas siRNA-mediated knockdown of JAM-A expression resulted in decreased motility and invasiveness of MDA-MB-231 and MCF-7 breast cancer cells. Our data identify JAM-A and fascin as novel targets of miR-145, firmly establishing a role for miR-145 in modulating breast cancer cell motility. Our data provide a rationale for future miR-145-targeted approaches of antimetastatic cancer therapy.

Prevalence of trachoma at sub-district level in ethiopia: determining when to stop mass azithromycin distribution.

PubMed

King, Jonathan D; Teferi, Tesfaye; Cromwell, Elizabeth A; Zerihun, Mulat; Ngondi, Jeremiah M; Damte, Mesele; Ayalew, Frew; Tadesse, Zerihun; Gebre, Teshome; Mulualem, Ayelign; Karie, Alemu; Melak, Berhanu; Adugna, Mitku; Gessesse, Demelash; Worku, Abebe; Endashaw, Tekola; Admassu Ayele, Fisseha; Stoller, Nicole E; King, Mary Rose A; Mosher, Aryc W; Gebregzabher, Tesfaye; Haileysus, Geremew; Odermatt, Peter; Utzinger, Jürg; Emerson, Paul M

2014-03-01

To eliminate blinding trachoma, the World Health Organization emphasizes implementing the SAFE strategy, which includes annual mass drug administration (MDA) with azithromycin to the whole population of endemic districts. Prevalence surveys to assess impact at the district level are recommended after at least 3 years of intervention. The decision to stop MDA is based on a prevalence of trachomatous inflammation follicular (TF) among children aged 1-9 years below 5% at the sub-district level, as determined by an additional round of surveys limited within districts where TF prevalence is below 10%. We conducted impact surveys powered to estimate prevalence simultaneously at the sub-district and district in two zones of Amhara, Ethiopia to determine whether MDA could be stopped. Seventy-two separate population-based, sub-district surveys were conducted in 25 districts. In each survey all residents from 10 randomly selected clusters were screened for clinical signs of trachoma. Data were weighted according to selection probabilities and adjusted for correlation due to clustering. Overall, 89,735 residents were registered from 21,327 households of whom 72,452 people (80.7%) were examined. The prevalence of TF in children aged 1-9 years was below 5% in six sub-districts and two districts. Sub-district level prevalence of TF in children aged 1-9 years ranged from 0.9-76.9% and district-level from 0.9-67.0%. In only one district was the prevalence of trichiasis below 0.1%. The experience from these zones in Ethiopia demonstrates that impact assessments designed to give a prevalence estimate of TF at sub-district level are possible, although the scale of the work was challenging. Given the assessed district-level prevalence of TF, sub-district-level surveys would have been warranted in only five districts. Interpretation was not as simple as stopping MDA in sub-districts below 5% given programmatic challenges of exempting sub-districts from a highly regarded program and the proximity of hyper-endemic sub-districts.

Study of oxidative stress biomarkers in chronic obstructive pulmonary disease and their correlation with disease severity in north Indian population cohort

PubMed Central

Bajpai, Jyoti; Prakash, Ved; Kant, Surya; Verma, Ajay Kumar; Srivastava, Anand; Bajaj, Darshan K; Ahmad, MK; Agarwal, Avinash

2017-01-01

Background: Oxidant-antioxidant imbalance forms a prime component in pathogenesis of chronic obstructive pulmonary disease (COPD). Studies of oxidative stress markers in South Asians were sparse. Methods: One hundred and eighty COPD patients and eighty healthy nonsmokers were enrolled in the study. Serum malondialdehyde (MDA) and iron levels were estimated for oxidative stress. Three antioxidant markers evaluated-catalase, superoxide dismutase (SOD), and serum copper. Patients on antioxidant therapy and with sepsis and chronic illness were excluded from the study. Results: The mean age of COPD patients was 59.29 ± 10.3 years. Serum levels of MDA and iron were significantly higher in COPD patients compared to controls (5.21 ± 1.9 vs. 0.71 ± 0.29 nmol MDA/ml, P = 0.0001 and 69.85 ± 85.49 vs. 79.32 ± 24.39 μg/dl, P = 0.0001, respectively). Mean level of all antioxidant enzymes catalase, SOD, and copper were significantly diminished in cases when compared to control population (P = 0.001). Levels of MDA and iron were found to be significantly elevated in higher Global Initiative for Chronic Obstructive Lung Disease (GOLD) classes (III, IV) when compared to lower GOLD Classes (I, II). The levels of serum antioxidants were significantly depleted in higher GOLD grades too. COPD patients who were male and smoked had significantly higher levels of oxidants and depleted antioxidant levels compared to female and nonsmoking compatriots. Serum MDA levels negatively correlated with forced expiratory volume 1 s and forced vital capacity (r = −0.19 and r = −0.21, P ≤ 0.01). The presence of a cough significantly correlated with higher levels of MDA and iron (P = 0.001). The levels of MDA negatively correlated with SOD and catalase levels. Conclusion: Oxidative markers (MDA and iron) are higher whereas antioxidants (catalase, copper, and SOD) are significantly reduced in patients of COPD. Serum MDA levels correlate with lung functions and disease severity. PMID:28671162

Community-based trial of annual versus biannual single-dose ivermectin plus albendazole against Wuchereria bancrofti infection in human and mosquito populations: study protocol for a cluster randomised controlled trial.

PubMed

de Souza, Dziedzom K; Ahorlu, Collins S; Adu-Amankwah, Susan; Otchere, Joseph; Mensah, Sedzro K; Larbi, Irene A; Mensah, George E; Biritwum, Nana-Kwadwo; Boakye, Daniel A

2017-10-02

The Global Programme for the Elimination of Lymphatic Filariasis (GPELF) has been in operation since the year 2000, with the aim of eliminating the disease by the year 2020, following five to six rounds of effective annual mass drug administration (MDA). The treatment regimen is ivermectin (IVM) in combination with diethylcarbamazine (DEC) or albendazole (ALB). In Ghana, MDA has been undertaken since 2001. While the disease has been eliminated in many areas, transmission has persisted in some implementation units that had experienced 15 or more rounds of MDA. Thus, new intervention strategies could eliminate residual infection in areas of persistent transmission and speed up the lymphatic filariasis (LF)-elimination process. This study, therefore, seeks to test the hypothesis that biannual treatment of LF-endemic communities will accelerate the interruption of LF in areas of persistent transmission. A cluster randomised trial will be implemented in LF-endemic communities in Ghana. The interventions will be yearly or twice-yearly MDA delivered to entire endemic communities. Allocation to study group will be by clusters identified using the prevalence of LF. Clusters will be randomised to one of two groups: receiving either (1) annual treatment with IVM + ALB or (2) annual MDA with IVM + ALB, followed by an additional MDA 6 months later. The primary outcome measure is the prevalence of LF infection, assessed by four cross-sectional surveys. Entomological assessments will also be undertaken to evaluate the transmission intensity of the disease in the study clusters. Costs and cost-effectiveness will be evaluated. Among a random subsample of participants, microfilaria prevalence will be assessed longitudinally. A nested process evaluation, using semi-structured interviews, focus group discussions and a stakeholder analysis, will investigate the community acceptability, feasibility and scale-up of each delivery system. It is expected that this study will add to the existing evidence on the need for alternative intervention strategies for the elimination of LF in Ghana and in other African countries that are facing similar challenges or are at the beginning of their LF-elimination programmes. ClinicalTrials.gov, ID: NCT03036059 . Registered on 26 January 2017. Pan African Clinical Trials Registry, ID: PACTR201702002012425 . Registered on 23 February 2017.

Effective adoptive immunotherapy of triple-negative breast cancer by folate receptor-alpha redirected CAR T cells is influenced by surface antigen expression level.

PubMed

Song, De-Gang; Ye, Qunrui; Poussin, Mathilde; Chacon, Jessica A; Figini, Mariangela; Powell, Daniel J

2016-07-20

The poor prognosis and the limited efficacy of targeted therapy in patients with triple-negative breast cancer (TNBC) have raised the need for alternative therapies. Recent studies have demonstrated that folate receptor-alpha (FRα) may represent an ideal tumor-associated marker for immunotherapy for TNBC. The aim of the present study was to apply a chimeric antigen receptor (CAR) approach for the targeting of FRα expressed on TNBC cells and evaluate the antitumor activity of CAR-engineered T cells in vitro and in vivo. We found that human T cells expressing a FRα-specific CAR were potent and specific killers of TNBC cells that express moderate levels of FRα in vitro and significantly inhibited tumor outgrowth following infusion into immunodeficient mice bearing an MDA-MB-231 tumor xenograft. However, the antitumor activity of the FRα CAR T cells was modest when compared to the same CAR T cells applied in an ovarian tumor xenograft model where FRα expression is more abundant. Notably, FRα CAR T cells induced superior tumor regression in vivo against MDA-MB-231 that was engineered for overexpression of FRα. Taken together, our results show that FRα CAR T cells can mediate antitumor activity against established TNBC tumor, particularly when FRα is expressed at higher levels. These results have significant implications for the pre-selection of patients with high antigen expression levels when utilizing CAR-based adoptive T cell therapies of cancer in future clinical trials.

Whole-grain and refined wheat flours show distinct metabolic profiles in rats as assessed by a 1H NMR-based metabonomic approach.

PubMed

Fardet, Anthony; Canlet, Cécile; Gottardi, Gaëlle; Lyan, Bernard; Llorach, Rafaël; Rémésy, Christian; Mazur, André; Paris, Alain; Scalbert, Augustin

2007-04-01

The protection against diabetes and cardiovascular disease provided by whole-grain cereal consumption has been attributed to the fiber and micronutrients present in the bran. But exactly how this occurs remains unclear due to both diversity of bran constituents and the complexity of the metabolic responses to each of these constituents. We investigated the metabolic responses of 2 groups of rats (n = 10/group) fed 2 diets, for 2 wk each, in a crossover design. One diet contained 60 g/100 g whole-grain wheat flour (WGF) and the other contained 60 g/100 g refined wheat flour (RF). Markers of oxidative stress [urinary isoprostanes and malondialdehydes (MDA), plasma ferric-reducing ability of plasma, MDA, and vitamins E and C] and lipid status (liver and plasma triglycerides and cholesterol) were measured. Urine samples collected during the feeding periods and plasma and liver samples collected at the end of experiment were analyzed by (1)H NMR spectroscopy. Metabonomic analyses showed that each group reached a new metabolic balance within 48 h of changing the diet. Urinary excretion of some tricarboxylic acid cycle intermediates, aromatic amino acids, and hippurate was significantly greater in rats fed the WGF diet. Although the diets did not affect conventional lipid and oxidative stress markers, there were decreases in some liver lipids and increases in liver reduced glutathione and betaine as shown by metabonomic analyses. These suggest that the WGF diet improved the redox and lipid status.

Assessment of radionuclide contents in food in Hong Kong

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, K.N.; Mao, S.Y.

1999-12-01

Baseline values of concentrations of the natural radionuclides ({sup 238}U, {sup 226}Ra, {sup 228}Ra/{sup 232}Th, {sup 210}Pb) and artificial radionuclides ({sup 137}Cs, {sup 60}Co) in food and drinks (tap water, milk, and water-based drinks) were determined by gamma spectroscopy. All food and drinks were found to contain detectable {sup 40}K contents: 0.1 to 160 Bq Kg{sup {minus}1} for food and 0.006 to 61 Bq L{sup {minus}1} for drinks. Most of the other natural radionuclides in solid food were found to have contents below the minimum detectable activities (MDA). More samples in the leafy vegetable, tomato, carrot and potato categories containedmore » detectable amounts of {sup 228}Ra than the meat, cereal, and fish categories, with concentrations up to 1.2 Bq kg{sup {minus}1} for the former categories and 0.35 Bq kg{sup {minus}1} for the latter categories. The {sup 238}U and {sup 226}Ra radionuclides were detectable in most of the water-based drink samples, and the {sup 228}Ra and {sup 210}Pb radionuclides were detectable in fewer water-based drink samples. The {sup 137}Cs contents in solid food were detectable in most of the solid food samples (reaching 0.59 Bq kg{sup {minus}1}), but in drinks the {sup 137}Cs contents were very low and normally lower than the MDA values. Nearly all the {sup 60}Co contents in food and drinks were below the MDA values and their contents were below those of {sup 137}Cs.« less

Context dependent reversion of tumor phenotype by connexin-43 expression in MDA-MB231 cells and MCF-7 cells: Role of β-catenin/connexin43 association

DOE Office of Scientific and Technical Information (OSTI.GOV)

Talhouk, Rabih S., E-mail: rtalhouk@aub.edu.lb; Fares, Mohamed-Bilal; Rahme, Gilbert J.

Connexins (Cx), gap junction (GJ) proteins, are regarded as tumor suppressors, and Cx43 expression is often down regulated in breast tumors. We assessed the effect of Cx43 over-expression in 2D and 3D cultures of two breast adenocarcinoma cell lines: MCF-7 and MDA-MB-231. While Cx43 over-expression decreased proliferation of 2D and 3D cultures of MCF-7 by 56% and 80% respectively, MDA-MB-231 growth was not altered in 2D cultures, but exhibited 35% reduction in 3D cultures. C-terminus truncated Cx43 did not alter proliferation. Untransfected MCF-7 cells formed spherical aggregates in 3D cultures, and MDA-MB-231 cells formed stellar aggregates. However, MCF-7 cells over-expressingmore » Cx43 formed smaller sized clusters and Cx43 expressing MDA-MB-231 cells lost their stellar morphology. Extravasation ability of both MCF-7 and MDA-MB-231 cells was reduced by 60% and 30% respectively. On the other hand, silencing Cx43 in MCF10A cells, nonneoplastic human mammary cell line, increased proliferation in both 2D and 3D cultures, and disrupted acinar morphology. Although Cx43 over-expression did not affect total levels of β-catenin, α-catenin and ZO-2, it decreased nuclear levels of β-catenin in 2D and 3D cultures of MCF-7 cells, and in 3D cultures of MDA-MB-231 cells. Cx43 associated at the membrane with α-catenin, β-catenin and ZO-2 in 2D and 3D cultures of MCF-7 cells, and only in 3D conditions in MDA-MB-231 cells. This study suggests that Cx43 exerts tumor suppressive effects in a context-dependent manner where GJ assembly with α-catenin, β-catenin and ZO-2 may be implicated in reducing growth rate, invasiveness, and, malignant phenotype of 2D and 3D cultures of MCF-7 cells, and 3D cultures of MDA-MB-231 cells, by sequestering β-catenin away from nucleus. - Highlights: • Cx43 over-expressing MCF-7 and MDA-MB-231 were grown in 2D and 3D cultures. • Proliferation and growth morphology were affected in a context dependent manner. • Extravasation ability of both MCF-7 and MDA-MB-231 cells was reduced. • Cx43-mediated gap junction complex assembly correlated with observed changes. • We propose that membranous Cx43 sequesters β-catenin away from the nucleus.« less

Non-destructive determination of Malondialdehyde (MDA) distribution in oilseed rape leaves by laboratory scale NIR hyperspectral imaging

NASA Astrophysics Data System (ADS)

Kong, Wenwen; Liu, Fei; Zhang, Chu; Zhang, Jianfeng; Feng, Hailin

2016-10-01

The feasibility of hyperspectral imaging with 400-1000 nm was investigated to detect malondialdehyde (MDA) content in oilseed rape leaves under herbicide stress. After comparing the performance of different preprocessing methods, linear and nonlinear calibration models, the optimal prediction performance was achieved by extreme learning machine (ELM) model with only 23 wavelengths selected by competitive adaptive reweighted sampling (CARS), and the result was RP = 0.929 and RMSEP = 2.951. Furthermore, MDA distribution map was successfully achieved by partial least squares (PLS) model with CARS. This study indicated that hyperspectral imaging technology provided a fast and nondestructive solution for MDA content detection in plant leaves.

Mass Treatment with Azithromycin for Trachoma: When Is One Round Enough? Results from the PRET Trial in The Gambia

PubMed Central

Harding-Esch, Emma M.; Sillah, Ansumana; Edwards, Tansy; Burr, Sarah E.; Hart, John D.; Joof, Hassan; Laye, Mass; Makalo, Pateh; Manjang, Ahmed; Molina, Sandra; Sarr-Sissoho, Isatou; Quinn, Thomas C.; Lietman, Tom; Holland, Martin J.; Mabey, David; West, Sheila K.; Bailey, Robin

2013-01-01

Background The World Health Organization has recommended three rounds of mass drug administration (MDA) with antibiotics in districts where the prevalence of follicular trachoma (TF) is ≥10% in children aged 1–9 years, with treatment coverage of at least 80%. For districts at 5–10% TF prevalence it was recommended that TF be assessed in 1–9 year olds in each community within the district, with three rounds of MDA provided to any community where TF≥10%. Worldwide, over 40 million people live in districts whose TF prevalence is estimated to be between 5 and 10%. The best way to treat these districts, and the optimum role of testing for infection in deciding whether to initiate or discontinue MDA, are unknown. Methods In a community randomized trial with a factorial design, we randomly assigned 48 communities in four Gambian districts, in which the prevalence of trachoma was known or suspected to be above 10%, to receive annual mass treatment with expected coverage of 80–89% (“Standard”), or to receive an additional visit in an attempt to achieve coverage of 90% or more (“Enhanced”). The same 48 communities were randomised to receive mass treatment annually for three years (“3×”), or to have treatment discontinued if Chlamydia trachomatis (Ct) infection was not detected in a sample of children in the community after mass treatment (stopping rule(“SR”)). Primary outcomes were the prevalence of TF and of Ct infection in 0–5 year olds at 36 months. Results The baseline prevalence of TF and of Ct infection in the target communities was 6.5% and 0.8% respectively. At 36 months the prevalence of TF was 2.8%, and that of Ct infection was 0.5%. No differences were found between the arms in TF or Ct infection prevalence either at baseline (Standard-3×: TF 5.6%, Ct 0.7%; Standard-SR: TF 6.1%, Ct 0.2%; Enhanced-3×: TF 7.4%, Ct 0.9%; and Enhanced-SR: TF 6.2%, Ct 1.2%); or at 36 months (Standard-3×: TF 2.3%, Ct 1.0%; Standard-SR TF 2.5%, Ct 0.2%; Enhanced-3× TF 3.0%, Ct 0.2%; and Enhanced-SR TF 3.2%, Ct 0.7% ). The implementation of the stopping rule led to treatment stopping after one round of MDA in all communities in both SR arms. Mean treatment coverage of children aged 0–9 in communities randomised to standard treatment was 87.7% at baseline and 84.8% and 88.8% at one and two years, respectively. Mean coverage of children in communities randomized to enhanced treatment was 90.0% at baseline and 94.2% and 93.8% at one and two years, respectively. There was no evidence of any difference in TF or Ct prevalence at 36 months resulting from enhanced coverage or from one round of MDA compared to three. Conclusions The Gambia is close to the elimination target for active trachoma. In districts prioritised for three MDA rounds, one round of MDA reduced active trachoma to low levels and Ct infection was not detectable in any community. There was no additional benefit to giving two further rounds of MDA. Programmes could save scarce resources by determining when to initiate or to discontinue MDA based on testing for Ct infection, and one round of MDA may be all that is necessary in some settings to reduce TF below the elimination threshold. PMID:23785525

Community health workers' experiences and perspectives on mass drug administration for schistosomiasis control in western Kenya: the SCORE Project.

PubMed

Omedo, Martin O; Matey, Elizabeth J; Awiti, Alphonce; Ogutu, Michael; Alaii, Jane; Karanja, Diana M S; Montgomery, Susan P; Secor, W Evan; Mwinzi, Pauline N M

2012-12-01

Abstract. The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) includes communitywide treatment in areas with ≥ 25% prevalence of schistosomiasis along the shores of Lake Victoria using community health workers (CHWs). The CHWs are key drivers in community-owned mass drug administration (MDA) intervention programs. We explored their experiences and perceptions after initial MDA participation. Unstructured open-ended group discussions were conducted after completion of MDA activities. Narratives were obtained from CHWs using a digital audio recorder during the group discussion, transcribed verbatim and translated into English where applicable. Thematic decomposition of data was done using ATLAS.t.i. software. From the perspective of the CHWs, factors influencing MDA compliance included drug side effects, food supply stability, and conspiracy theories about the "real" purpose of treatment. The interest of CHWs to serve as community drug distributors stemmed from both intrinsic and extrinsic factors. Feedback from CHWs can promote more effective MDA in rural Kenyan communities.

Coverage and Awareness of and Compliance with Mass Drug Administration for Elimination of Lymphatic Filariasis in Burdwan District, West Bengal, India

PubMed Central

Sarkar, Aditya Prasad; Misra, Raghunath; Chakroborty, Amitava; Mondal, Tusar Kanti; Bag, Kanad

2013-01-01

India adopted WHO's strategy of repeated rounds of mass drug administration (MDA) with diethylcarbamazine to eliminate lymphatic filariasis. The present study attempted to assess the coverage and awareness of and compliance with MDA for elimination of lymphatic filariasis in Burdwan district of India, following MDA round in July 2010. A cross-sectional study was conducted among the four randomly-selected clusters in the district of Burdwan, West Bengal, India, covering 603 individuals from 154 households, using a predesigned pretested schedule. The drug distribution coverage, compliance, and effective coverage were 48.76 %, 70.07%, and 34.16% respectively. Only 41.4% of the study population was aware of the MDA activity. This evaluation study noted that MDA is restricted to tablet distribution only. There is an urgent need to improve compliance with drug intake through strengthening of the awareness programme involving both government health workers and community volunteers. PMID:23930334

Acute and subacute toxicities effect of oxytetracycline pharmaceutical wastewater on Zebrafish

NASA Astrophysics Data System (ADS)

Wu, Pengpeng; Shen, Hong-Yan

2018-02-01

Oxytetracycline wastewater is a major category of pharmaceutical wastewater, and its toxic effects on aquatic organisms have aroused people’s attention. In this study, Zebrafish were separately exposed to four Oxytetracycline wastewater treatments (20%, 40%, 60%, 80%) and a control group were sampled on days 3, 6, 9, 12, and 15. Superoxide dismutase (SOD) activities showed significant inhibition, but the highest SOD activity was found in 20% and 40% the treatment groups (195.12U/mgprot, 187.43U/mgprot, respectively) on the 12th day. MDA contents increased significantly compared with control group. MDA contents showed that the higher the volume concentration, the higher the contents of MDA with the increase of exposure time. The highest MDA content shown in 60% exposure group (5.49nmol/mgprot) on the 12th day. And SOD activities and MDA contents showed a trend of “Λ” type. In conclusion, Oxytetracycline wastewater induced oxidative stress and toxicity in Zebrafish muscle tissue.

Oxidation-specific epitopes restrain bone formation.

PubMed

Ambrogini, Elena; Que, Xuchu; Wang, Shuling; Yamaguchi, Fumihiro; Weinstein, Robert S; Tsimikas, Sotirios; Manolagas, Stavros C; Witztum, Joseph L; Jilka, Robert L

2018-06-06

Atherosclerosis and osteoporosis are epidemiologically linked and oxidation specific epitopes (OSEs), such as phosphocholine (PC) of oxidized phospholipids (PC-OxPL) and malondialdehyde (MDA), are pathogenic in both. The proatherogenic effects of OSEs are opposed by innate immune antibodies. Here we show that high-fat diet (HFD)-induced bone loss is attenuated in mice expressing a single chain variable region fragment of the IgM E06 (E06-scFv) that neutralizes PC-OxPL, by increasing osteoblast number and stimulating bone formation. Similarly, HFD-induced bone loss is attenuated in mice expressing IK17-scFv, which neutralizes MDA. Notably, E06-scFv also increases bone mass in mice fed a normal diet. Moreover, the levels of anti-PC IgM decrease in aged mice. We conclude that OSEs, whether produced chronically or increased by HFD, restrain bone formation, and that diminished defense against OSEs may contribute to age-related bone loss. Anti-OSEs, therefore, may represent a novel therapeutic approach against osteoporosis and atherosclerosis simultaneously.

microRNA-145 regulates the RLR signaling pathway in miiuy croaker after poly(I:C) stimulation via targeting MDA5.

PubMed

Han, Jingjing; Sun, Yuena; Song, Weihua; Xu, Tianjun

2017-03-01

MicroRNAs (miRNAs) are endogenous small non-coding RNAs that participate in diverse biological processes via degrading the target mRNAs or repressing translation. In this study, the regulation of miRNA to the RLR (RIG-I-like receptor) signaling pathway by degrading the target mRNAs was researched in miiuy croaker. MDA5, a microRNA-145-5p (miR-145-5p) putative target gene, was predicted by bioinformatics, and the target sites from the 3'untranslated region of MDA5 transcripts were confirmed using luciferase reporter assays. Pre-miR-145 was more effective in inhibiting MDA5 than miR-145-5p mimic, and the effect was dose- and time-dependent. The expression patterns of miR-145-5p and MDA5 were analyzed in liver and kidney from miiuy croaker. Results implied that miR-145-5p may function via degrading the MDA5 mRNAs, thereby regulating the RLR signaling pathway. Studies on miR-145-5p will enrich knowledge of its functions in immune response regulation in fish, as well as offer a basis for regulatory networks that are composed of numerous miRNAs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Use of Multiple Displacement Amplification as Pre-polymerase Chain Reaction (Pre-PCR) to amplify genomic DNA of siphonapterids preserved for long periods in scientific collections.

PubMed

Avelar, Daniel M; Linardi, Pedro M

2010-09-15

The recently developed Multiple Displacement Amplification technique (MDA) allows for the production of a large quantity of high quality genomic DNA from low amounts of the original DNA. The goal of this study was to evaluate the performance of the MDA technique to amplify genomic DNA of siphonapterids that have been stored for long periods in 70% ethanol at room temperature. We subjected each DNA sample to two different methodologies: (1) amplification of mitochondrial 16S sequences without MDA; (2) amplification of 16S after MDA. All the samples obtained from these procedures were then sequenced. Only 4 samples (15.4%) subjected to method 1 showed amplification. In contrast, the application of MDA (method 2) improved the performance substantially, with 24 samples (92.3%) showing amplification, with significant difference. Interestingly, one of the samples successfully amplified with this method was originally collected in 1909. All of the sequenced samples displayed satisfactory results in quality evaluations (Phred ≥ 20) and good similarities, as identified with the BLASTn tool. Our results demonstrate that the use of MDA may be an effective tool in molecular studies involving specimens of fleas that have traditionally been considered inadequately preserved for such purposes.

Use of Multiple Displacement Amplification as Pre-polymerase Chain Reaction (Pre-PCR) to amplify genomic DNA of siphonapterids preserved for long periods in scientific collections

PubMed Central

2010-01-01

The recently developed Multiple Displacement Amplification technique (MDA) allows for the production of a large quantity of high quality genomic DNA from low amounts of the original DNA. The goal of this study was to evaluate the performance of the MDA technique to amplify genomic DNA of siphonapterids that have been stored for long periods in 70% ethanol at room temperature. We subjected each DNA sample to two different methodologies: (1) amplification of mitochondrial 16S sequences without MDA; (2) amplification of 16S after MDA. All the samples obtained from these procedures were then sequenced. Only 4 samples (15.4%) subjected to method 1 showed amplification. In contrast, the application of MDA (method 2) improved the performance substantially, with 24 samples (92.3%) showing amplification, with significant difference. Interestingly, one of the samples successfully amplified with this method was originally collected in 1909. All of the sequenced samples displayed satisfactory results in quality evaluations (Phred ≥ 20) and good similarities, as identified with the BLASTn tool. Our results demonstrate that the use of MDA may be an effective tool in molecular studies involving specimens of fleas that have traditionally been considered inadequately preserved for such purposes. PMID:20840790

Patient-centered communication of community treatment assistants in Tanzania predicts coverage of future mass drug administration for trachoma.

PubMed

Jenson, Alexander; Roter, Debra L; Mkocha, Harran; Munoz, Beatriz; West, Sheila

2018-06-01

Prevention of Trachoma, the leading cause of infectious blindness, requires community treatment assistants (CTAs) to perform mass drug administration (MDA) of azithromycin. Previous research has shown that female CTAs have higher MDA coverage, but no studies have focused on the content of conversation. We hypothesize that female CTAs had more patient-centered communication and higher MDA coverage. In 2011, CTAs from 23 distribution sites undergoing MDA as part of the Partnership for Rapid Elimination of Trachoma were selected. CTA - villager interactions were audio recorded. Audio was analyzed using an adaptation of the Roter Interaction Analysis System. The outcome of interest was the proportion of adults receiving MDA in 2011 who returned in 2012. 58 CTAs and 3122 interactions were included. Sites with female CTAs had significantly higher patient-centeredness ratio (0.548 vs 0.400) when compared to sites with male CTAs. Sites with more patient-centered interactions had higher proportion of patients return (p = 0.009). Female CTAs had higher proportion of patient-centered communication. Patient centered communication was associated with higher rates of return for MDA. Greater patient-centered connection with health care providers affects participation in public health efforts, even when those providers are lay health workers. Copyright © 2018 Elsevier B.V. All rights reserved.

Analysis of a carcinogen, 4,4'-methylenedianiline, from thermosetting polyurethane during sterilization.

PubMed

Shintani, H; Nakamura, A

1989-01-01

Polyurethane (PU) is widely used in medical devices such as potting material in artificial dialysis devices, plasma separators, etc. Gamma-ray irradiation is frequently used for the sterilization of such devices. This paper reports that a carcinogen, 4,4'-methylenedianiline (MDA, p,p'-diaminodiphenylmethane), is produced from medical thermosetting PU by gamma-ray irradiation. Gamma-ray irradiated PU was immersed in methanol or equine serum. The serum was treated with a mixture of 5N HCIO4:acetonitrile (1:10) in order to deproteinate and recover MDA. It was found that MDA is formed from thermosetting PU at around a few ppm in the original sample. The production of MDA increased with increasing irradiation dose. The MDA amount formed was related to the irradiation dose by a second order equation. Results of methanol and serum extraction were similar. Pressurized steam (autoclave) sterilization in place of gamma-ray sterilization was also examined. MDA production was not found in autoclave sterilization procedures. Gel permeation chromatography (GPC) of methanol or N,N-dimethylformamide (DMF) extract of irradiated PU showed that the PU oligomers eluted. Time course of methanol extract of irradiated PU was detected at 245.5 nm. This showed an exponential decline regardless of doses of irradiation.

[Inhibitory effect of exogenous insulin-like growth factor binding protein 7 on proliferation of human breast cancer cell line MDA-MB-453 and its mechanism].

PubMed

Yuan, Lei; Fan, Wen-Juan; Yang, Xu-Guang; Rao, Shu-Mei; Song, Jin-Ling; Song, Guo-Hua

2013-10-25

The present study was to investigate the effects of exogenous insulin-like growth factor binding protein 7 (IGFBP7) on the proliferation of human breast cancer cell line MDA-MB-453 and its possible mechanism. By means of MTT method in vitro, the results showed exogenous IGFBP7 inhibited the growth of MDA-MB-453 cells (IC50 of IGFBP7 = 8.49 μg/mL) in time- and concentration-dependent manner. SB203580, p38(MAPK) inhibitor, blocked the anti-proliferative effect of exogenous IGFBP7. The flow cytometry assay showed that exogenous IGFBP7 remarkably induced G0/G1 arrest in MDA-MB-453 cells. The Western blot showed that exogenous IGFBP7 promoted phosphorylation of p38(MAPK), up-regulated expression of p21(CIP1/WAF1), and inhibited phosphorylation of Rb. SB203580 restrained exogenous IGFBP7-induced regulation of p21(CIP1/WAF1) and p-Rb in MDA-MB-453 cells. In conclusion, the present study suggests that exogenous IGFBP7 could activate the p38(MAPK) signaling pathway, upregulate p21(CIP1/WAF1) expression, inhibit phosphorylation of Rb, and finally induce G0/G1 arrest in MDA-MB-453 cells.

Salivary Lipid Peroxidation and Total Sialic Acid Levels in Smokers and Smokeless Tobacco Users as Maraş Powder

PubMed Central

Kurtul, Naciye; Gökpınar, Engin

2012-01-01

Maraş powder (MP), a different type of smokeless tobacco (ST) and prepared from a tobacco of species Nicotiana rustica Linn, is widely used in Turkey. We aimed to investigate the effects of MP on salivary total sialic acid (TSA) and malondialdehyde (MDA) levels and to compare these parameters in smokers and MP users (MPUs). The salivary TSA and MDA concentrations were significantly higher in the smokers and MPU than those of control subjects and also in MPU than that of smokers. We have also observed that as the number of cigarettes consumed and MP amount increases, TSA and MDA levels increase too. In smokers, MDA values were significantly correlated with the number of cigarettes smoked and the duration of smoking. In MPU, both MDA and TSA levels were significantly correlated with the duration of MP use and the amount of daily consumed MP. We have concluded increased salivary TSA and MDA levels associated in MPU and smokers. Results can help to evaluate harmful effects of these habits. It is important to point out that bigger change in the measured parameters has been observed for MP use. This observation may be an important indication of harmful effects of ST use as MP. PMID:22577253

P16-positive continuous minimal deviation adenocarcinoma and gastric type adenocarcinoma in a patient with Peutz-Jeghers syndrome.

PubMed

Peng, Wei-Xia; Kure, Shoko; Ishino, Kousuke; Kurose, Keisuke; Yoneyama, Koichi; Wada, Ryuichi; Naito, Zenya

2015-01-01

We report a case of Peutz-Jeghers syndrome (PJS) in a 33-year-old female patient with synchronous uterine cervical minimal deviation adenocarcinoma (MDA) and gastric type adenocarcinoma (GTA). The patient was diagnosed with PJS at the age of 10. At the time of consultation, she complained of watery discharge. Magnetic resonance imaging of the pelvis showed a poorly circumscribed mass in the uterine cervix. Histologically, both MDA and GTA components, as well as their transitional area, were observed. Both components were diffusely positive for MUC6, CK7 and, robustly, for p16. Moreover, the components were negative for ER, PgR and CEA, while HIK1083 and CK20 positive cells were found focally. Ki-67 labeling index in the MDA component was 5% while that in the GTA component was 50%. This case of GTA accompanied by MDA in a patient with PJS is distinct from the single previously-reported comparable case of which we are aware, with respect to the overexpression of p16 protein, an event considered rare in these tumors, and the continuity between the MDA and GTA components. This continuity favors the hypothesis that GTA arises from the dedifferentiation of MDA.

P16-positive continuous minimal deviation adenocarcinoma and gastric type adenocarcinoma in a patient with Peutz-Jeghers syndrome

PubMed Central

Peng, Wei-Xia; Kure, Shoko; Ishino, Kousuke; Kurose, Keisuke; Yoneyama, Koichi; Wada, Ryuichi; Naito, Zenya

2015-01-01

We report a case of Peutz-Jeghers syndrome (PJS) in a 33-year-old female patient with synchronous uterine cervical minimal deviation adenocarcinoma (MDA) and gastric type adenocarcinoma (GTA). The patient was diagnosed with PJS at the age of 10. At the time of consultation, she complained of watery discharge. Magnetic resonance imaging of the pelvis showed a poorly circumscribed mass in the uterine cervix. Histologically, both MDA and GTA components, as well as their transitional area, were observed. Both components were diffusely positive for MUC6, CK7 and, robustly, for p16. Moreover, the components were negative for ER, PgR and CEA, while HIK1083 and CK20 positive cells were found focally. Ki-67 labeling index in the MDA component was 5% while that in the GTA component was 50%. This case of GTA accompanied by MDA in a patient with PJS is distinct from the single previously-reported comparable case of which we are aware, with respect to the overexpression of p16 protein, an event considered rare in these tumors, and the continuity between the MDA and GTA components. This continuity favors the hypothesis that GTA arises from the dedifferentiation of MDA. PMID:26191312

Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice

PubMed Central

Weismann, David; Jäckel, Sven; Walenbergh, Sofie M. A.; Rendeiro, André F.; Weißer, Juliane; Puhm, Florian; Hladik, Anastasiya; Göderle, Laura; Papac-Milicevic, Nikolina; Haas, Gerald; Millischer, Vincent; Subramaniam, Saravanan; Knapp, Sylvia; Bennett, Keiryn L.; Bock, Christoph; Reinhardt, Christoph; Shiri-Sverdlov, Ronit; Binder, Christoph J.

2018-01-01

Background and Rationale Diet-related health issues such as non-alcoholic fatty liver disease and cardiovascular disorders are known to have a major inflammatory component. However, the exact pathways linking diet-induced changes e.g. hyperlipidemia, and the ensuing inflammation have remained elusive so far. Main Results We identified biological processes related to innate immunity and oxidative stress as prime response pathways in livers of Ldlr-/- mice on Western-type diet using RNA sequencing and in silico functional analyses of transcriptome data. The observed changes were independent of the presence of microbiota and thus indicative of a role for sterile triggers. We further show that MDA epitopes, products of lipid peroxidation and markers for enhanced oxidative stress, are detectable in hepatic inflammation predominantly on dying cells and stimulate cytokine secretion as well as leukocyte recruitment in vitro and in vivo. MDA-induced cytokine secretion in vitro was dependent on the presence of scavenger receptors CD36 and MSR1. Moreover, in vivo neutralization of endogenously generated MDA epitopes by intravenous injection of a specific MDA antibody results in decreased hepatic inflammation in Ldlr-/- mice on Western-type diet. Conclusions Accumulation of MDA epitopes plays a major role during diet-induced hepatic inflammation and can be ameliorated by administration of an anti-MDA antibody. PMID:27981604

Advanced glycation end products and antioxidant status in type 2 diabetic patients with and without peripheral artery disease.

PubMed

Lapolla, Annunziata; Piarulli, Francesco; Sartore, Giovanni; Ceriello, Antonio; Ragazzi, Eugenio; Reitano, Rachele; Baccarin, Lorenzo; Laverda, Barbara; Fedele, Domenico

2007-03-01

Advanced glycation end products (AGEs), pentosidine and malondialdehyde (MDA), are elevated in type 2 diabetic subjects with coronary and carotid angiopathy. We investigated the relationship of AGEs, MDA, total reactive antioxidant potentials (TRAPs), and vitamin E in type 2 diabetic patients with and without peripheral artery disease (PAD). AGEs, pentosidine, MDA, TRAP, vitamin E, and ankle-brachial index (ABI) were measured in 99 consecutive type 2 diabetic subjects and 20 control subjects. AGEs, pentosidine, and MDA were higher and vitamin E and TRAP were lower in patients with PAD (ABI <0.9) than in patients without PAD (ABI >0.9) (P < 0.001). After multiple regression analysis, a correlation between AGEs and pentosidine, as independent variables, and ABI, as the dependent variable, was found in both patients with and without PAD (r = 0.9198, P < 0.001 and r = 0.5764, P < 0.001, respectively) but not in control subjects. When individual regression coefficients were evaluated, only that due to pentosidine was confirmed as significant. For patients with PAD, considering TRAP, vitamin E, and MDA as independent variables and ABI as the dependent variable produced an overall significant regression (r = 0.6913, P < 0.001). The regression coefficients for TRAP and vitamin E were not significant, indicating that the model is best explained by a single linear regression between MDA and ABI. These findings were also confirmed by principal component analysis. Results show that pentosidine and MDA are strongly associated with PAD in type 2 diabetic patients.

Apigenin inhibits the inducible expression of programmed death ligand 1 by human and mouse mammary carcinoma cells.

PubMed

Coombs, Melanie R Power; Harrison, Megan E; Hoskin, David W

2016-10-01

Programmed death ligand 1 (PD-L1) is expressed by many cancer cell types, as well as by activated T cells and antigen-presenting cells. Constitutive and inducible PD-L1 expression contributes to immune evasion by breast cancer (BC) cells. We show here that the dietary phytochemical apigenin inhibited interferon (IFN)-γ-induced PD-L1 upregulation by triple-negative MDA-MB-468 BC cells, HER2(+) SK-BR-3 BC cells, and 4T1 mouse mammary carcinoma cells, as well as human mammary epithelial cells, but did not affect constitutive PD-L1 expression by triple-negative MDA-MB-231 BC cells. IFN-β-induced expression of PD-L1 by MDA-MB-468 cells was also inhibited by apigenin. In addition, luteolin, the major metabolite of apigenin, inhibited IFN-γ-induced PD-L1 expression by MDA-MB-468 cells. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 and 4T1 cells was associated with reduced phosphorylation of STAT1, which was early and transient at Tyr701 and sustained at Ser727. Apigenin-mediated inhibition of IFN-γ-induced PD-L1 expression by MDA-MB-468 cells also increased proliferation and interleukin-2 synthesis by PD-1-expressing Jurkat T cells that were co-cultured with MDA-MB-468 cells. Apigenin therefore has the potential to increase the vulnerability of BC cells to T cell-mediated anti-tumor immune responses. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[Extensive digital necrosis during dermatomyositis associated with MDA-5 antibodies].

PubMed

Charbit, L; Bursztejn, A-C; Mohamed, S; Kaminsky, P; Lerondeau, B; Barbaud, A; Deibener-Kaminsky, J; Schmutz, J-L

2016-01-01

Dermatomyositis (DM) is an inflammatory disease associated with auto-antibodies in 50 to 70% of cases. A new antibody, anti MDA-5, has been described in association with a specific type of DM involving severe interstitial lung disease and minimal muscle disease. We report the first case of DM with MDA-5 antibodies and with interstitial lung disease and rapidly extensive digital necrosis. A 28-year-old male was hospitalized for asthenia, myalgia and subacute dyspnea. Examination demonstrated skin lesions with edema on every digit associated with purpuric and cyanotic lesions, as well as erythematous papules on the helix and the elbows, and Gottron's papules. Systemic corticosteroid therapy was initiated. The immunoprecipitation results indicated the presence of anti-MDA-5 antibodies. Despite corticosteroid therapy, the patient's respiratory status gradually deteriorated towards pulmonary fibrosis and rapidly extensive necrosis appeared on all fingers and toes. Theses effects were resistant to cyclophosphamide and immunoglobulin but were stabilized by cyclosporine. Anti-MDA-5 antibodies are specific to DM and constitute a risk factor for severe interstitial lung disease (70% of cases) with a higher risk of mortality (40%). The cutaneous presentation of this DM is specific with palmar papules and mucocutaneous ulceration. Rapidly extensive digital necrosis has not been previously reported. No treatment has demonstrated superiority. We report the first case of DM with anti-MDA-5 antibodies involving interstitial lung disease and massive digital necrosis. Because of the pulmonary risk, in the presence of clinical lesions containing anti-MDA-5 DM, screening for these antibodies should be carried out. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Wasabi-derived 6-(methylsulfinyl)hexyl isothiocyanate induces apoptosis in human breast cancer by possible involvement of the NF-κB pathways.

PubMed

Fuke, Yoko; Hishinuma, Madoka; Namikawa, Mayumi; Oishi, Yoshie; Matsuzaki, Takeshi

2014-01-01

6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a bioactive ingredient of wasabi (Wasabia japonica), which is a popular spice in Japan. 6-MSITC has been reported to inhibit the proliferation of breast cancer and melanoma cell lines. We inoculated 30 female Balb-nu/nu mice with MDA-MB-231 or -453 cells, and orally administered varying concentrations of 6-MSITC for 12 days following tumor growth. The tumor volumes and tumor weights from mice inoculated with MDA-MB-231 cells, and the tumor volumes of MDA-MB-453 cells were significantly inhibited by 6-MSITC on Days 9 and 11 after drug administration. DNA fragmentation, DNA ladder, and caspase 3/7 activity performed in vitro revealed that 6-MSITC induced apoptosis of MDA-MB-231, MDA-MB-453, and MCF-7 cells. Furthermore, nuclear factor-κB (NF-κB) expression in the nuclei and phosphorylation of inhibitor κBα (IκBα) was downregulated by 6-MSITC in a concentration-dependent manner; however, this activity was not observed in MCF-7 cells. Moreover, this downregulation of phosphorylated IκBα by 6-MSITC in MDA-MB-231 and -453 cells supports its inhibitory effects on NF-κB activity. The expression of phosphorylated AKT (pAKT) reduced by 6-MSITC was confirmed in MDA-MB-231 cells. Thus, we conclude that 6-MITC promotes apoptosis of breast cancer cells by inhibiting NF-kB and therefore releasing its control of the PI3K/AKT pathway.

Special Analysis: Disposal Plan for Pit 38 at Technical Area 54, Area G

DOE Office of Scientific and Technical Information (OSTI.GOV)

French, Sean B.; Shuman, Rob

2012-06-26

Los Alamos National Laboratory (LANL) generates radioactive waste as a result of various activities. Operational waste is generated from a wide variety of research and development activities including nuclear weapons development, energy production, and medical research; environmental restoration (ER), and decontamination and decommissioning (D&D) waste is generated as contaminated sites and facilities at LANL undergo cleanup or remediation. The majority of this waste is low-level radioactive waste (LLW) and is disposed of at the Technical Area 54 (TA-54), Area G disposal facility. U.S. Department of Energy (DOE) Order 435.1 (DOE, 2001) requires that radioactive waste be managed in a mannermore » that protects public health and safety, and the environment. To comply with this order, DOE field sites must prepare site-specific radiological performance assessments for LLW disposal facilities that accept waste after September 26, 1988. Furthermore, sites are required to conduct composite analyses that account for the cumulative impacts of all waste that has been (or will be) disposed of at the facilities and other sources of radioactive material that may interact with the facilities. Revision 4 of the Area G performance assessment and composite analysis was issued in 2008 (LANL, 2008). These analyses estimate rates of radionuclide release from the waste disposed of at the facility, simulate the movement of radionuclides through the environment, and project potential radiation doses to humans for several on- and off-site exposure scenarios. The assessments are based on existing site and disposal facility data, and on assumptions about future rates and methods of waste disposal. The Area G disposal facility consists of Material Disposal Area (MDA) G and the Zone 4 expansion area. To date, disposal operations have been confined to MDA G and are scheduled to continue in that region until MDA G undergoes final closure at the end of 2013. Given its impending closure, efforts have been made to utilize the remaining disposal capacity within MDA G to the greatest extent possible. One approach for doing this has been to dispose of low-activity waste from cleanup operations at LANL in the headspace of selected disposal pits. Waste acceptance criteria (WAC) for the material placed in the headspace of pits 15, 37, and 38 have been developed (LANL, 2010) and the impacts of placing waste in the headspace of these units has been evaluated (LANL, 2012a). The efforts to maximize disposal efficiency have taken on renewed importance because of the disposal demands placed on MDA G by the large volumes of waste that are being generated at LANL by cleanup efforts. For example, large quantities of waste were recently generated by the retrieval of waste formerly disposed of at TA-21, MDA B. A portion of this material has been disposed of in the headspace of pit 38 in compliance with the WAC developed for that disposal strategy; a large amount of waste has also been sent to off-site facilities for disposal. Nevertheless, large quantities of MDA B waste remain that require disposal. An extension of pit 38 was proposed to provide the disposal capacity that will be needed to dispose of institutional waste and MDA B waste through 2013. A special analysis was prepared to evaluate the impacts of the pit extension (LANL, 2012b). The analysis concluded that the disposal unit could be extended with modest increases in the exposures projected for the Area G performance assessment and composite analysis, as long as limits were placed on the radionuclide concentrations in the waste that is placed in the headspace of the pit. Based, in part, on the results of the special analysis, the extension of pit 38 was approved and excavation of the additional disposal capacity was started in May 2012. The special analysis presented here uses performance modeling to identify a disposal plan for the placement of waste in pit 38. The modeling uses a refined design of the disposal unit and updated radionuclide inventories to identify a disposal configuration that promotes efficient utilization of the pit and ensures continued compliance with DOE Order 435.1 performance objectives. Section 2 describes the methods used to conduct the analysis; the results of the evaluation are provided in Section 3. The disposal plan for pit 38 is provided in Section 4 and the conclusions of the investigation are provided in Section 5. Throughout the report, pit 38 is used to refer to the entire disposal unit, including the existing pit and the extension that is currently under construction. Where a distinction between the two portions of the pit is necessary, the existing unit is referred to as pit 38 proper and the new portion of the pit as the pit 38 extension or, more simply, the extension.« less

Accuracy of Coverage Survey Recall following an Integrated Mass Drug Administration for Lymphatic Filariasis, Schistosomiasis, and Soil-Transmitted Helminthiasis.

PubMed

Budge, Philip J; Sognikin, Edmond; Akosa, Amanda; Mathieu, Els M; Deming, Michael

2016-01-01

Achieving target coverage levels for mass drug administration (MDA) is essential to elimination and control efforts for several neglected tropical diseases (NTD). To ensure program goals are met, coverage reported by drug distributors may be validated through household coverage surveys that rely on respondent recall. This is the first study to assess accuracy in such surveys. Recall accuracy was tested in a series of coverage surveys conducted at 1, 6, and 12 months after an integrated MDA in Togo during which three drugs (albendazole, ivermectin, and praziquantel) were distributed. Drug distribution was observed during the MDA to ensure accurate recording of persons treated during the MDA. Information was obtained for 506, 1131, and 947 persons surveyed at 1, 6, and 12 months, respectively. Coverage (defined as the percentage of persons taking at least one of the MDA medications) within these groups was respectively 88.3%, 87.4%, and 80.0%, according to the treatment registers; it was 87.9%, 91.4% and 89.4%, according to survey responses. Concordance between respondents and registers on swallowing at least one pill was >95% at 1 month and >86% at 12 months; the lower concordance at 12 months was more likely due to difficulty matching survey respondents with the year-old treatment register rather than inaccurate responses. Respondents generally distinguished between pills similar in appearance; concordance for recall of which pills were taken was over 80% in each survey. In this population, coverage surveys provided remarkably consistent coverage estimates for up to one year following an integrated MDA. It is not clear if similar consistency will be seen in other settings, however, these data suggest that in some settings coverage surveys might be conducted as much as one year following an MDA without compromising results. This might enable integration of post-MDA coverage measurement into large, multipurpose, periodic surveys, thereby conserving resources.

Effects of Chinese medicinal herbs on expression of brain-derived Neurotrophic factor (BDNF) and its interaction with human breast cancer MDA-MB-231 cells and endothelial HUVECs.

PubMed

Chiu, Jen-Hwey; Chen, Fang-Pey; Tsai, Yi-Fang; Lin, Man-Ting; Tseng, Ling-Ming; Shyr, Yi-Ming

2017-08-12

Our previous study demonstrated that an up-regulation of the Brain-Derived Neurotrophic Factor (BDNF) signaling pathway is involved the mechanism causing the recurrence of triple negative breast cancer. The aim of this study is to investigate the effects of commonly used Chinese medicinal herbs on MDA-MB-231 and HUVEC cells and how they interact with BDNF. Human TNBC MDA-MB-231 cells and human endothelial HUVEC cells were used to explore the effect of commonly used Chinese herbal medicines on cancer cells alone, on endothelial cells alone and on cancer cell/endothelial cell interactions; this was done via functional studies, including migration and invasion assays. Furthermore, Western blot analysis and real-time PCR investigations were also used to investigate migration signal transduction, invasion signal transduction, and angiogenic signal transduction in these systems. Finally, the effect of the Chinese medicinal herbs on cancer cell/endothelial cell interactions was assessed using co-culture and ELISA. In terms of autoregulation, BDNF up-regulated TrkB gene expression in both MDA-MB-231 and HUVEC cells. Furthermore, BDNF enhanced migration by MDA-MB-231 cells via Rac, Cdc42 and MMP, while also increasing the migration of HUVEC cells via MMP and COX-2 expression. As measured by ELISA, the Chinese herbal medicinal herbs A. membranaceus, P. lactiflora, L. chuanxiong, P. suffruticosa and L. lucidum increased BDNF secretion by MDA-MB-231 cells. Similarly, using a co-culture system with MDA-MB-231 cells, A. membranaceus and L. lucidum modulated BDNF-TrkB signaling by HUVEC cells. We conclude that BDNF plays an important role in the metastatic interaction between MDA-MB-231 and HUVEC cells. Some Chinese medicinal herbs are able to enhance the BDNF-related metastatic potential of the interaction between cancer cells and endothelial cells. These findings provide important information that should help with the development of integrated medical therapies for breast cancer patients.

The effect of a low carotenoid diet on malondialdehyde-thiobarbituric acid (MDA-TBA) concentrations in women: a placebo-controlled double-blind study.

PubMed

Dixon, Z R; Shie, F S; Warden, B A; Burri, B J; Neidlinger, T R

1998-02-01

The purpose of the study was to evaluate the effect of a low carotenoid diet (83 micrograms Beta-carotene) on malondialdehyde-thiobarbituric acid (MDA-TBA) concentrations of nine pre-menopausal women. Subjects lived on the metabolic research unit of the Western Human Nutrition Research Center (WHNRC), where diet, exercise and other activities were controlled. Five subjects (Group C, control group) consumed a low carotenoid diet and received an additional 0.5 mg/day of Beta-carotene while four subjects (Group P, placebo group) received only the low carotenoid diet during days 1 to 60 (period 1). All subjects received 0.5 mg/day of Beta-carotene during days 60 to 100 (period 2), plus three capsules/day mixed carotenoid supplement (Neo-Life Company) during study days 100 to 120. Changes in MDA-TBA concentrations were analyzed during the study periods and between the groups. At the start of the study (day 1), no significant difference in the MDA-TBA concentration was observed between the control (Group C) and the placebo (Group P) subjects. During period 1 (days 2 to 60), when Group P subjects consumed the low carotenoid diet without supplementation, the MDA-TBA values for Group P rose markedly and were significantly (p < 0.05) higher than the MDA-TBA values for Group C subjects who were receiving carotenoid supplementation. During period 2 (days 60 to 100) when both groups received carotenoid supplementation, the MDA-TBA values of Group P subjects were significantly (p < 0.05) reduced to the point where they were similar to the MDA-TBA values for Group C subjects. These findings provide evidence to support the beneficial effects of carotenoids in preventing lipid peroxidation in the cells. Further studies are needed to identify the exact mechanism by which carotenoids prevent lipid peroxidation and the amount needed for normal activity.

A Review of Factors That Influence Individual Compliance with Mass Drug Administration for Elimination of Lymphatic Filariasis

PubMed Central

Krentel, Alison; Fischer, Peter U.; Weil, Gary J.

2013-01-01

Background The success of programs to eliminate lymphatic filariasis (LF) depends in large part on their ability to achieve and sustain high levels of compliance with mass drug administration (MDA). This paper reports results from a comprehensive review of factors that affect compliance with MDA. Methodology/Principal Findings Papers published between 2000 and 2012 were considered, and 79 publications were included in the final dataset for analysis after two rounds of selection. While results varied in different settings, some common features were associated with successful programs and with compliance by individuals. Training and motivation of drug distributors is critically important, because these people directly interact with target populations, and their actions can affect MDA compliance decisions by families and individuals. Other important programmatic issues include thorough preparation of personnel, supplies, and logistics for implementation and preparation of the population for MDA. Demographic factors (age, sex, income level, and area of residence) are often associated with compliance by individuals, but compliance decisions are also affected by perceptions of the potential benefits of participation versus the risk of adverse events. Trust and information can sometimes offset fear of the unknown. While no single formula can ensure success MDA in all settings, five key ingredients were identified: engender trust, tailor programs to local conditions, take actions to minimize the impact of adverse events, promote the broader benefits of the MDA program, and directly address the issue of systematic non-compliance, which harms communities by prolonging their exposure to LF. Conclusions/Significance This review has identified factors that promote coverage and compliance with MDA for LF elimination across countries. This information may be helpful for explaining results that do not meet expectations and for developing remedies for ailing MDA programs. Our review has also identified gaps in understanding and suggested priority areas for further research. PMID:24278486

HLA-DRB1 Alleles as Genetic Risk Factors for the Development of Anti-MDA5 Antibodies in Patients with Dermatomyositis.

PubMed

Chen, Zhiyong; Wang, Yan; Kuwana, Masataka; Xu, Xue; Hu, Wei; Feng, Xuebing; Wang, Hong; Kimura, Akinori; Sun, Lingyun

2017-09-01

Patients with polymyositis/dermatomyositis (PM/DM) who express anti-melanoma differentiation associated protein 5 (anti-MDA5) antibodies frequently present with interstitial lung disease (ILD). The aim of this study was to investigate the association of HLA-DRB1 with anti-MDA5 expression in PM/DM. The frequency of DRB1 alleles was compared among 70 patients with PM, 104 patients with DM, and 400 healthy controls in a Han Chinese population. Frequencies of DRB1*04:01 [17.0% vs 1.3%, corrected p value (p c ) = 3.8 × 10 -8 , OR 16.2, 95% CI 6.6-39.7] and *12:02 (42.6% vs 19.3%, p c = 0.008, OR 3.1, 95% CI 1.7-5.7) were significantly higher in anti-MDA5-positive patients with PM/DM compared with the controls. The frequencies of DRB1*04:01 (p = 5.2 × 10 -6 , OR 17.1, 95% CI 5.3-54.9) and *12:02 (p = 3.8 × 10 -4 , OR 3.1, 95% CI 1.7-5.7) in anti-MDA5-positive patients with DM-ILD were higher than in the controls, whereas the frequencies of DRB1*04:01 and *12:02 did not differ between the anti-MDA5-negative patients with DM-ILD and controls. No difference in the frequency of DRB1 alleles, other than *04:01, carrying the "shared epitope" (SE), i.e., *01:01, *01:02, *04:05, and *10:01, was observed between the controls and patients with DM stratified by the presence of anti-MDA5 and ILD. DRB1*04:01 and *12:02 confer susceptibility to anti-MDA5 antibody production in DM, which cannot be explained by the SE hypothesis.

Altered lipid peroxidation markers are related to post-traumatic stress disorder (PTSD) and not trauma itself in earthquake survivors.

PubMed

Atli, Abdullah; Bulut, Mahmut; Bez, Yasin; Kaplan, İbrahim; Özdemir, Pınar Güzel; Uysal, Cem; Selçuk, Hilal; Sir, Aytekin

2016-06-01

The traumatic life events, including earthquakes, war, and interpersonal conflicts, cause a cascade of psychological and biological changes known as post-traumatic stress disorder (PTSD). Malondialdehyde (MDA) is a reliable marker of lipid peroxidation, and paraoxonase is a known antioxidant enzyme. The aims of this study were to investigate the relationship between earthquake trauma, PTSD effects on oxidative stress and the levels of serum paraoxonase 1 (PON1) enzyme activity, and levels of serum MDA. The study was carried out on three groups called: the PTSD group, the traumatized with earthquake exercise group, and healthy control group, which contained 32, 31, and 38 individuals, respectively. Serum MDA levels and PON1 enzyme activities from all participants were measured, and the results were compared across all groups. There were no significant differences between the PTSD patients and non-PTSD earthquake survivors in terms of the study variables. The mean PON1 enzyme activity from PTSD patients was significantly lower, while the mean MDA level was significantly higher than that of the healthy control group (p < 0.01 for both measurements). Similarly, earthquake survivors who did not develop PTSD showed higher MDA levels and lower PON1 activity when compared to healthy controls. However, the differences between these groups did not reach a statistically significant level. Increased MDA level and decreased PON1 activity measured in PTSD patients after earthquake and may suggest increased oxidative stress in these patients. The nonsignificant trends that are observed in lipid peroxidation markers of earthquake survivors may indicate higher impact of PTSD development on these markers than trauma itself. For example, PTSD diagnosis seems to add to the effect of trauma on serum MDA levels and PON1 enzyme activity. Thus, serum MDA levels and PON1 enzyme activity may serve as biochemical markers of PTSD diagnosis.

Accuracy of Coverage Survey Recall following an Integrated Mass Drug Administration for Lymphatic Filariasis, Schistosomiasis, and Soil-Transmitted Helminthiasis

PubMed Central

Budge, Philip J.; Sognikin, Edmond; Akosa, Amanda; Mathieu, Els M.; Deming, Michael

2016-01-01

Background Achieving target coverage levels for mass drug administration (MDA) is essential to elimination and control efforts for several neglected tropical diseases (NTD). To ensure program goals are met, coverage reported by drug distributors may be validated through household coverage surveys that rely on respondent recall. This is the first study to assess accuracy in such surveys. Methodology/Principal Findings Recall accuracy was tested in a series of coverage surveys conducted at 1, 6, and 12 months after an integrated MDA in Togo during which three drugs (albendazole, ivermectin, and praziquantel) were distributed. Drug distribution was observed during the MDA to ensure accurate recording of persons treated during the MDA. Information was obtained for 506, 1131, and 947 persons surveyed at 1, 6, and 12 months, respectively. Coverage (defined as the percentage of persons taking at least one of the MDA medications) within these groups was respectively 88.3%, 87.4%, and 80.0%, according to the treatment registers; it was 87.9%, 91.4% and 89.4%, according to survey responses. Concordance between respondents and registers on swallowing at least one pill was >95% at 1 month and >86% at 12 months; the lower concordance at 12 months was more likely due to difficulty matching survey respondents with the year-old treatment register rather than inaccurate responses. Respondents generally distinguished between pills similar in appearance; concordance for recall of which pills were taken was over 80% in each survey. Significance In this population, coverage surveys provided remarkably consistent coverage estimates for up to one year following an integrated MDA. It is not clear if similar consistency will be seen in other settings, however, these data suggest that in some settings coverage surveys might be conducted as much as one year following an MDA without compromising results. This might enable integration of post-MDA coverage measurement into large, multipurpose, periodic surveys, thereby conserving resources. PMID:26766287

Lipid peroxidation and antioxidant status in rat: effect of food restriction and wheel running.

PubMed

Filaire, Edith; Rouveix, Matthieu; Massart, Alain; Gladine, Cécile; Davicco, Marie Jeanne; Durand, Denys

2009-09-01

Using the activity-based anorexia model, the aim of this investigation was to explore antioxidant enzyme activity (catalase, superoxide dismutase), total antioxidant status (TAS), and alpha-tocopherol in blood, liver, and gastrocnemius muscle associated with the food restriction and voluntary wheel running during 8 days. In addition, lipid peroxidation was measured by measurements of malondialdehyde (MDA). Wistars rats (n = 56) were randomly assigned to one of four groups: an ad lib sedentary group, a control wheel activity group, a food restriction-induced hyperactivity group (1 h/day ad lib food, 23 h/day ad lib wheel access), and a food-restricted sedentary group. The animals were killed when the rats in the food-restricted group had lost 25% of their free feeding weight. Antioxidant enzyme activities and TAS in blood, liver, and gastrocnemius muscle were unaffected by voluntary wheel running. A wheel activity effect (P < 0.05) was obtained for the MDA concentrations in plasma, with lower concentrations in trained animals. Food restriction effects were obtained for antioxidant capacity in liver, as well as for CAT activity in the gastrocnemius muscle and plasma MDA concentrations with lower values in the restricted animals. On the other hand, the food-restricted rats showed higher plasma TAS concentrations (P < 0.05) and higher alpha-tocopherol concentrations in the liver (P < 0.05) when compared to animals fed ad libitum. Our results also showed that food restriction coupled to wheel running decreased antioxidant parameters in liver, and plasmatic MDA concentrations and increased TAS plasma concentrations when compared to the ad libitum sedentary situation.

Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation.

PubMed

El-Naggar, Mohamed; Eldehna, Wagdy M; Almahli, Hadia; Elgez, Amr; Fares, Mohamed; Elaasser, Mahmoud M; Abdel-Aziz, Hatem A

2018-06-12

In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates ( 4a ⁻ n ) and thiazolo[3,2- a ]benzimidazolone-isatin conjugates ( 7a ⁻ d ), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC 50 = 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds 4m and 7b were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid 4m induced a fourfold increase in the percentage of cells at Sub-G₁, with concurrent arrest in G₂-M phase by 2.5-folds. Furthermore, hybrid 4m resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates 4m and 7b displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study.

Exhaled Breath Condensate as a Suitable Matrix to Assess Lung Dose and Effects in Workers Exposed to Cobalt and Tungsten

PubMed Central

Goldoni, Matteo; Catalani, Simona; De Palma, Giuseppe; Manini, Paola; Acampa, Olga; Corradi, Massimo; Bergonzi, Roberto; Apostoli, Pietro; Mutti, Antonio

2004-01-01

The aim of the present study was to investigate whether exhaled breath condensate (EBC), a fluid formed by cooling exhaled air, can be used as a suitable matrix to assess target tissue dose and effects of inhaled cobalt and tungsten, using EBC malondialdehyde (MDA) as a biomarker of pulmonary oxidative stress. Thirty-three workers exposed to Co and W in workshops producing either diamond tools or hard-metal mechanical parts participated in this study. Two EBC and urinary samples were collected: one before and one at the end of the work shift. Controls were selected among nonexposed workers. Co, W, and MDA in EBC were analyzed with analytical methods based on mass spectrometric reference techniques. In the EBC from controls, Co was detectable at ultratrace levels, whereas W was undetectable. In exposed workers, EBC Co ranged from a few to several hundred nanomoles per liter. Corresponding W levels ranged from undetectable to several tens of nanomoles per liter. A parallel trend was observed for much higher urinary levels. Both Co and W in biological media were higher at the end of the work shift in comparison with preexposure values. In EBC, MDA levels were increased depending on Co concentration and were enhanced by coexposure to W. Such a correlation between EBC MDA and both Co and W levels was not observed with urinary concentration of either element. These results suggest the potential usefulness of EBC to complete and integrate biomonitoring and health surveillance procedures among workers exposed to mixtures of transition elements and hard metals. PMID:15345342

Effects of intravesical dexpanthenol use on lipid peroxidation and bladder histology in a chemical cystitis animal model.

PubMed

Bayrak, Omer; Seckiner, Ilker; Solakhan, Mehmet; Karakok, Metin; Erturhan, Sakip M; Yagci, Faruk

2012-05-01

To demonstrate the effects of intravesical dexpanthenol use on bladder histology and lipid peroxidation in a chemical cystitis animal model. Thirty-five New Zealand rabbits were divided into 3 groups. Cystitis was conducted with transurethral intravesical hydrochloric acid instillation on the subjects in groups I and II. Then, Group I subjects were transurethrally administered intravesical dexpanthenol therapy twice a week, Group II subjects were given only intravesical isotonic NaCl instillation, and Group III subjects were administered intravesical isotonic NaCl instillation without conducting chemical cystitis to create the same stress. Treatment schemes of all groups were arranged in the same manner. After 6-week therapy, the rabbits were sacrificed and histopathologic investigations were carried out to demonstrate changes in the urinary bladder. Serum and tissue malondialdehyde (MDA) values were examined to investigate the effect of dexpanthenol on lipid peroxidation. We observed that the basal membrane and mucosal integrity were maintained, inflammatory cells were suppressed, and MDA levels decreased in group I, which received dexpanthenol therapy. However, it was also observed that mucosal integrity was spoiled, numerous inflammatory cells were accumulated, and MDA levels were significantly increased in group II, which was administered isotonic NaCl. In light of our findings, intravesical dexpanthenol therapy could be a new therapeutic approach in the treatment of interstitial cystitis because of its low cost and acceptable side effects. Copyright © 2012 Elsevier Inc. All rights reserved.

Medical Data Architecture (MDA) Project Status

NASA Technical Reports Server (NTRS)

Krihak, M.; Middour, C.; Gurram, M.; Wolfe, S.; Marker, N.; Winther, S.; Ronzano, K.; Bolles, D.; Toscano, W.; Shaw, T.

2018-01-01

The Medical Data Architecture (MDA) project supports the Exploration Medical Capability (ExMC) risk to minimize or reduce the risk of adverse health outcomes and decrements in performance due to in-flight medical capabilities on human exploration missions. To mitigate this risk, the ExMC MDA project addresses the technical limitations identified in ExMC Gap Med 07: We do not have the capability to comprehensively process medically-relevant information to support medical operations during exploration missions. This gap identifies that the current in-flight medical data management includes a combination of data collection and distribution methods that are minimally integrated with on-board medical devices and systems. Furthermore, there are a variety of data sources and methods of data collection. For an exploration mission, the seamless management of such data will enable a more medically autonomous crew than the current paradigm. The medical system requirements are being developed in parallel with the exploration mission architecture and vehicle design. ExMC has recognized that in order to make informed decisions about a medical data architecture framework, current methods for medical data management must not only be understood, but an architecture must also be identified that provides the crew with actionable insight to medical conditions. This medical data architecture will provide the necessary functionality to address the challenges of executing a self-contained medical system that approaches crew health care delivery without assistance from ground support. Hence, the products supported by current prototype development will directly inform exploration medical system requirements.

Landsat D Thematic Mapper image dimensionality reduction and geometric correction accuracy

NASA Technical Reports Server (NTRS)

Ford, G. E.

1986-01-01

To characterize and quantify the performance of the Landsat thematic mapper (TM), techniques for dimensionality reduction by linear transformation have been studied and evaluated and the accuracy of the correction of geometric errors in TM images analyzed. Theoretical evaluations and comparisons for existing methods for the design of linear transformation for dimensionality reduction are presented. These methods include the discrete Karhunen Loeve (KL) expansion, Multiple Discriminant Analysis (MDA), Thematic Mapper (TM)-Tasseled Cap Linear Transformation and Singular Value Decomposition (SVD). A unified approach to these design problems is presented in which each method involves optimizing an objective function with respect to the linear transformation matrix. From these studies, four modified methods are proposed. They are referred to as the Space Variant Linear Transformation, the KL Transform-MDA hybrid method, and the First and Second Version of the Weighted MDA method. The modifications involve the assignment of weights to classes to achieve improvements in the class conditional probability of error for classes with high weights. Experimental evaluations of the existing and proposed methods have been performed using the six reflective bands of the TM data. It is shown that in terms of probability of classification error and the percentage of the cumulative eigenvalues, the six reflective bands of the TM data require only a three dimensional feature space. It is shown experimentally as well that for the proposed methods, the classes with high weights have improvements in class conditional probability of error estimates as expected.

Detection of increased 64Cu uptake by human copper transporter 1 gene overexpression using PET with 64CuCl2 in human breast cancer xenograft model.

PubMed

Kim, Kwang Il; Jang, Su Jin; Park, Ju Hui; Lee, Yong Jin; Lee, Tae Sup; Woo, Kwang Sun; Park, Hyun; Choe, Jae Gol; An, Gwang Il; Kang, Joo Hyun

2014-10-01

Copper is an essential cofactor for a variety of biochemical processes including oxidative phosphorylation, cellular antioxidant activity, and elimination of free radicals. The copper transporter 1 is known to be involved in cellular uptake of copper ions. In this study, we evaluated the utility of human copper transporter 1 (hCTR1) gene as a new reporter gene for (64)Cu PET imaging. Human breast cancer cells (MDA-MB-231) were infected with a lentiviral vector constitutively expressing the hCTR1 gene under super cytomegalovirus promoter, and positive clones (MDA-MB-231-hCTR1) were selected. The expression of hCTR1 gene in MDA-MB-231-hCTR1 cells was measured by reverse transcription polymerase chain reaction, Western blot, and (64)Cu uptake assay. To evaluate the cytotoxic effects induced by hCTR1 expression, the dose-dependent cell survival rate after treatment with cisplatin (Cis-diaminedichloroplatinum (II) [CDDP]) was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue dye exclusion. Small-animal PET images were acquired in tumor-bearing mice from 2 to 48 h after an intravenous injection of (64)Cu. The hCTR1 gene expression in MDA-MB-231-hCTR1 cells was confirmed at the RNA and protein expression and the cellular (64)Cu uptake level. MTT assay and trypan blue dye exclusion showed that the cell viability of MDA-MB-231-hCTR1 cells decreased more rapidly than that of MDA-MB-231 cells after treatment with CDDP for 96 or 72 h, respectively. Small-animal PET imaging revealed a higher accumulation of (64)Cu in MDA-MB-231-hCTR1 tumors than in MDA-MB-231 tumors. With respect to the biodistribution data, the percentage injected dose per gram of (64)Cu in the MDA-MB-231 tumors and MDA-MB-231-hCTR1 tumors at 48 h after (64)Cu injection was 2.581 ± 0.254 and 5.373 ± 1.098, respectively. An increase in (64)Cu uptake induced by the expression of hCTR1 gene was demonstrated in vivo and in vitro, suggesting the potential use of hCTR1 gene as a new imaging reporter gene for PET with (64)CuCl2. © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease.

PubMed

Rhee, Yong-Hee; Ko, Ji-Yun; Chang, Mi-Yoon; Yi, Sang-Hoon; Kim, Dohoon; Kim, Chun-Hyung; Shim, Jae-Won; Jo, A-Young; Kim, Byung-Woo; Lee, Hyunsu; Lee, Suk-Ho; Suh, Wonhee; Park, Chang-Hwan; Koh, Hyun-Chul; Lee, Yong-Sung; Lanza, Robert; Kim, Kwang-Soo; Lee, Sang-Hun

2011-06-01

Parkinson disease (PD) involves the selective loss of midbrain dopamine (mDA) neurons and is a possible target disease for stem cell-based therapy. Human induced pluripotent stem cells (hiPSCs) are a potentially unlimited source of patient-specific cells for transplantation. However, it is critical to evaluate the safety of hiPSCs generated by different reprogramming methods. Here, we compared multiple hiPSC lines derived by virus- and protein-based reprogramming to human ES cells (hESCs). Neuronal precursor cells (NPCs) and dopamine (DA) neurons delivered from lentivirus-based hiPSCs exhibited residual expression of exogenous reprogramming genes, but those cells derived from retrovirus- and protein-based hiPSCs did not. Furthermore, NPCs derived from virus-based hiPSCs exhibited early senescence and apoptotic cell death during passaging, which was preceded by abrupt induction of p53. In contrast, NPCs derived from hESCs and protein-based hiPSCs were highly expandable without senescence. DA neurons derived from protein-based hiPSCs exhibited gene expression, physiological, and electrophysiological properties similar to those of mDA neurons. Transplantation of these cells into rats with striatal lesions, a model of PD, significantly rescued motor deficits. These data support the clinical potential of protein-based hiPSCs for personalized cell therapy of PD.

Assessing Progress in Reducing the At-Risk Population after 13 Years of the Global Programme to Eliminate Lymphatic Filariasis

PubMed Central

Hooper, Pamela J.; Chu, Brian K.; Mikhailov, Alexei; Ottesen, Eric A.; Bradley, Mark

2014-01-01

Background In 1997, the World Health Assembly adopted Resolution 50.29, committing to the elimination of lymphatic filariasis (LF) as a public health problem, subsequently targeted for 2020. The initial estimates were that 1.2 billion people were at-risk for LF infection globally. Now, 13 years after the Global Programme to Eliminate Lymphatic Filariasis (GPELF) began implementing mass drug administration (MDA) against LF in 2000—during which over 4.4 billion treatments have been distributed in 56 endemic countries—it is most appropriate to estimate the impact that the MDA has had on reducing the population at risk of LF. Methodology/Principal Findings To assess GPELF progress in reducing the population at-risk for LF, we developed a model based on defining reductions in risk of infection among cohorts of treated populations following each round of MDA. The model estimates that the number of people currently at risk of infection decreased by 46% to 789 million through 2012. Conclusions/Significance Important progress has been made in the global efforts to eliminate LF, but significant scale-up is required over the next 8 years to reach the 2020 elimination goal. PMID:25411843

Neutrophils Express Distinct RNA Receptors in a Non-canonical Way*

PubMed Central

Berger, Michael; Hsieh, Chin-Yuan; Bakele, Martina; Marcos, Veronica; Rieber, Nikolaus; Kormann, Michael; Mays, Lauren; Hofer, Laura; Neth, Olaf; Vitkov, Ljubomir; Krautgartner, Wolf Dietrich; von Schweinitz, Dietrich; Kappler, Roland; Hector, Andreas; Weber, Alexander; Hartl, Dominik

2012-01-01

RNAs are capable of modulating immune responses by binding to specific receptors. Neutrophils represent the major fraction of circulating immune cells, but receptors and mechanisms by which neutrophils sense RNA are poorly defined. Here, we analyzed the mRNA and protein expression patterns and the subcellular localization of the RNA receptors RIG-I, MDA-5, TLR3, TLR7, and TLR8 in primary neutrophils and immortalized neutrophil-like differentiated HL-60 cells. Our results demonstrate that both neutrophils and differentiated HL-60 cells express RIG-I, MDA-5, and TLR8 at the mRNA and protein levels, whereas TLR3 and TLR7 are not expressed at the protein level. Subcellular fractionation, flow cytometry, confocal laser scanning microscopy, and immuno-transmission electron microscopy provided evidence that, besides the cytoplasm, RIG-I and MDA-5 are stored in secretory vesicles of neutrophils and showed that RIG-I and its ligand, 3p-RNA, co-localize at the cell surface without triggering neutrophil activation. In summary, this study demonstrates that neutrophils express a distinct pattern of RNA recognition receptors in a non-canonical way, which could have essential implications for future RNA-based therapeutics. PMID:22532562

A linear concatenation strategy to construct 5'-enriched amplified cDNA libraries using multiple displacement amplification.

PubMed

Gadkar, Vijay J; Filion, Martin

2013-06-01

In various experimental systems, limiting available amounts of RNA may prevent a researcher from performing large-scale analyses of gene transcripts. One way to circumvent this is to 'pre-amplify' the starting RNA/cDNA, so that sufficient amounts are available for any downstream analysis. In the present study, we report the development of a novel protocol for constructing amplified cDNA libraries using the Phi29 DNA polymerase based multiple displacement amplification (MDA) system. Using as little as 200 ng of total RNA, we developed a linear concatenation strategy to make the single-stranded cDNA template amenable for MDA. The concatenation, made possible by the template switching property of the reverse transcriptase enzyme, resulted in the amplified cDNA library with intact 5' ends. MDA generated micrograms of template, allowing large-scale polymerase chain reaction analyses or other large-scale downstream applications. As the amplified cDNA library contains intact 5' ends, it is also compatible with 5' RACE analyses of specific gene transcripts. Empirical validation of this protocol is demonstrated on a highly characterized (tomato) and an uncharacterized (corn gromwell) experimental system.

Economic analysis of HPAI control in the Netherlands II: comparison of control strategies.

PubMed

Longworth, N; Mourits, M C M; Saatkamp, H W

2014-06-01

A combined epidemiological-economic modelling approach was used to analyse strategies for highly pathogenic avian influenza (HPAI) control for the Netherlands. The modelling framework used was InterSpread Plus (ISP), a spatially based, stochastic and dynamic simulation model. A total of eight control strategies were analysed, including pre-emptive depopulation and vaccination strategies. The analysis was carried out for three different regions in the Netherlands: high-, medium- and low-density areas (HDA, MDA and LDA, respectively). The analysis included the veterinary impact (e.g. number of infected premises and duration), but was particularly focused on the impact on direct costs (DC) and direct consequential costs. The efficient set of control strategies for HDA and MDA included strategies based on either pre-emptive depopulation only or combined vaccination and pre-emptive depopulation: D2 (pre-emptive depopulation within a radius of 2 km), RV3 + D1 (ring vaccination within a radius of 3 km and additional pre-emptive depopulation within a radius of 1 km) and PV + D1 (preventive vaccination in non-affected HDAs and pre-emptive depopulation within a radius of 1 km in the affected HDA). Although control solely based on depopulation in most cases showed to be effective for LDA, pre-emptive depopulation showed to have an additional advantage in these areas, that is, prevention of 'virus jumps' to other areas. The pros and cons of the efficient control strategies were discussed, for example, public perception and risk of export restrictions. It was concluded that for the Netherlands control of HPAI preferably should be carried out using strategies including pre-emptive depopulation with or without vaccination. Particularly, the short- and long-term implications on export, that is, indirect consequential costs (ICC) and aftermath costs of these strategies, should be analysed further. © 2012 Blackwell Verlag GmbH.

Non-destructive determination of Malondialdehyde (MDA) distribution in oilseed rape leaves by laboratory scale NIR hyperspectral imaging

PubMed Central

Kong, Wenwen; Liu, Fei; Zhang, Chu; Zhang, Jianfeng; Feng, Hailin

2016-01-01

The feasibility of hyperspectral imaging with 400–1000 nm was investigated to detect malondialdehyde (MDA) content in oilseed rape leaves under herbicide stress. After comparing the performance of different preprocessing methods, linear and nonlinear calibration models, the optimal prediction performance was achieved by extreme learning machine (ELM) model with only 23 wavelengths selected by competitive adaptive reweighted sampling (CARS), and the result was RP = 0.929 and RMSEP = 2.951. Furthermore, MDA distribution map was successfully achieved by partial least squares (PLS) model with CARS. This study indicated that hyperspectral imaging technology provided a fast and nondestructive solution for MDA content detection in plant leaves. PMID:27739491

Assessing the effectiveness of household-level focal mass drug administration and community-wide mass drug administration for reducing malaria parasite infection prevalence and incidence in Southern Province, Zambia: study protocol for a community randomized controlled trial.

PubMed

Eisele, Thomas P; Silumbe, Kafula; Finn, Timothy; Chalwe, Victor; Kamuliwo, Mukalwa; Hamainza, Busiku; Moonga, Hawela; Bennett, Adam; Yukich, Josh; Keating, Joseph; Steketee, Richard W; Miller, John M

2015-08-13

Mass drug administration (MDA) and focal MDA (fMDA) using dihydroartemisinin plus piperaquine (DHAp), represent two strategies to maximize the use of existing information to achieve greater clearance of human infection and reduce the parasite reservoir, and provide longer chemoprophylactic protection against new infections. The primary aim of this study is to quantify the relative effectiveness of MDA and fMDA with DHAp against no mass treatment (standard of care) for reducing Plasmodium falciparum prevalence and incidence. The study will be conducted along Lake Kariba in Southern Province, Zambia; an area of low to moderate malaria transmission and high coverage of vector control. A community randomized controlled trial (CRCT) of 60 health facility catchment areas (HFCAs) will be used to evaluate the impact of two rounds of MDA and fMDA interventions, relative to a control of no mass treatment, stratified by high and low transmission. Community residents in MDA HFCAs will be treated with DHAp at the end of the dry season (round one: November to December 2014) and the beginning of the rainy season (round two: February to March 2015). Community residents in fMDA HFCAs will be tested during the same two rounds for malaria parasites with a rapid diagnostic test; all positive individuals and all individuals living in their household will be treated with DHAp. Primary outcomes include malaria parasite prevalence (n = 5,640 children aged one month to under five-years-old), as measured by pre- and post-surveys, and malaria parasite infection incidence (n = 2,250 person-years among individuals aged three months and older), as measured by a monthly longitudinal cohort. The study is powered to detect approximately a 50 % relative reduction in these outcomes between each intervention group versus the control. Strengths of this trial include: a robust study design (CRCT); cross-sectional parasite surveys as well as a longitudinal cohort; and stratification of high and low transmission areas. Primary limitations include: statistical power to detect only a 50 % reduction in primary outcomes within high and low transmission strata; potential for contamination; and potential for misclassification of exposure. Identifier: Clinicaltrials.gov: NCT02329301 . Registration date: 30 December 2014.

Morbillivirus Control of the Interferon Response: Relevance of STAT2 and mda5 but Not STAT1 for Canine Distemper Virus Virulence in Ferrets

PubMed Central

Svitek, Nicholas; Gerhauser, Ingo; Goncalves, Christophe; Grabski, Elena; Döring, Marius; Kalinke, Ulrich; Anderson, Danielle E.; Cattaneo, Roberto

2014-01-01

ABSTRACT The V proteins of paramyxoviruses control the innate immune response. In particular, the V protein of the genus Morbillivirus interferes with the signal transducer and activator of transcription 1 (STAT1), STAT2, and melanoma differentiation-associated protein 5 (mda5) signaling pathways. To characterize the contributions of these pathways to canine distemper virus (CDV) pathogenesis, we took advantage of the knowledge about the mechanisms of interaction between the measles virus V protein with these key regulators of innate immunity. We generated recombinant CDVs with V proteins unable to properly interact with STAT1, STAT2, or mda5. A virus with combined STAT2 and mda5 deficiencies was also generated, and available wild-type and V-protein-knockout viruses were used as controls. Ferrets infected with wild-type and STAT1-blind viruses developed severe leukopenia and loss of lymphocyte proliferation activity and succumbed to the disease within 14 days. In contrast, animals infected with viruses with STAT2 or mda5 defect or both STAT2 and mda5 defects developed a mild self-limiting disease similar to that associated with the V-knockout virus. This study demonstrates the importance of interference with STAT2 and mda5 signaling for CDV immune evasion and provides a starting point for the development of morbillivirus vectors with reduced immunosuppressive properties. IMPORTANCE The V proteins of paramyxoviruses interfere with the recognition of the virus by the immune system of the host. For morbilliviruses, the V protein is known to interact with the signal transducer and activator of transcription 1 (STAT1) and STAT2 and the melanoma differentiation-associated protein 5 (mda5), which are involved in interferon signaling. Here, we examined the contribution of each of these signaling pathways to the pathogenesis of the carnivore morbillivirus canine distemper virus. Using viruses selectively unable to interfere with the respective signaling pathway to infect ferrets, we found that inhibition of STAT2 and mda5 signaling was critical for lethal disease. Our findings provide new insights in the mechanisms of morbillivirus immune evasion and may lead to the development of new vaccines and oncolytic vectors. PMID:24371065

Action of hexachlorobenzene on tumor growth and metastasis in different experimental models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pontillo, Carolina Andrea, E-mail: caroponti@hotmail.com; Rojas, Paola, E-mail: parojas2010@gmail.com; Chiappini, Florencia, E-mail: florenciachiappini@hotmail.com

Hexachlorobenzene (HCB) is a widespread organochlorine pesticide, considered a possible human carcinogen. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR). We have found that HCB activates c-Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways and cell migration, in an AhR-dependent manner in MDA-MB-231 breast cancer cells. The aim of this study was to investigate in vitro the effect of HCB (0.005, 0.05, 0.5, 5 μM) on cell invasion and metalloproteases (MMPs) 2 and 9 activation in MDA-MB-231 cells. Furthermore, we examined in vivo the effect of HCB (0.3, 3, 30 mg/kg b.w.) on tumor growth, MMP2more » and MMP9 expression, and metastasis using MDA-MB-231 xenografts and two syngeneic mouse breast cancer models (spontaneous metastasis using C4-HI and lung experimental metastasis using LM3). Our results show that HCB (5 μM) enhances MMP2 expression, as well as cell invasion, through AhR, c-Src/HER1 pathway and MMPs. Moreover, HCB increases MMP9 expression, secretion and activity through a HER1 and AhR-dependent mechanism, in MDA-MB-231 cells. HCB (0.3 and 3 mg/kg b.w.) enhances subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivo models. In vivo, using MDA-MB-231 model, the pesticide (0.3, 3 and 30 mg/kg b.w.) activated c-Src, HER1, STAT5b, and ERK1/2 signaling pathways and increased MMP2 and MMP9 protein levels. Furthermore, we observed that HCB stimulated lung metastasis regardless the tumor hormone-receptor status. Our findings suggest that HCB may be a risk factor for human breast cancer progression. - Highlights: ► HCB enhances MMP2 and MMP9 expression and cell invasion in MDA-MB-231, in vitro. ► HCB-effects are mediated through AhR, HER1 and/or c-Src. ► HCB increases subcutaneous tumor growth in MDA-MB-231 and C4-HI in vivo models. ► HCB activates c-Src/HER1 pathway and increases MMPs levels in MDA-MB-231 tumors. ► HCB stimulates lung metastasis in C4-HI and LM3 in vivo models.« less

Improved multiple displacement amplification (iMDA) and ultraclean reagents.

PubMed

Motley, S Timothy; Picuri, John M; Crowder, Chris D; Minich, Jeremiah J; Hofstadler, Steven A; Eshoo, Mark W

2014-06-06

Next-generation sequencing sample preparation requires nanogram to microgram quantities of DNA; however, many relevant samples are comprised of only a few cells. Genomic analysis of these samples requires a whole genome amplification method that is unbiased and free of exogenous DNA contamination. To address these challenges we have developed protocols for the production of DNA-free consumables including reagents and have improved upon multiple displacement amplification (iMDA). A specialized ethylene oxide treatment was developed that renders free DNA and DNA present within Gram positive bacterial cells undetectable by qPCR. To reduce DNA contamination in amplification reagents, a combination of ion exchange chromatography, filtration, and lot testing protocols were developed. Our multiple displacement amplification protocol employs a second strand-displacing DNA polymerase, improved buffers, improved reaction conditions and DNA free reagents. The iMDA protocol, when used in combination with DNA-free laboratory consumables and reagents, significantly improved efficiency and accuracy of amplification and sequencing of specimens with moderate to low levels of DNA. The sensitivity and specificity of sequencing of amplified DNA prepared using iMDA was compared to that of DNA obtained with two commercial whole genome amplification kits using 10 fg (~1-2 bacterial cells worth) of bacterial genomic DNA as a template. Analysis showed >99% of the iMDA reads mapped to the template organism whereas only 0.02% of the reads from the commercial kits mapped to the template. To assess the ability of iMDA to achieve balanced genomic coverage, a non-stochastic amount of bacterial genomic DNA (1 pg) was amplified and sequenced, and data obtained were compared to sequencing data obtained directly from genomic DNA. The iMDA DNA and genomic DNA sequencing had comparable coverage 99.98% of the reference genome at ≥1X coverage and 99.9% at ≥5X coverage while maintaining both balance and representation of the genome. The iMDA protocol in combination with DNA-free laboratory consumables, significantly improved the ability to sequence specimens with low levels of DNA. iMDA has broad utility in metagenomics, diagnostics, ancient DNA analysis, pre-implantation embryo screening, single-cell genomics, whole genome sequencing of unculturable organisms, and forensic applications for both human and microbial targets.

Cellular effect of styrene substituted biscoumarin caused cellular apoptosis and cell cycle arrest in human breast cancer cells.

PubMed

Perumalsamy, Haribalan; Sankarapandian, Karuppasamy; Kandaswamy, Narendran; Balusamy, Sri Renukadevi; Periyathambi, Dhaiveegan; Raveendiran, Nanthini

2017-11-01

Coumarins occurs naturally across plant kingdoms exhibits significant pharmacological properties and pharmacokinetic activity. The conventional, therapeutic agents are often associated with poor stability, absorption and increased side effects. Therefore, identification of a drug that has little or no-side effect on humans is consequential. Here, we investigated the antiproliferative activity of styrene substituted biscoumarin against various human breast cancer cell lines, such as MCF-7, (ER-) MDA-MB-231 and (AR+) MDA-MB-453. Styrene substituted biscoumarin induced cell death by apoptosis in MDA-MB-231 cell line was analyzed. Antiproliferative activity of Styrene substituted biscoumarin was performed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Styrene substituted biscoumarin induced apoptosis was assessed by Hoechst staining, Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining and flow cytometric analysis. Migratory and proliferating characteristic of breast cancer cell line MDA-MB-231 was also analyzed by wound healing and colony formation assay. Furthermore, mRNA expression of BAX and BCL-2 were quantified using qRT-PCR and protein expression level analyzed by Western blot. The inhibition concentration (IC 50 ) of styrene substituted biscoumarin was assayed against three breast cancer cell lines. The inhibition concentration (IC 50 ) value of styrene substituted biscoumarin toward MDA-MB-231, MDA-MB-453 and MCF-7 cell lines was 5.63, 7.30 and 10.84μg/ml respectively. Styrene substituted biscoumarin induced apoptosis was detected by Hoechst staining, DAPI/PI analysis and flow-cytometric analysis. The migration and proliferative efficiency of MDA-MB-231 cells were completely arrested upon styrene substituted biscoumarin treatment. Also, mRNA gene expression and protein expression of pro-apoptotic (BAX) and anti-apoptotic (BCL-2) genes were analyzed by qRT-PCR and western blot analysis upon styrene substituted biscoumarin treatment to MDA-MB-231 cells. Our results showed that styrene substituted biscoumarin downregulated BCL-2 gene expression and upregulated BAX gene expression to trigger apoptotic process. Styrene substituted biscoumarin could induce apoptosis through intrinsic mitochondrial pathway in breast cancer cell lines, particularly in MDA-MB-231. Our data suggest that styrene substituted biscoumarin may act as a potential chemotherapeutic agent against breast cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Morbillivirus control of the interferon response: relevance of STAT2 and mda5 but not STAT1 for canine distemper virus virulence in ferrets.

PubMed

Svitek, Nicholas; Gerhauser, Ingo; Goncalves, Christophe; Grabski, Elena; Döring, Marius; Kalinke, Ulrich; Anderson, Danielle E; Cattaneo, Roberto; von Messling, Veronika

2014-03-01

The V proteins of paramyxoviruses control the innate immune response. In particular, the V protein of the genus Morbillivirus interferes with the signal transducer and activator of transcription 1 (STAT1), STAT2, and melanoma differentiation-associated protein 5 (mda5) signaling pathways. To characterize the contributions of these pathways to canine distemper virus (CDV) pathogenesis, we took advantage of the knowledge about the mechanisms of interaction between the measles virus V protein with these key regulators of innate immunity. We generated recombinant CDVs with V proteins unable to properly interact with STAT1, STAT2, or mda5. A virus with combined STAT2 and mda5 deficiencies was also generated, and available wild-type and V-protein-knockout viruses were used as controls. Ferrets infected with wild-type and STAT1-blind viruses developed severe leukopenia and loss of lymphocyte proliferation activity and succumbed to the disease within 14 days. In contrast, animals infected with viruses with STAT2 or mda5 defect or both STAT2 and mda5 defects developed a mild self-limiting disease similar to that associated with the V-knockout virus. This study demonstrates the importance of interference with STAT2 and mda5 signaling for CDV immune evasion and provides a starting point for the development of morbillivirus vectors with reduced immunosuppressive properties. The V proteins of paramyxoviruses interfere with the recognition of the virus by the immune system of the host. For morbilliviruses, the V protein is known to interact with the signal transducer and activator of transcription 1 (STAT1) and STAT2 and the melanoma differentiation-associated protein 5 (mda5), which are involved in interferon signaling. Here, we examined the contribution of each of these signaling pathways to the pathogenesis of the carnivore morbillivirus canine distemper virus. Using viruses selectively unable to interfere with the respective signaling pathway to infect ferrets, we found that inhibition of STAT2 and mda5 signaling was critical for lethal disease. Our findings provide new insights in the mechanisms of morbillivirus immune evasion and may lead to the development of new vaccines and oncolytic vectors.

A development framework for semantically interoperable health information systems.

PubMed

Lopez, Diego M; Blobel, Bernd G M E

2009-02-01

Semantic interoperability is a basic challenge to be met for new generations of distributed, communicating and co-operating health information systems (HIS) enabling shared care and e-Health. Analysis, design, implementation and maintenance of such systems and intrinsic architectures have to follow a unified development methodology. The Generic Component Model (GCM) is used as a framework for modeling any system to evaluate and harmonize state of the art architecture development approaches and standards for health information systems as well as to derive a coherent architecture development framework for sustainable, semantically interoperable HIS and their components. The proposed methodology is based on the Rational Unified Process (RUP), taking advantage of its flexibility to be configured for integrating other architectural approaches such as Service-Oriented Architecture (SOA), Model-Driven Architecture (MDA), ISO 10746, and HL7 Development Framework (HDF). Existing architectural approaches have been analyzed, compared and finally harmonized towards an architecture development framework for advanced health information systems. Starting with the requirements for semantic interoperability derived from paradigm changes for health information systems, and supported in formal software process engineering methods, an appropriate development framework for semantically interoperable HIS has been provided. The usability of the framework has been exemplified in a public health scenario.

Electrophysiological Correlates of Amnestic Mild Cognitive Impairment in a Simon Task

PubMed Central

Cespón, Jesús; Galdo-Álvarez, Santiago; Díaz, Fernando

2013-01-01

Amnestic mild cognitive impairment (aMCI) represents a prodromal stage of Alzheimer`s disease (AD), especially when additional cognitive domains are affected (Petersen et al., 2009). Thus, single-domain amnestic MCI (sdaMCI) and multiple-domain-amnestic MCI (mdaMCI) biomarkers are important for enabling early interventions to help slow down progression of the disease. Recording event-related potentials (ERPs) is a non-invasive and inexpensive measure of brain activity associated with cognitive processes, and it is of interest from a clinical point of view. The ERP technique may also be useful for obtaining early sdaMCI and mdaMCI biomarkers because ERPs are sensitive to impairment in processes that are not manifested at behavioral or clinical levels. In the present study, EEG activity was recorded in 25 healthy participants and 30 amnestic MCI patients (17 sdaMCI and 13 mdaMCI) while they performed a Simon task. The ERPs associated with visuospatial (N2 posterior-contralateral – N2pc -) and motor (lateralized readiness potential – LRP –) processes were examined. The N2pc amplitude was smaller in participants with mdaMCI than in healthy participants, which indicated a decline in the correlates of allocation of attentional resources to the target stimulus. In addition, N2pc amplitude proved to be a moderately good biomarker of mdaMCI subtype (0.77 sensitivity, 0.76 specificity). However, the LRP amplitude was smaller in the two MCI groups (sdaMCI and mdaMCI) than in healthy participants, revealing a reduction in the motor resources available to execute the response in sdaMCI and mdaMCI patients. Furthermore, the LRP amplitude proved to be a valid biomarker (0.80 sensitivity, 0.92 specificity) of both amnestic MCI subtypes. PMID:24339941

Ischemia-modified albümin and malondialdehyde levels in patients with overt and subclinical hyperthyroidism: effects of treatment on oxidative stress.

PubMed

Erem, Cihangir; Suleyman, Akile Karacin; Civan, Nadim; Mentese, Ahmet; Nuhoglu, İrfan; Uzun, Aysegul; Ersoz, Halil Onder; Deger, Orhan

2015-01-01

The main purpose of this study was to evaluate the levels of ischemia-modified albumin (IMA) and malondialdehyde (MDA) in patients with OHyper and SHyper, to assess the effects of antithyroid drug (ATD) therapy on the oxidative stress (OS) parameters. Forty-five untreated patients with overt hyperthyroidism (OHyper), 20 untreated patients with subclinical hyperthyroidism (SHyper) and 30 age-and sex-matched healthy controls were prospectively included in the study. Biochemical and hormonal parameters were evaluated in all patients before and after treatment. Compared with the control subjects, the levels of MDA, glucose and TG were significantly increased in patients with SHyper (p<0.05), whereas LDL-C levels were significantly decreased (p<0.01). Patients with OHyper showed significantly elevated MDA and glucose levels (p<0.001) and significantly decreased LDL-C and HDL-C levels compared with the controls (p<0.01). In patients with Graves' disease, serum TSH levels were inversely correlated with plasma MDA levels (r: -0.42, p<0.05). Plasma MDA levels significantly decreased and levels of TC, LDL-C and HDL-C significantly increased in the groups of OHyper and SHyper after treatment. Serum IMA levels did not significantly change at baseline and with the therapy in all subjects. In conclusion, increased MDA levels in both patient groups represent increased lipid peroxidation which might play an important role in the pathogenesis of the atherosclerosis in these patients. Increased oxidative stress in patients with SHyper and OHyper could be improved by ATD therapy. Also, MDA can be used as a reliable marker of OS and oxidative damage, while IMA is considered to be inappropriate.

Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC.

PubMed

Haidari, Mehran; Zhang, Wei; Wakame, Koji

2013-12-18

The effect of antioxidants on treatment of cancer is still controversial. Previously, we demonstrated that interaction of breast cancer cells with endothelial cells leads to tyrosine phosphorylation of VE-cadherin and disruption of endothelial adherens junction (EAJ). The molecular mechanism underlying the anti-metastatic effects of mushroom-derived active hexode correlated compound (AHCC) remains elusive. Several cellular and biochemical techniques were used to determine the contribution of oxidative stress in the disruption of EAJ and to test this hypothesis that AHCC inhibits the breast cancer cell-induced disruption of EAJ. Interaction of breast cancer cells (MDA-MB-231 cells) with human umbilical vein endothelial cells (HUVECs) leads to an increase in generation of reactive oxygen species (ROS). Treatment of HUVECs with H2O2 or phorbol myristate acetate (PMA) led to tyrosine phosphorylation of VE-cadherin, dissociation of β-catenin from VE-cadherin complex and increased transendothelial migration (TEM) of MDA-MB-231 cells. Induction of VE-cadherin tyrosine phosphorylation by PMA or by interaction of MDA-MB-231 cells with HUVECs was mediated by HRas and protein kinase C-α signaling pathways. Disruption of EAJ and phosphorylation of VE-cadherin induced by interaction of MDA-MB-231 cells with HUVECs were attenuated when HUVECs were pretreated with an antioxidant, N-acetylcysteine (NAC) or AHCC. AHCC inhibited TEM of MDA-MB-231 cells and generation of ROS induced by interaction of MDA-MB-231 cells with HUVECs. Our studies suggest that ROS contributes to disruption of EAJ induced by interaction of MDA-MB-231 cells with HUVECs and AHCC attenuates this alteration. Copyright © 2013 Elsevier Inc. All rights reserved.

Increased levels of urinary biomarkers of lipid peroxidation products among workers occupationally exposed to diesel engine exhaust.

PubMed

Bin, Ping; Shen, Meili; Li, Haibin; Sun, Xin; Niu, Yong; Meng, Tao; Yu, Tao; Zhang, Xiao; Dai, Yufei; Gao, Weimin; Gu, Guizhen; Yu, Shanfa; Zheng, Yuxin

2016-08-01

Diesel engine exhaust (DEE) was found to induce lipid peroxidation (LPO) in animal exposure studies. LPO is a class of oxidative stress and can be reflected by detecting the levels of its production, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and etheno-DNA adducts including 1,N(6)-etheno-2'-deoxyadenosine (ɛdA) and 3,N(4)-etheno-2'-deoxycytidine (ɛdC). However, the impact of DEE exposure on LPO has not been explored in humans. In this study, we evaluated urinary MDA, 4-HNE, ɛdA, and ɛdC levels as biomarkers of LPO among 108 workers with exclusive exposure to DEE and 109 non-DEE-exposed workers. Results showed that increased levels of urinary MDA and ɛdA were observed in subjects occupationally exposed to DEE before and after age, body mass index (BMI), smoking status, and alcohol use were adjusted (all p < 0.001). There was a statistically significant relationship between the internal exposure dose (urinary ΣOH-PAHs) and MDA, 4-HNE, and ɛdA (all p < 0.001). Furthermore, significant increased relations between urinary etheno-DNA adduct and MDA, 4-HNE were observed (all p < 0.05). The findings of this study suggested that the level of LPO products (MDA and ɛdA) was increased in DEE-exposed workers, and urinary MDA and ɛdA might be feasible biomarkers for DEE exposure. LPO induced DNA damage might be involved and further motivated the genomic instability could be one of the pathogeneses of cancer induced by DEE-exposure. However, additional investigations should be performed to understand these observations.

Killing of Human Melanoma Cells Induced by Activation of Class I Interferon–Regulated Signaling Pathways via MDA-7/IL-24

PubMed Central

Ekmekcioglu, Suhendan; Mumm, John B.; Udtha, Malini; Chada, Sunil; Grimm, Elizabeth A.

2008-01-01

Restoration of the tumor-suppression function by gene transfer of the melanoma differentiation-associated gene 7 (MDA7)/interleukin 24 (IL-24) successfully induces apoptosis in melanoma tumors in vivo. To address the molecular mechanisms involved, we previously revealed that MDA7/IL-24 treatment of melanoma cells down-regulates interferon regulatory factor (IRF)-1 expression and concomitantly up-regulates IRF-2 expression, which competes with the activity of IRF-1 and reverses the induction of IRF-1–regulated inducible nitric oxide synthase (iNOS). Interferons (IFNs) influence melanoma cell survival by modulating apoptosis. A class I IFN (IFN alfa) has been approved for the treatment of advanced melanoma with some limited success. A class II IFN (IFN gamma), on the other hand, supports melanoma cell survival, possibly through constitutive activation of iNOS expression. We therefore conducted this study to explore the molecular pathways of MDA7/IL-24 regulation of apoptosis via the intracellular induction of IFNs in melanoma. We hypothesized that the restoration of the MDA7/IL-24 axis leads to upregulation of Class I IFNs and induction of the apoptotic cascade. We found that MDA7/IL-24 induces the secretion of endogenous IFN beta, another class I IFN, leading to the arrest of melanoma cell growth and apoptosis. We also identified a series of apoptotic markers that play a role in this pathway, including the regulation of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and Fas-FasL. In summary, we described a novel pathway of MDA7/IL-24 regulation of apoptosis in melanoma tumors via endogenous IFN beta induction followed by IRF regulation and TRAIL/FasL system activation. PMID:18511292

Exhaled breath malondialdehyde, spirometric results and dust exposure assessment in ceramics production workers.

PubMed

Sakhvidi, Mohammad Javad Zare; Biabani Ardekani, Javad; Firoozichahak, Ali; Zavarreza, Javad; Hajaghazade, Mohammad; Mostaghaci, Mehrdad; Mehrparvar, Amirhooshang; Barkhordari, Abolfazl

2015-01-01

The study aimed at measuring exhaled breath malondialdehyde (EBC-MDA) in workers exposed to dust containing silica and at its comparison with the non-exposed control group. The cross sectional, case-control study (N = 50) was performed in a tile and ceramics production factory in Yazd, Iran. EBC-MDA was quantified in exhaled breath of the participants by a lab made breath sampler. Exposure intensity was measured according to the NIOSH 0600 method in selected homogeneous exposure groups. Additionally, spirometry test was conducted to investigate a correlation between EBC-MDA and spirometric findings in the exposed workers. There was no difference in the observed exposure intensities of silica containing dust in different units. However, "coating preparation" was the unit with the highest concentration of dust. Although, the level of EBC-MDA in the cases was slightly higher than in the controls, the difference was not statistically significant (U = 252, p = 0.464). A significant and positive correlation was found between dust exposure intensity in working units and the measured EBC-MDA of workers (r = 0.467, N = 25, p = 0.027). There were also no statistically significant differences among job categories in the exposed group for the values of FEV1% (F(3, 44) = 0.656, p = 0.584), FVC% (F(3, 44) = 1.417, p = 0.172), and FEV1/FVC% (F(3, 44) = 1.929, p = 0.139). The results showed a significant correlation between respirable dust exposure intensity and the level of EBC-MDA of the exposed subjects. However, our results did not show a significant correlation between lung function decreases and EBC-MDA. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Mass drug administration of azithromycin for trachoma reduces the prevalence of genital Chlamydia trachomatis infection in the Solomon Islands.

PubMed

Marks, M; Bottomley, C; Tome, H; Pitakaka, R; Butcher, R; Sokana, O; Kako, H; Solomon, A W; Mabey, D C

2016-06-01

Chlamydia trachomatis is the most common bacterial sexually transmitted infection and is frequently asymptomatic; ocular C. trachomatis strains cause trachoma. Mass drug administration (MDA) of azithromycin for trachoma might also reduce the prevalence of genital C. trachomatis. In a survey conducted in the Solomon Islands in 2014, prior to MDA, the prevalence of genital C. trachomatis was 20.3% (95% CI 15.9% to 25.4%). We conducted a survey to establish the impact of MDA with azithromycin on genital C. trachomatis. Women attending three community outpatient clinics, predominantly for antenatal care, 10 months after MDA with azithromycin given for trachoma elimination, were enrolled in this survey. Self-taken high vaginal swabs were for C. trachomatis and Neisseria gonorrhoeae using the BD Probetec strand displacement assay. 298 women were enrolled. C. trachomatis infection was diagnosed in 43 women (14.4%, 95% CI 10.6% to 18.9%) and N. gonorrhoeae in 9 (3%, 95% CI 1.4% to 5.7%). The age-adjusted OR for C. trachomatis infection was consistent with a significant decrease in the prevalence of C. trachomatis following MDA (OR 0.58, 95% CI 0.37 to 0.94, p=0.027). There was no change in the prevalence of N. gonorrhoeae between following MDA (OR 0.51, 95% CI 0.22 to 1.22, p=0.13). This study demonstrated a 40% reduction in the age-adjusted prevalence of genital C. trachomatis infection following azithromycin MDA for trachoma elimination. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Missile Defense: Assessment of DODs Reports on Status of Efforts and Options for Improving Homeland Missile Defense

DTIC Science & Technology

2016-02-17

However, MDA may encounter challenges with the RKV’s contract strategy, industry collaboration efforts, and schedule because MDA has not yet...negotiated the terms of the RKV modification with the prime contractor, is relying on potential industry competitors to collaborate on developing the RKV...interfaces and standards for its subsystems, called modules. Under the DSC, MDA plans to form a cross industry team consisting of Boeing, Raytheon, and

Personnel Security Research - Prescreening and Background Investigations

DTIC Science & Technology

1986-06-01

military unit, base, station, ship, or aircraft nf a controlled substance with the intent to distribute. Hallucinogens/ Psychedelics . A group of...and psychedelic amphetamine variants (STP, MDA). Although a unique drug, for purposes of this certificate phencyclidine (PCP) will be labeled in this

Characterization of metabolic profile of intact non-tumor and tumor breast cells by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy.

PubMed

Maria, Roberta M; Altei, Wanessa F; Andricopulo, Adriano D; Becceneri, Amanda B; Cominetti, Márcia R; Venâncio, Tiago; Colnago, Luiz A

2015-11-01

(1)H high-resolution magic angle spinning nuclear magnetic resonance ((1)H HR-MAS NMR) spectroscopy was used to analyze the metabolic profile of an intact non-tumor breast cell line (MCF-10A) and intact breast tumor cell lines (MCF-7 and MDA-MB-231). In the spectra of MCF-10A cells, six metabolites were assigned, with glucose and ethanol in higher concentrations. Fifteen metabolites were assigned in MCF-7 and MDA-MB-231 (1)H HR-MAS NMR spectra. They did not show glucose and ethanol, and the major component in both tumor cells was phosphocholine (higher in MDA-MB-231 than in MCF-7), which can be considered as a tumor biomarker of breast cancer malignant transformation. These tumor cells also show acetone signal that was higher in MDA-MB-231 cells than in MCF-7 cells. The high acetone level may be an indication of high demand for energy in MDA-MB-231 to maintain cell proliferation. The higher acetone and phosphocholine levels in MDA-MB-231 cells indicate the higher malignance of the cell line. Therefore, HR-MAS is a rapid reproducible method to study the metabolic profile of intact breast cells, with minimal sample preparation and contamination, which are critical in the analyses of slow-growth cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Decursin exerts anti-cancer activity in MDA-MB-231 breast cancer cells via inhibition of the Pin1 activity and enhancement of the Pin1/p53 association.

PubMed

Kim, Ji-Hyun; Jung, Ji Hoon; Kim, Sung-Hoon; Jeong, Soo-Jin

2014-02-01

The peptidyl-prolyl cis/trans isomerase Pin1 is overexpressed in a wide variety of cancer cells and thus considered as an important target molecule for cancer therapy. This study demonstrates that decursin, a bioactive compound from Angelica gigas, exert the anti-cancer effect against breast cancer cells via regulation of Pin1 and its related signaling molecules. We observed that decursin induced G1 arrest with decrease in cyclin D1 level in Pin1-expressing breast cancer cells MDA-MB-231, but not Pin1-non-expressing breast cancer cells MDA-MB-157. In addition, decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Further, we found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, our current study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1 protein. Copyright © 2013 John Wiley & Sons, Ltd.

Multiple displacement amplification on single cell and possible PGD applications.

PubMed

Hellani, Ali; Coskun, Serdar; Benkhalifa, Moncef; Tbakhi, Abelghani; Sakati, Nadia; Al-Odaib, Ali; Ozand, Pinar

2004-11-01

Multiple displacement amplification (MDA) is a technique used in the amplification of very low amounts of DNA and reported to yield large quantities of high-quality DNA. We used MDA to amplify the whole genome directly from a single cell. The most common techniques used in PGD are PCR and fluorescent in-situ hybridization (FISH). There are many limitations to these techniques including, the number of chromosomes diagnosed for FISH or the quality of DNA issued from a single cell PCR. This report shows, for the first time, use of MDA for single cell whole genome amplification. A total of 16 short tandem repeats (STRs) were amplified successfully with a similar pattern to the genomic DNA. Furthermore, allelic drop out (ADO) derived from MDA was assessed in 40 single cells by analysing (i) heterozygosity for a known beta globin mutation (IVSI-5 C-G) and by studying (ii) the heterozygous loci present in the STRs. ADO turned out to be 10.25% for the beta globin gene sequencing and 5% for the fluorescent PCR analysis of STRs. Moreover, the amplification accuracy of MDA permitted the detection of trisomy 21 on a single cell using comparative genome hybridization-array. Altogether, these data suggest that MDA can be used for single cell molecular karyotyping and the diagnosis of any single gene disorder in PGD.

Oxidative stress and genetic damage among workers exposed primarily to organophosphate and pyrethroid pesticides.

PubMed

Zepeda-Arce, Rigoberto; Rojas-García, Aurora Elizabeth; Benitez-Trinidad, Alma; Herrera-Moreno, José Francisco; Medina-Díaz, Irma Martha; Barrón-Vivanco, Briscia S; Villegas, Germán Pier; Hernández-Ochoa, Isabel; Sólis Heredia, María de Jesús; Bernal-Hernández, Yael Y

2017-06-01

The indiscriminate use of pesticides in agriculture and public health campaigns has been associated with an increase of oxidative stress and DNA damage, resulting in health outcomes. Some defense mechanisms against free radical-induced oxidative damage include the antioxidant enzyme systems. The aim of this study was to determine the levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and the relationship of antioxidant enzyme levels with DNA damage among sprayers (workers) occupationally exposed to pesticides. The determinations of MDA and antioxidant enzymes were performed spectrophotometrically. The genotoxic effects were evaluated using the comet assay. The results showed a marginally significant decrease in SOD and CAT activities in the high exposure group compared to the control group. For MDA, statistically significant differences were found among people working long term vs. those working temporarily (P = 0.02) as sprayers. In the moderate exposure group, a positive correlation was observed between MDA levels and GPx activity. In the high exposure group, a negative correlation was observed between GR and CAT activities, and between MDA levels and GPx activities. Furthermore, in the high exposure group, a positive correlation between DNA damage parameters and MDA levels was observed. The results suggest an important role of antioxidant enzymes for the protection of DNA damage caused by occupational exposure to pesticides. © 2017 Wiley Periodicals, Inc.

Migration and invasion induced by linoleic acid are mediated through fascin in MDA-MB-231 breast cancer cells.

PubMed

Gonzalez-Reyes, Christian; Marcial-Medina, Cleofas; Cervantes-Anaya, Nancy; Cortes-Reynosa, Pedro; Salazar, Eduardo Perez

2018-06-01

Epidemiological studies strongly suggest an association between high levels of dietary fat intake and an increased risk of developing breast cancer. Linoleic acid (LA) is an essential omega-6 PUFA and the major fatty acid in occidental diets. In breast cancer cells, LA induces expression of plasminogen activator inhibitor-1, proliferation, migration, and invasion. Fascin is an actin crosslinker globular protein that generates actin bundles made of parallel actin filaments, which mediate formation and stability of microspikes, stress fibers, membrane ruffles, and filopodia. However, the role of fascin in migration and invasion induced by LA in MDA-MB-231 breast cancer cells remains to be studied. We demonstrate here that LA induces an increase of fascin expression in MDA-MB-231 and MCF12A mammary epithelial cells. Particularly, LA induces the formation of filopodia and lamellipodia and the localization of fascin in these actin structures in MDA-MB-231 breast cancer cells. However, LA only induces formation of microspikes and the localization of fascin in these actin structures in mammary non-tumorigenic epithelial cells MCF12A. In addition, LA induces migration, invasion, and matrix metalloproteinase-9 secretion through a fascin-dependent pathway in MDA-MB-231 cells. In summary, our findings demonstrate that fascin is required for migration and invasion induced by LA in MDA-MB-231 breast cancer cells.

Dissecting the role of Engrailed in adult dopaminergic neurons--Insights into Parkinson disease pathogenesis.

PubMed

Rekaik, Hocine; Blaudin de Thé, François-Xavier; Prochiantz, Alain; Fuchs, Julia; Joshi, Rajiv L

2015-12-21

The homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development, but continues to exert neuroprotective and physiological functions in adult mDA neurons. Loss of one En1 allele in the mouse leads to progressive demise of mDA neurons in the ventral midbrain starting from 6 weeks of age. These mice also develop Parkinson disease-like motor and non-motor symptoms. The characterization of En1 heterozygous mice have revealed striking parallels to central mechanisms of Parkinson disease pathogenesis, mainly related to mitochondrial dysfunction and retrograde degeneration. Thanks to the ability of homeoproteins to transduce cells, En1/2 proteins have also been used to protect mDA neurons in various experimental models of Parkinson disease. This neuroprotection is partly linked to the ability of En1/2 to regulate the translation of certain nuclear-encoded mitochondrial mRNAs for complex I subunits. Other transcription factors that govern mDA neuron development (e.g. Foxa1/2, Lmx1a/b, Nurr1, Otx2, Pitx3) also continue to function for the survival and maintenance of mDA neurons in the adult and act through partially overlapping but also diverse mechanisms. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

THE USE OF MULTIPLE DISPLACEMENT AMPLIFICATION TO INCREASE THE DETECTION AND GENOTYPING OF TRYPANOSOMA SPECIES SAMPLES IMMOBILISED ON FTA FILTERS

PubMed Central

MORRISON, LIAM J.; McCORMACK, GILLIAN; SWEENEY, LINDSAY; LIKEUFACK, ANNE C. L.; TRUC, PHILIPPE; TURNER, C. MICHAEL; TAIT, ANDY; MacLEOD, ANNETTE

2007-01-01

Whole genome amplification methods are a recently developed tool for amplifying DNA from limited template. We report its application in trypanosome infections, characterised by low parasitaemias. Multiple Displacement Amplification (MDA) amplifies DNA with a simple in vitro step, and was evaluated on mouse blood samples on FTA filter cards with known numbers of Trypanosoma brucei parasites. The data showed a twenty-fold increase in the number of PCRs possible per sample, using primers diagnostic for the multi-copy ribosomal ITS region or 177 bp repeats, and a twenty-fold increase in sensitivity over nested PCR against a single copy microsatellite. Using MDA for microsatellite genotyping caused allele dropout at low DNA concentrations, which was overcome by pooling multiple MDA reactions. The validity of using MDA was established with samples from Human African Trypanosomiasis patients. The use of MDA allows maximal use of finite DNA samples and may prove a valuable tool in studies where multiple reactions are necessary, such as population genetic analyses. PMID:17556624

Pharbilignan C induces apoptosis through a mitochondria-mediated intrinsic pathway in human breast cancer cells.

PubMed

Park, Yong Joo; Choi, Chang-Ik; Chung, Kyu Hyuck; Kim, Ki Hyun

2016-10-01

Pharbitidis Semen, the seed of Morning glory (Pharbitis nil), is a medicinal agent that has traditionally been used as a purgative in Korea. Pharbilignan C (PLC) is a dihydro[b]-benzofuran-type neolignan from Pharbitidis Semen, which reportedly exhibited the most potent cytotoxicity against human tumor cells. To further study the antiproliferative activity of PLC, its molecular mechanisms of action in two breast adenocarcinoma cells, MCF-7 and MDA-MB 231 cells were investigated. PLC inhibited the proliferation of MDA-MB 231 and MCF-7 cells, in order of sensitivity (IC50 of MDA-MB 231 cells: 7.0±2.0μM). PLC induced apoptosis in MDA-MB 231 cells with down regulation of Bcl-2 and up-regulation of Bax expression. It also decreased mitochondrial membrane potential accompanied with increasing initiator caspase, caspase-9 activation and executioner caspase, caspase-3 activation. This study demonstrates that PLC inhibited proliferation of MDA-MB 231 cells by inducing apoptosis via the mitochondria-mediated intrinsic pathway. Copyright © 2016 Elsevier Ltd. All rights reserved.

Community-based intermittent mass testing and treatment for malaria in an area of high transmission intensity, western Kenya: study design and methodology for a cluster randomized controlled trial.

PubMed

Samuels, Aaron M; Awino, Nobert; Odongo, Wycliffe; Abong'o, Benard; Gimnig, John; Otieno, Kephas; Shi, Ya Ping; Were, Vincent; Allen, Denise Roth; Were, Florence; Sang, Tony; Obor, David; Williamson, John; Hamel, Mary J; Patrick Kachur, S; Slutsker, Laurence; Lindblade, Kim A; Kariuki, Simon; Desai, Meghna

2017-06-07

Most human Plasmodium infections in western Kenya are asymptomatic and are believed to contribute importantly to malaria transmission. Elimination of asymptomatic infections requires active treatment approaches, such as mass testing and treatment (MTaT) or mass drug administration (MDA), as infected persons do not seek care for their infection. Evaluations of community-based approaches that are designed to reduce malaria transmission require careful attention to study design to ensure that important effects can be measured accurately. This manuscript describes the study design and methodology of a cluster-randomized controlled trial to evaluate a MTaT approach for malaria transmission reduction in an area of high malaria transmission. Ten health facilities in western Kenya were purposively selected for inclusion. The communities within 3 km of each health facility were divided into three clusters of approximately equal population size. Two clusters around each health facility were randomly assigned to the control arm, and one to the intervention arm. Three times per year for 2 years, after the long and short rains, and again before the long rains, teams of community health volunteers visited every household within the intervention arm, tested all consenting individuals with malaria rapid diagnostic tests, and treated all positive individuals with an effective anti-malarial. The effect of mass testing and treatment on malaria transmission was measured through population-based longitudinal cohorts, outpatient visits for clinical malaria, periodic population-based cross-sectional surveys, and entomological indices.

Changes in thrombin-stimulated platelet malondialdehyde production during the menstrual cycle.

PubMed Central

Tindall, H; Zuzel, M; Paton, R C; McNicol, G P

1981-01-01

Forty normal women had thrombin-stimulated platelet malondialdehyde (MDA) production measured during their menstrual cycle. Twenty women in this group were taking the combined oral contraceptive pill (OCP). Platelet MDA production was found to fall by 30% during normal menstruation and the week when the subjects were not taking a combined OCP, but it remained constant throughout the remainder of the cycle. No significant change in initial platelet aggregation response to stimulation by thrombin, change in plasma thrombin clotting time, plasma heparin neutralising activity (HNA), or plasma antithrombin III (AT-III) activity was seen when the platelet MDA production was reduced. The bleeding time results showed some variation throughout the menstrual cycle but these did not appear to be related to the variation in platelet MDA production. PMID:7251901

Polymyositis: Medical Management

MedlinePlus

... Donate Search MDA.org Close Polymyositis (PM) Medical Management Polymyositis (PM) is a highly treatable disease. Some ... PM) Signs and Symptoms Diagnosis Causes/Inheritance Medical Management Research Find your MDA Care Center Grants at ...

Mass and molecular composition of vesicular stomatitis virus: a scanning transmission electron microscopy analysis.

PubMed

Thomas, D; Newcomb, W W; Brown, J C; Wall, J S; Hainfeld, J F; Trus, B L; Steven, A C

1985-05-01

Dark-field scanning transmission electron microscopy was used to perform mass analyses of purified vesicular stomatitis virions, pronase-treated virions, and nucleocapsids, leading to a complete self-consistent account of the molecular composition of vesicular stomatitis virus. The masses obtained were 265.6 +/- 13.3 megadaltons (MDa) for the native virion, 197.5 +/- 8.4 MDa for the pronase-treated virion, and 69.4 +/- 4.9 MDa for the nucleocapsid. The reduction in mass effected by pronase treatment, which corresponds to excision of the external domains (spikes) of G protein, leads to an average of 1,205 molecules of G protein per virion. The nucleocapsid mass, after compensation for the RNA (3.7 MDa) and residual amounts of other proteins, yielded a complement of 1,258 copies of N protein. Calibration of the amounts of M, NS, and L proteins relative to N protein by biochemical quantitation yielded values of 1,826, 466, and 50 molecules, respectively, per virion. Assuming that the remaining virion mass is contributed by lipids in the viral envelope, we obtained a value of 56.1 MDa for its lipid content. In addition, four different electron microscopy procedures were applied to determine the nucleocapsid length, which we conclude to be 3.5 to 3.7 micron. The nucleocapsid comprises a strand of repeating units which have a center-to-center spacing of 3.3 nm as measured along the middle of the strand. We show that these repeating units represent monomers of N protein, each of which is associated with 9 +/- 1 bases of single-stranded RNA. From scanning transmission electron microscopy images of negatively stained nucleocapsids, we inferred that N protein has a wedge-shaped, bilobed structure with dimensions of approximately 9.0 nm (length), approximately 5.0 nm (depth), and approximately 3.3 nm (width, at the midpoint of its long axis). In the coiled configuration of the in situ nucleocapsid, the long axis of N protein is directed radially, and its depth corresponds to the pitch of the nucleocapsid helix.

Mass and molecular composition of vesicular stomatitis virus: a scanning transmission electron microscopy analysis.

PubMed Central

Thomas, D; Newcomb, W W; Brown, J C; Wall, J S; Hainfeld, J F; Trus, B L; Steven, A C

1985-01-01

Dark-field scanning transmission electron microscopy was used to perform mass analyses of purified vesicular stomatitis virions, pronase-treated virions, and nucleocapsids, leading to a complete self-consistent account of the molecular composition of vesicular stomatitis virus. The masses obtained were 265.6 +/- 13.3 megadaltons (MDa) for the native virion, 197.5 +/- 8.4 MDa for the pronase-treated virion, and 69.4 +/- 4.9 MDa for the nucleocapsid. The reduction in mass effected by pronase treatment, which corresponds to excision of the external domains (spikes) of G protein, leads to an average of 1,205 molecules of G protein per virion. The nucleocapsid mass, after compensation for the RNA (3.7 MDa) and residual amounts of other proteins, yielded a complement of 1,258 copies of N protein. Calibration of the amounts of M, NS, and L proteins relative to N protein by biochemical quantitation yielded values of 1,826, 466, and 50 molecules, respectively, per virion. Assuming that the remaining virion mass is contributed by lipids in the viral envelope, we obtained a value of 56.1 MDa for its lipid content. In addition, four different electron microscopy procedures were applied to determine the nucleocapsid length, which we conclude to be 3.5 to 3.7 micron. The nucleocapsid comprises a strand of repeating units which have a center-to-center spacing of 3.3 nm as measured along the middle of the strand. We show that these repeating units represent monomers of N protein, each of which is associated with 9 +/- 1 bases of single-stranded RNA. From scanning transmission electron microscopy images of negatively stained nucleocapsids, we inferred that N protein has a wedge-shaped, bilobed structure with dimensions of approximately 9.0 nm (length), approximately 5.0 nm (depth), and approximately 3.3 nm (width, at the midpoint of its long axis). In the coiled configuration of the in situ nucleocapsid, the long axis of N protein is directed radially, and its depth corresponds to the pitch of the nucleocapsid helix. Images PMID:2985822

The Need for Software Architecture Evaluation in the Acquisition of Software-Intensive Sysetms

DTIC Science & Technology

2014-01-01

Function and Performance Specification GIG Global Information Grid ISO International Standard Organisation MDA Model Driven Architecture...architecture and design, which is a key part of knowledge-based economy UNCLASSIFIED DSTO-TR-2936 UNCLASSIFIED 24  Allow Australian SMEs to

Polymyositis: Diagnosis

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Dermatomyositis: Diagnosis

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Model-driven methodology for rapid deployment of smart spaces based on resource-oriented architectures.

PubMed

Corredor, Iván; Bernardos, Ana M; Iglesias, Josué; Casar, José R

2012-01-01

Advances in electronics nowadays facilitate the design of smart spaces based on physical mash-ups of sensor and actuator devices. At the same time, software paradigms such as Internet of Things (IoT) and Web of Things (WoT) are motivating the creation of technology to support the development and deployment of web-enabled embedded sensor and actuator devices with two major objectives: (i) to integrate sensing and actuating functionalities into everyday objects, and (ii) to easily allow a diversity of devices to plug into the Internet. Currently, developers who are applying this Internet-oriented approach need to have solid understanding about specific platforms and web technologies. In order to alleviate this development process, this research proposes a Resource-Oriented and Ontology-Driven Development (ROOD) methodology based on the Model Driven Architecture (MDA). This methodology aims at enabling the development of smart spaces through a set of modeling tools and semantic technologies that support the definition of the smart space and the automatic generation of code at hardware level. ROOD feasibility is demonstrated by building an adaptive health monitoring service for a Smart Gym.

Melanoma Differentiation-associated Gene 7/IL-24 Exerts Cytotoxic Effects by Altering the Alternative Splicing of Bcl-x Pre-mRNA via the SRC/PKCδ Signaling Axis*

PubMed Central

Shapiro, Brian A.; Vu, Ngoc T.; Shultz, Michael D.; Shultz, Jacqueline C.; Mietla, Jennifer A.; Gouda, Mazen M.; Yacoub, Adly; Dent, Paul; Fisher, Paul B.; Park, Margaret A.; Chalfant, Charles E.

2016-01-01

Melanoma differentiation-associated gene 7 (MDA-7/IL-24) exhibits cytotoxic effects on tumor cells while sparing untransformed cells, and Bcl-x(L) is reported to efficiently block the induction of cell death by MDA-7/IL-24. The expression of Bcl-x(L) is regulated at the level of RNA splicing via alternative 5′ splice site selection within exon 2 to produce either the pro-apoptotic Bcl-x(s) or the anti-apoptotic Bcl-x(L). Our laboratory previously reported that Bcl-x RNA splicing is dysregulated in a large percentage of human non-small cell lung cancer (NSCLC) tumors. Therefore, we investigated whether the alternative RNA splicing of Bcl-x pre-mRNA was modulated by MDA-7/IL-24, which would suggest that specific NSCLC tumors are valid targets for this cytokine therapy. Adenovirus-delivered MDA-7/IL-24 (Ad.mda-7) reduced the viability of NSCLC cells of varying oncogenotypes, which was preceded by a decrease in the ratio of Bcl-x(L)/Bcl-x(s) mRNA and Bcl-x(L) protein expression. Importantly, both the expression of Bcl-x(L) and the loss of cell viability were “rescued” in Ad.mda-7-treated cells incubated with Bcl-x(s) siRNA. In addition, NSCLC cells ectopically expressing Bcl-x(s) exhibited significantly reduced Bcl-x(L) expression, which was again restored by Bcl-x(s) siRNA, suggesting the existence of a novel mechanism by which Bcl-x(s) mRNA restrains the expression of Bcl-x(L). In additional mechanistic studies, inhibition of SRC and PKCδ completely ablated the ability of MDA-7/IL-24 to reduce the Bcl-x(L)/(s) mRNA ratio and cell viability. These findings show that Bcl-x(s) expression is an important mediator of MDA-7/IL-24-induced cytotoxicity requiring the SRC/PKCδ signaling axis in NSCLC cells. PMID:27519412

MDA, MDMA, and other "mescaline-like" substances in the US military's search for a truth drug (1940s to 1960s).

PubMed

Passie, Torsten; Benzenhöfer, Udo

2018-01-01

This article describes the context in which 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and other mescaline-like compounds were explored as hallucinogens for military and intelligence purposes from the 1940s to the 1960s. Germans first tested mescaline as a "truth drug" in a military context. In the 1940s, the United States military started testing hallucinogenic substances as truth drugs for interrogation and behavior manipulation. After tests carried out using mescaline and other drugs in 1950, some derivatives of mescaline were synthesized by the Army for the exploration of possible "speech-inducing" effects. After insufficient animal testing, the substances were given to patients at the New York State Psychiatric Institute (NYSPI). 3,4-Methylenedioxy-N-ethylamphetamine (MDE), a compound almost identical to MDMA, was among the compounds delivered for testing at the NYSPI. During tests with other derivatives (3,4-dimethoxyphenethylamine (DMA), 3,4-methylenedioxyphenethylamine (MDPEA), MDA) in 1952-53, an unwitting patient died in these tests, which was kept secret from the public. Research was interrupted and toxicological animal testing procedures were initiated. The secret animal studies run in 1953/1954 revealed that some of the "mescaline derivatives" tested (e.g. MDA, MDE, DMA, 3,4,5-trimethoxyamphetamine (TMA), MDMA) were considered for further testing in humans. In 1955, the military changed focus to lysergic acid diethylamide (LSD), but some interest in mescaline-like compounds remained for their ability to change mood and habit without interfering with cognition and sensory perception. Based on the known documents, it remains unclear (but probable) whether any of the mescaline derivatives tested were being used operationally. Copyright © 2017 John Wiley & Sons, Ltd.

Paclitaxel sensitivity of breast cancer cells requires efficient mitotic arrest and disruption of Bcl-xL/Bak interaction.

PubMed

Flores, M Luz; Castilla, Carolina; Ávila, Rainiero; Ruiz-Borrego, Manuel; Sáez, Carmen; Japón, Miguel A

2012-06-01

Taxanes are being used for the treatment of breast cancer. However, cancer cells frequently develop resistance to these drugs with the subsequent recurrence of the tumor. MDA-MB-231 and T-47D breast cancer cell lines were used to assess the effect of paclitaxel treatment on apoptosis and cell cycle, the possible mechanisms of paclitaxel resistance as well as the enhancement of paclitaxel-induced apoptosis based on its combination with phenylethyl isothiocyanate (PEITC). T-47D cells undergo apoptosis in response to paclitaxel treatment. The induction of apoptosis was associated with a robust mitotic arrest and the disruption of Bcl-xL/Bak interaction. By contrary, MDA-MB-231 cells were insensitive to paclitaxel-induced apoptosis and this was associated with a high percentage of cells that slip out of paclitaxel-imposed mitotic arrest and also with the maintenance of Bcl-xL/Bak interaction. The sequential treatment of MDA-MB-231 cells with PEITC followed by paclitaxel inhibited the slippage induced by paclitaxel and increased the apoptosis induction achieved with any of the drugs alone. In breast cancer tissues, high Bcl-xL expression was correlated with a shorter time of disease-free survival in patients treated with a chemotherapeutic regimen that contains paclitaxel, in a statistically significant way. Thus, resistance to paclitaxel in MDA-MB-231 cells is related to the inability to disrupt the Bcl-xL/Bak interaction and increased slippage. In this context, the combination of a drug that induces a strong mitotic arrest, such as paclitaxel, with another that inhibits slippage, such as PEITC, translates into increased apoptotic induction.

R516Q mutation in Melanoma differentiation-associated protein 5 (MDA5) and its pathogenic role towards rare Singleton-Merten syndrome; a signature associated molecular dynamics study.

PubMed

Raghuraman, P; Sudandiradoss, C

2018-02-20

Singleton-Merten syndrome, a critical and rare multifactorial disorder that is closely linked to R516Q mutation in MDA5 protein associated with an enhanced interferon response in the affected individual. In the present study, we provide conclusive key evidence on R516Q mutation and their connectivity towards sequence-structural basis dysfunction of MDA5 protein. Among the various mutations, we found R516Q is the most pathogenic mutation based on mutational signature Q-A-[RE]-G-R-[GA]-R-A-[ED]-[DE]-S-[ST]-Y-[TSAV]-L-V designed from our work. Further, we derived a distant ortholog for this mutational signature from which we identified 343 intra-residue interactions that fall communally in the position required to maintain the structural and functional integration of protein architecture. This identification served us to understand the critical role of hot spots in residual aggregation that holds a native form of folding conformation in the functional region. In addition, the long-range molecular dynamics simulation demarcated the residual dependencies of conformational transition in distinct regions ( L29 360-370 α18 , α19 380-410 L31 , α21 430-480 L33-α22-L35 and α24 510-520 L38 ) occurring upon R516Q mutation. Together, our results emphasise that the dislocation of functional hot spots Pro229, Arg414, Val498, Met510, Ala513, Gly515 and Arg516 in MDA5 protein which is important for interior structural packing and fold arrangements. In a nutshell, our findings are perfectly conceded with other experimental reports and will have potential implications in immune therapeutical advancement for rare singleton-merten syndrome.

A new chemotherapy agent-free theranostic system composed of graphene oxide nano-complex and aptamers for treatment of cancer cells.

PubMed

Bahreyni, Amirhossein; Yazdian-Robati, Rezvan; Hashemitabar, Shirin; Ramezani, Mohammad; Ramezani, Pouria; Abnous, Khalil; Taghdisi, Seyed Mohammad

2017-06-30

The common cancer treatment strategies like chemotherapy and radiotherapy are nonspecific and can trigger severe side effects by damaging normal cells. So, targeted cancer therapies, such as apoptosis induction, have attracted great attention in recent years. In this project, two nano-complexes, MUC1 aptamer-NAS-24 aptamer-Graphene oxide (GO) and MUC1 aptamer-Cytochrome C aptamer-GO, were designed to induce cell programmed death in MDA-MB-231 and MCF-7 cells (breast cancer cell lines) and to verify the level of apoptosis in both cell lines. MUC1 aptamer was a molecular recognition probe that led the internalization of two nano-complexes into MDA-MB-231 and MCF-7 cells (MUC1 positive cells) but not into HepG2 cell (liver cancer cell line, MUC1 negative cells). The apoptosis induction relied on binding of NAS-24 aptamer to its target, vimentin, in MDA-MB-231 and MCF-7 (target cells) with different levels of vimentin content. The function of first nano-complex was confirmed by binding of FAM-labeled cytochrome C aptamer to its target (cytochrome C) which was released from mitochondria, based on the function of the first nano-complex. Fluorometric analysis and gel retardation assay proved the formation of nano-complexes. The results of flow cytometry and fluorescence microscopy indicated efficient apoptosis induction just in target cells (MDA-MB-231 and MCF-7 cells) but not in non-target cells (HepG2 cell). The results of MTT assay also confirmed cell death process. Overall, our results proved excellent targeted apoptosis in breast cancer cells by designed nano-complexes which can be applied as an efficient cancer therapy method. Copyright © 2017 Elsevier B.V. All rights reserved.

Assessing "First Mile" Supply Chain Factors Affecting Timeliness of School-Based Deworming Interventions: Supply and Logistics Performance Indicators.

PubMed

Koporc, Kimberly M; Strunz, Eric; Holloway, Cassandra; Addiss, David G; Lin, William

2015-12-01

Between 2007 and 2012, Children Without Worms (CWW) oversaw the Johnson & Johnson (J&J) donation of Vermox (mebendazole) for treatment of school-age children to control soil-transmitted helminthiasis (STH). To identify factors associated with on-time, delayed, or missed mass drug administration (MDA) interventions, and explore possible indicators for supply chain performance for drug donation programs, we reviewed program data for the 14 STH-endemic countries CWW supported during 2007-2012. Data from drug applications, shipping records, and annual treatment reports were tracked using Microsoft Excel. Qualitative data from interviews with key personnel were used to provide additional context on the causes of delayed or missed MDAs. Four possible contributory factors to delayed or missed MDAs were considered: production, shipping, customs clearance, and miscellaneous in-country issues. Coverage rates were calculated by dividing the number of treatments administered by the number of children targeted during the MDA. Of the approved requests for 78 MDAs, 54 MDAs (69%) were successfully implemented during or before the scheduled month. Ten MDAs (13%) were classified as delayed; seven of these were delayed by one month or less. An additional 14 MDAs (18%) were classified as missed. For the 64 on-time or delayed MDAs, the mean coverage was approximately 88%. To continue to assess the supply chain processes and identify areas for improvement, we identified four indicators or metrics for supply chain performance that can be applied across all neglected tropical disease (NTD) drug donation programs: (1) donor having available inventory to satisfy the country request for donation; (2) donor shipping the approved number of doses; (3) shipment arriving at the Central Medical Stores one month in advance of the scheduled MDA date; and (4) country programs implementing the MDA as scheduled.

Nutritional channels in breast cancer.

PubMed

Godoy, Alejandro; Salazar, Katherine; Figueroa, Carlos; Smith, Gary J; de Los Angeles Garcia, Maria; Nualart, Francisco J

2009-09-01

Breast cancers increase glucose uptake by increasing expression of the facilitative glucose transporters (GLUTs), mainly GLUT1. However, little is known about the relationship between GLUT1 expression and malignant potential in breast cancer. In this study, expression and subcellular localization of GLUT1 was analysed in vivo in breast cancer tissue specimens with differing malignant potential, based on the Scarff-Bloom-Richardson (SBRI, II, III) histological grading system, and in vitro in the breast cancer cell lines, MDA-MB-468 and MCF-7, and in MDA-MB-468 cells grown as xenografts in nude athymic BALB/c male mice. In situ hybridization analyses demonstrated similar levels of GLUT1 mRNA expression in tissue sections from breast cancers of all histological grades. However, GLUT1 protein was expressed at higher levels in grade SBRII cancer, compared with SBRI and SBRIII, and associated with the expression of the proliferation marker PCNA. Immunolocalization analyses in SBRII cancers demonstrated a preferential localization of GLUT1 to the portions of the cellular membrane that faced neighbouring cells and formed 'canaliculi-like structures', that we hypothesize could have a potential role as 'nutritional channels'. A similar pattern of GLUT1 localization was observed in confluent cultures of MDA-MB-468 and MCF-7, and in MDA-MB-468 cells grown as xenografts, but not in the normal breast epithelial cell line HMEC. However, no relationship between GLUT1 expression and malignant potential of human breast cancer was observed. Preferential subcellular localization of GLUT1 could represent a physiological adaptation of a subset of breast cancer cells that form infiltrative tumours with a nodular growth pattern and that therefore need a major diffusion of glucose from blood vessels.

Quantification of circulating cell-free DNA in the serum of patients with obstructive sleep apnea-hypopnea syndrome.

PubMed

Ye, Liang; Ma, Guan-Hua; Chen, Ling; Li, Min; Liu, Jia-Lin; Yang, Kun; Li, Qing-Yun; Li, Ning; Wan, Huan-Ying

2010-12-01

Serum cell-free DNA concentrations have been reported to increase in many acute diseases as well as in some chronic conditions such as cancer and autoimmune diseases. The aim of this study was to examine whether serum DNA concentrations were elevated in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). The effects of nasal continuous positive airway pressure (nCPAP) on serum DNA were also investigated. One hundred twenty-seven people diagnosed with OSAHS by polysomnography (PSG) were admitted into the OSAHS group, and 52 subjects without OSAHS were recruited for the control group. The OSAHS group was further divided into mild, moderate, and severe OSAHS subgroups based on their apnea-hypopnea index (AHI) during sleep. Ten patients with moderate and severe OSAHS were treated with nCPAP. Serum DNA, interleukin-6 (IL-6), and malonaldehyde (MDA) concentrations were measured and were found to be significantly higher in patients with moderate and severe OSAHS groups than those in the mild OSAHS and control groups (p < 0.05). Univariate analysis showed that serum DNA correlated positively with AHI, oxygen desaturation index (ODI), IL-6, and MDA, and negatively correlated with minimal oxygen saturation (miniSaO(2)) (all p < 0.05). In stepwise multiple regression analysis, only MDA and miniSaO(2) were suggested as significant independent predictors for the serum DNA concentrations. After 6 months of nCPAP therapy, serum concentrations of DNA, IL-6, and MDA were significantly decreased (p < 0.05). The increasing concentration of serum DNA in patients with OSAHS was positively correlated with disease severity. Serum DNA may become an important parameter for monitoring the severity of OSAHS and effectiveness of therapy.

Serum oxidant and antioxidant levels in diesel exposed toll collectors.

PubMed

Arbak, Peri; Yavuz, Ozlem; Bukan, Neslihan; Balbay, Oner; Ulger, Füsun; Annakkaya, Ali Nihat

2004-07-01

It has been suggested that exposure to diesel exhaust may lead to adverse effects due to the generation of oxidants. To evaluate the end products of oxidative stress in DE exposure, toll collectors who are considered a high risk group in regard to occupational toxins were compared to controls who had office-based occupations in the same company in this cross sectional study. A total of 38 toll collectors constituted the study group. All subjects were male. The toll collectors and 29 controls were similar regarding age, smoking status and duration of work. All subjects underwent a clinical examination and an interviewer-administrated questionnaire regarding respiratory symptoms, past medical and occupational history, and pulmonary function tests were performed in all subjects. Serum malondialdehyde (MDA), nitrite+nitrate and vitamin E levels were measured. Toll collectors showed higher serum MDA (5.76 +/- 2.15 micromol/L vs. 3.07 +/- 0.76 micromol/L, p=0.0001) and nitrite+nitrate levels (96.50 +/- 45.54 micromol/L vs. 19.32 +/- 11.77 micromol/L, p=0.0001) than controls. Vitamin E levels were similar in toll collectors and controls (10.57 +/- 3.44 mg/L and 9.72 +/- 2.44 mg/L, respectively, p=0.267). There was no difference between groups in terms of the findings of clinical examinations and respiratory symptoms. In pulmonary function parameters, only peak expiratory flow (PEF) in toll collectors was significantly lower than that of controls (88.9% predicted and 104.2% predicted, respectively, p=0.012). In conclusion, we suggest that serum MDA and nitrite+nitrate levels may be used as biological markers of oxidative stress related to DE exposure, but prospective controlled clinical studies are necessary to clarify the possible association between concentrations of MDA and nitrite+nitrate and pulmonary diseases related to DE exposure.

Effect of modified wuzi yanzong granule on patients with mild cognitive impairment from oxidative damage aspect.

PubMed

Wang, Xue-mei; Fu, Hong; Liu, Geng-xin; Zhu, Wei; Li, Li; Yang, Jin-xia

2007-12-01

To observe the effects of modified Wuzi Yanzong Granule (WYG) on memory function and the activity of serum superoxide dismutase (SOD), malondialdehyde (MDA) levels, leukocyte mitochondrial DNA (mtDNA) deletion rate and beta-amyloid protein(1-28) (A beta(1-28)) in patients with mild cognitive impairment (MCI). Thirty-six patients with MCI were selected based on the internationally recognized Petersen's criteria, and equally and randomly assigned to two groups. The treated group was treated with WYG and the control group was treated with placebo for 3 months. In addition, 20 healthy subjects were included in the study as the normal control group. Changes of memory function, SOD activity, MDA content, leukocyte mtDNA deletion rate and A beta(1-28) content were observed before and after treatment. Compared with the normal control group, the memory quotient and SOD activity in patients with MCI decreased significantly (P < 0.01), while MDA, A beta(1-28) levels and the leukocyte mtDNA deletion rate increased significantly (P < 0.01). After treatment, levels of memory quotient and serum SOD activity increased while the serum MDA level, leukocyte mtDNA deletion rate and A beta(1-28) level decreased in the treated group compared with those before treatment (P<0.01, P<0.05). Meanwhile, leukocyte mtDNA deletion rate and A beta(1-28) content in the treated group were all lower than those in the control group (P<0.05). WYG could improve memory function in patients with MCI and the therapeutic mechanism is possibly related to the increased activity of anti-oxidase, the improved free radical metabolism and the alleviation of leukocyte mtDNA oxidation damage. WYG shows clinical significance in delaying the progression of MCI.

[10]-Gingerol, a major phenolic constituent of ginger root, induces cell cycle arrest and apoptosis in triple-negative breast cancer cells.

PubMed

Bernard, Megan M; McConnery, Jason R; Hoskin, David W

2017-04-01

The ginger rhizome is rich in bioactive compounds, including [6]-gingerol, [8]-gingerol, and [10]-gingerol; however, to date, most research on the anti-cancer activities of gingerols have focused on [6]-gingerol. In this study, we compared [10]-gingerol with [8]-gingerol and [6]-gingerol in terms of their ability to inhibit the growth of human and mouse mammary carcinoma cells. A colorimetric assay based on the enzymatic reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide revealed that [10]-gingerol was more potent than [6]-gingerol and at least as potent as [8]-gingerol for the inhibition of triple-negative human (MDA-MB-231, MDA-MB-468) and mouse (4T1, E0771) mammary carcinoma cell growth. Further investigation of [10]-gingerol showed that it suppressed the growth of estrogen receptor-bearing (MCF-7, T47D) and HER2-overexpressing (SKBR3) breast cancer cells. The inhibitory effect of [10]-gingerol on the growth of MDA-MB-231 cells was associated with a reduction in the number of rounds of cell division and evidence of S phase-cell cycle arrest, as well as induction of apoptosis due to mitochondrial outer membrane permeabilization and the release of proapoptotic mitochondrial cytochrome c and SMAC/DIABLO into the cytoplasm. Surprisingly, killing of MDA-MB-231 cells by [10]-gingerol was not affected by a pan-caspase inhibitor (zVAD-fmk) or an anti-oxidant (N-acetylcysteine), suggesting that the cytotoxic effect of [10]-gingerol did not require caspase activation or the accumulation of reactive oxygen species. These findings suggest that further investigation of [10]-gingerol is warranted for its possible use in the treatment of breast cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Update on the distribution of Mansonella perstans in the southern part of Cameroon: influence of ecological factors and mass drug administration with ivermectin.

PubMed

Wanji, Samuel; Tayong, Dizzle Bita; Layland, Laura E; Datchoua Poutcheu, Fabrice R; Ndongmo, Winston Patrick Chounna; Kengne-Ouafo, Jonas Arnaud; Ritter, Manuel; Amvongo-Adjia, Nathalie; Fombad, Fanny Fri; Njeshi, Charity Nya; Nkwescheu, Armand Seraphin; Enyong, Peter A; Hoerauf, Achim

2016-05-31

Mansonellosis remains one of the most neglected of tropical diseases and its current distribution in the entire forest block of southern Cameroon is unknown. In order to address this issue, we have surveyed the distribution of Mansonella perstans in different bioecological zones and in addition, elucidated the influence of multiple rounds of ivermectin (IVM) based mass drug administration (MDA). A mixed design was used. Between 2000 and 2014, both cross-sectional and longitudinal surveys were carried out in 137 communities selected from 12 health districts belonging to five main bioecological zones of the southern part of Cameroon. The zones comprised of grassland savanna (GS), mosaic forest savanna (MFS), forested savanna (FS), deciduous equatorial rainforest (DERF) and the dense humid equatorial rainforest (DHERF). The survey was carried out in some areas with no treatment history as well as those currently under IVM MDA. Individuals within the participatory communities were screened for the presence of M. perstans microfilariae (mf) in peripheral blood by the calibrated thick film method to determine both prevalence and geometric mean intensities at the community level. Apart from sporadic cases in savanna areas, distribution of M. perstans was strongly linked to the equatorial rainforest zones. Before CDTI, the highest mean prevalence (70.0 %) and intensity (17,382.2 mf/ml) were obtained in communities in Mamfes' DHERF areas followed by communities in the DHERF zone of Lolodorf (53.8 % and 7,814.8 mf/ml, respectively). A longitudinal survey in Mamfe further showed that M. perstans infections had reduced by 34.5 % in DERF (P < 0.001) but not DHERF zones after ten years of IVM MDA. Further data from the cross-sectional study revealed that there was a decrease in prevalence in DHERF zones only after ten years of MDA. In DERF zones however, the infection was relatively lower after four years of MDA. The distribution of M. perstans in the southern part of Cameroon varies with bioecological zones and IVM MDA history. The zones with high prevalence and intensities lie in forested areas while those with low endemicity are in the savanna areas. MDA with ivermectin induced significant reduction in the endemicity of mansonellosis in the decidious equatorial rainforest. In contrast, the prevalence and intensity remained relatively high and stable in the dense humid equatorial rainforest zones even after a decade of mass drug administration with ivermectin. Since it is known that M. perstans down-regulates host's immune system, the findings from this work would be useful in designing studies to understand the impact of M. perstans on host immune response to vaccination and co-infection with other pathogens such as Mycobacterium spp. and Plasmodium spp. in areas of contrasting endemicities.

Signs and Symptoms

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Optical isomer analysis of 3,4-methylene-dioxyamphetamine analogues and their stereoselective disposition in rats.

PubMed

Matsushima, K; Nagai, T; Kamiyama, S

1998-01-01

Identification of the optical activity and simultaneous analysis of racemates (+/-) of three hallucinogens, 3,4-methylenedioxy-amphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA), and the urinary excretion of their optical isomers in rats was performed by high-performance liquid chromatographic analysis. Analysis of optical enantiomers of three N-alkyl MDA derivatives was performed within 50 min using two different detectors, polarimetry (OR) and ultraviolet spectroscopy (UV). The OR detector proved suitable for identification of the optically active forms, whereas the UV detector was suitable for simultaneous analysis of the enantiomers in urine. After the administration of each of the three N-alkylated derivatives, rat urine specimens were collected over four intervals, 0-4, 4-12, 12-20, and 20-24 h. After the administration of 30 mg/kg of racemic MDA and MDMA, somewhat less of the S(+)-forms of unchanged MDA and MDMA than of the R(-)-forms in each urine specimen were detected, which gave R/S ratios greater than 1.00 (p < 0.01). Conversely, after the administration of 30 mg/kg of racemic MDEA, more of the S(+)-form than the R(-)-form was found in the urine, thus giving R/S ratios less than 1.00 (p < 0.01). The percentage of the dose excreted up to 24 h was approximately 29.4% of the administered dose for MDA [S(+) 13.40% and R(-) 15.98%], 5.8% for MDMA [S(+) 1.96% and R(-) 3.79%], and 7.3% for MDEA [S(+) 3.89% and R(-) 3.43%]. Urinary excretion of optical isomers of N-dealkylated MDA from MDMA and MDEA origin were the opposite of those of the unchanged forms, and their R/S ratios up to 24 h were 0.48 to 0.72 (p < 0.01) and 1.31 to 1.50 (p < 0.01), respectively. The urinary excretion rates up to 24 h were approximately 4.3% for N-dealkylated MDA from MDMA origin [S(+) 2.72% and R(-) 1.63%] and 0.8% for N-dealkylated MDA from MDEA origin [S(+) 0.36% and R(-) 0.47%]. The total percent of unchanged forms and N-dealkylated MDA was approximately 10.1% for MDMA [S(+) 4.68% and R(-) 5.42%] and 8.2% for MDEA [S(+) 4.25% and R(-) 3.91%]. The total R/S ratio of MDMA was found to be 1.95 (p < 0.01), whereas that of MDEA was 0.88 (p < 0.01). The total R/S ratio of MDA was 1.20 (p < 0.01 ), which was comparable with that of MDMA. These three R/S ratios did not conform to the theoretical values for three N-alkyl derivatives used and neither did the R/S ratios of urine specimens collected at the four interval. These results suggested the stereoselective disposition of three N-alkyl MDA analogues in rat. The method would be suitable for the forensic chemistry and toxicology analysis of specimens obtained from hallucinogen abusers.

Cooperative multi-targeting of signaling networks by angiomiR-204 inhibits vasculogenic mimicry in breast cancer cells.

PubMed

Salinas-Vera, Yarely M; Marchat, Laurence A; García-Vázquez, Raúl; González de la Rosa, Claudia Haydée; Castañeda-Saucedo, Eduardo; Tito, Napoleón Navarro; Flores, Carlos Palma; Pérez-Plasencia, Carlos; Cruz-Colin, José L; Carlos-Reyes, Ángeles; López-González, José Sullivan; Álvarez-Sánchez, María Elizbeth; López-Camarillo, César

2018-06-06

RNA-based multi-target therapies focused in the blocking of signaling pathways represent an attractive approach in cancer. Here, we uncovered a miR-204 cooperative targeting of multiple signaling transducers involved in vasculogenic mimicry (VM). Our data showed that invasive triple negative MDA-MB-231 and Hs-578T breast cancer cells, but not poorly invasive MCF-7 cells, efficiently undergoes matrix-associated VM under hypoxia. Ectopic restoration of miR-204 in MDA-MB-231 cells leads to a potent inhibition of VM and reduction of number of branch points and patterned 3D channels. Further analysis of activation state of multiple signaling pathways using Phosphorylation Antibody Arrays revealed that miR-204 reduced the expression and phosphorylation levels of 13 proteins involved in PI3K/AKT, RAF1/MAPK, VEGF, and FAK/SRC signaling. In agreement with phospho-proteomic profiling, VM was impaired following pharmacological administration of PI3K and SRC inhibitors. Mechanistic studies confirmed that miR-204 exerts a negative post-transcriptional regulation of PI3K-α and c-SRC proto-oncogenes. Moreover, overall survival analysis of a large cohort of breast cancer patients indicates that low miR-204 and high FAK/SRC levels were associated with worst outcomes. In conclusion, our study provides novel lines of evidence indicating that miR-204 may exerts a fine-tuning regulation of the synergistic transduction of PI3K/AKT/FAK mediators critical in VM formation. Copyright © 2018 Elsevier B.V. All rights reserved.

Agile Datacube Analytics (not just) for the Earth Sciences

NASA Astrophysics Data System (ADS)

Misev, Dimitar; Merticariu, Vlad; Baumann, Peter

2017-04-01

Metadata are considered small, smart, and queryable; data, on the other hand, are known as big, clumsy, hard to analyze. Consequently, gridded data - such as images, image timeseries, and climate datacubes - are managed separately from the metadata, and with different, restricted retrieval capabilities. One reason for this silo approach is that databases, while good at tables, XML hierarchies, RDF graphs, etc., traditionally do not support multi-dimensional arrays well. This gap is being closed by Array Databases which extend the SQL paradigm of "any query, anytime" to NoSQL arrays. They introduce semantically rich modelling combined with declarative, high-level query languages on n-D arrays. On Server side, such queries can be optimized, parallelized, and distributed based on partitioned array storage. This way, they offer new vistas in flexibility, scalability, performance, and data integration. In this respect, the forthcoming ISO SQL extension MDA ("Multi-dimensional Arrays") will be a game changer in Big Data Analytics. We introduce concepts and opportunities through the example of rasdaman ("raster data manager") which in fact has pioneered the field of Array Databases and forms the blueprint for ISO SQL/MDA and further Big Data standards, such as OGC WCPS for querying spatio-temporal Earth datacubes. With operational installations exceeding 140 TB queries have been split across more than one thousand cloud nodes, using CPUs as well as GPUs. Installations can easily be mashed up securely, enabling large-scale location-transparent query processing in federations. Federation queries have been demonstrated live at EGU 2016 spanning Europe and Australia in the context of the intercontinental EarthServer initiative, visualized through NASA WorldWind.

Agile Datacube Analytics (not just) for the Earth Sciences

NASA Astrophysics Data System (ADS)

Baumann, P.

2016-12-01

Metadata are considered small, smart, and queryable; data, on the other hand, are known as big, clumsy, hard to analyze. Consequently, gridded data - such as images, image timeseries, and climate datacubes - are managed separately from the metadata, and with different, restricted retrieval capabilities. One reason for this silo approach is that databases, while good at tables, XML hierarchies, RDF graphs, etc., traditionally do not support multi-dimensional arrays well.This gap is being closed by Array Databases which extend the SQL paradigm of "any query, anytime" to NoSQL arrays. They introduce semantically rich modelling combined with declarative, high-level query languages on n-D arrays. On Server side, such queries can be optimized, parallelized, and distributed based on partitioned array storage. This way, they offer new vistas in flexibility, scalability, performance, and data integration. In this respect, the forthcoming ISO SQL extension MDA ("Multi-dimensional Arrays") will be a game changer in Big Data Analytics.We introduce concepts and opportunities through the example of rasdaman ("raster data manager") which in fact has pioneered the field of Array Databases and forms the blueprint for ISO SQL/MDA and further Big Data standards, such as OGC WCPS for querying spatio-temporal Earth datacubes. With operational installations exceeding 140 TB queries have been split across more than one thousand cloud nodes, using CPUs as well as GPUs. Installations can easily be mashed up securely, enabling large-scale location-transparent query processing in federations. Federation queries have been demonstrated live at EGU 2016 spanning Europe and Australia in the context of the intercontinental EarthServer initiative, visualized through NASA WorldWind.

Radiation Nanomedicine for EGFR-Positive Breast Cancer: Panitumumab-Modified Gold Nanoparticles Complexed to the β-Particle-Emitter, (177)Lu.

PubMed

Yook, Simmyung; Cai, Zhongli; Lu, Yijie; Winnik, Mitchell A; Pignol, Jean-Philippe; Reilly, Raymond M

2015-11-02

Our objective was to construct a novel radiation nanomedicine for treatment of breast cancer (BC) expressing epidermal growth factor receptors (EGFR), particularly triple-negative tumors (TNBC). Gold nanoparticles (AuNP; 30 nm) were modified with polyethylene glycol (PEG) chains (4 kDa) derivatized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the β-emitter, (177)Lu and with PEG chains (5 kDa) linked to panitumumab for targeting BC cells expressing EGFR. The AuNP were further coated with PEG chains (2 kDa) to stabilize the particles to aggregation. The binding and internalization of EGFR-targeted AuNP ((177)Lu-T-AuNP) into BC cells was studied and compared to nontargeted (177)Lu-NT-AuNP. The cytotoxicity of (177)Lu-T-AuNP and (177)Lu-NT-AuNP was measured in clonogenic assays using BC cells with widely different EGFR densities: MDA-MB-468 (10(6) receptors/cell), MDA-MB-231 (10(5) receptors/cell), and MCF-7 cells (10(4) receptors/cell). Radiation absorbed doses to the cell nucleus of MDA-MB-468 cells were estimated based on subcellular distribution. Darkfield and fluorescence microscopy as well as radioligand binding assays revealed that (177)Lu-T-AuNP were specifically bound by BC cells dependent on their EGFR density whereas the binding and internalization of (177)Lu-NT-AuNP was significantly lower. The affinity of binding of (177)Lu-T-AuNP to MDA-MB-468 cells was reduced by 2-fold compared to (123)I-labeled panitumumab (KD = 1.3 ± 0.2 nM vs 0.7 ± 0.4 nM, respectively). The cytotoxicity of (177)Lu-T-AuNP was dependent on the amount of radioactivity incubated with BC cells, their EGFR density and the radiosensitivity of the cells. The clonogenic survival (CS) of MDA-MB-468 cells overexpressing EGFR was reduced to <0.001% at the highest amount of (177)Lu-T-AuNP tested (4.5 MBq; 6 × 10(11) AuNP per 2.5 × 10(4)-1.2 × 10(5) cells). (177)Lu-T-AuNP were less effective for killing MDA-MB-231 cells or MCF-7 cells with moderate or low EGFR density (CS = 33.8 ± 1.6% and 25.8 ± 1.2%, respectively). Because the β-particles emitted by (177)Lu have a 2 mm range, (177)Lu-NT-AuNP were also cytotoxic to BC cells due to a cross-fire effect but (177)Lu-T-AuNP were significantly more potent for killing MDA-MB-468 cells overexpressing EGFR than (177)Lu-NT-AuNP at all amounts tested. The cross-fire effect of the β-particles emitted by (177)Lu may be valuable for eradicating BC cells in tumors that have low or moderate EGFR expression or cells that are not targeted by (177)Lu-T-AuNP as a consequence of heterogeneous intratumoral distribution. The radiation dose to the nucleus of a single MDA-MB-468 cell was 73.2 ± 6.7 Gy, whereas (177)Lu-NT-AuNP delivered 5.6 ± 0.6 Gy. We conclude that (177)Lu-T-AuNP is a promising novel radiation nanomedicine with potential application for treatment of TNBC, in which EGFR are often overexpressed.

Inclusion-Body Myositis: Diagnosis

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Learn About Neuromuscular Disease

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Limb-Girdle Muscular Dystrophy (LGMD)

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Dermatomyositis: Signs and Symptoms

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Genetics Home Reference: MDA5 deficiency

MedlinePlus

... the protein recognizes a molecule called double-stranded RNA (a chemical cousin of DNA), which certain viruses, ... When the MDA5 protein recognizes pieces of viral RNA inside the cell, it helps turn on the ...

C2 Product-Centric Approach to Transforming Current C4ISR Information Architectures

DTIC Science & Technology

2004-06-01

each type of environment . For “Cultural Feature” Entity Kind only the “Land” Domain is defined and for “ Environmental ” Entity Kind only the...take advantage of both worlds. In particular, the unifying concept of a Model-Driven Architecture (MDA) under development by the Object Management...Exchange Requirements (IER) to an XML environment . FCS [4] developers have embraced both UML and XML for their architectures and MIP [5] too is migrating

Herbal Extract SH003 Suppresses Tumor Growth and Metastasis of MDA-MB-231 Breast Cancer Cells by Inhibiting STAT3-IL-6 Signaling

PubMed Central

Woo, Sang-Mi; Park, Sunju; Shin, Yong Cheol; Ko, Seong-Gyu

2014-01-01

Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path. PMID:24976685

LGP2 Synergy with MDA5 in RLR-Mediated RNA Recognition and Antiviral Signaling

PubMed Central

Bruns, Annie M.; Horvath, Curt M.

2015-01-01

Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral response. Pattern recognition receptor proteins detect molecular signatures of virus infection and activate antiviral signaling. The RIG-I-like receptor (RLR) proteins are expressed in the cytoplasm of nearly all cells and specifically recognize virus-derived RNA species as a molecular feature discriminating the pathogen from the host. The RLR family is composed of three homologous proteins, RIG-I, MDA5, and LGP2. All RLRs have the ability to detect virus-derived dsRNA and hydrolyze ATP, but display individual differences in enzymatic activity, intrinsic ability to recognize RNA, and mechanisms of activation. Emerging evidence suggests that MDA5 and RIG-I utilize distinct mechanisms to form oligomeric complexes along dsRNA. Aligning of their signaling domains creates a platform capable of propagating and amplifying antiviral signaling responses. LGP2 with intact ATP hydrolysis is critical for the MDA5-mediated antiviral response, but LGP2 lacks the domains essential for activation of antiviral signaling, leaving the role of LGP2 in antiviral signaling unclear. Recent studies revealed a mechanistic basis of synergy between LGP2 and MDA5 leading to enhanced antiviral signaling. This review briefly summarizes the RLR system, and focuses on the relationship between LGP2 and MDA5, describing in detail how these two proteins work together to detect foreign RNA and generate a fully functional antiviral response. PMID:25794939

[Knock-down of BCL11A expression in breast cancer cells promotes MDA-MB-231 cell apoptosis].

PubMed

Li, Hongli; Gui, Chen; Yan, Lijun

2016-11-01

Objective To detect the expression and pathological significance of B-cell CLL/lymphoma 11A (BCL11A) in breast cancer and investigate the effect of its silencing on the apoptosis of human MDA-MB-231 breast cancer cells. MethodsImmunohistochemistry was used to detect the expression of BCL11A in 62 cases of human breast cancer tissues and 8 cases of normal tissues. We synthesized siRNA targeting BCL11A, and then siRNA was transfected into MDA-MB-231 cells. Forty-eight hours later, the suppression effect of siRNA on BCL11A was determined by quantitative real-time PCR and Western blotting. The apoptosis of MDA-MB-231 cells was detected by flow cytometry. Results The BCL11A protein was mainly expressed in cytoplasm. The expression level of BCL11A in breast cancer tissues was higher than that in paracancerous tissues. The expression had correlations with tumor grade, tumor stage, while it had no correlations with the patients' age and tumor size. BCL11A-siRNA significantly suppressed the expression of BCL11A mRNA and protein as compared with the control group. MDA-MB-231 cells transfected with BCL11A-siRNA had higher apoptosis rate compared with the control group. Conclusion The BCL11A protein is highly expressed in breast cancer and knock-down of BCL11A promotes the apoptosis of MDA-MB-231 cells.

Recognition of Porphyromonas gingivalis Gingipain Epitopes by Natural IgM Binding to Malondialdehyde Modified Low-Density Lipoprotein

PubMed Central

Turunen, S. Pauliina; Kummu, Outi; Harila, Kirsi; Veneskoski, Marja; Soliymani, Rabah; Baumann, Marc; Pussinen, Pirkko J.; Hörkkö, Sohvi

2012-01-01

Objective Increased risk for atherosclerosis is associated with infectious diseases including periodontitis. Natural IgM antibodies recognize pathogen-associated molecular patterns on bacteria, and oxidized lipid and protein epitopes on low-density lipoprotein (LDL) and apoptotic cells. We aimed to identify epitopes on periodontal pathogen Porphyromonas gingivalis recognized by natural IgM binding to malondialdehyde (MDA) modified LDL. Methods and Results Mouse monoclonal IgM (MDmAb) specific for MDA-LDL recognized epitopes on P. gingivalis on flow cytometry and chemiluminescence immunoassays. Immunization of C57BL/6 mice with P. gingivalis induced IgM, but not IgG, immune response to MDA-LDL and apoptotic cells. Immunization of LDLR−/− mice with P. gingivalis induced IgM, but not IgG, immune response to MDA-LDL and diminished aortic lipid deposition. On Western blot MDmAb bound to P. gingivalis fragments identified as arginine-specific gingipain (Rgp) by mass spectrometry. Recombinant domains of Rgp produced in E. coli were devoid of phosphocholine epitopes but contained epitopes recognized by MDmAb and human serum IgM. Serum IgM levels to P. gingivalis were associated with anti-MDA-LDL levels in humans. Conclusion Gingipain of P. gingivalis is recognized by natural IgM and shares molecular identity with epitopes on MDA-LDL. These findings suggest a role for natural antibodies in the pathogenesis of two related inflammatory diseases, atherosclerosis and periodontitis. PMID:22496875

Ziyuglycoside I Inhibits the Proliferation of MDA-MB-231 Breast Carcinoma Cells through Inducing p53-Mediated G2/M Cell Cycle Arrest and Intrinsic/Extrinsic Apoptosis.

PubMed

Zhu, Xue; Wang, Ke; Zhang, Kai; Zhang, Ting; Yin, Yongxiang; Xu, Fei

2016-11-22

Due to the aggressive clinical behavior, poor outcome, and lack of effective specific targeted therapies, triple-negative breast cancer (TNBC) has currently been recognized as one of the most malignant types of tumors. In the present study, we investigated the cytotoxic effect of ziyuglycoside I, one of the major components extracted from Chinese anti-tumor herbal Radix Sanguisorbae , on the TNBC cell line MDA-MB-231. The underlying molecular mechanism of the cytotoxic effect ziyuglycoside I on MDA-MB-231 cells was investigated with cell viability assay, flow cytometric analysis and Western blot. Compared to normal mammary gland Hs 578Bst cells, treatment of ziyuglycoside I resulted in a significant growth inhibitory effect on MDA-MB-231 cells. Ziyuglycoside I induced the G2/M phase arrest and apoptosis of MDA-MB-231 cells in a dose-dependent manner. These effects were found to be partially mediated through the up-regulation of p53 and p21 WAF1 , elevated Bax/Bcl-2 ratio, and the activation of both intrinsic (mitochondrial-initiated) and extrinsic (Fas/FasL-initiated) apoptotic pathways. Furthermore, the p53 specific siRNA attenuated these effects. Our study suggested that ziyuglycoside I-triggered MDA-MB-231 cell cycle arrest and apoptosis were probably mediated by p53. This suggests that ziyuglycoside I might be a potential drug candidate for treating TNBC.

Curcumin blocks RON tyrosine kinase-mediated invasion of breast carcinoma cells.

PubMed

Narasimhan, Madhusudhanan; Ammanamanchi, Sudhakar

2008-07-01

We have recently shown that macrophage-stimulating protein (MSP) promotes the invasion of recepteur d'origine nantais (RON), a tyrosine kinase receptor-positive MDA-MB-231, MDA-MB-468 breast cancer cells, and also identified the regulatory elements required for RON gene expression. In this report, we have analyzed the efficacy of a chemopreventive agent, curcumin, in blocking RON tyrosine kinase-mediated invasion of breast cancer cells. Reverse transcription-PCR and Western analysis indicated the down-regulation of the RON message and protein, respectively, in MDA-MB-231 and MDA-MB-468 cells. Significantly, curcumin-mediated inhibition of RON expression resulted in the blockade of RON ligand, MSP-induced invasion of breast cancer cells. We have identified two putative nuclear factor-kappaB p65 subunit binding sites on the RON promoter. Using chromatin immunoprecipitation analysis and site-directed mutagenesis of the RON promoter, we have confirmed the binding of p65 to the RON promoter. Our data show that curcumin reduces RON expression by affecting p65 protein expression and transcriptional activity. Treatment of MDA-MB-231 cells with pyrrolidine dithiocarbamate, an inhibitor of p65, or small interfering RNA knockdown of p65, blocked RON gene expression and MSP-mediated invasion of MDA-MB-231 cells. This is the first report showing the regulation of human RON gene expression by nuclear factor-kappaB and suggests a potential therapeutic role for curcumin in blocking RON tyrosine kinase-mediated invasion of carcinoma cells.

In vivo visualization and attenuation of oxidized lipid accumulation in hypercholesterolemic zebrafish

PubMed Central

Fang, Longhou; Green, Simone R.; Baek, Ji Sun; Lee, Sang-Hak; Ellett, Felix; Deer, Elena; Lieschke, Graham J.; Witztum, Joseph L.; Tsimikas, Sotirios; Miller, Yury I.

2011-01-01

Oxidative modification of LDL is an early pathological event in the development of atherosclerosis. Oxidation events such as malondialdehyde (MDA) formation may produce specific, immunogenic epitopes. Indeed, antibodies to MDA-derived epitopes are widely used in atherosclerosis research and have been demonstrated to enable cardiovascular imaging. In this study, we engineered a transgenic zebrafish with temperature-inducible expression of an EGFP-labeled single-chain human monoclonal antibody, IK17, which binds to MDA-LDL, and used optically transparent zebrafish larvae for imaging studies. Feeding a high-cholesterol diet (HCD) supplemented with a red fluorescent lipid marker to the transgenic zebrafish resulted in vascular lipid accumulation, quantified in live animals using confocal microscopy. After heat shock–induced expression of IK17-EGFP, we measured the time course of vascular accumulation of IK17-specific MDA epitopes. Treatment with either an antioxidant or a regression diet resulted in reduced IK17 binding to vascular lesions. Interestingly, homogenates of IK17-EGFP–expressing larvae bound to MDA-LDL and inhibited MDA-LDL binding to macrophages. Moreover, sustained expression of IK17-EGFP effectively prevented HCD-induced lipid accumulation in the vascular wall, suggesting that the antibody itself may have therapeutic effects. Thus, we conclude that HCD-fed zebrafish larvae with conditional expression of EGFP-labeled oxidation-specific antibodies afford an efficient method of testing dietary and/or other therapeutic antioxidant strategies that may ultimately be applied to humans. PMID:22105168

[Effects of trimetazidine on serum oxygen free radicals in congestive heart failure].

PubMed

Ma, Qi-lin; Xie, Yong; Zhang, Sai-dan

2002-12-28

To investigate the level of serum superoxide dismutase (SOD) and maiondialdehyde (MDA) and left ventricular systolic function in congestive heart failure (CHF) and to evaluate the influence of trimetazidine on them. Serum SOD and MDA were measured in 50 patients with heart function from grade two to four and 15 normal subjects. All the persons underwent echocardiography to determine the left ventricular end-systolic volume index (LVESVI) and the left ventricular ejection fraction (EF). The patients with CHF were randomly treated with trimetazidine plus routine therapy (n = 25) or routine therapy only (n = 25) for 8 weeks with evaluations made before and after the treatment. The SOD level and EF in the patients with CHF significantly decreased and the MDA level and LVESVI in those patients significantly increased compared with the normal subjects (P < 0.05); the severer the CHF, the greater the changes. After the treatment, the SOD level and EF increased significantly and MDA and LVESVI decreased significantly (P < 0.01) in both the trimetazidine and the conventional groups. And these changes were more obvious in the trimetazidine group than in the conventional group(P < 0.01). Oxygen free radicals play an important role in the pathophysiologic changes of CHF. The level of serum SOD and MDA can indicate the degree of CHF. Trimetazidine not only increases the level of SOD and decreases the level of MDA, but also improves the left ventricular systolic function.

Monodisperse Picoliter Droplets for Low-Bias and Contamination-Free Reactions in Single-Cell Whole Genome Amplification

PubMed Central

Maruyama, Toru; Yamagishi, Keisuke; Mori, Tetsushi; Takeyama, Haruko

2015-01-01

Whole genome amplification (WGA) is essential for obtaining genome sequences from single bacterial cells because the quantity of template DNA contained in a single cell is very low. Multiple displacement amplification (MDA), using Phi29 DNA polymerase and random primers, is the most widely used method for single-cell WGA. However, single-cell MDA usually results in uneven genome coverage because of amplification bias, background amplification of contaminating DNA, and formation of chimeras by linking of non-contiguous chromosomal regions. Here, we present a novel MDA method, termed droplet MDA, that minimizes amplification bias and amplification of contaminants by using picoliter-sized droplets for compartmentalized WGA reactions. Extracted DNA fragments from a lysed cell in MDA mixture are divided into 105 droplets (67 pL) within minutes via flow through simple microfluidic channels. Compartmentalized genome fragments can be individually amplified in these droplets without the risk of encounter with reagent-borne or environmental contaminants. Following quality assessment of WGA products from single Escherichia coli cells, we showed that droplet MDA minimized unexpected amplification and improved the percentage of genome recovery from 59% to 89%. Our results demonstrate that microfluidic-generated droplets show potential as an efficient tool for effective amplification of low-input DNA for single-cell genomics and greatly reduce the cost and labor investment required for determination of nearly complete genome sequences of uncultured bacteria from environmental samples. PMID:26389587

Withaferin A induced impaired autophagy and unfolded protein response in human breast cancer cell-lines MCF-7 and MDA-MB-231.

PubMed

Ghosh, Kamalini; De, Soumasree; Mukherjee, Srimoyee; Das, Sayantani; Ghosh, Amar Nath; Sengupta, Sumita Bandyopadhyay

2017-10-01

The autophagy-lysosome pathway and the ubiquitin-proteasome systems are the two major routes for eukaryotic intracellular protein clearance. Cancerous cells often display elevated protein synthesis and byproduct disposal, thus, inhibition of the protein degradation pathways became an emerging approach for cancer therapy. The present study revealed that withaferin-A (WA), the biologically active withanolide derived from Withania somnifera, initially induced formation of autophagosomes in human breast cancer cell-lines, MCF-7 and MDA-MB-231. WA treatment elevated the levels of autophagic substrate p62/SQSTM1 (p62) and both LC3-II and LC3-I (microtubule-associated protein 2 light chain 3) and simultaneously reduced the upstream autophagy markers like beclin-1 and ATG5-ATG12 complex, which indicate accumulation of autophagosomes in the cells. WA induced disruption of microtubular network through inhibition of tubulin polymerization and its hyper-acetylation, thus prevent the formation of autolysosome (by merging of autophagosomes with lysosomes) and its recycling process, leading to incomplete autophagy. Further, WA caused ER (Endoplasmic Reticulum) stress, which is evident from the activation of ER-related caspase-4 and increased levels of ER stress marker proteins. Thus, these findings altogether indicate that WA mediated inhibition of proteasomal degradation system and perturbation of autophagy, i.e. suppression of both the intracellular degradation systems caused accumulation of ubiquitinated proteins, which in turn led to unfolded protein response and ER stress mediated proteotoxicity in human breast cancer cell-lines, MCF-7 and MDA-MB-231. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Impact of siRNA-mediated down-regulation of CD147 on human breast cancer cells].

PubMed

Li, Zhenqian; Li, Daoming; Li, Jiangwei; Huang, Pei; Qin, Hui

2015-10-01

To investigate the influence of siRNA-mediated down-regulation of CD147 on growth, proliferation and movement of human breast cancer cell line MDA-MB-231. The protein expression of CD147, MMP-2 and TIMP-2 of the MDA-MB-231 cells were analyzed by ABC. Lentiviral expression vector of CD147 gene was constructed and transfected into MDA-MB-231 cells. RT-PCR and Western blot were used to detect the mRNA and protein level changes of CD147 genes to identify the optimal time point, followed by detection of changes of mRNA and protein expression of MMP-2 and TIMP-2 genes. CCK-8 reagent method and cell scratch test were used to detect the proliferation and migration change of MDA-MB-231 cells. The nude mouse model of breast cancer by hypodermic injection with MDA-MB-231 cells was established to document the effect of CD147 siRNA on the tumor transplants. After transfection of lentiviral expression vector of CD147 gene, protein of CD147, MMP-2 and TIMP-2 were weakly or negative expressed, significantly weaker than those of control group (P < 0.01). After 72 hours of transfection, average down-regulation rate of CD147 and MMP-2 were 96.03% ± 0.84% and 96.03% ± 0.84%, respectively. Both CD147 mRNA and MMP-2 mRNA expression were down-regulated (P < 0.05), while TIMP-2 mRNA expression showed no significant deference (P > 0.05). No less than 2 days after transfection, cell growth of MDA-MB-231 cell line was found significantly inhibited (P < 0.05). After 24 hours of transection, average migration distance of MDA-MB-231 cell line and control group were (0.64 ± 0.12) mm and (4.69 ± 0.85) mm, respectively, which indicated a lower migrate speed. Down regulation of CD147 led to reduction of volume and mass of nude mouses. The growth of the carcinoma transplant was inhibited upon siRNA-mediated down-regulation of CD147 (P < 0.05), with an average tumor mass of (1.85 ± 0.98) g and both reduction of tumor size and tumor mass. CD147 may alter the MMP-2/TIMP-2 balance in MDA-MB-231 cells. CD147 gene silencing inhibits the proliferation and migration of MDA-MB-231 cells and the growth of carcinoma transplants in nude mice.

Association between activities of SOD, MDA and Na+-K+-ATPase in peripheral blood of patients with acute myocardial infarction and the complication of varying degrees of arrhythmia.

PubMed

Yin, Yu; Han, Wei; Cao, Ying

2018-04-24

To investigate the changes of ambulatory electrocardiography and peripheral blood SOD, MDA and Na+-K+-ATP enzymes in patients of acute myocardial infarction (AMI) complicated with arrhythmia. From January 2012 to March 2015, 135 cases AMI complicated with arrhythmia in our hospital were divided into 2 groups: 70 cases in the AMI uncomplicated with arrhythmia and 65 cases in the AMI complicated with arrhythmia. 62 cases volunteers accepted physical examination in our hospital in the same period were collected as the control group. 24 hour-electrocardiogram detected by ambulatory electrocardiogram (AECG), SOD and MDA in peripheral blood detected by diagnostic reagent kit and Na+-K+-ATP enzymes in peripheral blood detected by malachite green Kit Method phosphate determination method were collected. ROC curve was used to evaluate the prognostic value of SOD, MDA and Na+-K+-ATP enzymes in AMI patients. Compared with the control group, the patients had unusual ambulatory electrocardiography had increased (P <0.05), peripheral blood SOD and Na+-K+-ATP enzymes had decreased, peripheral blood MDA had increased in 2 AMI groups (P <0.05). Compared with AMI uncomplicated with arrhythmia group, the patients had unusual ambulatory electrocardiography had increased (P <0.05), peripheral blood SOD and Na+-K+-ATP enzymes had decreased, peripheral blood MDA had increased in AMI complicated with arrhythmia group (P <0.05). Among 135 cases AMI patients, 120 (88.9%) survived and 15 (11.1%) died, of whom 11 cases were AMI complicated with arrhythmia group, 4 cases were AMI uncomplicated with arrhythmia group. Compared with the AMI uncomplicated with arrhythmia group, the dead patients were more in the AMI complicated with arrhythmia group (c2 = 4.287, P = 0.038). Compared with the survival group, the SOD and Na+-K+-ATP enzymes were significantly lower (P <0.05) and MDA significantly higher (P <0.05) in the death group. The area under the ROC curve of SOD, MDA and Na+-K+-ATP enzymes were 0.958, 0.954 and 0.993 respectively, and the cut-off values were 30.66 ng/ml, 576.70 nmol/ml and 57.42 nmol/mgh, respectively. Ambulatory electrocardiography has a close relationship with the peripheral blood SOD, MDA and Na+-K+-ATP enzymes in AMI patients complicated with arrhythmia, which might predict AMI condition. Copyright © 2018 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Novel microfluidic device for the continuous separation of cancer cells using dielectrophoresis.

PubMed

Alazzam, Anas; Mathew, Bobby; Alhammadi, Falah

2017-03-01

We describe the design, microfabrication, and testing of a microfluidic device for the separation of cancer cells based on dielectrophoresis. Cancer cells, specifically green fluorescent protein-labeled MDA-MB-231, are successfully separated from a heterogeneous mixture of the same and normal blood cells. MDA-MB-231 cancer cells are separated with an accuracy that enables precise detection and counting of circulating tumor cells present among normal blood cells. The separation is performed using a set of planar interdigitated transducer electrodes that are deposited on the surface of a glass wafer and slightly protrude into the separation microchannel at one side. The device includes two parts, namely, a glass wafer and polydimethylsiloxane element. The device is fabricated using standard microfabrication techniques. All experiments are conducted with low conductivity sucrose-dextrose isotonic medium. The variation in response between MDA-MB-231 cancer cells and normal cells to a certain band of alternating-current frequencies is used for continuous separation of cells. The fabrication of the microfluidic device, preparation of cells and medium, and flow conditions are detailed. The proposed microdevice can be used to detect and separate malignant cells from heterogeneous mixture of cells for the purpose of early screening for cancer. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bromelain in the early phase of healing in acute crush Achilles tendon injury.

PubMed

Aiyegbusi, A I; Duru, F I O; Anunobi, C C; Noronha, C C; Okanlawon, A O

2011-01-01

Bromelain, an enzyme extracted from the stem of the pineapple plant has been proposed as a treatment for reducing pain and swelling following acute muscle injuries but studies are yet to be done on its effect on tendon healing. This study therefore investigated the effects of bromelain on tenocyte proliferation and the tendon malondialdehyde (MDA) level in the early stage of healing in a crush injury to the Achilles tendon of Sprague-Dawley rats. Twenty four male rats were divided randomly into three groups; groups 2 and 3 had induced crush injury to the left Achilles tendon. Group 1; nil injury and nil treatment, Group 2; nil treatment, Group 3; oral bromelain treatment. Bromelain was given at a dosage of 7 mg/kg body weight daily over the first 14 days post-injury. On day 15 post injury, the animals were killed and the tendons excised and processed for histological study and MDA assay. The results showed a significant increase in the tenocyte population in the bromelain group; p < 0.05. There was, however, no significant difference in the MDA level. Based on this study, 600 GDU bromelain given once daily in acute tendon injury at a dosage of 7 mg/kg promoted healing by stimulating tenocyte proliferation. Copyright © 2010 John Wiley & Sons, Ltd.

Ferrous ion induced photon emission as a method to quantify oxidative stress in stored boar spermatozoa.

PubMed

Gogol, Piotr; Pieszka, Marek

2008-01-01

The aim of the study was to evaluate the effect of semen storage on ferrous ion induced luminescence of boar spermatozoa and to determine the relationship between parameters of this luminescence and lipid peroxidation as measured by malondialdehyde (MDA) contents. Boar semen samples were diluted in Biosolwens extender and stored for 12 days at 15 degrees C. Luminescence and MDA were measured directly after dilution (day 0) and at 6 and 12 days of semen storage. Luminescence was measured at 20 degrees C using a luminometer equipped with a cooled photomultiplier with a spectral response range from 370 to 620 nm. Emission was induced by adding FeSO4 solution (final concentration 0.05 mM). MDA content was measured by the HPLC method. The day of storage had a significant effect on some luminescence parameters and MDA content in spermatozoa. A significant correlation was observed between luminescence parameters and MDA concentration. The results of the study confirm that induced luminescence is strictly related to lipid peroxidation in spermatozoa that occur during boar semen storage. Parameters of luminescence treated as a holistic response of cells to oxidative stress can be useful for monitoring spermatozoa quality during semen preservation.

The relative safety of gamma-ray, autoclave, and ethylene oxide gas sterilization of thermosetting polyurethane.

PubMed

Shintani, H

1995-01-01

Sterilization of polyurethane (PU) produces 4,4'-methylenedianiline (MDA), a known carcinogen, and various other compounds. The relationships of the components of PU to the formation of these compounds by sterilization were studied. Specimens of PU fabricated from different combinations of isocyanates and polyols were obtained from dialyzers. The molecular weight of the particular polyol was found to influence the production of MDA by sterilization. Sterilization also produced many unidentified compounds. MDA production was not always associated with the production of the other compounds. Compared with gamma-ray irradiation and ethylene oxide gas (EOG) sterilization, autoclave sterilization eluted more hydrophilic compounds. This phenomenon was significant for PUs produced from smaller-molecular-weight polyols. The combination of autoclave sterilization and a PU produced from a larger-molecular-weight polyol is recommended to minimize the production of potentially toxic compounds. Of the techniques studied, EOG sterilization produced the least amounts of MDA and the other compounds, but the residue of EOG is itself problematic. The risk posed by the amounts of MDA extracted was not significant, but the biological safety of the other compounds remains to be determined.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sanchez, R.O.; Archer, W.E.

This paper describes the use of Formula 456, an aliphatic amine cured epoxy for impregnating coils and high voltage transformers. Sandia has evaluated a number of MDA-free epoxy encapsulants which relied on either anhydride or other aromatic amine curing agents. The use of aliphatic amine curing agents was more recently evaluated and has resulted in the definition of Formula 456 resin. Methylene dianiline (MDA) has been used for more than 20 years as the curing agent for various epoxy formulations throughout the Department of Energy and much of industry. Sandia National Laboratories began the process of replacing MDA with othermore » formulations because of regulations imposed by OSHA on the use of MDA. OSHA has regulated MDA because it is a suspect carcinogen. Typically the elimination of OSHA-regulated materials provides a rare opportunity to qualify new formulations in a range of demanding applications. It was important to take full advantage of that opportunity, although the associated materials qualification effort was costly. Small high voltage transformers are one of those demanding applications. The successful implementation of the new formulation for high reliability transformers will be described. The test results that demonstrate the parts are qualified for use in DOE weapon systems will be presented.« less

Phenylpropanoids isolated from Piper sarmentosum Roxb. induce apoptosis in breast cancer cells through reactive oxygen species and mitochondrial-dependent pathways.

PubMed

Hematpoor, Arshia; Paydar, Mohammadjavad; Liew, Sook Yee; Sivasothy, Yasodha; Mohebali, Nooshin; Looi, Chung Yeng; Wong, Won Fen; Azirun, Mohd Sofian; Awang, Khalijah

2018-01-05

The aim of the present study is to isolate bioactive compounds from the roots of Piper sarmentosum and examine the mechanism of action using human breast cancer cell line (MDA-MB-231). Bioassay guided-fractionation of methanolic extract led to the isolation of asaricin (1) and isoasarone (2). Asaricin (1) and isoasarone (2) had significant cytotoxicity towards MDA-MB-231. MCF-10A (human normal breast epithelial cells) cells are less sensitive than MDA-MB-231, but they respond to the treatment with the same unit of measurement. Both compounds increase reactive oxygen species (ROS), decrease mitochondrial membrane potential (MMP) and enhance cytochrome c release in treated MDA-MB-231 cells. Isoasarone (2) markedly elevated caspase -8 and -3/7 activities and caused a decline in nuclear NF-κB translocation, suggesting extrinsic, death receptor-linked apoptosis pathway. Quantitative PCR results of MDA-MB-231 treated with asaricin (1) and isoasarone (2) showed altered expression of Bcl-2: Bax level. The inhibitory potency of these isolates may support the therapeutic uses of these compounds in breast cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Decreased paraoxonase1 activity and increased malondialdehyde and oxidative DNA damage levels in primary open angle glaucoma

PubMed Central

Mumcu, Ugur Yilmaz; Kocer, Ibrahim; Ates, Orhan; Alp, H. Hakan

2016-01-01

To investigate the malondialdehyde (MDA) levels, paraoxonase1 (PON1) activity and 8-hydroxy 2-deoxyguanosine (8-OHdG) levels in the primary open angle glaucoma (POAG) patient. Blood samples from 52 healthy individuals and 53 patients with POAG were analyzed for MDA and 8-OHdG by HPLC (high-performance liquid chromatography) and PON1 by spectrophotometry. The data obtained were analyzed statistically. MDA levels were 10.46±8.4 and 4.70±1.79 µmol; PON1 levels were 121±39.55 and 161.62±60.22 U/mL; and 8-OHdG values were 1.32±0.53/106 dG and 0.47±0.27/106 dG in the POAG patients and the control group, respectively. The difference was significant in MDA levels, 8-OHdG levels and PON1 activity in POAG patients in comparison with controls (P<0.001). We concluded that the observed increase in MDA and 8-OHdG levels may be correlated with decreased PON1 activity. Oxidative stress plays an important role in glaucoma development. PMID:27803873

Investigations on the human hepatic cytochrome P450 isozymes involved in the metabolism of 3,4-methylenedioxy-amphetamine (MDA) and benzodioxolyl-butanamine (BDB) enantiomers.

PubMed

Meyer, Markus R; Peters, Frank T; Maurer, Hans H

2009-10-08

3,4-Methylenedioxy-amphetamine (MDA) and benzodioxolyl-butanamine (BDB) are chiral designer drugs distributed on the illicit drug market and they are also N-dealkyl metabolites of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy, Adam), 3,4-methylenedioxyethylamphetamine (MDEA, Eve), and N-methyl-benzodioxolyl-butanamine (MBDB, Eden), respectively. MDA and BDB are mainly metabolized via demethylenation to the corresponding catecholamines. The aim of the present work was to elucidate the contribution of the relevant human P450s in the demethylenation of the MDA and BDB enantiomers. They were incubated using heterologously expressed human P450s and the corresponding metabolites dihydroxyamphetamine and 1,2-dihydroxy-4-[2-amino-butyl]benzene were determined. Highest contributions to the demethylenation as calculated from the enzyme kinetic data were obtained for CYP2D6 (MDA and BDB) and additionally CYP3A4 in the case of BDB at substrate concentrations corresponding to plasma concentrations of recreational users. A preferred transformation of the S-enantiomer could be observed for the CYP2D6- and CYP3A4-catalyzed reactions.

Oxidative stress markers in patients with primary open-angle glaucoma.

PubMed

Ghanem, Asaad A; Arafa, Lamiaa F; El-Baz, Ayman

2010-04-01

To investigate the levels of antioxidant enzymes catalase (CAT), glutathione peroxidase (GPO), superoxide dismutase (SOD), and malondialdehyde (MDA) in human eyes with primary open-angle glaucoma (POAG) and to correlate their concentrations with severity of glaucoma. A prospective cases control study. Thirty patients with primary open-angle glaucoma and twenty-five patients with senile cataracts of matched age and gender were included in the study prospectively. Aqueous humor samples were obtained by paracentesis at the time of elective surgery for glaucomatous and cataractous patients. Aqueous humor were analyzed for CAT, GPO, SOD, and MDA status. GPO, SOD, and MDA enzyme levels revealed a high significant increase in aqueous humor of POAG patients with respect to the comparative group of cataract patients (P < 0.001). No significant difference in the activity of CAT enzyme in aqueous humor of POAG and cataract patient (P = 0.201). Significant correlation was found between the MDA enzyme level and severe visual field loss (P < 0.001) in POAG patients. Increased levels of aqueous humor GPO, SOD, and MDA may be associated with POAG. In addition, they may be useful antioxidant enzyme levels in aqueous humor of POAG patients as a result of glaucoma disease and not a cause.

Mass drug administration and the global control of schistosomiasis: successes, limitations and clinical outcomes.

PubMed

Olveda, David U; McManus, Donald P; Ross, Allen G P

2016-12-01

Preventive chemotherapy is advocated for the global control and elimination of schistosomiasis. Despite the well known short-term benefits of treating patients for schistosomiasis, the impact of mass drug administration (MDA) campaigns to control the disease in the long term remains unresolved. Many studies have advocated the success of MDA programs in order to attract donor funds for elimination efforts but such successes are often short-lived given the drug does not alter the life cycle of the organism or prevent reinfection. Within a matter of months to years after halting treatment, the prevalence, intensity of infection and morbidity of disease return to baseline levels. Other mitigating factors contribute to the failings of MDA campaigns namely: poverty, poor drug coverage, poor drug compliance, and, in the case of Asiatic schistosomiasis, zoonotic transmission. Genetic and innate and acquired immunologic mechanisms complicate the epidemiologic picture of schistosomiasis globally, and may contribute indirectly to MDA shortcomings. The possibility of drug resistance is an ever present concern because of the sole reliance on one drug, praziquantel. Preventive chemotherapy is advocated for the global control and elimination of schistosomiasis. The short-term benefits of MDA campaigns are well documented but the long-term benefits are questionable.

Investigating intracranial tumour growth patterns with multiparametric MRI incorporating Gd-DTPA and USPIO-enhanced imaging.

PubMed

Boult, Jessica K R; Borri, Marco; Jury, Alexa; Popov, Sergey; Box, Gary; Perryman, Lara; Eccles, Suzanne A; Jones, Chris; Robinson, Simon P

2016-11-01

High grade and metastatic brain tumours exhibit considerable spatial variations in proliferation, angiogenesis, invasion, necrosis and oedema. Vascular heterogeneity arising from vascular co-option in regions of invasive growth (in which the blood-brain barrier remains intact) and neoangiogenesis is a major challenge faced in the assessment of brain tumours by conventional MRI. A multiparametric MRI approach, incorporating native measurements and both Gd-DTPA (Magnevist) and ultrasmall superparamagnetic iron oxide (P904)-enhanced imaging, was used in combination with histogram and unsupervised cluster analysis using a k-means algorithm to examine the spatial distribution of vascular parameters, water diffusion characteristics and invasion in intracranially propagated rat RG2 gliomas and human MDA-MB-231 LM2-4 breast adenocarcinomas in mice. Both tumour models presented with higher ΔR 1 (the change in transverse relaxation rate R 1 induced by Gd-DTPA), fractional blood volume (fBV) and apparent diffusion coefficient than uninvolved regions of the brain. MDA-MB-231 LM2-4 tumours were less densely cellular than RG2 tumours and exhibited substantial local invasion, associated with oedema, whereas invasion in RG2 tumours was minimal. These additional features were reflected in the more heterogeneous appearance of MDA-MB-231 LM2-4 tumours on T 2 -weighted images and maps of functional MRI parameters. Unsupervised cluster analysis separated subregions with distinct functional properties; areas with a low fBV and relatively impermeable blood vessels (low ΔR 1 ) were predominantly located at the tumour margins, regions of MDA-MB-231 LM2-4 tumours with relatively high levels of water diffusion and low vascular permeability and/or fBV corresponded to histologically identified regions of invasion and oedema, and areas of mismatch between vascular permeability and blood volume were identified. We demonstrate that dual contrast MRI and evaluation of tissue diffusion properties, coupled with cluster analysis, allows for the assessment of heterogeneity within invasive brain tumours and the designation of functionally diverse subregions that may provide more informative predictive biomarkers. © 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

Myositis-specific autoantibodies are specific for myositis compared to genetic muscle disease.

PubMed

Mammen, Andrew L; Casciola-Rosen, Livia; Christopher-Stine, Lisa; Lloyd, Thomas E; Wagner, Kathryn R

2015-12-01

To determine the specificity of myositis-specific autoantibodies (MSAs) for autoimmune myopathy compared with inherited muscle diseases. Serum samples from 47 patients with genetically confirmed inherited muscle diseases were screened for the most common MSAs, including those recognizing TIF1γ, NXP2, Mi2, MDA5, Jo1, SRP, and HMGCR. We compared these results with the findings in a cohort of patients with dermatomyositis (DM) previously screened for anti-TIF1γ, -NXP2, -Mi2, -MDA5, and -Jo1. Overall, the presence of anti-TIF1γ, -NXP2, -Mi2, -MDA5, or -Jo1 was 96% specific and 67% sensitive for DM compared to patients with genetic muscle diseases. No patients with inherited muscle disease had anti-SRP or anti-HMGCR autoantibodies. Only 2 patients with genetic muscle disease had a MSA. One patient with anti-Mi2 autoantibodies had both genetically confirmed facioscapulohumeral dystrophy and dermatomyositis based on a typical skin rash and partial response to immunosuppressive medications. A second patient with anti-Jo-1 autoantibodies had both genetically defined limb-girdle muscular dystrophy type 2A (i.e., calpainopathy) and a systemic autoimmune process based on biopsy-confirmed lupus nephritis, sicca symptoms, and anti-Ro52 autoantibodies. The MSAs tested for in this study are highly specific for autoimmune muscle disease and are rarely, if ever, found in patients who only have genetic muscle disease. In patients with genetic muscle disease, the presence of a MSA should suggest the possibility of a coexisting autoimmune process.

Myositis-specific autoantibodies are specific for myositis compared to genetic muscle disease

PubMed Central

Casciola-Rosen, Livia; Christopher-Stine, Lisa; Lloyd, Thomas E.; Wagner, Kathryn R.

2015-01-01

Objective: To determine the specificity of myositis-specific autoantibodies (MSAs) for autoimmune myopathy compared with inherited muscle diseases. Methods: Serum samples from 47 patients with genetically confirmed inherited muscle diseases were screened for the most common MSAs, including those recognizing TIF1γ, NXP2, Mi2, MDA5, Jo1, SRP, and HMGCR. We compared these results with the findings in a cohort of patients with dermatomyositis (DM) previously screened for anti-TIF1γ, -NXP2, -Mi2, -MDA5, and -Jo1. Results: Overall, the presence of anti-TIF1γ, -NXP2, -Mi2, -MDA5, or -Jo1 was 96% specific and 67% sensitive for DM compared to patients with genetic muscle diseases. No patients with inherited muscle disease had anti-SRP or anti-HMGCR autoantibodies. Only 2 patients with genetic muscle disease had a MSA. One patient with anti-Mi2 autoantibodies had both genetically confirmed facioscapulohumeral dystrophy and dermatomyositis based on a typical skin rash and partial response to immunosuppressive medications. A second patient with anti-Jo-1 autoantibodies had both genetically defined limb-girdle muscular dystrophy type 2A (i.e., calpainopathy) and a systemic autoimmune process based on biopsy-confirmed lupus nephritis, sicca symptoms, and anti-Ro52 autoantibodies. Conclusions: The MSAs tested for in this study are highly specific for autoimmune muscle disease and are rarely, if ever, found in patients who only have genetic muscle disease. In patients with genetic muscle disease, the presence of a MSA should suggest the possibility of a coexisting autoimmune process. PMID:26668818

Small real time detection satellites for MDA using hyperspectral imaging

NASA Astrophysics Data System (ADS)

Nakaya, Daiki; Yanagida, Hiroki; Shin, Satori; Ito, Tomonori; Takeuchi, Yusuke

2017-10-01

Hyperspectral Images are now used in the field of agriculture, cosmetics, and space exploring. Behind this fact, there is a result of efforts to contrive miniaturization and decrease in costs. This paper describes low-cost and small Hyperspectral Camera (HSC) under development and a method of utilizing it. Real Time Detection System for MDA is that government agencies put those cameras in small satellites and use them for MDA (Maritime Domain Awareness). We assume early detection of unidentified floating objects to find out disguised fishing ships and submarines.

Colaborated Architechture Framework for Composition UML 2.0 in Zachman Framework

NASA Astrophysics Data System (ADS)

Hermawan; Hastarista, Fika

2016-01-01

Zachman Framework (ZF) is the framework of enterprise architechture that most widely adopted in the Enterprise Information System (EIS) development. In this study, has been developed Colaborated Architechture Framework (CAF) to collaborate ZF with Unified Modeling Language (UML) 2.0 modeling. The CAF provides the composition of ZF matrix that each cell is consist of the Model Driven architechture (MDA) from the various UML models and many Software Requirement Specification (SRS) documents. Implementation of this modeling is used to develops Enterprise Resource Planning (ERP). Because ERP have a coverage of applications in large numbers and complexly relations, it is necessary to use Agile Model Driven Design (AMDD) approach as an advanced method to transforms MDA into components of application modules with efficiently and accurately. Finally, through the using of the CAF, give good achievement in fullfilment the needs from all stakeholders that are involved in the overall process stage of Rational Unified Process (RUP), and also obtaining a high satisfaction to fullfiled the functionality features of the ERP software in PT. Iglas (Persero) Gresik.

Neuroprotective effect of curcumin on spinal cord in rabbit model with ischemia/reperfusion.

PubMed

Liu, Zhi-Qiang; Xing, Shan-Shan; Zhang, Wei

2013-03-01

Ischemic/reperfusion (I/R) injury of the spinal cord is a serious complication that can result from thoracoabdominal aortic surgery. To investigate the neuroprotective effect of curcumin against I/R injury in a rabbit model. A total of 36 rabbits were randomly divided into three groups: sham, I/R, and curcumin-treated group. Rabbits were subject to 30-min aortic occlusion to induce transient spinal cord ischemia. Neurological function was observed after reperfusion and spinal cord segment (L3-L5) was collected for histopathological evaluation. Malondialdehyde (MDA) and total superoxide dismutase (SOD) activity were also assayed. Rabbits in I/R group were induced to paraplegia. While after 48-hour treatment, compared with I/R group, curcumin significantly improved neurological function, reduced cell apoptosis and MDA levels as well as increased SOD activity (P < 0.05). The results suggest that curcumin, at least in an animal model, can attenuate transient spinal cord ischemic injury potentially via reducing oxidative damage, which may provide a novel approach in the treatment of spinal cord ischemic injury.

ERK/p38 MAPK inhibition reduces radio-resistance to a pulsed proton beam in breast cancer stem cells

NASA Astrophysics Data System (ADS)

Jung, Myung-Hwan; Park, Jeong Chan

2015-10-01

Recent studies have identified highly tumorigenic cells with stem cell-like characteristics, termed cancer stem cells (CSCs) in human cancers. CSCs are resistant to conventional radiotherapy and chemotherapy owing to their high DNA repair ability and oncogene overexpression. However, the mechanisms regulating CSC radio-resistance, particularly proton beam resistance, remain unclear. We isolated CSCs from the breast cancer cell lines MCF-7 and MDA-MB-231, which expressed the characteristic breast CSC membrane protein markers CD44+/CD24-/ low , and irradiated the CSCs with pulsed proton beams. We confirmed that CSCs were resistant to pulsed proton beams and showed that treatment with p38 and ERK inhibitors reduced CSC radio-resistance. Based on these results, BCSC radio-resistance can be reduced during proton beam therapy by co-treatment with ERK1/2 or p38 inhibitors, a novel approach to breast cancer therapy.

Transforming Collaborative Process Models into Interface Process Models by Applying an MDA Approach

NASA Astrophysics Data System (ADS)

Lazarte, Ivanna M.; Chiotti, Omar; Villarreal, Pablo D.

Collaborative business models among enterprises require defining collaborative business processes. Enterprises implement B2B collaborations to execute these processes. In B2B collaborations the integration and interoperability of processes and systems of the enterprises are required to support the execution of collaborative processes. From a collaborative process model, which describes the global view of the enterprise interactions, each enterprise must define the interface process that represents the role it performs in the collaborative process in order to implement the process in a Business Process Management System. Hence, in this work we propose a method for the automatic generation of the interface process model of each enterprise from a collaborative process model. This method is based on a Model-Driven Architecture to transform collaborative process models into interface process models. By applying this method, interface processes are guaranteed to be interoperable and defined according to a collaborative process.

Consistent model driven architecture

NASA Astrophysics Data System (ADS)

Niepostyn, Stanisław J.

2015-09-01

The goal of the MDA is to produce software systems from abstract models in a way where human interaction is restricted to a minimum. These abstract models are based on the UML language. However, the semantics of UML models is defined in a natural language. Subsequently the verification of consistency of these diagrams is needed in order to identify errors in requirements at the early stage of the development process. The verification of consistency is difficult due to a semi-formal nature of UML diagrams. We propose automatic verification of consistency of the series of UML diagrams originating from abstract models implemented with our consistency rules. This Consistent Model Driven Architecture approach enables us to generate automatically complete workflow applications from consistent and complete models developed from abstract models (e.g. Business Context Diagram). Therefore, our method can be used to check practicability (feasibility) of software architecture models.

Biological monitoring of workers exposed to 4,4'-methylenediphenyl diisocyanate (MDI) in 19 French polyurethane industries.

PubMed

Robert, A; Ducos, P; Francin, J M; Marsan, P

2007-04-01

To study the range of urinary levels of 4,4'-methylenedianiline (MDA), a metabolite of methylenediphenyl diisocyanate (MDI), across factories in the polyurethane industries and to evaluate the validity of this biomarker to assess MDI occupational exposure. Workers exposed to MDI, as well as non-occupationally exposed subjects, were studied and pre- and post-shift urine samples were collected from 169 workers of 19 French factories and 120 controls. Details on work activities and practices were collected by a questionnaire and workers were classified into three job categories. The identification and quantification of the total urinary MDA were performed by high-performance liquid chromatography with electrochemical detection (HPLC/EC). For all the factories, MDA was detectable in 73% of the post-shift urine samples. These post-shift values, in the range of <0.10 (detection limit)-23.60 microg/l, were significantly higher than those of the pre-shift samples. Urinary MDA levels in the control group were in the range of < 0.10-0.80 microg/l. The degree of automation of the mixing operation (polyols and MDI) appears as a determinant in the extent of exposure levels. The highest amounts of MDA in urine were found in the spraying or hot processes. The excretion levels of the workers directly exposed to the hardener containing the MDI monomer were significantly higher than those of the other workers. In addition, skin exposure to MDI monomer or to polyurethane resin during the curing step were always associated with significant MDA levels in urine. Total MDA in post-shift urine samples is a reliable biomarker to assess occupational exposure to MDI in various industrial applications and to help factories to improve their manufacturing processes and working practices. A biological guiding value not exceeding 7 microg/l (5 microg/g creatinine) could be proposed in France.

Blueberry Phytochemicals Inhibit Growth and Metastatic Potential of MDA-MB-231 Breast Cancer Cells Through Modulation of the Phosphatidylinositol 3-Kinase Pathway

PubMed Central

Adams, Lynn S.; Phung, Sheryl; Yee, Natalie; Seeram, Navindra P.; Li, Liya; Chen, Shiuan

2010-01-01

Dietary phytochemicals are known to exhibit a variety of anti-carcinogenic properties. This study investigated the chemopreventive activity of blueberry extract in triple negative breast cancer cell lines in vitro and in vivo. Blueberry decreased cell proliferation in HCC38, HCC1937 and MDA-MB-231 cells with no effect on the non-tumorigenic MCF-10A cell line. Decreased metastatic potential of MDA-MB-231 cells by blueberry was shown through inhibition of cell motility using wound healing assays and migration through a PET membrane. Blueberry treatment decreased the activity of matrix metalloproteinase 9 and the secretion of urokinase-type plasminogen activator while increasing tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1 secretion in MDA-MB-231 conditioned medium as shown by western blotting. Cell signaling pathways that control the expression/activation of these processes were investigated via western blotting and reporter gene assay. Treatment with blueberry decreased phosphatidylinositol 3-kinase (PI3K)/AKT and nuclear factor kappa-B (NFκB) activation in MDA-MB-231 cells where protein kinase C (PKC) and extracellular regulated kinase (ERK) were not affected. In vivo, the efficacy of blueberry to inhibit triple negative breast tumor growth was evaluated using the MDA-MB-231 xenograft model. Tumor weight and proliferation (Ki-67 expression) were decreased in blueberry treated mice, where apoptosis (caspase-3 expression) was increased compared to controls. Immunohistochemical analysis of tumors from blueberry-fed mice showed decreased activation of AKT and p65 NFκB signaling proteins with no effect on the phosphorylation of ERK. These data illustrate the inhibitory effect of blueberry phytochemicals on the growth and metastatic potential of MDA-MB-231 cells through modulation of the PI3K/AKT/NFκB pathway. PMID:20388778

3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKenna, D.J.; Guan, X.M.; Shulgin, A.T.

1991-03-01

The effect of various analogues of the neurotoxic amphetamine derivative, MDA (3,4-methylenedioxyamphetamine) on carrier-mediated, calcium-independent release of 3H-5-HT and 3H-DA from rat brain synaptosomes was investigated. Both enantiomers of the neurotoxic analogues MDA and MDMA (3,4-methylenedioxymethamphetamine) induce synaptosomal release of 3H-5-HT and 3H-DA in vitro. The release of 3H-5-HT induced by MDMA is partially blocked by 10(-6) M fluoxetine. The (+) enantiomers of both MDA and MDMA are more potent than the (-) enantiomers as releasers of both 3H-5-HT and 3H-DA. Eleven analogues, differing from MDA with respect to the nature and number of ring and/or side chain substituents, alsomore » show some activity in the release experiments, and are more potent as releasers of 3H-5-HT than of 3H-DA. The amphetamine derivatives {plus minus}fenfluramine, {plus minus}norfenfluramine, {plus minus}MDE, {plus minus}PCA, and d-methamphetamine are all potent releasers of 3H-5-HT and show varying degrees of activity as 3H-DA releasers. The hallucinogen DOM does not cause significant release of either 3H-monoamine. Possible long-term serotonergic neurotoxicity was assessed by quantifying the density of 5-HT uptake sites in rats treated with multiple doses of selected analogues using 3H-paroxetine to label 5-HT uptake sites. In the neurotoxicity study of the compounds investigated, only (+)MDA caused a significant loss of 5-HT uptake sites in comparison to saline-treated controls. These results are discussed in terms of the apparent structure-activity properties affecting 3H-monoamine release and their possible relevance to neurotoxicity in this series of MDA congeners.« less

Salivary thiobarbituric acid reacting substances and malondialdehyde--their relationship to reported smoking and to parodontal status described by the papillary bleeding index.

PubMed

Celec, Peter; Hodosy, Július; Celecová, Viera; Vodrázka, Ján; Cervenka, Tomás; Halcák, Lukác; Bozek, Peter; Kopáni, Martin; Kúdela, Matús

2005-01-01

Thiobarbituric reacting substances (TBARS) are markers of lipoperoxidation. The best-known specific TBARS is malondialdehyde (MDA). Results from our previous studies have shown that TBARS can be measured in saliva and are increased in patients with gingivitis. Whether MDA is the main TBARS in saliva from patients with altered parodontal status is unknown. Aim. To observe the relationship between the parodontal status and TBARS, MDA and the number of epithelial cells in saliva. In Study I saliva and plasma samples of 15 patients (8F, 7M) suffering from inflammatory periodontal diseases were gathered and TBARS levels were measured in these samples. In Study II saliva samples from 217 consecutive stomatologic patients were collected and analysed for TBARS spectrofluorometrically, MDA by high-performance liquid chromatography and epithelial cell count by light microscopy. Papillary bleeding index (PBI) was determined in standard stomatologic examination. In Study I results from our previous studies showing no correlation between salivary and plasma TBARS levels were confirmed. This indicates that the local salivary level of TBARS is unlikely to be directly affected by systemic oxidative stress. In Study II higher PBI was associated independently (adjusted for age and sex) tightly with higher TBARS (p<0.001) and with lower number of epithelial cells in saliva (p<0.05). Smokers had higher salivary MDA levels (p<0.003) and lower number of epithelial cells in saliva (p<0.01). Salivary TBARS are a simple parameter that partially reflects the parodontal status with a potential usefulness in the clinical stomatology. We show herein that salivary MDA is dependent on age and smoking, but there is no correlation between MDA and PBI. Further studies should uncover the main salivary TBARS compound in patients with altered parodontal status and trace the origin of these salivary lipoperoxidation markers.

Modeling the Economic and Epidemiologic Impact of Hookworm Vaccine and Mass Drug Administration (MDA) in Brazil, a High Transmission Setting

PubMed Central

Bartsch, Sarah M.; Hotez, Peter J.; Hertenstein, Daniel L.; Diemert, David J.; Zapf, Kristina M.; Bottazzi, Maria Elena; Bethony, Jeffrey M.; Brown, Shawn T.; Lee, Bruce Y.

2017-01-01

Background Although mass drug administration (MDA) has helped reduce morbidity attributed to soil-transmitted helminth infections in children, its limitations for hookworm infection have motivated the development of a human hookworm vaccine to both improve morbidity control and ultimately help block hookworm transmission leading to elimination. However, the potential economic and epidemiologic impact of a preventive vaccine has not been fully evaluated. Methods We developed a dynamic compartment model coupled to a clinical and economics outcomes model representing both the human and hookworm populations in a high transmission region of Brazil. Experiments simulated different implementation scenarios of MDA and vaccination under varying circumstances. Results Considering only intervention costs, both annual MDA and vaccination were highly cost-effective (ICERs ≤$790/DALY averted) compared to no intervention, with vaccination resulting in lower incremental cost-effectiveness ratios (ICERs ≤$444/DALY averted). From the societal perspective, vaccination was economically dominant (i.e., less costly and more effective) than annual MDA in all tested scenarios, except when vaccination was less efficacious (20% efficacy, 5 year duration) and MDA coverage was 75%. Increasing the vaccine's duration of protection and efficacy, and including a booster injection in adulthood all increased the benefits of vaccination (i.e., resulted in lower hookworm prevalence, averted more disability-adjusted life years, and saved more costs). Assuming its target product profile, a pediatric hookworm vaccine drastically decreased hookworm prevalence in children to 14.6% after 20 years, compared to 57.2% with no intervention and 54.1% with MDA. The addition of a booster in adulthood further reduced the overall prevalence from 68.0% to 36.0%, nearly eliminated hookworm infection in children. Conclusion Using a human hookworm vaccine would be cost-effective and in many cases economically dominant, providing both health benefits and cost-savings. It could become a key technology in effecting control and elimination efforts for hookworm globally. PMID:27002501

Sprague-Dawley rats display metabolism-mediated sex differences in the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fonsart, Julien; Menet, Marie-Claude; Decleves, Xavier

The use of the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been associated with unexplained deaths. Male humans and rodents are more sensitive to acute toxicity than are females, including a potentially lethal hyperthermia. MDMA is highly metabolized to five main metabolites, by the enzymes CYP1A2 and CYP2D. The major metabolite in rats, 3,4-methylenedioxyamphetamine (MDA), also causes hyperthermia. We postulated that the reported sex difference in rats is due to a sexual dimorphism(s). We therefore determined (1) the LD50 of MDMA and MDA, (2) their hyperthermic effects, (3) the activities of liver CYP1A2 and CYP2D, (4) the liver microsomal metabolism ofmore » MDMA and MDA, (5) and the plasma concentrations of MDMA and its metabolites 3 h after giving male and female Sprague-Dawley (SD) rats MDMA (5 mg.kg{sup -1} sc). The LD50 of MDMA was 2.4-times lower in males than in females. MDMA induced greater hyperthermia (0.9 deg. C) in males. The plasma MDA concentration was 1.3-fold higher in males, as were CYP1A2 activity (twice) and N-demethylation to MDA (3.3-fold), but the plasma MDMA concentration (1.4-fold) and CYP2D activity (1.3-fold) were higher in females. These results suggest that male SD rats are more sensitive to MDMA acute toxicity than are females, probably because their CYP1A2 is more active, leading to higher N-demethylation and plasma MDA concentration. This metabolic pathway could be responsible for the lethality of MDMA, as the LD50 of MDA is the same in both sexes. These data strongly suggest that the toxicity of amphetamine-related drugs largely depends on metabolic differences.« less

Elimination of lymphatic filariasis as a public health problem from the Cook Islands.

PubMed

Ave, Charlie; Kapa, D Ramaiah; Ottesen, Eric

2018-01-01

The Cook Islands has a long history of high-endemicity lymphatic filariasis (LF) transmitted by Aedes vector mosquitoes. Though the infection prevalence had declined between 1975 and 1999 following episodic treatment activities, still infection was widespread with pockets of persistent infection. Beginning in 1999, the Cook Islands embarked on a national program, in partnership with Pacific Programme to Eliminate LF (PacELF), to eliminate LF as a public health problem. All 12 inhabited islands were identified as endemic, and six rounds of mass drug administration (MDA) with once-yearly, single-dose albendazole plus diethylcarbamazine (DEC) were implemented during 2000-2006 to interrupt transmission of LF. Surveys carried out at the baseline, mid-term, stop-MDA, and post-MDA periods assessed LF antigen (Ag) prevalence in children and adults. Historical data, health workers' observations, and hospital records were used to assess the trend and burden of chronic disease. The baseline Ag prevalence (1999) ranged from 2.0% in Manihiki to > 18.0% in Aitutaki, Mitiaro, and Pukapuka, and the national average Ag prevalence was 8.6%. MDA, carried out with a national treatment coverage over six annual rounds of MDA ranging from 63.5 to 96.7% in different years, was stopped in 2007. By then, the national Ag prevalence had declined to 0.27%. The post-MDA surveillance survey results (2013-2014) showed that Ag prevalence had fallen to 0% in 11/12 islands, and the national prevalence was only 0.03%. Chronic filarial disease had almost entirely disappeared. The Cook Islands met all the criteria required for the World Health Organization (WHO) to acknowledge elimination of LF as a public health problem, as it did officially in 2016. This success also confirms that LF, even when transmitted by Aedes mosquitoes that are recognized to be more efficient than other vector species, can be eliminated as a public health problem by six rounds of MDA.

Modeling the economic and epidemiologic impact of hookworm vaccine and mass drug administration (MDA) in Brazil, a high transmission setting.

PubMed

Bartsch, Sarah M; Hotez, Peter J; Hertenstein, Daniel L; Diemert, David J; Zapf, Kristina M; Bottazzi, Maria Elena; Bethony, Jeffrey M; Brown, Shawn T; Lee, Bruce Y

2016-04-27

Although mass drug administration (MDA) has helped reduce morbidity attributed to soil-transmitted helminth infections in children, its limitations for hookworm infection have motivated the development of a human hookworm vaccine to both improve morbidity control and ultimately help block hookworm transmission leading to elimination. However, the potential economic and epidemiologic impact of a preventive vaccine has not been fully evaluated. We developed a dynamic compartment model coupled to a clinical and economics outcomes model representing both the human and hookworm populations in a high transmission region of Brazil. Experiments simulated different implementation scenarios of MDA and vaccination under varying circumstances. Considering only intervention costs, both annual MDA and vaccination were highly cost-effective (ICERs ≤ $790/DALY averted) compared to no intervention, with vaccination resulting in lower incremental cost-effectiveness ratios (ICERs ≤ $444/DALY averted). From the societal perspective, vaccination was economically dominant (i.e., less costly and more effective) versus annual MDA in all tested scenarios, except when vaccination was less efficacious (20% efficacy, 5 year duration) and MDA coverage was 75%. Increasing the vaccine's duration of protection and efficacy, and including a booster injection in adulthood all increased the benefits of vaccination (i.e., resulted in lower hookworm prevalence, averted more disability-adjusted life years, and saved more costs). Assuming its target product profile, a pediatric hookworm vaccine drastically decreased hookworm prevalence in children to 14.6% after 20 years, compared to 57.2% with no intervention and 54.1% with MDA. The addition of a booster in adulthood further reduced the overall prevalence from 68.0% to 36.0% and nearly eliminated hookworm infection in children. Using a human hookworm vaccine would be cost-effective and in many cases economically dominant, providing both health benefits and cost-savings. It could become a key technology in effecting control and elimination efforts for hookworm globally. Copyright © 2016 Elsevier Ltd. All rights reserved.

Atorvastatin reduces malondialdehyde concentrations in patients with polycystic ovary syndrome.

PubMed

Sathyapalan, Thozhukat; Shepherd, John; Coady, Anne-Marie; Kilpatrick, Eric S; Atkin, Stephen L

2012-11-01

It has been shown that there is an increase in oxidative stress in polycystic ovary syndrome (PCOS). Statins are considered to have a pleiotropic effect other than their lipid-lowering effect. These effects may be mediated in part by reducing oxidative stress. This randomized, double-blind, placebo-controlled study was conducted to assess the effect of atorvastatin on serum malondialdehyde (MDA) concentrations as a marker of oxidative stress in patients with PCOS. Forty medication-naïve patients with PCOS were randomized to either atorvastatin 20 mg daily or placebo for 3 months. A 3-month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. There was a significant decrease of MDA concentrations with atorvastatin [mean (sem)] [0.29 (0.04) vs. 0.25 (0.02) μmol/liter; P < 0.01] compared with placebo [0.28 (0.02) vs. 0.29 (0.12) μmol/liter; P = 0.52]. Three months treatment with metformin resulted in further reduction of MDA levels with atorvastatin compared with baseline [0.25 (0.02) baseline vs. 0.23 (0.03) μmol/liter for atorvastatin treated; P = 0.02]. There was also a significant correlation between the reduction in MDA with a reduction in high-sensitivity C-reactive protein (r = 0.71, P < 0.01), an increase in 25-hydroxyvitamin D (25OHD; r = -0.68, P = 0.02), and a reduction in testosterone levels (r = 0.63, P = 0.01). Multiple linear regression analysis revealed Δ25OHD, ΔC-reactive protein, and Δtestosterone were independent predictors of changes in MDA after atorvastatin treatment. No correlation was observed between the reductions in serum MDA concentrations with changes in the lipid parameters. Twelve weeks of atorvastatin led to a significant reduction in oxidative stress as determined by MDA concentrations among patients with polycystic ovary syndrome that was independently predicted by changes in testosterone, 25OHD, and high-sensitivity C-reactive protein.

Skylab

NASA Image and Video Library

1970-01-01

This cutaway drawing details the internal design of the Skylab Multiple Docking Adapter (MDA). The MDA, built under the direction of the Marshall Space Flight Center, housed various Skylab control and experiment units, and provided a docking port for the Apollo Command Module (CM).

Non-destructive inspections of illicit drugs in envelope using terahertz time-domain spectroscopy

NASA Astrophysics Data System (ADS)

Li, Ning; Shen, Jingling; Lu, Meihong; Jia, Yan; Sun, Jinhai; Liang, Laishun; Shi, Yanning; Xu, Xiaoyu; Zhang, Cunlin

2006-09-01

The absorption spectra of two illicit drugs, methylenedioxyamphetarnine (MDA) and methamphetamine (MA), within and without two conventional envelopes are studied using terahertz time-domain spectroscopy technique. The characteristic absorption spectra of MDA and MA are obtained in the range of 0.2 THz to 2.5 THz. MDA has an obvious absorption peak at 1.41 THz while MA has obvious absorption peaks at 1.23 THz, 1.67 THz, 1.84 THz and 2.43 THz. We find that the absorption peaks of MDA and MA within the envelopes are almost the same as those without the envelopes respectively although the two envelopes have some different absorption in THz waveband. This result indicates that the type of illicit drugs in envelopes can be determined by identifying their characteristic absorption peaks, and THz time-domain spectroscopy is one of the most powerful candidates for illicit drugs inspection.

Development of Targeted Nanobubbles for Ultrasound Imaging and Ablation of Metastatic Prostate Cancer Lesions

DTIC Science & Technology

2014-08-01

AD_________________ Award Number: W81XWH-12-1-0284 TITLE: Development of Targeted Nanobubbles for...matrix, optically transparent fibrin-based gel phantom embedded with a layer of PC-3 and C4-2B of human prostate cancer, and MDA-MB-231 of breast

The Industrial Base and National Security: A New Strategy

DTIC Science & Technology

1993-04-01

addresses this issue in her article entitled, " Managing Innovation on the Factory Floor": Manufacturing managers often buy the most advanced...Incentives Program." Government Contract Number MDA903-85-C-0139 Final Report, 1986. 31 11. Tyre, Marcie J. " Managing Innovation On The Factory Floor

Impact of Education Campaign on Community-Based Vector Control in Hastening the Process of Elimination of Lymphatic Filariasis in Tamil Nadu, South India

ERIC Educational Resources Information Center

Nandha, B.; Krishnamoorthy, K.

2012-01-01

Globally mosquito-borne lymphatic filariasis (LF) is targeted for elimination by 2020. Towards this goal, the scope of community-based vector control as a supplementary strategy to mass drug administration (MDA) was assessed through an intensive education campaign and evaluated using pre- and post-educational surveys in an intervention and…

CFD flowfield simulation of Delta Launch Vehicles in a power-on configuration

NASA Technical Reports Server (NTRS)

Pavish, D. L.; Gielda, T. P.; Soni, B. K.; Deese, J. E.; Agarwal, R. K.

1993-01-01

This paper summarizes recent work at McDonnell Douglas Aerospace (MDA) to develop and validate computational fluid dynamic (CFD) simulations of under expanded rocket plume external flowfields for multibody expendable launch vehicles (ELVs). Multi engine reacting gas flowfield predictions of ELV base pressures are needed to define vehicle base drag and base heating rates for sizing external nozzle and base region insulation thicknesses. Previous ELV design programs used expensive multibody power-on wind tunnel tests that employed chamber/nozzle injected high pressure cold or hot-air. Base heating and pressure measurements were belatedly made during the first flights of past ELV's to correct estimates from semi-empirical engineering models or scale model tests. Presently, CFD methods for use in ELV design are being jointly developed at the Space Transportation Division (MDA-STD) and New Aircraft Missiles Division (MDA-NAMD). An explicit three dimensional, zonal, finite-volume, full Navier-Stokes (FNS) solver with finite rate hydrocarbon/air and aluminum combustion kinetics was developed to accurately compute ELV power-on flowfields. Mississippi State University's GENIE++ general purpose interactive grid generation code was chosen to create zonal, finite volume viscous grids. Axisymmetric, time dependent, turbulent CFD simulations of a Delta DSV-2A vehicle with a MB-3 liquid main engine burning RJ-1/LOX were first completed. Hydrocarbon chemical kinetics and a k-epsilon turbulence model were employed and predictions were validated with flight measurements of base pressure and temperature. Zonal internal/external grids were created for a Delta DSV-2C vehicle with a MB-3 and three Castor-1 solid motors burning and a Delta-2 with an RS-27 main engine (LOX/RP-1) and 9 GEM's attached/6 burning. Cold air, time dependent FNS calculations were performed for DSV-2C during 1992. Single phase simulations that employ finite rate hydrocarbon and aluminum (solid fuel) combustion chemistry are currently in progress. Reliable and efficient Eulerian algorithms are needed to model two phase (solid-gas) momentum and energy transfer mechanisms for solid motor fuel combustion products.

CFD flowfield simulation of Delta Launch Vehicles in a power-on configuration

NASA Astrophysics Data System (ADS)

Pavish, D. L.; Gielda, T. P.; Soni, B. K.; Deese, J. E.; Agarwal, R. K.

1993-07-01

This paper summarizes recent work at McDonnell Douglas Aerospace (MDA) to develop and validate computational fluid dynamic (CFD) simulations of under expanded rocket plume external flowfields for multibody expendable launch vehicles (ELVs). Multi engine reacting gas flowfield predictions of ELV base pressures are needed to define vehicle base drag and base heating rates for sizing external nozzle and base region insulation thicknesses. Previous ELV design programs used expensive multibody power-on wind tunnel tests that employed chamber/nozzle injected high pressure cold or hot-air. Base heating and pressure measurements were belatedly made during the first flights of past ELV's to correct estimates from semi-empirical engineering models or scale model tests. Presently, CFD methods for use in ELV design are being jointly developed at the Space Transportation Division (MDA-STD) and New Aircraft Missiles Division (MDA-NAMD). An explicit three dimensional, zonal, finite-volume, full Navier-Stokes (FNS) solver with finite rate hydrocarbon/air and aluminum combustion kinetics was developed to accurately compute ELV power-on flowfields. Mississippi State University's GENIE++ general purpose interactive grid generation code was chosen to create zonal, finite volume viscous grids. Axisymmetric, time dependent, turbulent CFD simulations of a Delta DSV-2A vehicle with a MB-3 liquid main engine burning RJ-1/LOX were first completed. Hydrocarbon chemical kinetics and a k-epsilon turbulence model were employed and predictions were validated with flight measurements of base pressure and temperature. Zonal internal/external grids were created for a Delta DSV-2C vehicle with a MB-3 and three Castor-1 solid motors burning and a Delta-2 with an RS-27 main engine (LOX/RP-1) and 9 GEM's attached/6 burning. Cold air, time dependent FNS calculations were performed for DSV-2C during 1992. Single phase simulations that employ finite rate hydrocarbon and aluminum (solid fuel) combustion chemistry are currently in progress. Reliable and efficient Eulerian algorithms are needed to model two phase (solid-gas) momentum and energy transfer mechanisms for solid motor fuel combustion products.

Robust high-performance nanoliter-volume single-cell multiple displacement amplification on planar substrates.

PubMed

Leung, Kaston; Klaus, Anders; Lin, Bill K; Laks, Emma; Biele, Justina; Lai, Daniel; Bashashati, Ali; Huang, Yi-Fei; Aniba, Radhouane; Moksa, Michelle; Steif, Adi; Mes-Masson, Anne-Marie; Hirst, Martin; Shah, Sohrab P; Aparicio, Samuel; Hansen, Carl L

2016-07-26

The genomes of large numbers of single cells must be sequenced to further understanding of the biological significance of genomic heterogeneity in complex systems. Whole genome amplification (WGA) of single cells is generally the first step in such studies, but is prone to nonuniformity that can compromise genomic measurement accuracy. Despite recent advances, robust performance in high-throughput single-cell WGA remains elusive. Here, we introduce droplet multiple displacement amplification (MDA), a method that uses commercially available liquid dispensing to perform high-throughput single-cell MDA in nanoliter volumes. The performance of droplet MDA is characterized using a large dataset of 129 normal diploid cells, and is shown to exceed previously reported single-cell WGA methods in amplification uniformity, genome coverage, and/or robustness. We achieve up to 80% coverage of a single-cell genome at 5× sequencing depth, and demonstrate excellent single-nucleotide variant (SNV) detection using targeted sequencing of droplet MDA product to achieve a median allelic dropout of 15%, and using whole genome sequencing to achieve false and true positive rates of 9.66 × 10(-6) and 68.8%, respectively, in a G1-phase cell. We further show that droplet MDA allows for the detection of copy number variants (CNVs) as small as 30 kb in single cells of an ovarian cancer cell line and as small as 9 Mb in two high-grade serous ovarian cancer samples using only 0.02× depth. Droplet MDA provides an accessible and scalable method for performing robust and accurate CNV and SNV measurements on large numbers of single cells.

Effects of Agaricus blazei Murill Polysaccharide on Cadmium Poisoning on the MDA5 Signaling Pathway and Antioxidant Function of Chicken Peripheral Blood Lymphocytes.

PubMed

Lv, Ai; Ge, Ming; Hu, Xuequan; Liu, Wenjing; Li, Guangxing; Zhang, Ruili

2018-01-01

This experimental study investigated the effect of Agaricus blazei Murill polysaccharide (ABP) on cadmium (Cd) poisoning on the melanoma differentiation-associated gene 5 (MDA5) signaling pathway and antioxidant function of peripheral blood lymphocytes (PBLs) in chickens. The experiments were divided into four groups: 7-day-old chickens with normal saline (0.2 mL single/day), Cd (140 mg/kg), ABP (30 mg/mL, 0.2 mL single/day), and Cd + ABP(140 mg/kg/day + 0.2 mL ABP). Peripheral blood was collected on the 20th, 40th, and 60th days for each group, and PBLs were separated. We attempted to detect the expression of MDA5, downstream signaling molecules, and convergence protein (interferon promoter-stimulating factor 1); transcription factors (IRF3 and NF-κB); the content of cytokines (IL-1β, IL-6, TNF-α, and IFN-β) in PBLs; and the antioxidant index of superoxide dismutase (SOD), malondialdhyde (MDA), and glutathione peroxidase (GSH-Px). The results showed that ABP can reduce the accumulation of Cd in the peripheral blood of chickens; reduce the expression of MDA5 and downstream signaling molecules; and reduce the content of IL-1β, IL-6, TNF-α, and IFN-β in PBLs of chickens. The activity of antioxidant enzymes (SOD and GSH-Px) significantly increased, and the content of MDA decreased. These results showed that they have a certain protective effect of ABP on Cd poisoning in chicken PBLs caused by injury.

Geospatial Distribution and Clustering of Chlamydia trachomatis in Communities Undergoing Mass Azithromycin Treatment

PubMed Central

Yohannan, Jithin; He, Bing; Wang, Jiangxia; Greene, Gregory; Schein, Yvette; Mkocha, Harran; Munoz, Beatriz; Quinn, Thomas C.; Gaydos, Charlotte; West, Sheila K.

2014-01-01

Purpose. We detected spatial clustering of households with Chlamydia trachomatis infection (CI) and active trachoma (AT) in villages undergoing mass treatment with azithromycin (MDA) over time. Methods. We obtained global positioning system (GPS) coordinates for all households in four villages in Kongwa District, Tanzania. Every 6 months for a period of 42 months, our team examined all children under 10 for AT, and tested for CI with ocular swabbing and Amplicor. Villages underwent four rounds of annual MDA. We classified households as having ≥1 child with CI (or AT) or having 0 children with CI (or AT). We calculated the difference in the K function between households with and without CI or AT to detect clustering at each time point. Results. Between 918 and 991 households were included over the 42 months of this analysis. At baseline, 306 households (32.59%) had ≥1 child with CI, which declined to 73 households (7.50%) at 42 months. We observed borderline clustering of households with CI at 12 months after one round of MDA and statistically significant clustering with growing cluster sizes between 18 and 24 months after two rounds of MDA. Clusters diminished in size at 30 months after 3 rounds of MDA. Active trachoma did not cluster at any time point. Conclusions. This study demonstrates that CI clusters after multiple rounds of MDA. Clusters of infection may increase in size if the annual antibiotic pressure is removed. The absence of growth after the three rounds suggests the start of control of transmission. PMID:24906862

Crosstalk between stromal components and tumor cells of TNBC via secreted factors enhances tumor growth and metastasis

PubMed Central

Jin, Kideok; Pandey, Niranjan B.; Popel, Aleksander S.

2017-01-01

Triple negative breast cancer (TNBC) as a metastatic disease is currently incurable. Reliable and reproducible methods for testing drugs against metastasis are not available. Stromal cells may play a critical role in tumor progression and metastasis. In this study, we determined that fibroblasts and macrophages secreted IL-8 upon induction by tumor cell-conditioned media (TCM) from MDA-MB-231 cancer cells. Our data showed that the proliferation of MDA-MB-231 cells co-cultured with fibroblasts or macrophages was enhanced compared to the monoculture. Furthermore, TNBC cell migration, a key step in tumor metastasis, was promoted by conditioned media (CM) from TCM-induced fibroblasts or macrophages. Knockdown of the IL-8 receptor CXCR2 by CRISPR-Cas9 reduces MDA-MB-231 cell proliferation and migration compared to wild type. In a mouse xenograft tumor model, the growth of MDA-MB-231-CXCR2−/− tumor was significantly decreased compared to the growth of tumors from wild-type cells. In addition, the incidence of thoracic metastasis of MDA-MB-231-CXCR2−/− tumors was reduced compared to wild type. We found that the auto- and paracrine loop exists between TNBC cells and stroma, which results in enhanced IL-8 secretion from the stromal components. Significantly, inhibition of the IL-8 signaling pathway by reparixin, an inhibitor of the IL-8 receptor, CXCR1/2, reduced MDA-MB-231 tumor growth and metastasis. Taken together, these findings implicate IL-8 signaling as a critical event in TNBC tumor growth and metastasis via crosstalk with stromal components. PMID:28947965

3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of (/sup 3/H)paroxetine-labeled serotonin uptake sites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Battaglia, G.; Yeh, S.Y.; O'Hearn, E.

1987-09-01

This study examines the effects of repeated systemic administration (20 mg/kg s.c., twice daily for 4 days) of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on levels of brain monoamines, their metabolites and on the density of monoamine uptake sites in various regions of rat brain. Marked reductions (30-60%) in the concentration of 5-hydroxyindoleacetic acid were observed in cerebral cortex, hippocampus, striatum, hypothalamus and midbrain at 2 weeks after a 4-day treatment regimen of MDMA or MDA; less consistent reductions in serotonin (5-HT) content were observed in these brain regions. In addition, both MDMA and MDA caused comparable and substantial reductions (50-75%)more » in the density of (/sup 3/H)paroxetine-labeled 5-HT uptake sites in all brain regions examined. In contrast, neither MDMA nor MDA caused any widespread or long-term changes in the content of the catecholaminergic markers (i.e., norepinephrine, dopamine, 3,4 dihydroxyphenylacetic acid and homovanillic acid) or in the number of (/sup 3/H)mazindol-labeled norepinephrine or dopamine uptake sites in the brain regions examined. These data demonstrate that MDMA and MDA cause long-lasting neurotoxic effects with respect to both the functional and structural integrity of serotonergic neurons in brain. Furthermore, our measurement of reductions in the density of 5-HT uptake sites provides a means for quantification of the neurodegenerative effects of MDMA and MDA on presynaptic 5-HT terminals.« less

The Effect of Astaxanthin and Regular Training on Dynamic Pattern of Oxidative Stress on Male under Strenuous Exercise

NASA Astrophysics Data System (ADS)

Sylviana, N.; Gunawan, H.; Lesmana, R.; Purba, A.; Akbar, I. B.

2017-03-01

Strenuous physical activity will induced higher Reactive Oxygen Species (ROS) level in human body that can be measured by serum Malondialdehyde (MDA) level. Malondialdehyde is product of lipid peroxidation process that define as oxidative damage of lipid biomolecule by reactivity of reactive oxygen species. Still, the dynamic pattern of Malondialdehyde (MDA) level under strenuous exercise is not fully understood. Potent antioxidant such as Astaxanthin and training may be altered the level of MDA. Thus, purpose of this study is to understand effect of astaxanthin to MDA dynamic pattern on training male after strenuous physical activity. It was a double blind, experimental study, conducted on thirty young male age, divided into untrained and trained groups. Supplement Astaxanthin was given to 15 subject as well as placebo for one week after supplementation, Subjects were tested with anaerobic strenuous physical activity. The values were analyzed with ANOVA test followed by Duncan test showed that in every groups, mean of MDA before test was similar, start increase significantly after tested, begin decrease at 6th hour post test and back to baseline at 24th hour post-test ( p<0.05), except for group of untrained male with placebo still increase twice from baseline. The lowest mean of MDA was found on group of trained male with Astaxanthin supplementation and the highest was found on group of untrained male with placebo (p<0.05). These findings support that Astaxanthin and training might has positive effect to oxidative stress condition without altered its dynamic pattern in male after strenuous physical activity

Hydroxyl free radical production during torsional phacoemulsification.

PubMed

Aust, Steven D; Hebdon, Thomas; Humbert, Jordan; Dimalanta, Ramon

2010-12-01

To quantitate free radical generation during phacoemulsification using an ultrasonic phacoemulsification device that includes a torsional mode and evaluate tip designs specific to the torsional mode. Chemistry and Biochemistry Department, Utah State University, Logan, Utah, USA. Experimental study. Experiments were performed using the Infiniti Vision System and OZil handpiece. Hydroxyl radical concentrations in the aspirated irrigation solution during torsional phacoemulsification were quantitated as nanomolar malondialdehyde (nM MDA) and determined spectrophotometrically using the deoxyribose assay. The mean free radical production during phacoemulsification with torsional modality at 100% amplitude was 30.1 nM MDA ± 5.1 (SD) using a 0.9 mm 45-degree Kelman tapered ABS tip. With other tip designs intended for use with the torsional modality, free radical production was further reduced when fitted with the 0.9 mm 45-degree Kelman mini-flared ABS tip (13.2 ± 5.6 nM MDA) or the 0.9 mm 45-degree OZil-12 mini-flared ABS tip (14.3 ± 6.7 nM MDA). Although the measurements resulting from the use of the latter 2 tips were not statistically significantly different (P ≈ .25), they were different from those of the tapered tip (P<.0001). The MDA concentration in the aspirated irrigation solution using the torsional modality was approximately one half that reported for the handpiece's longitudinal modality in a previous study using the same bent-tip design (Kelman tapered, P<.0001). The level of MDA was further reduced approximately one half with torsional-specific tips. Copyright © 2010 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

Pain and mobility improvement and MDA plasma levels in degenerative osteoarthritis, low back pain, and rheumatoid arthritis after infrared A-irradiation.

PubMed

Siems, Werner; Bresgen, Nikolaus; Brenke, Rainer; Siems, Renate; Kitzing, Manfred; Harting, Heike; Eckl, Peter M

2010-01-01

Infrared (IR)-A irradiation can be useful in back and musculoskeletal pain therapy. In this study joint and vertebral column pain and mobility were measured during two weeks of IR-A irradiation treatment of patients suffering from degenerative osteoarthritis of hip and knee, low back pain, or rheumatoid arthritis. Additionally, before and after IR-A treatment MDA serum levels were measured to check if MDA variations accompany changes in pain intensity and mobility. Two-hundred and seven patients were divided into verum groups getting IR-irradiation, placebo groups getting visible, but not IR irradiation, and groups getting no irradiation. In osteoarthritis significant pain reduction according to Visual Analogue Scale and mobility improvements occurred in the verum group. Even though beneficial mean value changes occurred in the placebo group, the improvements in the placebo and No Irradiation groups were without statistical significance. In low back pain, pain and mobility improvements (by 35-40%) in the verum group were found, too. A delayed (2nd week) mobility improvement in rheumatoid arthritis was seen. However, pain relief was seen immediately. In patients suffering from low back pain or rheumatoid arthritis, the pain and mobility improvements were accompanied by significant changes of MDA serum levels. However, MDA appears not a sensitive biofactor for changes of the pain intensity in degenerative osteoarthritis. Nevertheless, unaffected or lowered MDA levels during intensive IR-A therapy argue against previous reports on free radical formation upon infrared. In conclusion, rapid beneficial effects of IR-A towards musculoskeletal pain and joint mobility loss were demonstrated.

Circulating and myometrial markers of oxidative stress in pregnant women with fetal growth restriction.

PubMed

Biberoglu, Ebru; Biberoglu, Kutay; Kirbas, Ayse; Daglar, Korkut; Genc, Metin; Avci, Aslihan; Danisman, Nuri

2016-01-01

The objective of this study was to identify the relationship between fetal growth restriction (FGR) and oxidative stress. The mechanisms that protect against oxidative stress in the local microenvironment were investigated by comparing the activities of the markers, both in the circulation and myometrium. Myometrial tissue and serum levels of malondialdehyde (MDA), xanthine oxidase (XO), catalase (CAT) and superoxide dismutase (SOD) markers were measured in 20 FGR and 20 healthy pregnancies. The mean duration of gestation at delivery was shorter (P = 0003) and the mean birthweight was lower P < 0001) in the FGR study group compared with the control group, as expected. While MDA and CAT concentrations were higher in the serum (P < 0.02 and P < 0.01, respectively), but lower in the myometrial samples (P < 0.01) in the FGR versus the control group, XO and myometrial SOD values were comparable in both groups. Although our data demonstrated that FGR is associated with oxidative stress, the exact role and mechanism of the oxidant and antioxidant imbalance is obscure. We speculate that despite limited local synthesis of CAT, effective and efficient removal of MDA in the uterine environment explains high MDA and CAT serum concentrations in women with FGR. Alternatively, a well-functioning myometrial system could rescue the fetus from reactive oxygen species, as demonstrated by lowered MDA and depleted CAT resulting from hyperconsumption. Elevated serum MDA and CAT levels in the serum may reflect the 'spillover' of these markers from the uterus to the circulation. © 2015 Japan Society of Obstetrics and Gynecology.

Quasi-metagenomics and realtime sequencing aided detection and subtyping of Salmonella enterica from food samples.

PubMed

Hyeon, Ji-Yeon; Li, Shaoting; Mann, David A; Zhang, Shaokang; Li, Zhen; Chen, Yi; Deng, Xiangyu

2017-12-01

Metagenomics analysis of food samples promises isolation-independent detection and subtyping of foodborne bacterial pathogens in a single workflow. Selective concentration of Salmonella genomic DNA through immunomagnetic separation (IMS) and multiple displacement amplification (MDA) were shown to shorten culture enrichment of Salmonella -spiked raw chicken breast samples by over 12 hours while permitting serotyping and high-fidelity single nucleotide polymorphisms (SNP) typing of the pathogen using short shotgun sequencing reads. The herein termed quasi-metagenomics approach was evaluated on Salmonella -spiked lettuce and black peppercorn samples as well as retail chicken parts naturally contaminated with different serotypes of Salmonella. Between 8 and 24 h culture enrichment was required for detecting and subtyping naturally occurring Salmonella from unspiked chicken parts compared with 4 to 12 h culture enrichment when Salmonella -spiked food samples were analyzed, indicating the likely need for longer culture enrichment to revive low levels of stressed or injured Salmonella cells in food. Further acceleration of the workflow was achieved by real-time nanopore sequencing. After 1.5 hours of analysis on a potable sequencer, sufficient data were generated from sequencing IMS-MDA product of a cultured-enriched lettuce sample to allow serotyping and robust phylogenetic placement of the inoculated isolate. Importance Both culture enrichment and next-generation sequencing remain to be time-consuming processes for food testing where rapid methods for pathogen detection are widely available. Our study demonstrated substantial acceleration of the respective process through IMS-MDA and real-time nanopore sequencing. In one example, the combined use of the two methods delivered a less than 24 h turnaround time from a Salmonella -contaminated lettuce sample to phylogenetic identification of the pathogen. Improved efficiency like this is important for further expanding the use of whole genome and metagenomics sequencing in microbial analysis of food. Our results suggest the potential of the quasi-metagenomics approach in areas where rapid detection and subtyping of foodborne pathogens is important, such as foodborne outbreak response and precision tracking and monitoring of foodborne pathogens in production environments and supply chains. Copyright © 2017 American Society for Microbiology.

Punica granatum fabricated platinum nanoparticles: A therapeutic pill for breast cancer

NASA Astrophysics Data System (ADS)

Jha, Babita; Rao, Mugdha; Chattopadhyay, A.; Bandyopadhyay, A.; Prasad, K.; Jha, Anal K.

2018-05-01

The current research highlights the fabrication of biocompatible platinum nanoparticles (Pt NPs) in first hand from arils of Punica granatum by using green chemistry approach. Formation of Pt NPs was determined by UV-visible, X-ray diffraction, and FTIR techniques. The anti-cancer potential of fabricated Pt NPs was evaluated by MTT assay on MCF7 and MDA-MB-231 breast cancer cell lines. This work is foreshadowing the prospect of Pt NPs application as a therapeutic drug for cancer treatment.

RAND’s Portfolio Analysis Tool (PAT): Theory, Methods, and Reference Manual

DTIC Science & Technology

2009-01-01

language , such as Analytica® (a product of Lumina Decision Systems, Inc., [www.lumina.com]). We used such a connection approach in our work for MDA...with $ signs ) so that the formulas will be automatically adjusted if they change PAT’s structure by, e.g., adding a column or row. Checking is...year, in real (inflation-protected) dollars. The sign is positive or negative, depending on whether one is receiving or paying and on the syntax of

Mass drug administration of ivermectin in south-eastern Senegal reduces the survivorship of wild-caught, blood fed malaria vectors

PubMed Central

2010-01-01

Background In south-eastern Senegal, malaria and onchocerciasis are co-endemic. Onchocerciasis in this region has been controlled by once or twice yearly mass drug administration (MDA) with ivermectin (IVM) for over fifteen years. Since laboratory-raised Anopheles gambiae s.s. are susceptible to ivermectin at concentrations found in human blood post-ingestion of IVM, it is plausible that a similar effect could be quantified in the field, and that IVM might have benefits as a malaria control tool. Methods In 2008 and 2009, wild-caught blood fed An. gambiae s.l. mosquitoes were collected from huts of three pairs of Senegalese villages before and after IVM MDAs. Mosquitoes were held in an insectary to assess their survival rate, subsequently identified to species, and their blood meals were identified. Differences in mosquito survival were statistically analysed using a Glimmix model. Lastly, changes in the daily probability of mosquito survivorship surrounding IVM MDAs were calculated, and these data were inserted into a previously developed, mosquito age-structured model of malaria transmission. Results Anopheles gambiae s.s. (P < 0.0001) and Anopheles arabiensis (P = 0.0191) from the treated villages had significantly reduced survival compared to those from control villages. Furthermore, An gambiae s.s. caught 1-6 days after MDA in treated villages had significantly reduced survival compared to control village collections (P = 0.0003), as well as those caught pre-MDA (P < 0.0001) and >7 days post-MDA (P < 0.0001). The daily probability of mosquito survival dropped >10% for the six days following MDA. The mosquito age-structured model of malaria transmission demonstrated that a single IVM MDA would reduce malaria transmission (Ro) below baseline for at least eleven days, and that repeated IVM MDAs would result in a sustained reduction in malaria Ro. Conclusions Ivermectin MDA significantly reduced the survivorship of An. gambiae s.s. for six days past the date of the MDA, which is sufficient to temporarily reduce malaria transmission. Repeated IVM MDAs could be a novel and integrative malaria control tool in areas with seasonal transmission, and which would have simultaneous impacts on neglected tropical diseases in the same villages. PMID:21171970

Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse.

PubMed

O'Callaghan, J P; Miller, D B

1994-08-01

Dopaminergic (DA) and serotonergic (5-HT) projections to striatum and cortex have been implicated as the primary targets of substituted amphetamine (AMP)-induced neurotoxicity, largely on the basis of the propensity of these compounds to cause protracted decrements in DA and 5-HT rather than on the basis of AMP-induced alterations of indices linked to neural damage. Moreover, most studies of AMP-induced neurotoxicity, regardless of the endpoints assessed, have been conducted using a rat model; relatively little attention has been focused on the effects of these compounds in the mouse. Here, we evaluated the potential neurotoxic effects of d-methamphetamine (d-METH), d-methylenedioxyamphetamine (d-MDA), d-methylene-dioxymethamphetamine (d-MDMA) and d-fenfluramine (d-FEN) in the C57BL6/J mouse. Astrogliosis, assessed by quantification of glial fibrillary acidic protein (GFAP), was taken as the main index of AMP-induced neural damage. A silver degeneration stain also was used to obtain direct evidence of AMP-induced neuronal damage. Assays of tyrosine hydroxylase (TH), DA and 5-HT were used to assess effects on DA and 5-HT systems. Mice received d-METH (10 mg/kg), d-MDA (20 mg/kg), d-MDMA (20 mg/kg) or d-FEN (25 mg/kg) every 2 hr for a total of four s.c. injections. d-METH, d-MDA and d-MDMA caused a large (300%) increase in striatal GFAP that resolved by 3 weeks and a 50 to 75% decrease in TH and DA that did not resolve. d-METH, d-MDA and d-MDMA also caused fiber and terminal degeneration in striatum as revealed by silver staining. d-FEN did not affect any parameters in striatum. d-METH, d-MDA and d-MDMA also increased GFAP in cortex, effects that were associated with small (10-25%) and transient decrements in cortical 5-HT. d-FEN caused prolonged (weeks) decrements (20%) in cortical 5-HT but did not affect cortical GFAP. The effects of d-METH, d-MDA and d-MDMA were stereoselective and were blocked by pretreatment with MK-801. Core temperature was slightly elevated by d-METH, d-MDA and d-MDMA but was dramatically lowered by d-FEN. The data suggest that d-METH, d-MDA and d-MDMA, but not d-FEN, produce damage to neural elements of mouse striatum and cortex.

Methanol extract of Codium fragile inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 and invasiveness of MDA-MB-231 cells by suppressing nuclear factor-κB activation.

PubMed

Dilshara, Matharage Gayani; Jayasooriya, Rajapaksha Gedara Prasad Tharanga; Kang, Chang-Hee; Choi, Yung-Hyun; Kim, Gi-Young

2016-06-01

To evaluate whether the methanol extract of Codium fragile (MECF) regulates tumor necrosis factor-α (TNF-α)-induced invasion of human breast cancer MDA-MB-231 cells by suppressing matrix metalloproteinase-9 (MMP-9). Reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis were performed to analyze the expression of MMP-9 and nuclear factor-κB (NF-κB) subunits, p65 and p50, and IκB in MDA-MB-231 cells. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used for cell viability. MMP-9 activity and invasion were measured by gelatin zymography and a matrigel invasion assay, respectively. NF-κB activity was measured by an electrophoretic mobility shift assay and luciferase activity. MECF had no effect on cell viability up to a concentration of 100 μg/mL in human breast cancer MDA-MB-231 cells regardless of the presence of TNF-α. MDA-MB-231 cells that were stimulated with TNF-α showed a marked increase of invasion compared to the untreated control, whereas pretreatment with MECF downregulated the TNF-α-induced invasion of MDA-MB-231 cells. Additionally, zymography, western blot analysis, and RT-PCR confirmed that MECF decreased TNF-α-induced MMP-9 expression and activity which is a key regulator for cancer invasion. According to an electrophoretic morbidity shift assay, pretreatment with MECF in MDA-MB-231 cells significantly decreased the TNF-α-induced DNA-binding activity of NF-κB, which is an important transcription factor for regulating cancer invasion-related genes such as MMP-9. Furthermore, treatment with MECF sustained the expression of p65 and p50 in response to TNF-α in the cytosolic compartment. The luciferase assay demonstrated that MECF attenuated TNF-α-induced NF-κB luciferase activity. MECF exhibited its anti-invasive capability by downregulating TNF-α-induced MMP-9 expression, resulting from the suppression of NF-κB activity in the human breast cancer cell line MDA-MB-231. Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

Thermal Conductivity Enhancement by Optical Phonon Sub-Band Engineering of Nanostructures Based on C and BN

DTIC Science & Technology

2002-01-01

Thermal Conductivity Enhancement by Optical Phono n Sub-Band Engineering of Nanostructures Based on C and BN DARPA CONTRACT MDA972-02-C-0044... Engineering in 3-D Nanostructures Based on C an d BN Nanotubes " 1.3.1a. Phonon dynamics and thermal properties of zigzag carbon nanotubes Content I...Conductivity. Enhancement by Optical Phonon Sub-Bands Engineering in 3-D Nanostructure s Based on C and BN Nanotubes " . Here, the dynamics of the heat

Thermal Conductivity Enhancement by Optical Phonon Sub-Band Engineering of Nanostructures Based on C and BN

DTIC Science & Technology

2005-09-01

Thermal Conductivity Enhancement by Optical Phonon Sub-Band Engineering of Nanostructures Based on C and BN DARPA CONTRACT MDA972-02-C-0044...AND SUBTITLE Thermal Conductivity Enhancement by Optical Phonon Sub-Band Engineering of Nanostructures Based on C and BN 5a. CONTRACT NUMBER 5b...Conductivity. Enhancement by Optical Phonon Sub-Bands Engineering in 3-D Nanostructures Based on C and BN Nanotubes" 1.3.1a. Phonon dynamics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akhrymuk, Ivan; Frolov, Ilya; Frolova, Elena I., E-mail: evfrolova@UAB.edu

Alphaviruses are a family of positive-strand RNA viruses that circulate on all continents between mosquito vectors and vertebrate hosts. Despite a significant public health threat, their biology is not sufficiently investigated, and the mechanisms of alphavirus replication and virus–host interaction are insufficiently understood. In this study, we have applied a variety of experimental systems to further understand the mechanism by which infected cells detect replicating alphaviruses. Our new data strongly suggest that activation of the antiviral response by alphavirus-infected cells is determined by the integrity of viral genes encoding proteins with nuclear functions, and by the presence of two cellularmore » pattern recognition receptors (PRRs), RIG-I and MDA5. No type I IFN response is induced in their absence. The presence of either of these PRRs is sufficient for detecting virus replication. However, type I IFN activation in response to pathogenic alphaviruses depends on the basal levels of RIG-I or MDA5. - Highlights: • Both RIG-I and MDA5 detect alphavirus replication. • Alphavirus-induced transcriptional shutoff affects type I IFN induction. • Sensing of alphavirus replication by RIG-I and MDA5 depends on their concentrations. • High basal level of RIG-I and MDA5 allows IFN induction by pathogenic alphaviruses. • This dependence determines the discrepancy between the in vivo and in vitro data.« less