Social Learning Theory: Toward a Unified Approach of Pediatric Procedural Pain

ERIC Educational Resources Information Center

Page, Lynn Olson; Blanchette, Jennifer A.

2009-01-01

Undermanaged procedural pain has been shown to have short and long term effects on children. While significant progress regarding empirically supported treatments has been made, theoretical bases for the development and management of procedural pain are lacking. This paper examines the role of social learning theory in our current understanding of…

Zinc Finger Transcription Factors as Novel Genetic Switches to Modulate Metastatic Progression of Breast Tumors

DTIC Science & Technology

2008-05-01

critical level of significance set up at P < 0.05, and significant differences between groups of treatments were analyzed with post hoc Turkish test ...2008 differences between groups of treatments were analyzed with post hoc Turkish test . As shown in Fig. 2A, particular ATFs synergized with chromatin...using ANOVA test and the post hoc Turkish test ; critical level of significance was set up at P < 0.05. B, real- time expression analysis of maspin mRNA

Quantitative magnetic resonance imaging assessments of autosomal recessive polycystic kidney disease progression and response to therapy in an animal model.

PubMed

Erokwu, Bernadette O; Anderson, Christian E; Flask, Chris A; Dell, Katherine M

2018-05-01

BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is associated with significant mortality and morbidity, and currently, there are no disease-specific treatments available for ARPKD patients. One major limitation in establishing new therapies for ARPKD is a lack of sensitive measures of kidney disease progression. Magnetic resonance imaging (MRI) can provide multiple quantitative assessments of the disease.MethodsWe applied quantitative image analysis of high-resolution (noncontrast) T2-weighted MRI techniques to study cystic kidney disease progression and response to therapy in the PCK rat model of ARPKD.ResultsSerial imaging over a 2-month period demonstrated that renal cystic burden (RCB, %)=[total cyst volume (TCV)/total kidney volume (TKV) × 100], TCV, and, to a lesser extent, TKV detected cystic kidney disease progression, as well as the therapeutic effect of octreotide, a clinically available medication shown previously to slow both kidney and liver disease progression in this model. All three MRI measures correlated significantly with histologic measures of renal cystic area, although the correlation of RCB and TCV was stronger than that of TKV.ConclusionThese preclinical MRI results provide a basis for applying these quantitative MRI techniques in clinical studies, to stage and measure progression in human ARPKD kidney disease.

Current concepts on burn wound conversion-A review of recent advances in understanding the secondary progressions of burns.

PubMed

Salibian, Ara A; Rosario, Angelica Tan Del; Severo, Lucio De Almeida Moura; Nguyen, Long; Banyard, Derek A; Toranto, Jason D; Evans, Gregory R D; Widgerow, Alan D

2016-08-01

Burn wound conversion describes the process by which superficial partial thickness burns convert into deeper burns necessitating surgical intervention. Fully understanding and thus controlling this phenomenon continues to defy burn surgeons. However, potentially guiding burn wound progression so as to obviate the need for surgery while still bringing about healing with limited scarring is the major unmet challenge. Comprehending the pathophysiologic background contributing to deeper progression of these burns is an essential prerequisite to planning any intervention. In this study, a review of articles examining burn wound progression over the last five years was conducted to analyze trends in recent burn progression research, determine changes in understanding of the pathogenesis of burn conversion, and subsequently examine the direction for future research in developing therapies. The majority of recent research focuses on applying therapies from other disease processes to common underlying pathogenic mechanisms in burn conversion. While ischemia, inflammation, and free oxygen radicals continue to demonstrate a critical role in secondary necrosis, novel mechanisms such as autophagy have also been shown to contribute affect significantly burn progression significantly. Further research will have to determine whether multiple mechanisms should be targeted when developing clinical therapies. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

Treatment outcome of anti-angiogenesis through VEGF-pathway in the management of gastric cancer: a systematic review of phase II and III clinical trials.

PubMed

Mawalla, Brian; Yuan, Xianglin; Luo, Xiaoxiao; Chalya, Phillip L

2018-01-12

Advanced gastric cancer poses a therapeutic challenge worldwide. In randomised clinical trials, anti-VEGF has been reported as an essential agent for the treatment of advanced gastric cancer. This review aims at assessing the treatment outcome of anti-angiogenesis therapy through the VEGF pathway in the management of patients with advanced gastric cancer. During this review, 38 clinical trials were identified. Of these, 30 clinical trials were excluded, leaving eight trials of phase II and III. Ramucirumab, as a second line treatment of advanced gastric cancer, decreases the risk of disease progression (37-52%) and death (19-22%). Compare ramucirumab and bevacizumab in combination with traditional chemotherapy; ramucirumab has shown to improve progression-free survival and overall survival. Apatinib tyrosine kinase inhibitor combined with traditional chemotherapy has shown to improve overall response rate and progression-free survival with marginal improvements in overall survival. Chemotherapy, in combination with anti-VEGF drugs, in the management of advanced gastric cancer significantly improves the outcome of overall response rate, progression-free survival and overall survival when compared to chemotherapy alone. Therefore, we recommend that anti-VEGF drugs are the drugs of choice in the management of patients with advanced gastric cancer.

The Role of Calgranulin Overexpression in Breast Cancer Progression

DTIC Science & Technology

2005-09-01

transfected cells. As shown in Figure 4, exposure of MCF-7 cells to 25ng/ml OSM for 24 hours caused a very significant increase in Cal A levels . Interestingly...Cal A expression was not observed in the parental or vector alone cells, but the transfected cells showed an elevation in Cal A levels . The

What Works to Improve Reading Outcomes in Latin-America? A Systematic Review of the Evidence

ERIC Educational Resources Information Center

de Hoop, Thomas; Klochikin, Evgeny; Stone, Rebecca

2016-01-01

Improvements in students' learning achievement have lagged behind in low-and middle-income countries despite significant progress in school enrollment numbers. Large-scale early grade reading assessments (e.g., "Annual Status of Education Report" [ASER], 2013; EdData II, n.d.) have shown low reading rates and worryingly high…

The Factor Structure of Curriculum-Based Writing Indices at Grades 3, 7, and 10

ERIC Educational Resources Information Center

Brown, Alec Judd

2012-01-01

National assessment data indicate that the large majority of students in America perform below expected proficiency levels in the area of writing. Given the importance of writing skills, this is a significant problem. Curriculum-based measurement, when used for progress monitoring and intervention planning, has been shown to lead to improved…

Angiogenesis extent and macrophage density increase simultaneously with pathological progression in B-cell non-Hodgkin's lymphomas

PubMed Central

Vacca, A; Ribatti, D; Ruco, L; Giacchetta, F; Nico, B; Quondamatteo, F; Ria, R; Iurlaro, M; Dammacco, F

1999-01-01

Node biopsies of 30 benign lymphadenopathies and 71 B-cell non-Hodgkin's lymphomas (B-NHLs) were investigated for microvessel and macrophage counts using immunohistochemistry and morphometric analysis. Both counts were significantly higher in B-NHL. Moreover, when these were grouped into low-grade and high-grade lymphomas, according to the Kiel classification and Working Formulation (WF), statistically significant higher counts were found in the high-grade tumours. Immunohistochemistry and electron microscopy revealed a close spatial association between microvessels and macrophages. Overall, the results suggest that, in analogy to what has already been shown in solid tumours, angiogenesis occurring in B-NHLs increases with tumour progression, and that macrophages promote the induction of angiogenesis via the release of their angiogenic factors. © 1999 Cancer Research Campaign PMID:10070898

Monitoring the Durability Performance of Concrete in Nuclear Waste Containment. Technical Progress Report No. 4

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

Ulm, Franz-Josef

2000-06-30

OAK-B135 Monitoring the Durability Performance of Concrete in Nuclear Waste Containment. Technical Progress Report No. 4. The analysis of the effect of cracks on the acceleration of the calcium leaching process of cement-based materials has been pursued. During the last period (Technical Progress Report No 3), we have introduced a modeling accounting for the high diffusivity of fractures in comparison with the weak solid material diffusivity. It has been shown through dimensional and asymptotic analysis that small fractures do not significantly accelerate the material aging process. This important result for the overall structural aging kinetics of containment structure has beenmore » developed in a paper submitted to the international journal ''Transport in Porous Media''.« less

Assessment of factors regulating the thermal lens profile and lateral brightness in high power diode lasers

NASA Astrophysics Data System (ADS)

Rieprich, J.; Winterfeldt, M.; Tomm, J.; Kernke, R.; Crump, P.

2017-02-01

The lateral beam parameter product, BPPlat, and resulting lateral brightness of GaAs-based high-power broad-area diode lasers is strongly influenced by the thermal lens profile. We present latest progress in efforts using FEM simulation to interpret how variation in chip construction influences the thermal lens profile, itself determined experimentally using thermography (thermal camera). Important factors are shown to include the vertical (epitaxial) structure, the properties of the submount and the transition between chip and submount, whose behavior is shown to be consistent with the presence of a significant thermal barrier.

Prevalence of Late Functional Tricuspid Regurgitation in Degenerative Mitral Regurgitation Surgery.

PubMed

Vaturi, Mordehay; Kotler, Tali; Shapira, Yaron; Weisenberg, Daniel; Monakier, Daniel; Sagie, Alexander

2016-03-01

Although significant late tricuspid regurgitation (TR) may develop after surgery for degenerative mitral regurgitation (MR), the use of routine tricuspid annuloplasty is debatable. The study aim was to determine the prevalence and predictors of significant late TR after surgery for degenerative MR. A total of 112 patients who had undergone surgery for degenerative MR without concomitant tricuspid valve repair (average follow up 7.7 ± 4.0 years) was studied retrospectively. The prevalence of post-surgical TR and predictors of progression were determined. The majority of patients (97%) had non-significant TR (less than moderate) prior to surgery, although an overall trend of progression towards significant TR (grades 2 or 3) was noted in 17 patients (p = 0.0006). Of the 18 patients (16%) with late postoperative significant TR, only nine (8%) had severe TR with only a single referral to surgery. New-onset post-surgical atrial fibrillation was more common in patients who developed late significant TR (p = 0.002). Multivariate analysis of the pre-surgery variables, age >65 years and left ventricular dysfunction were shown to be independent predictors of late functional TR. Significant progression in TR after surgery for degenerative MR was rare in this patient cohort. The impact of older age and left ventricular dysfunction at the time of surgery showed a strong association with post-surgical atrial fibrillation.

The influence of parity and gravidity on first trimester markers of chromosomal abnormality.

PubMed

Spencer, K; Ong, C Y; Liao, A W; Nicolaides, K H

2000-10-01

We have studied changes in first trimester fetal nuchal translucency (NT) and maternal serum free beta-hCG and PAPP-A with gravidity and parity in 3252 singleton pregnancies unaffected by chromosomal abnormality or major pregnancy complications. We have shown that gravidity and parity is associated with a small but progressive decrease in fetal NT and a small but progressive increase in free beta-hCG and PAPP-A. None of these small changes with increasing gravidity or parity are statistically significant and hence correction for these variables is not necessary when considering first trimester screening for chromosomal abnormalities. Copyright 2000 John Wiley & Sons, Ltd.

α2-adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression

PubMed Central

Lamkin, Donald M.; Sung, Ha Yeon; Yang, Gyu Sik; David, John M.; Ma, Jeffrey C.Y.; Cole, Steve W.; Sloan, Erica K.

2014-01-01

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of β-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase β-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective α-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective β-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of β-adrenergic signaling on tumor progression-relevant biology. PMID:25462899

Spotlight on agalsidase beta in Fabry disease.

PubMed

Keating, Gillian M; Simpson, Dene

2007-01-01

Agalsidase beta (Fabrazyme) is a recombinant human alpha-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life-threatening disorder caused by a deficiency of alpha-galactosidase A. This deficiency results in accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of alpha-galactosidase A. Intravenous agalsidase beta is effective and well tolerated in patients with Fabry disease. In a phase III trial, agalsidase beta was shown to clear GL-3 from various target cells and, in a subsequent extension of this trial, prevent GL-3 reaccumulation. In a post-approval trial, agalsidase beta was shown to provide significant clinical benefit by reducing the risk of a major clinical event. Thus, agalsidase beta represents an important advance in the treatment of Fabry disease, and agalsidase beta therapy should be strongly considered in patients with Fabry disease who are suitable candidates.

Agalsidase Beta: a review of its use in the management of Fabry disease.

PubMed

Keating, Gillian M; Simpson, Dene

2007-01-01

Agalsidase beta (Fabrazyme) is a recombinant human alpha-galactosidase A enzyme approved for intravenous use in the treatment of Fabry disease. Fabry disease is a progressive, multisystemic, potentially life threatening disorder caused by a deficiency of alpha-galactosidase A. This deficiency results in accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), in the lysosomes of various tissues. This accumulation is the underlying driver of disease progression. Agalsidase beta provides an exogenous source of alpha-galactosidase A.Intravenous agalsidase beta is effective and well tolerated in patients with Fabry disease. In a phase III trial, agalsidase beta was shown to clear GL-3 from various target cells and, in a subsequent extension of this trial, prevent GL-3 reaccumulation. In a post-approval trial, agalsidase beta was shown to provide significant clinical benefit by reducing the risk of a major clinical event. Thus, agalsidase beta represents an important advance in the treatment of Fabry disease, and agalsidase beta therapy should be strongly considered in patients with Fabry disease who are suitable candidates.

Relative fundamental frequency during vocal onset and offset in older speakers with and without Parkinson's disease.

PubMed

Stepp, Cara E

2013-03-01

The relative fundamental frequency (RFF) surrounding production of a voiceless consonant has previously been shown to be lower in speakers with hypokinetic dysarthria and Parkinson's disease (PD) relative to age/sex matched controls. Here RFF was calculated in 32 speakers with PD without overt hypokinetic dysarthria and 32 age and sex matched controls to better understand the relationships between RFF and PD progression, medication status, and sex. Results showed that RFF was statistically significantly lower in individuals with PD compared with healthy age-matched controls and was statistically significantly lower in individuals diagnosed at least 5 yrs prior to experimentation relative to individuals recorded less than 5 yrs past diagnosis. Contrary to previous trends, no effect of medication was found. However, a statistically significant effect of sex on offset RFF was shown, with lower values in males relative to females. Future work examining the physiological bases of RFF is warranted.

Design and fabrication of the progressive addition lenses

NASA Astrophysics Data System (ADS)

Qin, Linling; Qian, Lin; Yu, Jingchi

2011-11-01

The use of progressive addition lenses (PALs) for the correction of presbyopia has increased dramatically in recent years. These lenses are now being used as the preferred alternative to bifocal and trifocal lenses in many parts of the world. Progressive addition lenses are a kind of opthalmic lenses with freeform surface. The surface curvature of the Progressive addition lenses varies gradually from a minimum value in the upper area, to a maximum value in the lower area. Thus a PAL has a surface with three zones which have very small astigmatism: far-view zone, near-view zone, and intermediate zone. The far view zone and near view zone have relatively constant powers and connected by the intermediate zone with power varies progressively. The design and fabrication technologies of progressive addition lenses have fast progresses because of the massive development of the optical simulation software, multi-axis ultraprecision machining technologies and CNC machining technologies. The design principles of progressive addition lenses are discussed in a historic review. Several kinds of design methods are illustrated, and their advantages and disadvantages are also represented. In the current study, it is shown that the optical characteristics of the different progressive addition lenses designs are significantly different from one another. The different fabrication technologies of Progressive addition lenses are also discussed in the paper. Plastic injection molding and precision-machine turning are the common fabrication technologies for exterior PALs and Interior PALs respectively.

Selected aspects of lunar mare geology from Apollo orbital photography. [of lunar craters

NASA Technical Reports Server (NTRS)

Young, R. A.; Brennan, W. J.

1976-01-01

Crater size-frequency distributions were studied (100-500 m) and are shown to provide significant integrated information concerning mare surface ages, subsurface stratigraphy, and surficial geology. Equilibrium cratering is discussed gradually reducing the relative numbers of craters smaller than 300-400 m in diameter as surfaces age and regolith thickens. Results for surface ages are in good agreement with other published crater ages. The existing correlations of large ring structures among various circular mare basins are shown to be based on criteria that are inconsistent and nonstandardized. A means of comparing equivalent ring structures in the different maria is proposed which takes into account the important characteristics of young unflooded basins (Orientale) as well as the progressive development of tectonic and volcanic features within the older flooded maria. Specific geologic aspects of several of the lunar maria are discussed and especially Mare Smythii, because of its great age and significantly different surface morphology. Lunar photographs and maps are shown.

S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy.

PubMed

Kim, W T; Kim, J; Yan, C; Jeong, P; Choi, S Y; Lee, O J; Chae, Y B; Yun, S J; Lee, S C; Kim, W J

2014-05-01

In our previous gene expression profile analysis, IL1B, S100A8, S100A9, and EGFR were shown to be important mediators of muscle invasive bladder cancer (MIBC) progression. The aim of the present study was to investigate the ability of these gene signatures to predict disease progression after chemotherapy in patients with locally recurrent or metastatic MIBC. Patients with locally advanced MIBC who received chemotherapy were enrolled. The expression signatures of four genes were measured and carried out further functional analysis to confirm our findings. Two of the four genes, S100A9 and EGFR, were determined to significantly influence disease progression (P = 0.023, 0.045, respectively). Based on a receiver operating characteristic curve, a cut-off value for disease progression was determined. Patients with the good-prognostic signature group had a significantly longer time to progression and cancer-specific survival time than those with the poor-prognostic signature group (P < 0.001, 0.042, respectively). In the multivariate Cox regression analysis, gene signature was the only factor that significantly influenced disease progression [hazard ratio: 4.726, confidence interval: 1.623-13.763, P = 0.004]. In immunohistochemical analysis, S100A9 and EGFR positivity were associated with disease progression after chemotherapy. Protein expression of S100A9/EGFR showed modest correlation with gene expression of S100A9/EGFR (r = 0.395, P = 0.014 and r = 0.453, P = 0.004). Our functional analysis provided the evidence demonstrating that expression of S100A9 and EGFR closely associated chemoresistance, and that inhibition of S100A9 and EGFR may sensitize bladder tumor cells to the cisplatin-based chemotherapy. The S100A9/EGFR level is a novel prognostic marker to predict the chemoresponsiveness of patients with locally recurrent or metastatic MIBC.

Regression of Nonalcoholic Fatty Liver Disease with Zinc and Selenium Co-supplementation after Disease Progression in Rats.

PubMed

Shidfar, Farzad; Faghihi, Amirhosein; Amiri, Hamid Lorvand; Mousavi, Seyedeh Neda

2018-01-01

Studies have shown that zinc and selenium deficiency is common in nonalcoholic fatty liver disease (NAFLD). However, the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD are not clear enough. The aim of this study was to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD prognosis. Forty male Sprague-Dawley rats (197±4 g) were randomly assigned to 4 dietary groups: normal-fat diet (NFD; receiving 9% of calories as fat), high-fat diet (HFD; receiving 82% of calories as fat), supplementation before disease progression (S+HFD), and supplementation after disease progression (HFD+S). The diets were implemented over a 20-week period in all the groups. Biochemical and histologic parameters were compared between the 4 groups, and between-group comparisons were also carried out. There were significant differences in the average food dietary intake (P<0.001), weight (P<0.001), fasting blood sugar (P=0.005), triglyceride (P<0.001), total cholesterol (P<0.001), low-density lipoprotein cholesterol (P=0.002), high-density lipoprotein cholesterol (P=0.001), alanine aminotransferase (P<0.001), and aspartate aminotransferase (P<0.001) between the 4 dietary groups. Serum triglyceride and total cholesterol were significantly lower in the HFD+S Group than in the S+HFD Group (P<0.001 and P=0.003, respectively). Fat accumulation was significantly reduced in the HFD+S Group (P<0.001). Zinc and selenium co-supplementation after disease progression improved biochemical and histologic parameters in an experimental model of NAFLD.

Improved Student Reasoning About Carbon-Transforming Processes Through Inquiry-Based Learning Activities Derived from an Empirically Validated Learning Progression

NASA Astrophysics Data System (ADS)

JW, Schramm; Jin, H.; Keeling, EG; Johnson, M.; Shin, HJ

2017-05-01

This paper reports on our use of a fine-grained learning progression to assess secondary students' reasoning through carbon-transforming processes (photosynthesis, respiration, biosynthesis). Based on previous studies, we developed a learning progression with four progress variables: explaining mass changes, explaining energy transformations, explaining subsystems, and explaining large-scale systems. For this study, we developed a 2-week teaching module integrating these progress variables. Students were assessed before and after instruction, with the learning progression framework driving data analysis. Our work revealed significant overall learning gains for all students, with the mean post-test person proficiency estimates higher by 0.6 logits than the pre-test proficiency estimates. Further, instructional effects were statistically similar across all grades included in the study (7th-12th) with students in the lowest third of initial proficiency evidencing the largest learning gains. Students showed significant gains in explaining the processes of photosynthesis and respiration and in explaining transformations of mass and energy, areas where prior research has shown that student misconceptions are prevalent. Student gains on items about large-scale systems were higher than with other variables (although absolute proficiency was still lower). Gains across each of the biological processes tested were similar, despite the different levels of emphasis each had in the teaching unit. Together, these results indicate that students can benefit from instruction addressing these processes more explicitly. This requires pedagogical design quite different from that usually practiced with students at this level.

[Dyslipidemias : Diagnostics and management].

PubMed

Sinning, D; Landmesser, U

2017-09-01

For disorders of lipid metabolism the risk-adapted adjustment of low-density lipoprotein (LDL) cholesterol remains the primary treatment target, as a causal role in minimizing the progression of ACVD has been shown. Because of their efficacy in reducing cardiovascular morbidity and mortality, statins are recommended as first-line pharmacological treatment in dyslipidemias. Additionally, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have been shown to significantly reduce cardiovascular events in high-risk patients. Life style changes can improve the plasma lipid profile, particularly in the setting of hypertriglyceridemia. Evaluation of high-density lipoprotein (HDL) cholesterol and lipoprotein(a) provides further information when assessing the individual cardiovascular risk, but direct evidence that pharmacologically targeting HDL cholesterol or Lp(a) results in a reduction of cardiovascular events has not yet been shown.

Electric and hybrid vehicles program

NASA Astrophysics Data System (ADS)

1990-04-01

This thirteenth annual report on the implementation of the Electric and Hybrid Vehicle Research, Development and Demonstration Act of 1976 (Public Law 94-413), referred to as the Act, complies with the reporting requirements established in section 14 of the Act. In addition to informing Congress of the progress and plans of the Department of Energy's Electric and Hybrid Vehicles Program, this report is intended to serve as a communication link between the Department and all of the public and private interests involved in making the program a success. During FY 1989, significant progress was made in this program. There has been continuing interest shown by both the automobile manufacturers and supply sectors of our economy in electric and hybrid vehicles. The three major domestic automobile manufacturers all are devoting some effort towards electric vehicles. Their participation includes cost-shared contracts with Department of Energy and the Electric Power Research Institute as well as independently funded activities. Research and development efforts in batteries and propulsion components continue to achieve significant progress in providing industry with technology that will result in vehicles that will be more economically competitive.

Southern California Coastal Processes Annotated Bibliography.

DTIC Science & Technology

1985-12-01

05/01/71 TITLE : Avalon Transportation Wharf CITATION : Journal of Waterways, Harbors and Coastal Engineering Division, ASCE, N. Y., Vol. 97, No. WW2 ...105, No. WW2 ; ASCE, N. Y., pp. 131-147 DESCRIPTION s Effect of various offshore structures as significant barriers to normal wave progress...California, 33 pp. DESCRIPTION Infrared satellite images are shown for each of two areas near +- the California coast, Cape Mendocino and Point

Identification and Characterization of Novel FMRP-Associated miRNAs

DTIC Science & Technology

2014-12-01

further - primarily because of advantages of the approaches described below (Figures 6 and 7). We next tried FMRP antibody covalently crosslinked to...hands, crosslinked FMRP antibody did not always efficiently pull down FMRP from fly brain extract (as shown in Figure 3A) and inconsistently pulled...these goals has shed light on the molecular pathogenesis of FXS. Progress towards completion of aims: First, after significant setbacks developing novel

Integrating language models into classifiers for BCI communication: a review

NASA Astrophysics Data System (ADS)

Speier, W.; Arnold, C.; Pouratian, N.

2016-06-01

Objective. The present review systematically examines the integration of language models to improve classifier performance in brain-computer interface (BCI) communication systems. Approach. The domain of natural language has been studied extensively in linguistics and has been used in the natural language processing field in applications including information extraction, machine translation, and speech recognition. While these methods have been used for years in traditional augmentative and assistive communication devices, information about the output domain has largely been ignored in BCI communication systems. Over the last few years, BCI communication systems have started to leverage this information through the inclusion of language models. Main results. Although this movement began only recently, studies have already shown the potential of language integration in BCI communication and it has become a growing field in BCI research. BCI communication systems using language models in their classifiers have progressed down several parallel paths, including: word completion; signal classification; integration of process models; dynamic stopping; unsupervised learning; error correction; and evaluation. Significance. Each of these methods have shown significant progress, but have largely been addressed separately. Combining these methods could use the full potential of language model, yielding further performance improvements. This integration should be a priority as the field works to create a BCI system that meets the needs of the amyotrophic lateral sclerosis population.

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

Thorstad, B.L.; Russell, C.D.; Dubovsky, E.V.

A case of renovascular hypertension is presented in which the (/sup 131/I)hippuran renogram was initially normal, but became strikingly abnormal upon administration of the angiotensin converting enzyme (ACE) inhibitor captopril. The patient presented with fibromuscular dysplasia of the renal arteries, which was shown by hippuran renography to be functionally significant on the right side. She became normotensive after angioplasty of the right renal artery. Hypertension recurred a year later, at which time the renogram was normal without captopril, but showed functionally significant left renal artery stenosis with captopril challenge. Both the conventional agent, (/sup 131/I)hippuran, and an experimental new /supmore » 99m/Tc-labeled hippuran analog, (/sup 99m/Tc)MAG3, were used. Angiography confirmed progression of disease on the left side, which was successfully treated by angioplasty. Functionally significant unilateral renal artery stenosis was thus demonstrated first on the right side and then, 1 yr later, on the left side, using hippuran and (/sup 99m/Tc)MAG3. Anatomic progression of disease was documented by angiography.« less

Microglial SMAD4 regulated by microRNA-146a promotes migration of microglia which support tumor progression in a glioma environment

PubMed Central

Karthikeyan, Aparna; Gupta, Neelima; Tang, Carol; Mallilankaraman, Karthik; Silambarasan, Maskomani; Shi, Meng; Lu, Lei; Ang, Beng Ti; Ling, Eng-Ang; Dheen, S. Thameem

2018-01-01

Glioma tumors constitute a significant portion of microglial cells, which are known to support tumor progression. The present study demonstrates that transforming growth factor-β (TGFβ) signaling pathway in microglia in a glioma environment is involved in tumor progression and pathogenesis. It has been shown that the TGFβ level is elevated in higher grades of gliomas and its signaling pathway regulates tumor progression through phosphorylation of SMAD2 and SMAD3, which form a complex with SMAD4 to regulate target gene transcription. In an in vitro cell line-based model increased protein levels of pSMAD2/3, total SMAD2/3 and SMAD4 were observed in murine BV2 microglia cultured in glioma conditioned medium (GCM), indicative of the activated TGFβ signaling pathway in microglia associated with glioma environment. Immunofluorescence labeling further revealed the expression of SMAD4 in microglial and non-microglial cells of human glioblastomas tissue in vivo. Functional analysis through shRNA-mediated stable knockdown of SMAD4 in microglia revealed the downregulation of the expression of matrix metalloproteinase 9 (MMP9), which has been shown to be involved in tumor progression and cell migration. Further, knockdown of SMAD4 in microglia decreased the migration of microglial cells towards GCM, indicating that SMAD4 promotes microglial migration in glioma environment. In addition, SMAD4 has been shown to be post-transcriptionally regulated by microRNA-146a, which was downregulated in microglia treated with GCM. Overexpression of miR-146a resulted in decreased expression of SMAD4 together with tumor supportive gene MMP9 in microglia, and subsequently suppressed microglial migration towards GCM, possibly through regulation of SMAD4. On the other hand, the cell viability assay revealed decreased viability of glioma cells when they were treated with conditioned medium derived from SMAD4 knockdown microglia or miR-146a overexpressed microglia as compared to glioma cells treated with the medium from control microglial cells. Taken together, the present study suggests that microglial SMAD4 which is epigenetically regulated by miR-146a promotes microglial migration in gliomas and glioma cell viability.

The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy.

PubMed

Regier, Debra S; Proia, Richard L; D'Azzo, Alessandra; Tifft, Cynthia J

2016-06-01

The gangliosidoses are lysosomal storage disorders caused by accumulation of GM1 or GM2 gangliosides. GM1 gangliosidosis has both central nervous system and systemic findings; while, GM2 gangliosidosis is restricted primarily to the central nervous system. Both disorders have autosomal recessive modes of inheritance and a continuum of clinical presentations from a severe infantile form to a milder, chronic adult form. Both are devastating diseases without cure or specific treatment however, with the use of supportive aggressive medical management, the lifespan and quality of life has been extended for both diseases. Naturally occurring and engineered animal models that mimic the human diseases have enhanced our understanding of the pathogenesis of disease progression. Some models have shown significant improvement in symptoms and lifespan with enzyme replacement, substrate reduction, and anti-inflammatory treatments alone or in combination. More recently gene therapy has shown impressive results in large and small animal models. Treatment with FDA-approved glucose analogs to reduce the amount of ganglioside substrate is used as off-label treatments for some patients. Therapies also under clinical development include small molecule chaperones and gene therapy.

Molecular targeted therapy for advanced gastric cancer.

PubMed

Kim, Jong Gwang

2013-03-01

Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration; the median survival is approximately 7 to 11 months, and survival at 2 years is exceptionally > 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, many molecular targeting agents have been evaluated in international randomized studies, and trastuzumab, an anti-HER-2 monoclonal antibody, has shown antitumor activity against HER-2-positive AGC. However, this benefit is limited to only ~20% of patients with AGC (patients with HER-2-positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of molecular predictive and prognostic markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.

Status of nickel/zinc and nickel/iron battery technology for electric vehicle applications

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

Yao, N.P.; Christianson, C.C.; Elliott, R.C.

1980-01-01

Significant progress in nickel/zinc and nickel/iron technology has been made towards achieving the battery technical performance goals necessary for widespread use of these battery systems in electric vehicle applications. This progress is reviewed. Nickel/zinc module test data have shown a specific energy of nearly 70 Whr/kg and a specific power of 130 W/kg. However, cycle life improvements are still needed (presently demonstrated capability of 120 cycles) and are expected to be demonstrated during 1980. Nickel/iron modules have demonstrated a specific energy of nearly 50 Wh/kg and a specific power of 100 W/kg. Indications are that improved performance in these areasmore » can be shown during 1980. Nickel/iron modules cycle lives of 300 have been achieved during early 1980 and testing continues. Energy efficiency has been improved from less than 50% to over 65%. Cost reduction (both initial and operating) continues to receive major emphasis at developers of both nickel/zinc and nickel/iron batteries in order to achieve the lowest possible life cycle cost to the battery user.« less

The relation between cerebral serotonin levels and conditioned behaviour in the rat following the administration of LSD-25 and UML.

PubMed

Torre, M; Torre, E; Bogetto, F

1975-01-01

Successive daily injections of LSD-25 and UML (1-methyl-d-lysergic acid butanolamide) caused progressive depression of brain 5-HT levels in the rat. On the fourth day, the decrease was significant with respect to the highly significant fall observed after a single administration, whereas it had been shown earlier that conditioned behaviour is no longer affected by LSD-25 after 3 days and that simultaneous administration of a single dose of LSD-25 and UML is equally ineffective in this respect. Its depression of 5-HT levels, however, has now been shown to be equal to that of LSD-25 alone at doses that influence conditioned behaviour. The findings indicate that changes in such behaviour are not dependent on brain 5-HT levels and that no link exists between such levels and the psychotomimetic effect of LSD-25 in man.

Laser-induced-fluorescence spectroscopy for improved chemical analysis. Progress report, 1978-1983

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

Gelbwachs, J.A.

1983-09-01

This report summarizes the progress achieved over the past five years in the laser-induced fluorescence spectroscopy (LIFS) for improved chemical analysis program. Our initial efforts yielded significantly lower detection limits for trace elemental analysis by the use of both cw and pulsed laser excitations. New methods of LIFS were developed that were shown to overcome many of the traditional limitations to LIFS techniques. LIFS methods have been applied to yield fundamental scientific data that further the understanding of forces between atoms and other atoms and molecules. In recent work, two-photon ionization was combined with LIFS and applied, for the firstmore » time, to the study of energy transfer in ions.« less

Laser-induced-fluorescence spectroscopy for improved chemical analysis. Progress report, 1978-1983

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

Gelbwachs, J.A.

1983-09-01

This report summarizes the progress achieved over the past five years in the laser-induced-fluorescence spectroscopy (LIFS) for improved chemical-analysis program. Our initial efforts yielded significantly lower detection limits for trace elemental analysis by the use of both cw and pulsed-laser excitations. New methods of LIFS were developed that were shown to overcome many of the traditional limitations to LIFS techniques. LIFS methods have been applied to yield fundamental scientific data that further the understanding of forces between atoms and other atoms and molecules. In recent work, two-photon ionization was combined with LIFS and applied, for the first time, to themore » study of energy transfer in ions.« less

Comparison of Electrochemical Immunosensors and Aptasensors for Detection of Small Organic Molecules in Environment, Food Safety, Clinical and Public Security.

PubMed

Piro, Benoit; Shi, Shihui; Reisberg, Steeve; Noël, Vincent; Anquetin, Guillaume

2016-02-29

We review here the most frequently reported targets among the electrochemical immunosensors and aptasensors: antibiotics, bisphenol A, cocaine, ochratoxin A and estradiol. In each case, the immobilization procedures are described as well as the transduction schemes and the limits of detection. It is shown that limits of detections are generally two to three orders of magnitude lower for immunosensors than for aptasensors, due to the highest affinities of antibodies. No significant progresses have been made to improve these affinities, but transduction schemes were improved instead, which lead to a regular improvement of the limit of detections corresponding to ca. five orders of magnitude over these last 10 years. These progresses depend on the target, however.

Guideline of transthyretin-related hereditary amyloidosis for clinicians

PubMed Central

2013-01-01

Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic unpredictability and variability, transthyretin amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. This article aims to help physicians better understand transthyretin amyloidosis—and, specifically, familial amyloidotic polyneuropathy—so they can recognize and manage the disease more easily and discuss it with their patients. We provide guidance on making a definitive diagnosis, explain methods for disease staging and evaluation of disease progression, and discuss symptom mitigation and treatment strategies, including liver transplant and several pharmacotherapies that have shown promise in clinical trials. PMID:23425518

Particulate matter induced enhancement of inflammatory markers in the brains of apolipoprotein E knockout mice.

PubMed

Campbell, Arezoo; Araujo, Jesus A; Li, Huihui; Sioutas, Constantinos; Kleinman, Michael

2009-08-01

Exposure to air particulate matter (PM) present in urban environments have been shown to induce systemic prooxidant and proinflammatory effects in apolipoprotein E knockout (ApoE-/-) mice and proinflammatory central nervous system (CNS) effects in BALB/c mice. We hypothesize that ApoE-/- mice would exhibit a greater propensity to develop PM-induced CNS effects due to their greater susceptibility to CNS inflammation. We studied the brains of ApoE-/- mice exposed in a previous study to concentrated air particles of different sizes (fine vs. ultrafine) or filtered-air to evaluate the effect of PM exposure on the development of CNS proinflammatory effects in a genetically susceptible background. This was important because, although the use of nano-sized materials opens an exciting potential for their use as diagnostic or therapeutic tools, not much is known about the possible CNS toxicity of these particles. Neuroinflammation has been shown to exacerbate progression of neurodegeneration. Since the onset and progression of idiopathic forms of neurodegenerative disorders are likely to be multifactorial and involve gene-environment interactions, we determined the possibility of particles in ambient air pollution to enhance neuroinflammation. Our results indicate that in the brain, there was significant modulation in the activation of the transcription factors NF-kappaB and AP-1 after exposure to the ultrafine fractions. Levels of two pro-inflammatory cytokines (TNF-alpha and IL-1alpha) were also increased in the brain of exposed animals and this was independent of the size fraction of PM. Since inflammatory processes have been shown to contribute to the pathology associated with neurodegenerative diseases, it will be important to further evaluate the role ambient particles may play in the potentiation of existing CNS damage and progression of neurodegenerative disorders.

New candidate markers of head and neck squamous cell carcinoma progression

NASA Astrophysics Data System (ADS)

Kakurina, G. V.; Kolegova, E. S.; Cheremisina, O. V.; Kulbakin, D. E.; Choinzonov, E. L.

2017-09-01

The tumor progression in head and neck squamous cell carcinoma (HNSCC) is one of the main causes of high mortality of the patients with HNSCC. The tumor progression, particularly the metastasis, is characterized by the changes in the composition, functions and structure of different proteins. We have previously shown that serum of HNSCC patients contains the proteins which regulate various cellular processes—adenylyl cyclase associated protein 1 (CAP1), protein phosphatase 1 B (PPM1B), etc. The levels of CAP1 and PPM1B were determined using the enzyme immunoassay. The results of this study show that CAP1 and PPM1B take a part in the progression of HNSCC. The levels of CAP1 and PPM1B in the tumor and in morphologically normal tissue depended on the prevalence of the tumor process. The CAP1 and PPM1B levels were significantly higher in tumor tissue of the patients with regional metastasis. Our data allow assuming the potential possibility for predicting the outcome of the HNSCC measuring the level of tissue CAP1.

Trends of quality of life changes in amyotrophic lateral sclerosis patients.

PubMed

Shamshiri, Hosein; Fatehi, Farzad; Abolfazli, Roya; Harirchian, Mohammad Hossein; Sedighi, Behnaz; Zamani, Babak; Roudbari, Ali; Razazian, Nazanin; Khamseh, Fatemeh; Nafissi, Shahriar

2016-09-15

Amyotrophic lateral sclerosis (ALS) is an incurable progressive neurodegenerative disease and thus the assessment of quality of life (QOL) changes and factors that may influence its course is valuable in the meantime. The present study aimed to assess the deterioration rate of QOL and influencing factors in different subgroups of Iranian ALS patients. 132 patients were evaluated in this prospective multicenter observational study. QOL was measured using ALS Assessment Questionnaire (ALSAQ-40) during 1year follow up and its progression rate was assessed in different subgroups of patients according to age, sex, stage of disease, riluzole consumption, onset type. Also physical disability and functional disability were measured using MMT and ALSFRS-R scores respectively and their progression rates were compared with ALSAQ-40 changes. Significant deterioration of the scores of ALSAQ-40 during study was consistent in all of its domains (p=0.000). There was a significant negative correlation between ALSFRS-R and MMT changes and ALSAQ-40 change (p=0.000) and this was consistently observed in all domains of ALSAQ-40 (p=0.00). ALSAQ-40 deterioration rate was shown to be significantly lower in severe/terminal stages compared to mild/moderate stages (p=0.00). Significantly higher deterioration rate was observed in bulbar onset versus limb onset patients [F (1,130)=4.52, p=0.04] but no significant difference was observed among other subgroups according to age, sex and riluzole consumption. All domains of QOL significantly deteriorate during ALS course and there is a significant correlation between their changes and progression of physical and functional disabilities. Rate of degradation of QOL may be different at different stages of the disease. QOL worsens independent of factors such as sex, age and consumption of riluzole; but onset type (bulbar versus limb) is an imperative factor in quality of life changes during the disease course. Copyright © 2016 Elsevier B.V. All rights reserved.

The Culture of the Independent Progressive School

ERIC Educational Resources Information Center

Kloss, Dean

2018-01-01

Even in this "Age of Data," independent progressive schools have shown a remarkable persistence in offering an alternative educational model. As Traditional Public Schools (TPS) become even more committed to a testing model of achievement, there are schools that continue to operate on identified progressive educational principles. This…

Application of Diffusion Tensor Imaging Parameters to Detect Change in Longitudinal Studies in Cerebral Small Vessel Disease.

PubMed

Zeestraten, Eva Anna; Benjamin, Philip; Lambert, Christian; Lawrence, Andrew John; Williams, Owen Alan; Morris, Robin Guy; Barrick, Thomas Richard; Markus, Hugh Stephen

2016-01-01

Cerebral small vessel disease (SVD) is the major cause of vascular cognitive impairment, resulting in significant disability and reduced quality of life. Cognitive tests have been shown to be insensitive to change in longitudinal studies and, therefore, sensitive surrogate markers are needed to monitor disease progression and assess treatment effects in clinical trials. Diffusion tensor imaging (DTI) is thought to offer great potential in this regard. Sensitivity of the various parameters that can be derived from DTI is however unknown. We aimed to evaluate the differential sensitivity of DTI markers to detect SVD progression, and to estimate sample sizes required to assess therapeutic interventions aimed at halting decline based on DTI data. We investigated 99 patients with symptomatic SVD, defined as clinical lacunar syndrome with MRI confirmation of a corresponding infarct as well as confluent white matter hyperintensities over a 3 year follow-up period. We evaluated change in DTI histogram parameters using linear mixed effect models and calculated sample size estimates. Over a three-year follow-up period we observed a decline in fractional anisotropy and increase in diffusivity in white matter tissue and most parameters changed significantly. Mean diffusivity peak height was the most sensitive marker for SVD progression as it had the smallest sample size estimate. This suggests disease progression can be monitored sensitively using DTI histogram analysis and confirms DTI's potential as surrogate marker for SVD.

Zinc and Selenium Co-supplementation Reduces Some Lipid Peroxidation and Angiogenesis Markers in a Rat Model of NAFLD-Fed High Fat Diet.

PubMed

Mousavi, Seyedeh Neda; Faghihi, Amirhosein; Motaghinejad, Majid; Shiasi, Maryam; Imanparast, Fatemeh; Amiri, Hamid Lorvand; Shidfar, Farzad

2018-02-01

Studies have shown that non-alcoholic fatty liver disease (NAFLD) patients are more prone to cardiovascular disease (CVD). Zinc and selenium deficiency are common in NAFLD. But the effects of zinc and selenium co-supplementation before and/or after disease progression on CVD markers are not clear in NAFLD patients. This study aimed to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on some of the CVD markers in an experimental model of NAFLD. Forty male Sprague Dawley rats (197 ± 4 g) were randomly assigned into four dietary groups: control group (C; received 9% of calorie as fat), model group (M; received 82% of calorie as fat), and supplementation before (BS) or after (AS) disease progression. Animals were fed diets for 20 weeks in all groups. Fasting plasma glucose (FPG), insulin, HOMA-IR, ALT, AST, lipid profile, malondialdehyde (MDA) and vascular endothelial growth factor (VEGF) levels were measured as CVD indices. Serum ALT, AST, FPG, insulin, MDA, VEGF and HOMA-IR were significantly higher in the M than C group. Co-supplementation reduced serum ALT and AST levels in the BS and AS groups compared with the M group. FPG, insulin, HOMA-IR, VEGF, MDA, LDL/HDL-c and TC/HDL-c ratio were significantly reduced in the AS compared with the M group. TG/HDL-c ratio was significantly reduced in the BS and AS compared with the M group. Serum MDA, VEGF, Insulin and HOMA-IR were significantly lowered in the AS than BS group (p < 0.05). Zinc and selenium co-supplementation after NAFLD progression reduced CVD risk indices in an experimental model.

The Use of Electrochemiluminescence Assays to Predict Autoantibody and Glycemic Progression Toward Type 1 Diabetes in Individuals with Single Autoantibodies.

PubMed

Sosenko, Jay M; Yu, Liping; Skyler, Jay S; Krischer, Jeffrey P; Gottlieb, Peter A; Boulware, David; Miao, Dongmei; Palmer, Jerry P; Steck, Andrea K

2017-03-01

Electrochemiluminescence (ECL) assays have shown promise for enhancing the prediction of type 1 diabetes (T1D) with autoantibodies. We thus studied relatives of T1D patients to determine whether ECL assays can be used to refine risk assessments for T1D among individuals either positive for single GADA or single mIAA autoantibodies. TrialNet Pathway to Prevention (PTP) study participants with either GADA or mIAA single autoantibodies were tested for ECL positivity during their participation in the TrialNet PTP study. Those ECL positive (ECL + ) were compared with those ECL negative (ECL - ) for conversion to multiple autoantibodies, 6-month glycemic progression (PS6M), and the progression to T1D. The progression to multiple autoantibodies was significantly higher for those GADA/ECL + (n = 107) than those GADA/ECL - (n = 78) (P = 0.001) and for those mIAA/ECL + (n = 24) than those mIAA/ECL - (n = 63) (P < 0.001). The hazard ratios with 95% confidence intervals were 3.42 (1.58-7.39; P < 0.01) for GADA and 8.15 (3.02-22.00; P < 0.001) for mIAA. GADA/ECL + and mIAA/ECL + participants had significantly higher PS6M values than their ECL - counterparts (P = 0.001 for GADA and P = 0.009 for mIAA). Of those GADA/ECL + , 14% progressed to T1D; of those mIAA/ECL + , 17% progressed to T1D. Only 1 individual (positive for GADA) of the 141 who was ECL - progressed to T1D (median follow-up: 5 years). ECL measurements appear to have utility for natural history studies and prevention trials of individuals with single autoantibodies. Those ECL + are at appreciable risk for developing multiple autoantibodies and for glycemic progression toward T1D, whereas those ECL - are at very low risk.

Carcinogen-induced squamous papillomas and oncogenic progression in the absence of the SSeCKS/AKAP12 metastasis suppressor correlates with FAK upregulation

PubMed Central

Akakura, Shin; Bouchard, Rene; Bshara, Wiam; Morrison, Carl; Gelman, Irwin H.

2011-01-01

The ability of SSeCKS/Gravin/AKAP12 (SSeCKS) to negatively regulate cell cycle progression is thought to relate to its spatiotemporal scaffolding activity for key signaling molecules such as protein kinase A and C, calmodulin, and cyclins. SSeCKS is downregulated upon progression to malignancy in many cancer types, including melanoma and non-melanoma skin cancer. The forced re-expression of SSeCKS is especially potent in suppressing metastasis through the inhibition of VEGF-mediated neovascularization. We have previously shown that SSeCKS-null (KO) mice exhibit hyperplasia and focal dysplasia in the prostate marked by activated Akt. To address whether KO-mice exhibit increased skin carcinogenesis, WT and KO C57BL/6 mice were treated topically with 12-O-tetradecanoylphorbol-13-acetate and 7,12-dimethylbenzanthracene. Compared to WT mice, KO mice developed squamous papillomas more rapidly and in greater numbers, and also exhibited significantly increased progression to squamous cell carcinoma. Untreated KO epidermal layers were thicker than those in age-matched WT mice, and exhibited significantly increased levels of FAK and phospho-ERK1/2, known mediators of carcinogen-induced squamous papilloma progression to carcinoma. Compared to protein levels in WT mouse embryo fibroblasts (MEF), SSeCKS levels were increased in FAK-null cells whereas FAK levels were increased in SSeCKS-null cells. RNAi studies in WT MEF cells suggest that SSeCKS and FAK attenuate each other’s expression. Our study implicates a role for SSeCKS in preventing of skin cancer progression possibly through negatively regulating FAK expression. PMID:21128249

Atrial Fibrillation Ablation and its Impact on Stroke.

PubMed

Graves, Kevin G; Jacobs, Victoria; May, Heidi T; Cutler, Michael J; Day, John D; Bunch, T Jared

2018-01-24

Atrial fibrillation (AF) is a commonly encountered arrhythmia, which is not yet fully understood. Catheter ablation has shown to be an effective strategy for rhythm management and several small or retrospective studies have shown that stroke rates are decreased in ablated AF patients compared to those medically managed. Several studies even show that ablation returns stroke risk to that of non-AF patients. Large scale, prospective trials will further illuminate this connection and provide mechanistic understanding of the role of the procedure versus the process of selection for the procedure and peri- and post-procedural therapy and management. Furthermore, modification of risk factors associated with AF show a significant increase in the sustained success of AF ablation and can also moderate the progression of AF.

In Vitro Screening for Cytotoxic Activity of Herbal Extracts

PubMed Central

Lombardi, Valter R. M.; Cacabelos, Ramón

2017-01-01

Experimental studies have shown that a variety of chemopreventive plant components affect tumor initiation, promotion, and progression and the main difference, between botanical medicines and synthetic drugs, resides in the presence of complex metabolite mixtures shown by botanical medicine which in turn exert their action on different levels and via different mechanisms. In the present study, we performed an in vitro screening of ethanol extracts from commercial plants in order to investigate potential antitumor activity against human tumor cell lines. Experimental results obtained through a variety of methods and techniques indicated that extracts of I. verum, G. glabra, R. Frangula, and L. usitatissimum present significant reduction in in vitro tumor cell proliferation, suggesting these extracts as possible chemotherapeutical adjuvants for different cancer treatments. PMID:28386288

Multi-parametric spinal cord MRI as potential progression marker in amyotrophic lateral sclerosis.

PubMed

El Mendili, Mohamed-Mounir; Cohen-Adad, Julien; Pelegrini-Issac, Mélanie; Rossignol, Serge; Morizot-Koutlidis, Régine; Marchand-Pauvert, Véronique; Iglesias, Caroline; Sangari, Sina; Katz, Rose; Lehericy, Stéphane; Benali, Habib; Pradat, Pierre-François

2014-01-01

To evaluate multimodal MRI of the spinal cord in predicting disease progression and one-year clinical status in amyotrophic lateral sclerosis (ALS) patients. After a first MRI (MRI1), 29 ALS patients were clinically followed during 12 months; 14/29 patients underwent a second MRI (MRI2) at 11±3 months. Cross-sectional area (CSA) that has been shown to be a marker of lower motor neuron degeneration was measured in cervical and upper thoracic spinal cord from T2-weighted images. Fractional anisotropy (FA), axial/radial/mean diffusivities (λ⊥, λ//, MD) and magnetization transfer ratio (MTR) were measured within the lateral corticospinal tract in the cervical region. Imaging metrics were compared with clinical scales: Revised ALS Functional Rating Scale (ALSFRS-R) and manual muscle testing (MMT) score. At MRI1, CSA correlated significantly (P<0.05) with MMT and arm ALSFRS-R scores. FA correlated significantly with leg ALFSRS-R scores. One year after MRI1, CSA predicted (P<0.01) arm ALSFSR-R subscore and FA predicted (P<0.01) leg ALSFRS-R subscore. From MRI1 to MRI2, significant changes (P<0.01) were detected for CSA and MTR. CSA rate of change (i.e. atrophy) highly correlated (P<0.01) with arm ALSFRS-R and arm MMT subscores rate of change. Atrophy and DTI metrics predicted ALS disease progression. Cord atrophy was a better biomarker of disease progression than diffusion and MTR. Our study suggests that multimodal MRI could provide surrogate markers of ALS that may help monitoring the effect of disease-modifying drugs.

Glaucoma Progression Detection by Retinal Nerve Fiber Layer Measurement Using Scanning Laser Polarimetry: Event and Trend Analysis

PubMed Central

Moon, Byung Gil; Cho, Jung Woo; Kang, Sung Yong; Yun, Sung-Cheol; Na, Jung Hwa; Lee, Youngrok; Kook, Michael S.

2012-01-01

Purpose To evaluate the use of scanning laser polarimetry (SLP, GDx VCC) to measure the retinal nerve fiber layer (RNFL) thickness in order to evaluate the progression of glaucoma. Methods Test-retest measurement variability was determined in 47 glaucomatous eyes. One eye each from 152 glaucomatous patients with at least 4 years of follow-up was enrolled. Visual field (VF) loss progression was determined by both event analysis (EA, Humphrey guided progression analysis) and trend analysis (TA, linear regression analysis of the visual field index). SLP progression was defined as a reduction of RNFL exceeding the predetermined repeatability coefficient in three consecutive exams, as compared to the baseline measure (EA). The slope of RNFL thickness change over time was determined by linear regression analysis (TA). Results Twenty-two eyes (14.5%) progressed according to the VF EA, 16 (10.5%) by VF TA, 37 (24.3%) by SLP EA and 19 (12.5%) by SLP TA. Agreement between VF and SLP progression was poor in both EA and TA (VF EA vs. SLP EA, k = 0.110; VF TA vs. SLP TA, k = 0.129). The mean (±standard deviation) progression rate of RNFL thickness as measured by SLP TA did not significantly differ between VF EA progressors and non-progressors (-0.224 ± 0.148 µm/yr vs. -0.218 ± 0.151 µm/yr, p = 0.874). SLP TA and EA showed similar levels of sensitivity when VF progression was considered as the reference standard. Conclusions RNFL thickness as measurement by SLP was shown to be capable of detecting glaucoma progression. Both EA and TA of SLP showed poor agreement with VF outcomes in detecting glaucoma progression. PMID:22670073

Glaucoma progression detection by retinal nerve fiber layer measurement using scanning laser polarimetry: event and trend analysis.

PubMed

Moon, Byung Gil; Sung, Kyung Rim; Cho, Jung Woo; Kang, Sung Yong; Yun, Sung-Cheol; Na, Jung Hwa; Lee, Youngrok; Kook, Michael S

2012-06-01

To evaluate the use of scanning laser polarimetry (SLP, GDx VCC) to measure the retinal nerve fiber layer (RNFL) thickness in order to evaluate the progression of glaucoma. Test-retest measurement variability was determined in 47 glaucomatous eyes. One eye each from 152 glaucomatous patients with at least 4 years of follow-up was enrolled. Visual field (VF) loss progression was determined by both event analysis (EA, Humphrey guided progression analysis) and trend analysis (TA, linear regression analysis of the visual field index). SLP progression was defined as a reduction of RNFL exceeding the predetermined repeatability coefficient in three consecutive exams, as compared to the baseline measure (EA). The slope of RNFL thickness change over time was determined by linear regression analysis (TA). Twenty-two eyes (14.5%) progressed according to the VF EA, 16 (10.5%) by VF TA, 37 (24.3%) by SLP EA and 19 (12.5%) by SLP TA. Agreement between VF and SLP progression was poor in both EA and TA (VF EA vs. SLP EA, k = 0.110; VF TA vs. SLP TA, k = 0.129). The mean (±standard deviation) progression rate of RNFL thickness as measured by SLP TA did not significantly differ between VF EA progressors and non-progressors (-0.224 ± 0.148 µm/yr vs. -0.218 ± 0.151 µm/yr, p = 0.874). SLP TA and EA showed similar levels of sensitivity when VF progression was considered as the reference standard. RNFL thickness as measurement by SLP was shown to be capable of detecting glaucoma progression. Both EA and TA of SLP showed poor agreement with VF outcomes in detecting glaucoma progression.

Ocrelizumab: a B-cell depleting therapy for multiple sclerosis.

PubMed

Jakimovski, Dejan; Weinstock-Guttman, Bianca; Ramanathan, Murali; Kolb, Channa; Hojnacki, David; Minagar, Alireza; Zivadinov, Robert

2017-09-01

Multiple sclerosis (MS) is the most common neurological disease responsible for early disability in the young working population. In the last two decades, based on retrospective/prospective data, the use of disease-modifying therapies has been shown to slow the rate of disability progression and prolonged the time to conversion into secondary-progressive MS (SPMS). However, despite the availability of several approved therapies, disability progression cannot be halted significantly in all MS patients. Areas covered: This article reviews the immunopathology of the B-cells, and their role in pathogenesis of MS and their attractiveness as a potential therapeutic target in MS. The review focuses on the recently published ocrelizumab phase III trials in terms of its efficacy, safety, and tolerability as well as its future considerations. Expert opinion: B lymphocyte cell depletion therapy offers a compelling and promising new option for MS patients. Nonetheless, there is a need for heightened vigilance and awareness in detecting potential long-term consequences that currently remain unknown.

Impact of SSRI Therapy on Risk of Conversion From Mild Cognitive Impairment to Alzheimer's Dementia in Individuals With Previous Depression.

PubMed

Bartels, Claudia; Wagner, Michael; Wolfsgruber, Steffen; Ehrenreich, Hannelore; Schneider, Anja

2018-03-01

Depression is associated with an increased risk of Alzheimer's disease. Research has shown that the selective serotonin reuptake inhibitor (SSRI) citalopram decreases amyloid-β generation and plaque load. The authors evaluated the impact of SSRI treatment on CSF biomarkers and progression from mild cognitive impairment (MCI) to Alzheimer's dementia. Data sets from 755 currently nondepressed participants from the longitudinal Alzheimer's Disease Neuroimaging Initiative were evaluated by Kaplan-Meier analysis and analyses of variance and covariance with ApoE4 status and age as covariates. In MCI patients with a history of depression, long-term SSRI treatment (>4 years) was significantly associated with a delayed progression to Alzheimer's dementia by approximately 3 years, compared with short-term SSRI treatment, treatment with other antidepressants, or no treatment and compared with MCI patients without a history of depression. No differences in CSF biomarker levels were observed between treatment groups. Long-term SSRI treatment may delay progression from MCI to Alzheimer's dementia.

Progression of Neurovisceral Storage Disease With Supranuclear Ophthalmoplegia Following Orthotopic Liver Transplantation

PubMed Central

Gartner, J. Carlton; Bergman, Ira; Malatack, J. Jeffrey; Zitelli, Basil J.; Jaffe, Ronald; Watkins, John B.; Shaw, Byers W.; Iwatsuki, Shunzaburo; Starzl, Thomas E.

2011-01-01

A 7-year-old girl with progressive ataxia, spasticity, supranuclear ophthalmoplegia, and sea-blue histiocytes in her bone marrow underwent orthotopic liver transplantation for hepatocellular carcinoma. After an initial period of stabilization, she has shown progression of neurologic symptoms with recurrence of storage material in the transplanted liver. PMID:2999691

Comparison of Electrochemical Immunosensors and Aptasensors for Detection of Small Organic Molecules in Environment, Food Safety, Clinical and Public Security

PubMed Central

Piro, Benoit; Shi, Shihui; Reisberg, Steeve; Noël, Vincent; Anquetin, Guillaume

2016-01-01

We review here the most frequently reported targets among the electrochemical immunosensors and aptasensors: antibiotics, bisphenol A, cocaine, ochratoxin A and estradiol. In each case, the immobilization procedures are described as well as the transduction schemes and the limits of detection. It is shown that limits of detections are generally two to three orders of magnitude lower for immunosensors than for aptasensors, due to the highest affinities of antibodies. No significant progresses have been made to improve these affinities, but transduction schemes were improved instead, which lead to a regular improvement of the limit of detections corresponding to ca. five orders of magnitude over these last 10 years. These progresses depend on the target, however. PMID:26938570

Persistent, circulative transmission of begomoviruses by whitefly vectors.

PubMed

Rosen, Ran; Kanakala, Surapathrudu; Kliot, Adi; Cathrin Pakkianathan, Britto; Farich, Basheer Abu; Santana-Magal, Nadine; Elimelech, Meytar; Kontsedalov, Svetlana; Lebedev, Galina; Cilia, Michelle; Ghanim, Murad

2015-12-01

Begomoviruses comprise an emerging and economically important group of plant viruses exclusively transmitted by the sweetpotato whitefly Bemisia tabaci in many regions of the world. The past twenty years have witnessed significant progress in studying the molecular interactions between members of this virus group and B. tabaci. Mechanisms and proteins encoded by the insect vector and its bacterial symbionts, which have been shown to be important for virus transmission, have been identified and thoroughly studied. Despite the economic importance of this group of viruses and their impact on the global agriculture, progress in investigating the virus-vector interactions is moving slowly when compared with similar virus-vector systems in plants and animals. Major advances in this field and future perspectives will be discussed in this review. Copyright © 2015 Elsevier B.V. All rights reserved.

Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer

PubMed Central

Yashiro, Masakazu; Matsuoka, Tasuku

2016-01-01

Fibroblast growth factor receptors (FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer. PMID:26937130

Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer.

PubMed

Yashiro, Masakazu; Matsuoka, Tasuku

2016-02-28

Fibroblast growth factor receptors (FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer.

Expression of spermidine/spermine N(1) -acetyl transferase (SSAT) in human prostate tissues is related to prostate cancer progression and metastasis.

PubMed

Huang, Wei; Eickhoff, Jens C; Mehraein-Ghomi, Farideh; Church, Dawn R; Wilding, George; Basu, Hirak S

2015-08-01

Prostate cancer (PCa) in many patients remains indolent for the rest of their lives, but in some patients, it progresses to lethal metastatic disease. Gleason score is the current clinical method for PCa prognosis. It cannot reliably identify aggressive PCa, when GS is ≤ 7. It is shown that oxidative stress plays a key role in PCa progression. We have shown that in cultured human PCa cells, an activation of spermidine/spermine N(1) -acetyl transferase (SSAT; EC 2.3.1.57) enzyme initiates a polyamine oxidation pathway and generates copious amounts of reactive oxygen species in polyamine-rich PCa cells. We used RNA in situ hybridization and immunohistochemistry methods to detect SSAT mRNA and protein expression in two tissue microarrays (TMA) created from patient's prostate tissues. We analyzed 423 patient's prostate tissues in the two TMAs. Our data show that there is a significant increase in both SSAT mRNA and the enzyme protein in the PCa cells as compared to their benign counterpart. This increase is even more pronounced in metastatic PCa tissues as compared to the PCa localized in the prostate. In the prostatectomy tissues from early-stage patients, the SSAT protein level is also high in the tissues obtained from the patients who ultimately progress to advanced metastatic disease. Based on these results combined with published data from our and other laboratories, we propose an activation of an autocrine feed-forward loop of PCa cell proliferation in the absence of androgen as a possible mechanism of castrate-resistant prostate cancer growth. © 2015 Wiley Periodicals, Inc.

The Interplay between inflammation and fibrosis in kidney transplantation.

PubMed

Torres, Irina B; Moreso, Francesc; Sarró, Eduard; Meseguer, Anna; Serón, Daniel

2014-01-01

Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis.

The Interplay between Inflammation and Fibrosis in Kidney Transplantation

PubMed Central

Torres, Irina B.; Moreso, Francesc; Sarró, Eduard; Serón, Daniel

2014-01-01

Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis. PMID:24991565

The Impact of Combination Therapy with a-Blockers and 5ARIs on the Progression of BPH.

PubMed

Sountoulides, Petros; Gravas, Stavros

2015-01-01

Benign prostatic hyperplasia (BPH) can be a progressive disease for some men with significant impact on their quality of life due to worsening of symptoms, risk of acute urinary retention (AUR) and surgery. Certain clinical parameters such as age, prostate volume and PSA are able to predict those patients with BPH-associated LUTS that are at risk of disease progression. These patients will likely benefit most from medical therapy that provides symptom relief while at the same time may prevent disease progression. Studies have shown that a-blockers, although able to rapidly alleviate symptoms, have no effect on prostate volume, risk for AUR and BPH-related surgery. On the other hand 5ARIs have proven their efficacy in reducing prostate size, the risk of AUR and prostate surgery. Therefore combination therapy with an a-blocker and a 5ARI can be the mainstay of treatment for those patients at risk of BPH progression. Patients' perspective and their needs and expectations from treatment are other crucial parameters to consider in order selecting the optimal management of BPH. Therefore physicians should take into consideration the drug properties and also the patients' preferences before deciding on the optimal pharmacological treatment for BPH-associated LUTS.

Comparing self-guided learning and educator-guided learning formats for simulation-based clinical training.

PubMed

Brydges, Ryan; Carnahan, Heather; Rose, Don; Dubrowski, Adam

2010-08-01

In this paper, we tested the over-arching hypothesis that progressive self-guided learning offers equivalent learning benefit vs. proficiency-based training while limiting the need to set proficiency standards. We have shown that self-guided learning is enhanced when students learn on simulators that progressively increase in fidelity during practice. Proficiency-based training, a current gold-standard training approach, requires achievement of a criterion score before students advance to the next learning level. Baccalaureate nursing students (n = 15/group) practised intravenous catheterization using simulators that differed in fidelity (i.e. students' perceived realism). Data were collected in 2008. Proficiency-based students advanced from low- to mid- to high-fidelity after achieving a proficiency criterion at each level. Progressive students self-guided their progression from low- to mid- to high-fidelity. Yoked control students followed an experimenter-defined progressive practice schedule. Open-ended students moved freely between the simulators. One week after practice, blinded experts evaluated students' skill transfer on a standardized patient simulation. Group differences were examined using analyses of variance. Proficiency-based students scored highest on the high-fidelity post-test (effect size = 1.22). An interaction effect showed that the Progressive and Open-ended groups maintained their performance from post-test to transfer test, whereas the Proficiency-based and Yoked control groups experienced a significant decrease (P < 0.05). Surprisingly, most Open-ended students (73%) chose the progressive practice schedule. Progressive training and proficiency-based training resulted in equivalent transfer test performance, suggesting that progressive students effectively self-guided when to transition between simulators. Students' preference for the progressive practice schedule indicates that educators should consider this sequence for simulation-based training.

Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling

PubMed Central

Yuen, Hiu-Fung; Chan, Ka-Kui; Platt-Higgins, Angela; Dakir, El-Habib; Matchett, Kyle B.; Haggag, Yusuf Ahmed; Jithesh, Puthen V.; Habib, Tanwir; Faheem, Ahmed; Dean, Fennell A.; Morgan, Richard; Rudland, Philip S.; El-Tanani, Mohamed

2016-01-01

It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival. Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion. In a cell line model where Met amplification has previously been shown to contribute to gefitinib resistance, Ran knockdown sensitized cells to gefitinib-mediated inhibition of Akt and ERK1/2 phosphorylation and consequently reduced cell proliferation. We further demonstrate that Met reduction-mediated by knockdown of Ran, occurs at the post-transcriptional level, probably via a matrix metalloproteinase. Moreover, the level of immunoreactive Ran and Met are positively associated in human breast cancer specimens, suggesting that a high level of Ran may be a pre-requisite for Met overexpression. Interestingly, a high level of immunoreactive Ran dictates the prognostic significance of Met, indicating that the co-overexpression of Met and Ran may be associated with cancer progression and could be used in combination as a prognostic indicator. PMID:27716616

Changing treatment paradigms for the management of inflammatory bowel disease.

PubMed

Im, Jong Pil; Ye, Byong Duk; Kim, You Sun; Kim, Joo Sung

2018-01-01

Inflammatory bowel disease (IBD) is a chronic and progressive inf lammatory condition of the gastrointestinal tract causing bowel damage, hospitalizations, surgeries, and disability. Although there has been much progress in the management of IBD with established and evolving therapies, most current approaches have failed to change the natural course. Therefore, the treatment approach and follow-up of patients with IBD have undergone a significant change. Usage of immunosuppressants and/or biologics early during the course of the disease, known as top-down or accelerated step-up approach, was shown to be superior to conventional management in patients who had been recently diagnosed with IBD. This approach can be applied to selected groups based on prognostic factors to control disease activity and prevent progressive disease. Therapeutic targets have been shifted from clinical remission mainly based on symptoms to objective parameters such as endoscopic healing due to the discrepancies observed between symptoms, objectively evaluated inf lammatory activity, and intestinal damage. The concept of treat-to-target in IBD has been supported by population-based cohort studies, post hoc analysis of clinical trials, and meta-analysis, but more evidence is needed to support this concept to be applied to the clinical practice. In addition, individualized approach with tight monitoring of non-invasive biomarker such as C-reactive protein and fecal calprotectin and drug concentration has shown to improve clinical and endoscopic outcomes. An appropriate de-escalation strategy is considered based on patient demographics, disease features, current disease status, and patients' preferences.

INEL BNCT Research Program annual report, 1992

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

Venhuizen, J.R.

1993-05-01

This report is a summary of the progress and research produced for the Idaho National Engineering Laboratory Boron Neutron Capture Therapy (BNCT) Research Program for calendar year 1992. Contributions from all the principal investigators about their individual projects are included, specifically, chemistry (pituitary tumor targeting compounds, boron drug development including liposomes, lipoproteins, and carboranylalanine derivatives), pharmacology (murine screenings, toxicity testing, inductively coupled plasma-atomic emission spectroscopy (ICP-AES) analysis of biological samples), physics (radiation dosimetry software, neutron beam and filter design, neutron beam measurement dosimetry), and radiation biology (small and large animal models tissue studies and efficacy studies). Information on the potentialmore » toxicity of borocaptate sodium and boronophenylalanine is presented, results of 21 spontaneous-tumor-bearing dogs that have been treated with BNCT at the Brookhaven National Laboratory (BNL) Medical Research Reactor (BMRR) are discussed, and predictions for an epithermal-neutron beam at the Georgia Tech Research Reactor (GTRR) are shown. Cellular-level boron detection and localization by secondary ion mass spectrometry, sputter-initiated resonance ionization spectroscopy, low atomization resonance ionization spectroscopy, and alpha track are presented. Boron detection by ICP-AES is discussed in detail. Several boron carrying drugs exhibiting good tumor uptake are described. Significant progress in the potential of treating pituitary tumors with BNCT is presented. Measurement of the epithermal-neutron flux at BNL and comparison to predictions are shown. Calculations comparing the GTRR and BMRR epithermal-neutron beams are also presented. Individual progress reports described herein are separately abstracted and indexed for the database.« less

The Progress of Pupils in Their First School Year across Classes and Educational Systems

ERIC Educational Resources Information Center

Tymms, Peter; Merrell, Christine; Wildy, Helen

2015-01-01

Educational effectiveness research has identified school membership as being and important factor in relation to academic progress but it has also pointed to the importance of teachers. Additionally, districts have been shown to be of minor importance for progress once key variables are taken into account while data from international studies…

Monitoring Academic and Social Skills in Elementary School: A Psychometric Evaluation of the Classroom Performance Survey

ERIC Educational Resources Information Center

Caldarella, Paul; Larsen, Ross A. A.; Williams, Leslie; Wehby, Joseph H.; Wills, Howard; Kamps, Debra

2017-01-01

Numerous well-validated academic progress monitoring tools are used in schools, but there are fewer behavioral progress monitoring measures available. Some brief behavior rating scales have been shown to be effective in monitoring students' progress, but most focus only on students' social skills and do not address critical academic-related…

Monitoring Academic and Social Skills in Elementary School: A Psychometric Evaluation of the Classroom Performance Survey

ERIC Educational Resources Information Center

Caldarella, Paul; Larsen, Ross A. A.; Williams, Leslie; Wehby, Joseph H.; Wills, Howard P.; Kamps, Debra M.

2017-01-01

Numerous well validated academic progress monitoring tools are used in schools, but there are fewer behavioral progress monitoring measures available. Some brief behavior rating scales have been shown to be effective in monitoring students' progress, but most focus only on students' social skills and do not address critical academic-related…

Combined Diffusion Tensor Imaging and Apparent Transverse Relaxation Rate Differentiate Parkinson Disease and Atypical Parkinsonism.

PubMed

Du, G; Lewis, M M; Kanekar, S; Sterling, N W; He, L; Kong, L; Li, R; Huang, X

2017-05-01

Both diffusion tensor imaging and the apparent transverse relaxation rate have shown promise in differentiating Parkinson disease from atypical parkinsonism (particularly multiple system atrophy and progressive supranuclear palsy). The objective of the study was to assess the ability of DTI, the apparent transverse relaxation rate, and their combination for differentiating Parkinson disease, multiple system atrophy, progressive supranuclear palsy, and controls. A total of 106 subjects (36 controls, 35 patients with Parkinson disease, 16 with multiple system atrophy, and 19 with progressive supranuclear palsy) were included. DTI and the apparent transverse relaxation rate measures from the striatal, midbrain, limbic, and cerebellar regions were obtained and compared among groups. The discrimination performance of DTI and the apparent transverse relaxation rate among groups was assessed by using Elastic-Net machine learning and receiver operating characteristic curve analysis. Compared with controls, patients with Parkinson disease showed significant apparent transverse relaxation rate differences in the red nucleus. Compared to those with Parkinson disease, patients with both multiple system atrophy and progressive supranuclear palsy showed more widespread changes, extending from the midbrain to striatal and cerebellar structures. The pattern of changes, however, was different between the 2 groups. For instance, patients with multiple system atrophy showed decreased fractional anisotropy and an increased apparent transverse relaxation rate in the subthalamic nucleus, whereas patients with progressive supranuclear palsy showed an increased mean diffusivity in the hippocampus. Combined, DTI and the apparent transverse relaxation rate were significantly better than DTI or the apparent transverse relaxation rate alone in separating controls from those with Parkinson disease/multiple system atrophy/progressive supranuclear palsy; controls from those with Parkinson disease; those with Parkinson disease from those with multiple system atrophy/progressive supranuclear palsy; and those with Parkinson disease from those with multiple system atrophy; but not those with Parkinson disease from those with progressive supranuclear palsy, or those with multiple system atrophy from those with progressive supranuclear palsy. DTI and the apparent transverse relaxation rate provide different but complementary information for different parkinsonisms. Combined DTI and apparent transverse relaxation rate may be a superior marker for the differential diagnosis of parkinsonisms. © 2017 by American Journal of Neuroradiology.

Application of Diffusion Tensor Imaging Parameters to Detect Change in Longitudinal Studies in Cerebral Small Vessel Disease

PubMed Central

Zeestraten, Eva Anna; Benjamin, Philip; Lambert, Christian; Lawrence, Andrew John; Williams, Owen Alan; Morris, Robin Guy; Barrick, Thomas Richard; Markus, Hugh Stephen

2016-01-01

Cerebral small vessel disease (SVD) is the major cause of vascular cognitive impairment, resulting in significant disability and reduced quality of life. Cognitive tests have been shown to be insensitive to change in longitudinal studies and, therefore, sensitive surrogate markers are needed to monitor disease progression and assess treatment effects in clinical trials. Diffusion tensor imaging (DTI) is thought to offer great potential in this regard. Sensitivity of the various parameters that can be derived from DTI is however unknown. We aimed to evaluate the differential sensitivity of DTI markers to detect SVD progression, and to estimate sample sizes required to assess therapeutic interventions aimed at halting decline based on DTI data. We investigated 99 patients with symptomatic SVD, defined as clinical lacunar syndrome with MRI confirmation of a corresponding infarct as well as confluent white matter hyperintensities over a 3 year follow-up period. We evaluated change in DTI histogram parameters using linear mixed effect models and calculated sample size estimates. Over a three-year follow-up period we observed a decline in fractional anisotropy and increase in diffusivity in white matter tissue and most parameters changed significantly. Mean diffusivity peak height was the most sensitive marker for SVD progression as it had the smallest sample size estimate. This suggests disease progression can be monitored sensitively using DTI histogram analysis and confirms DTI’s potential as surrogate marker for SVD. PMID:26808982

The evolving field of kinase inhibitors in thyroid cancer.

PubMed

Marotta, V; Sciammarella, C; Vitale, M; Colao, A; Faggiano, A

2015-01-01

Most of the genetic events implicated in the pathogenesis of thyroid cancer (TC) involve genes with kinase activity. Thus, kinase inhibitors (KIs) are very relevant in this field. KIs are considered the most suitable treatment for patients with iodine-refractory differentiated TC; these patients comprise the subgroup with the poorer prognosis. To date, only sorafenib has been approved for this indication, but promising results have been reported with several other KIs. In particular, lenvatinib has demonstrated excellent efficacy, with both progression-free survival and objective tumour response being better than with sorafenib. Despite being considered to be well tolerated, both sorafenib and lenvatinib have shown a remarkable toxicity, which has led to dose reductions in the majority of patients and to treatment discontinuation in a significant proportion of cases. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). Vandetanib and cabozantinib have been approved for the treatment of advanced, progressive medullary TC (MTC). Nevertheless, the toxicity of both compounds suggests their selective use in those patients with strong disease progression. Treatment with the mTOR-inhibitor everolimus, alone or in combination with somatostatin analogues, should be studied in metastatic MTC patients with slow progression of disease, these representing the vast majority of patients. KIs did not significantly impact on the clinical features of anaplastic TC (ATC). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Current evaluation and management of spondylolysis and spondylolisthesis.

PubMed

McTimoney, C A Michelle; Micheli, Lyle J

2003-02-01

Spondylolysis occurs with a prevalence of 4% to 6% in the general population. Although the etiology of this lesion is still unclear, it has been shown to have both hereditary and acquired risk factors, with an increased prevalence in men and athletes participating in certain high-risk sports. Spondylolisthesis occurs in a significant proportion of individuals with bilateral spondylolysis. Predicting risk factors for progression of the slip in spondylolisthesis has proven difficult. Multiple imaging techniques are helpful in the diagnosis of spondylolysis and spondylolisthesis, with recent research addressing the utility of magnetic resonance imaging in the diagnosis and management of pars lesions. The management guidelines have remained largely unchanged since early recommendations. Recently, the addition of a bone growth stimulator to the management of difficult cases has shown promise.

Biomechanics of Far Cortical Locking

PubMed Central

Bottlang, Michael; Feist, Florian

2011-01-01

The development of FCL was motivated by a conundrum: locked plating constructs provide inherently rigid stabilization, yet they should facilitate biological fixation and secondary bone healing that relies on flexible fixation to stimulate callus formation. Recent studies have confirmed that the high stiffness of standard locked plating constructs can suppress interfragmentary motion to a level that is insufficient to reliably promote secondary fracture healing by callus formation. Furthermore, rigid locking screws cause an uneven stress distribution that may lead to stress fracture at the end screw and stress shielding under the plate. This review summarizes four key features of FCL constructs that have shown to enhance fixation and fracture healing: Flexible fixation, load distribution, progressive stiffening, and parallel interfragmentary motion. Specifically, flexible fixation provided by FCL reduces the stiffness of a locked plating construct by 80–88% to actively promote callus proliferation similar to an external fixator. Load distribution is evenly shared between FCL screws to mitigate stress risers at the end screw. Progressive stiffening occurs by near cortex support of FCL screws and provides additional support under elevated loading. Finally, parallel interfragmentary motion by s-shaped flexion of FCL screws has shown to induce symmetric callus formation. In combination, these features of FCL constructs have shown to induce more callus and to yield significantly stronger and more consistent healing compared to standard locked plating constructs. As such, FCL constructs function as true internal fixators by replicating the biomechanical behavior and biological healing response of external fixators. PMID:21248556

Multi-Parametric Spinal Cord MRI as Potential Progression Marker in Amyotrophic Lateral Sclerosis

PubMed Central

El Mendili, Mohamed-Mounir; Cohen-Adad, Julien; Pelegrini-Issac, Mélanie; Rossignol, Serge; Morizot-Koutlidis, Régine; Marchand-Pauvert, Véronique; Iglesias, Caroline; Sangari, Sina; Katz, Rose; Lehericy, Stéphane; Benali, Habib; Pradat, Pierre-François

2014-01-01

Objective To evaluate multimodal MRI of the spinal cord in predicting disease progression and one-year clinical status in amyotrophic lateral sclerosis (ALS) patients. Materials and Methods After a first MRI (MRI1), 29 ALS patients were clinically followed during 12 months; 14/29 patients underwent a second MRI (MRI2) at 11±3 months. Cross-sectional area (CSA) that has been shown to be a marker of lower motor neuron degeneration was measured in cervical and upper thoracic spinal cord from T2-weighted images. Fractional anisotropy (FA), axial/radial/mean diffusivities (λ⊥, λ//, MD) and magnetization transfer ratio (MTR) were measured within the lateral corticospinal tract in the cervical region. Imaging metrics were compared with clinical scales: Revised ALS Functional Rating Scale (ALSFRS-R) and manual muscle testing (MMT) score. Results At MRI1, CSA correlated significantly (P<0.05) with MMT and arm ALSFRS-R scores. FA correlated significantly with leg ALFSRS-R scores. One year after MRI1, CSA predicted (P<0.01) arm ALSFSR-R subscore and FA predicted (P<0.01) leg ALSFRS-R subscore. From MRI1 to MRI2, significant changes (P<0.01) were detected for CSA and MTR. CSA rate of change (i.e. atrophy) highly correlated (P<0.01) with arm ALSFRS-R and arm MMT subscores rate of change. Conclusion Atrophy and DTI metrics predicted ALS disease progression. Cord atrophy was a better biomarker of disease progression than diffusion and MTR. Our study suggests that multimodal MRI could provide surrogate markers of ALS that may help monitoring the effect of disease-modifying drugs. PMID:24755826

The Physiological/Pathophysiological Significance of Vitamin D in Cancer, Cardiovascular Disorders and Beyond.

PubMed

AlMatar, Manaf; AlMandeal, Husam; Makky, Essam A; Kayar, Begum; Yarar, Emel; Var, Isıl; Koksal, Fatih

2017-01-01

Vitamin D, a molecular precursor of the potent steroid hormone calcitriol, has crucial functions and roles in physiology and pathophysiology. Tellingly, calcitriol has been shown to regulate various cellular signalling networks and cascades that have crucial role in cancer biology and diagnostics. Mounting lines of evidences from previous clinical and preclinical investigations indicate that the deficiency of vitamin D may contribute to the carcinogenesis risk. Concomitantly, recent reports suggested that significant reduction in the cancer occurrence and progression is more likely to appear after vitamin D supplementation. Furthermore, a pivotal role functioned by vitamin D in cardiovascular physiology indicates that the deficiency of vitamin D is significantly correlated with enhanced prevalence of stroke, hypertension and myocardial infarction. Notably, vitamin D status is more likely to be used as a lifestyle biomarker, since poor and unhealthy lifestyles are correlated with the deficiency of vitamin D, a feature which may result in cardiovascular complications. Moreover, recent reports revealed that the effect of vitamin D is to cover not only cardiovascular system but also skeletal system. Herein, we are highlighting the recent knowledge of vitamin D roles and functions with respect to pathophysiological disorders such as cancer, cardiovascular diseases, rheumatoid arthritis (RA) and debate the potential avails of vitamin D on slowing cancer, cardiovascular disease and RA progression. The findings of this review confirm that the importance of vitamin D metabolites or analogues which can provide a helpful platform to target some kinds of cancer, particularly when used in combination with existing therapies. Moreover, the correlation between vitamin D deficiencies with cardiovascular diseases and rheumatoid arthritis (RA) progression might suggest a pivotal role of vitamin D in either initiation or progression of these diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Marine Group II Archaea, potentially important players in the global ocean carbon cycle

PubMed Central

Zhang, Chuanlun L.; Xie, Wei; Martin-Cuadrado, Ana-Belen; Rodriguez-Valera, Francisco

2015-01-01

Marine Group (MG) I (currently known as Thaumarchaeota) and MG II Archaea were first reported over two decades ago. While significant progress has been made on MG I microbiology and ecology, the progress on MG II has been noticeably slower. The common understanding is that while MG I mainly function as chemolithoautotrophs and occur predominantly in the deep ocean, MG II reside mostly in the photic zone and live heterotrophically. Studies to date have shown that MG II are abundant in the marine aquatic environment and display great seasonal and spatial variation and phylogenetic diversity. They also show unique patterns of organic carbon degradation and their energy requirements may be augmented by light in the photic zone. However, no pure culture of MG II has been obtained and thus their precise ecological role remains elusive. PMID:26528260

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms.

PubMed

Baum, Richard P; Kulkarni, Harshad R; Singh, Aviral; Kaemmerer, Daniel; Mueller, Dirk; Prasad, Vikas; Hommann, Merten; Robiller, Franz C; Niepsch, Karin; Franz, Holger; Jochems, Arthur; Lambin, Philippe; Hörsch, Dieter

2018-03-30

Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. In our center, 2294 patients were screened between 2004 and 2014 by 68 Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90 Yttrium or 177 Lutetium-based PRRT. Progression free survival was determined by 68 Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68 Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy.

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms

PubMed Central

Baum, Richard P.; Kulkarni, Harshad R.; Singh, Aviral; Kaemmerer, Daniel; Mueller, Dirk; Prasad, Vikas; Hommann, Merten; Robiller, Franz C.; Niepsch, Karin; Franz, Holger; Jochems, Arthur; Lambin, Philippe; Hörsch, Dieter

2018-01-01

Introduction Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. Methods In our center, 2294 patients were screened between 2004 and 2014 by 68Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90Yttrium or 177Lutetium-based PRRT. Progression free survival was determined by 68Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. Results Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. Conclusion PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy. PMID:29682195

Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents metabolic dysfunction and Alzheimer's disease-related memory loss in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet.

PubMed

Kobayashi, Yutaro; Inagawa, Hiroyuki; Kohchi, Chie; Kazumura, Kimiko; Tsuchiya, Hiroshi; Miwa, Toshiyuki; Okazaki, Katsuichiro; Soma, Gen-Ichiro

2018-01-01

The pathogenesis of Alzheimer's disease (AD) remains unclear, but an imbalance between the production and clearance of amyloid-β (Aβ) peptides is known to play a critical role in AD progression. A promising preventative approach is to enhance the normal Aβ clearance activity of brain phagocytes such as microglia. In mice, the intraperitoneal injection of Toll-like receptor 4 agonist was shown to enhance Aβ clearance and exhibit a preventative effect on AD-related pathology. Our previous clinical study demonstrated that orally administered Pantoea agglomerans-derived lipopolysaccharide (LPSp) exhibited an LDL (low-density lipoprotein)-lowering effect in human volunteers with hyperlipidemia, a known risk factor for AD. In vitro studies have shown that LPSp treatment increases Aβ phagocytosis by microglial cells; however it is still unclear whether orally administered LPSp exhibits a preventive effect on AD progression. We show here that in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet, oral administration of LPSp at 0.3 or 1 mg/kg body weight·day for 18 weeks significantly improved glucose metabolism and lipid profiles. The LPSp treatment also reduced pro-inflammatory cytokine expression and oxidative-burst activity in the peripheral blood. Moreover, LPSp significantly reduced brain Aβ burden and memory impairment as seen in the water maze test, although we could not confirm a significant enhancement of Aβ phagocytosis in microglia isolated from the brains after treatment. Taken together, our results show that LPSp holds promise as a preventative therapy for AD or AD-related diseases induced by impairment of metabolic functions.

Clinicopathological Significance of Vimentin and Cytokeratin Protein in the Genesis of Squamous Cell Carcinoma of Cervix.

PubMed

Husain, Nazik Elmalaika O S; Babiker, Ali Yousif; Albutti, Aqel S; Alsahli, Mohammed A; Aly, Salah M; Rahmani, Arshad H

2016-01-01

Cervical cancer is one of the commonest types of cancers worldwide especially in developing countries. Intermediate filaments protein family has shown a role in the diagnosis of various cancers, but a few studies are available about the vimentin and cytokeratin roles in the cervical cancer. This case control study aimed to interpret the expression of vimentin and cytokeratin proteins in the development and progression of cervical cancer and its correlation with clinicopathological features. The cytoplasmic expression of vimentin was observed in 40% of cases, but not in inflammatory lesions of cervix. It was noticed that vimentin expression was increasing significantly with high grade of the tumour. Cytokeratin expression was observed in 48.33% and it was noticed that the expression was 62.5% in well differentiated (G1), 45% in moderately differentiated (G2), and 41.66% in poorly differentiated carcinoma, yet statistically insignificant. The expression of vimentin and cytokeratin proteins was not significantly associated with age groups. The current findings concluded a possible role of vimentin in the development and progression of cervical cancer and vimentin marker will be useful in the diagnosis and grading of cervical cancer.

Clinicopathological Significance of Vimentin and Cytokeratin Protein in the Genesis of Squamous Cell Carcinoma of Cervix

PubMed Central

Husain, Nazik Elmalaika O. S.; Babiker, Ali Yousif; Albutti, Aqel S.; Alsahli, Mohammed A.; Aly, Salah M.; Rahmani, Arshad H.

2016-01-01

Cervical cancer is one of the commonest types of cancers worldwide especially in developing countries. Intermediate filaments protein family has shown a role in the diagnosis of various cancers, but a few studies are available about the vimentin and cytokeratin roles in the cervical cancer. This case control study aimed to interpret the expression of vimentin and cytokeratin proteins in the development and progression of cervical cancer and its correlation with clinicopathological features. The cytoplasmic expression of vimentin was observed in 40% of cases, but not in inflammatory lesions of cervix. It was noticed that vimentin expression was increasing significantly with high grade of the tumour. Cytokeratin expression was observed in 48.33% and it was noticed that the expression was 62.5% in well differentiated (G1), 45% in moderately differentiated (G2), and 41.66% in poorly differentiated carcinoma, yet statistically insignificant. The expression of vimentin and cytokeratin proteins was not significantly associated with age groups. The current findings concluded a possible role of vimentin in the development and progression of cervical cancer and vimentin marker will be useful in the diagnosis and grading of cervical cancer. PMID:27190522

Assessment of Cortical and Trabecular Bone Changes in Two Models of Post-Traumatic Osteoarthritis

PubMed Central

Pauly, Hannah M; Larson, Blair E; Coatney, Garrett A; Button, Keith D.; DeCamp, Charlie E; Fajardo, Ryan S; Haut, Roger C; Donahue, Tammy L Haut

2015-01-01

Subchondral bone is thought to play a significant role in the initiation and progression of the post-traumatic osteoarthritis. The goal of this study was to document changes in tibial and femoral subchondral bone that occur as a result of two lapine models of anterior cruciate ligament injury, a modified ACL transection model and a closed-joint traumatic compressive impact model. Twelve weeks post-injury bones were scanned via micro-computed tomography. The subchondral bone of injured limbs from both models showed decreases in bone volume and bone mineral density. Surgical transection animals showed significant bone changes primarily in the medial hemijoint of femurs and tibias, while significant changes were noted in both the medial and lateral hemijoints of both bones for traumatic impact animals. It is believed that subchondral bone changes in the medial hemijoint were likely caused by compromised soft tissue structures seen in both models. Subchondral bone changes in the lateral hemijoint of traumatic impact animals are thought to be due to transmission of the compressive impact force through the joint. The joint-wide bone changes shown in the traumatic impact model were similar to clinical findings from studies investigating the progression of osteoarthritis in humans. PMID:26147652

The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein

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

Bruyere, Emilie; Jonckheere, Nicolas; Frenois, Frederic

2011-09-23

Highlights: {yields} Loss of MUC4 reduces proliferation of esophageal cancer cells. {yields} MUC4 inhibition impairs migration of esophageal cancer cells but not their invasion. {yields} Loss of MUC4 significantly reduces in vivo tumor growth. {yields} Decrease of S100A4 induced by MUC4 inhibition impairs proliferation and migration. -- Abstract: MUC4 is a membrane-bound mucin known to participate in tumor progression. It has been shown that MUC4 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplastic lesions to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is the gastro-esophageal reflux, and MUC4 was previously shown tomore » be upregulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC4 plays a role in biological properties of human esophageal cancer cells. For that stable MUC4-deficient cancer cell lines (shMUC4 cells) were established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of shMUC4 cells were analyzed. Our results show that shMUC4 cells were less proliferative, had decreased migration properties and did not express S100A4 protein when compared with MUC4 expressing cells. Absence of MUC4 did not impair shMUC4 invasiveness. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC4. Altogether, these data indicate that MUC4 plays a key role in proliferative and migrating properties of esophageal cancer cells as well as is a tumor growth promoter. MUC4 mucin appears thus as a good therapeutic target to slow-down esophageal tumor progression.« less

Mild cognitive impairment: an opportunity to identify patients at high risk for progression to Alzheimer's disease.

PubMed

Levey, Allan; Lah, James; Goldstein, Felicia; Steenland, Kyle; Bliwise, Donald

2006-07-01

There is increasing evidence that subtle losses in cognitive function may be symptomatic of a transition to early Alzheimer's disease (AD). Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to AD. Of the MCI subtypes, patients with amnestic MCI (a-MCI) are at greatest risk. The objectives of this article were to review the relationship between MCI, normal aging, and AD, and to summarize recent research on the diagnosis and potential treatment of MCI. Relevant articles were identified through searches of MEDLINE and EMBASE using the terms mild cognitive impairment; cognitive impairment, no dementia; and dementia prodrome, with no restrictions as to year. Additional papers of interest were identified from the reference lists of the identified articles. The search was current as of February 2006. Guidelines and recommendations are being developed to assist physicians in diagnosing MCI, identifying its subtype and etiology, understanding the risks for conversion to AD, and managing disease progression. Given the existence of a subset of individuals with a-MCI, who are at greatest risk for progression to AD but still have high levels of cognition and function, the ability to improve symptoms and delay progression to AD would be particularly beneficial. In a 3-year, randomized, double-blind, placebo-controlled study in 769 patients with a-MCI, treatment with the cholinesterase inhibitor donepezil was associated with a significantly lower rate of progression to AD compared with placebo during the first 12 months of treatment (hazard ratio=0.42; 95% CI, 0.24-0.76; P=0.004) but not at later time points. Of other types of agents that have been investigated (antioxidants, estrogen replacement therapy, cyclooxygenase-2-selective inhibitors), none have shown significant beneficial effects in delaying cognitive decline or progression to AD. New drugs such as secretase inhibitors, small molecules that disrupt amyloid aggregation, and immunotherapies are in preclinical development. MCI involves more substantial cognitive and memory decline than normal aging and represents a significant risk factor for the development of dementia. Further research is needed into treatments to delay the conversion from MCI to AD.

Influence of acute progressive hypoxia on cardiovascular variability in conscious spontaneously hypertensive rats

PubMed Central

Sugimura, Mitsutaka; Hirose, Yohsuke; Hanamoto, Hiroshi; Okada, Kenji; Boku, Aiji; Morimoto, Yoshinari; Taki, Kunitaka; Niwa, Hitoshi

2008-01-01

The purpose of this study is to examine the influence of acute progressive hypoxia on cardiovascular variability and striatal dopamine (DA) levels in conscious, spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). After preparation for measurement, the inspired oxygen concentration of rats was decreased to 10% within 5 min (descent stage), maintained at 10% for 10 min (fixed stage), and then elevated back to 20% over 5 min (recovery stage). The systolic blood pressure (SBP) and heart rate (HR) variability at each stage was calculated to evaluate the autonomic nervous system response using the wavelet method. Striatal DA during each stage was measured using in vivo microdialysis. We found that SHR showed a more profound hemodynamic response to progressive hypoxia as compared to WKY. Cardiac parasympathetic activity in SHR was significantly inhibited by acute progressive hypoxia during all stages, as shown by the decrease in the high frequency band of HR variability (HR-HF), along with transient increase in sympathetic activity during the early hypoxic phase. This decrease in the HR-HF continued even when SBP was elevated. Striatal DA levels showed the transient similar elevation in both groups. These findings suggest that acute progressive hypoxic stress in SHR inhibits cardiac parasympathetic activity through reduction of baroreceptor reflex sensitivity, with potentially severe deleterious effects on circulation, in particular on HR and circulatory control. Furthermore, it is thought that the influence of acute progressive hypoxia on striatal DA levels is similar in SHR and WKY. PMID:18599365

The Use of Electrochemiluminescence Assays to Predict Autoantibody and Glycemic Progression Toward Type 1 Diabetes in Individuals with Single Autoantibodies

PubMed Central

Yu, Liping; Skyler, Jay S.; Krischer, Jeffrey P.; Gottlieb, Peter A.; Boulware, David; Miao, Dongmei; Palmer, Jerry P.; Steck, Andrea K.

2017-01-01

Abstract Background: Electrochemiluminescence (ECL) assays have shown promise for enhancing the prediction of type 1 diabetes (T1D) with autoantibodies. We thus studied relatives of T1D patients to determine whether ECL assays can be used to refine risk assessments for T1D among individuals either positive for single GADA or single mIAA autoantibodies. Subjects and Methods: TrialNet Pathway to Prevention (PTP) study participants with either GADA or mIAA single autoantibodies were tested for ECL positivity during their participation in the TrialNet PTP study. Those ECL positive (ECL+) were compared with those ECL negative (ECL−) for conversion to multiple autoantibodies, 6-month glycemic progression (PS6M), and the progression to T1D. Results: The progression to multiple autoantibodies was significantly higher for those GADA/ECL+ (n = 107) than those GADA/ECL− (n = 78) (P = 0.001) and for those mIAA/ECL+ (n = 24) than those mIAA/ECL− (n = 63) (P < 0.001). The hazard ratios with 95% confidence intervals were 3.42 (1.58–7.39; P < 0.01) for GADA and 8.15 (3.02–22.00; P < 0.001) for mIAA. GADA/ECL+ and mIAA/ECL+ participants had significantly higher PS6M values than their ECL− counterparts (P = 0.001 for GADA and P = 0.009 for mIAA). Of those GADA/ECL+, 14% progressed to T1D; of those mIAA/ECL+, 17% progressed to T1D. Only 1 individual (positive for GADA) of the 141 who was ECL− progressed to T1D (median follow-up: 5 years). Conclusion: ECL measurements appear to have utility for natural history studies and prevention trials of individuals with single autoantibodies. Those ECL+ are at appreciable risk for developing multiple autoantibodies and for glycemic progression toward T1D, whereas those ECL− are at very low risk. PMID:28177779

Etiopathogenesis of Canine Hip Dysplasia, Prevalence, and Genetics.

PubMed

King, Michael D

2017-07-01

First identified in 1935, canine hip dysplasia is thought to be the most common orthopedic condition diagnosed in the dog. It is most prevalent in large and giant breed dogs, with a complex polygenic mode of inheritance, and relatively low heritability. External factors including caloric intake when growing have a significant effect on phenotypic expression. Initial joint laxity progresses to osteoarthritis due to subluxation and abnormal wearing. Selective breeding programs to attempt to decrease prevalence have shown modest results so far. Copyright © 2017 Elsevier Inc. All rights reserved.

Topical Atropine in the Control of Myopia

PubMed Central

GALVIS, Virgilio; TELLO, Alejandro; PARRA, M. Margarita; MERAYO-LLOVES, Jesus; LARREA, Jaime; JULIAN RODRIGUEZ, Carlos; CAMACHO, Paul Anthony

2016-01-01

Atropine has been used for more than a century to arrest myopia progression. Compelling evidence of its protective effect has been reported in well-designed clinical studies, mainly performed during the last two decades. However, its exact mechanism of action has not been determined. Experimental findings have shown that the mechanism is not related to accommodation, as was thought for decades. A review of the published literature revealed a significant amount of evidence supporting its safety and efficacy at a concentration of 1.0%, and at lower concentrations (as low as 0.01%). PMID:28293653

Acoustic analysis of the singing and speaking voice in singing students.

PubMed

Lundy, D S; Roy, S; Casiano, R R; Xue, J W; Evans, J

2000-12-01

The singing power ratio (SPR) is an objective means of quantifying the singer's formant. SPR has been shown to differentiate trained singers from nonsingers and sung from spoken tones. This study was designed to evaluate SPR and acoustic parameters in singing students to determine if the singer-in-training has an identifiable difference between sung and spoken voices. Digital audio recordings were made of both sung and spoken vowel sounds in 55 singing students for acoustic analysis. SPR values were not significantly different between the sung and spoken samples. Shimmer and noise-to-harmonic ratio were significantly higher in spoken samples. SPR analysis may provide an objective tool for monitoring the student's progress.

Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3-5.

PubMed

Kurnatowska, Ilona; Grzelak, Piotr; Masajtis-Zagajewska, Anna; Kaczmarska, Magdalena; Stefańczyk, Ludomir; Vermeer, Cees; Maresz, Katarzyna; Nowicki, Michał

2015-01-01

Observational studies have shown that high dietary intake of vitamin K2 is associated with reduced risk of coronary vascular disease and vascular calcification. We assessed the effect of vitamin K2 substitution on the progression of atherosclerosis and calcification in nondialyzed patients with CKD stages 3-5. The study included 42 nondialyzed patients with CKD. The following measurements were taken at baseline and after 270 ±12 days of supplementation with vitamin K2 at a dose of 90 μg (menaquinone, MK-7) together with 10 μg of cholecalciferol (K+D group) or 10 μg of cholecalciferol (group D): common carotid intima-media thickness (CCA-IMT), coronary artery calcification score (CACS), basic biochemical parameters, lipids, and calcification modulators: matrix Gla protein (MGP), desphosphorylated-uncarboxylated MGP (dp-ucMGP), osteoprotegerin (OPG), fetuin A, osteocalcin (OC), and fibroblast growth factor 23. The increase of CCA-IMT was significantly lower in the K+D group compared with the D group: from 0.95 ±0.2 mm to 1.01 ±0.3, P = 0.003 vs from 1.02 ±0.2 mm to 1.16 ±0.3, P = 0.003 (ΔCCA-IMT, 0.06 ±0.08 vs 0.136 ±0.05 mm, P = 0.005, respectively). The increase in CACS was slightly lower in the K+D group than in the D group (ΔCACS, 58.1 ±106.5 AU vs 74.4 ±127.1 AU, P = 0.7). In the K+D group, a significant decrease in the level of dp-ucMGP and total OC was observed. A 270-day course of vitamin K2 administration in patients with CKD stages 3-5 may reduce the progression of atherosclerosis, but does not significantly affect the progression of calcification. Vitamin K2 significantly changes the levels of calcification promoters and inhibitors: dp-ucMGP, OC, and OPG.

GABA(A) and dopamine receptors in the nucleus accumbens shell differentially influence performance of a water-reinforced progressive ratio task.

PubMed

Covelo, Ignacio R; Wirtshafter, David; Stratford, Thomas R

2012-03-01

Several authors have shown that injections of the GABA(A) agonist muscimol into the medial shell region of the nucleus accumbens (AcbSh) result in large increases in food, but not water, intake. In previous studies we demonstrated that intra-AcbSh injections of either muscimol or of the indirect dopamine agonist amphetamine increase response output on a food-reinforced progressive ratio schedule. In the current experiment we extended these observations by examining the effects of muscimol and amphetamine injections on the performance of a water-reinforced progressive ratio task in mildly deprived animals. We found that muscimol did not affect the number of responses made in the water-reinforced task, even though a marked increase in responding was observed after amphetamine. Muscimol did, however, significantly increase food intake in the same animals. The results suggest that the enhancing effects of intra-AcbSh muscimol differ from those of amphetamine in that they are selective for food-reinforced behaviors. Copyright © 2011. Published by Elsevier Inc.

Inflammatory mediators in osteoarthritis: A critical review of the state-of-the-art, current prospects, and future challenges.

PubMed

Rahmati, Maryam; Mobasheri, Ali; Mozafari, Masoud

2016-04-01

Osteoarthritis (OA) has traditionally been defined as a prototypical non-inflammatory arthropathy, but today there is compelling evidence to suggest that it has an inflammatory component. Many recent studies have shown the presence of synovitis in a large number of patients with OA and demonstrated a direct association between joint inflammation and the progression of OA. Pro-inflammatory cytokines, reactive oxygen species (ROS), nitric oxide, matrix degrading enzymes and biomechanical stress are major factors responsible for the progression of OA in synovial joints. The aim of this review is to discuss the significance of a wide range of implicated inflammatory mediators and their contribution to the progression of OA. We also discuss some of the currently available guidelines, practices, and prospects. In addition, this review argues for new innovation in methodologies and instrumentation for the non-invasive detection of inflammation in OA by modern imaging techniques. We propose that identifying early inflammatory events and targeting these alterations will help to ameliorate the major symptoms such as inflammation and pain in OA patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Exercise capacity and progression from prehypertension to hypertension.

PubMed

Faselis, Charles; Doumas, Michael; Kokkinos, John Peter; Panagiotakos, Demosthenes; Kheirbek, Raya; Sheriff, Helen M; Hare, Katherine; Papademetriou, Vasilios; Fletcher, Ross; Kokkinos, Peter

2012-08-01

Prehypertension is likely to progress to hypertension. The rate of progression is determined mostly by age and resting blood pressure but may also be attenuated by increased fitness. A graded exercise test was performed in 2303 men with prehypertension at the Veterans Affairs Medical Centers in Washington, DC. Four fitness categories were defined, based on peak metabolic equivalents (METs) achieved. We assessed the association between exercise capacity and rate of progression to hypertension (HTN). The median follow-up period was 7.8 years (mean (± SD) 9.2±6.1 years). The incidence rate of progression from prehypertension to hypertension was 34.4 per 1000 person-years. Exercise capacity was a strong and independent predictor of the rate of progression. Compared to the High-Fit individuals (>10.0 METs), the adjusted risk for developing HTN was 66% higher (hazard ratio, 1.66; 95% CI, 1.2 to 2.2; P=0.001) for the Low-Fit and, similarly, 72% higher (hazard ratio, 1.72; 95% CI, 1.2 to 2.3; P=0.001) for the Least-Fit individuals, whereas it was only 36% for the Moderate-Fit (hazard ratio, 1.36; 95% CI, 0.99 to 1.80; P=0.056). Significant predictors for the progression to HTN were also age (19% per 10 years), resting systolic blood pressure (16% per 10 mm Hg), body mass index (15.3% per 5 U), and type 2 diabetes mellitus (2-fold). In conclusion, an inverse, S-shaped association was shown between exercise capacity and the rate of progression from prehypertension to hypertension in middle-aged and older male veterans. The protective effects of fitness were evident when exercise capacity exceeded 8.5 METs. These findings emphasize the importance of fitness in the prevention of hypertension.

Key challenges and recent progress in batteries, fuel cells, and hydrogen storage for clean energy systems

NASA Astrophysics Data System (ADS)

Chalk, Steven G.; Miller, James F.

Reducing or eliminating the dependency on petroleum of transportation systems is a major element of US energy research activities. Batteries are a key enabling technology for the development of clean, fuel-efficient vehicles and are key to making today's hybrid electric vehicles a success. Fuel cells are the key enabling technology for a future hydrogen economy and have the potential to revolutionize the way we power our nations, offering cleaner, more efficient alternatives to today's technology. Additionally fuel cells are significantly more energy efficient than combustion-based power generation technologies. Fuel cells are projected to have energy efficiency twice that of internal combustion engines. However before fuel cells can realize their potential, significant challenges remain. The two most important are cost and durability for both automotive and stationary applications. Recent electrocatalyst developments have shown that Pt alloy catalysts have increased activity and greater durability than Pt catalysts. The durability of conventional fluorocarbon membranes is improving, and hydrocarbon-based membranes have also shown promise of equaling the performance of fluorocarbon membranes at lower cost. Recent announcements have also provided indications that fuel cells can start from freezing conditions without significant deterioration. Hydrogen storage systems for vehicles are inadequate to meet customer driving range expectations (>300 miles or 500 km) without intrusion into vehicle cargo or passenger space. The United States Department of Energy has established three centers of Excellence for hydrogen storage materials development. The centers are focused on complex metal hydrides that can be regenerated onboard a vehicle, chemical hydrides that require off-board reprocessing, and carbon-based storage materials. Recent developments have shown progress toward the 2010 DOE targets. In addition DOE has established an independent storage material testing center to verify storage capacity of promising materials. These developments point to a viable path to achieving the DOE/FreedomCAR cost and performance goals. The transition to hydrogen-powered fuel cell vehicles will occur over the next 10-15 years. In the interim, fossil fuel consumption will be reduced by increased penetration of battery/gasoline hybrid cars.

The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein.

PubMed

Bruyère, Emilie; Jonckheere, Nicolas; Frénois, Frédéric; Mariette, Christophe; Van Seuningen, Isabelle

2011-09-23

MUC4 is a membrane-bound mucin known to participate in tumor progression. It has been shown that MUC4 pattern of expression is modified during esophageal carcinogenesis, with a progressive increase from metaplastic lesions to adenocarcinoma. The principal cause of development of esophageal adenocarcinoma is the gastro-esophageal reflux, and MUC4 was previously shown to be upregulated by several bile acids present in reflux. In this report, our aim was thus to determine whether MUC4 plays a role in biological properties of human esophageal cancer cells. For that stable MUC4-deficient cancer cell lines (shMUC4 cells) were established using a shRNA approach. In vitro (proliferation, migration and invasion) and in vivo (tumor growth following subcutaneous xenografts in SCID mice) biological properties of shMUC4 cells were analyzed. Our results show that shMUC4 cells were less proliferative, had decreased migration properties and did not express S100A4 protein when compared with MUC4 expressing cells. Absence of MUC4 did not impair shMUC4 invasiveness. Subcutaneous xenografts showed a significant decrease in tumor size when cells did not express MUC4. Altogether, these data indicate that MUC4 plays a key role in proliferative and migrating properties of esophageal cancer cells as well as is a tumor growth promoter. MUC4 mucin appears thus as a good therapeutic target to slow-down esophageal tumor progression. Copyright © 2011 Elsevier Inc. All rights reserved.

[Research progress in pathogenesis, treatment and prognosis of HPV positive head and neck squamous cell carcinoma].

PubMed

Shui, C Y; Li, C; Liu, W; Cai, Y C; Jiang, J; Sun, R H; Zhou, Y Q; Qin, G

2018-05-07

Head and neck squamous cell carcinoma (HNSCC) is the sixth common malignant tumors of whole body with a high incidence, which accounts for 90% of the head and neck malignant tumors. Previous studies have shown the risk factors, such as tobacco and alcohol, are related to the occurrence and development of HNSCC. However, recent studies have shown that the non-tobacco and non-alcohol related HNSCC increased year by year. At the same time, more and more studies have shown that HNSCC is related to the infection with human papilloma virus (HPV), and the occurrence and development of HPV-positive HNSCC has own characteristics in epidemiology, pathogenesis, treatment and prognosis. In this paper the research progress for HPV-positive HNSCC is reviewed.

Relation between reflux of bile acids into the stomach and gastric mucosal atrophy, intestinal metaplasia in biopsy specimens.

PubMed

Matsuhisa, Takeshi; Tsukui, Taku

2012-05-01

During endoscopic examinations we collected fluid in the stomach that included reflux fluid from the duodenum, and assessed the effect of quantitatively determined bile acids on glandular atrophy and intestinal metaplasia using biopsy specimens. A total of 294 outpatients were enrolled in this study. Total bile acid concentration was measured by an enzyme immunoassay. Glandular atrophy and intestinal metaplasia scores were graded according to the Updated Sydney System. An effect of refluxed bile acids on atrophy and intestinal metaplasia was shown in the high-concentration reflux group in comparison with the control group. However, when the odds ratios (ORs) were calculated according to whether Helicobacter pylori (H. pylori) infection was present, no significant associations were shown between reflux bile acids and atrophy in either the H. pylori-positive cases or -negative cases. The same was true for intestinal metaplasia in the H. pylori-positive cases, whereas intestinal metaplasia was more pronounced in the high-concentration reflux group in the H. pylori-negative cases (OR 2.4, 95%CI 1.1-5.6). We could not clarify the effect of the reflux of bile acids into the stomach in the progression of atrophy. High-concentration bile acids had an effect on the progression of intestinal metaplasia in the H. pylori-negative cases.

Up-regulation of plakophilin-2 is correlated with the progression of glioma.

PubMed

Zhang, Degeng; Qian, Yuxia; Liu, Xiaoxing; Yu, Hong; Zhao, Niangao; Wu, Zhengdong

2017-06-01

Glioma is the most common type of primary brain tumor in the CNS. Due to its poor prognosis and high mortality rates, it is urgent to find out more effective therapies. Plakophilin-2 (PKP2) is a widespread desmosomal plaque protein. Recently, the important roles of PKP2 in the proliferation and migration of cancer cells and tumor progression has been shown. However, the expression and potential function of PKP2 in glioma was still unclear. In this study, we demonstrated that PKP2 protein expression level was increased in glioma tissues compared with normal brain tissues, and its level was significantly associated with the Ki-67 expression and WHO grade by Western blot analysis and immunohistochemistry. Clinically, high PKP2 expression was tightly related to poor prognosis of glioma patients. Interestingly, we found that down-regulated PKP2 expression was shown to inhibit the migration of cells in glioma. Moreover, cell counting kit (CCK)-8 and colony formation analyses proved that reduced expression of PKP2 could weaken glioma cell proliferation. Taken together, these data uncover a potential role for PKP2 in the pathogenic process of glioma, suggesting that PKP2 may be a promising therapeutic target of glioma. © 2017 Japanese Society of Neuropathology.

Functional food addressing heart health: do we have to target the gut microbiota?

PubMed

Ryan, Paul M; Ross, Reynolds Paul; Fitzgerald, Gerald F; Caplice, Noel M; Stanton, Catherine

2015-11-01

Health promoting functional food ingredients for cardiovascular health are generally aimed at modulating lipid metabolism in consumers. However, significant advances have furthered our understanding of the mechanisms involved in development, progression, and treatment of cardiovascular disease. In parallel, a central role of the gut microbiota, both in accelerating and attenuating cardiovascular disease, has emerged. Modulation of the gut microbiota, by use of prebiotics and probiotics, has recently shown promise in cardiovascular disease prevention. Certain prebiotics can promote a short chain fatty acid profile that alters hormone secretion and attenuates cholesterol synthesis, whereas bile salt hydrolase and exopolysaccharide-producing probiotics have been shown to actively correct hypercholesterolemia. Furthermore, specific microbial genera have been identified as potential cardiovascular disease risk factors. This effect is attributed to the ability of certain members of the gut microbiota to convert dietary quaternary amines to trimethylamine, the primary substrate of the putatively atherosclerosis-promoting compound trimethylamine-N-oxide. In this respect, current research is indicating trimethylamine-depleting Achaea - termed Archeabiotics as a potential novel dietary strategy for promoting heart health. The microbiota offers a modifiable target, which has the potential to progress or prevent cardiovascular disease development. Whereas host-targeted interventions remain the standard, current research implicates microbiota-mediated therapies as an effective means of modulating cardiovascular health.

Integrating language models into classifiers for BCI communication: a review.

PubMed

Speier, W; Arnold, C; Pouratian, N

2016-06-01

The present review systematically examines the integration of language models to improve classifier performance in brain-computer interface (BCI) communication systems. The domain of natural language has been studied extensively in linguistics and has been used in the natural language processing field in applications including information extraction, machine translation, and speech recognition. While these methods have been used for years in traditional augmentative and assistive communication devices, information about the output domain has largely been ignored in BCI communication systems. Over the last few years, BCI communication systems have started to leverage this information through the inclusion of language models. Although this movement began only recently, studies have already shown the potential of language integration in BCI communication and it has become a growing field in BCI research. BCI communication systems using language models in their classifiers have progressed down several parallel paths, including: word completion; signal classification; integration of process models; dynamic stopping; unsupervised learning; error correction; and evaluation. Each of these methods have shown significant progress, but have largely been addressed separately. Combining these methods could use the full potential of language model, yielding further performance improvements. This integration should be a priority as the field works to create a BCI system that meets the needs of the amyotrophic lateral sclerosis population.

Spindle pole body component 25 homolog expressed by ECM stiffening is required for lung cancer cell proliferation.

PubMed

Jeong, Jangho; Keum, Seula; Kim, Daehwan; You, Eunae; Ko, Panseon; Lee, Jieun; Kim, Jaegu; Kim, Jung-Woong; Rhee, Sangmyung

2018-06-12

Accumulating evidence has shown that matrix stiffening in cancer tissue by the deposition of extracellular matrix (ECM) is closely related with severe tumor progression. However, much less is known about the genes affected by matrix stiffness and its signaling for cancer progression. In the current research, we investigated the differential gene expression of a non-small lung adenocarcinoma cell line, H1299, cultured under the conditions of soft (∼0.5 kPa) and stiff (∼40 kPa) matrices, mimicking the mechanical environments of normal and cancerous tissues, respectively. For integrated transcriptome analysis, the genes identified by ECM stiffening were compared with 8248 genes retrieved from The Cancer Genome Atlas Lung Adenocarcinoma (TCGA). In stiff matrix, 29 genes were significantly upregulated, while 75 genes were downregulated. The screening of hazard ratios for these genes using the Kaplan-Meier Plotter identified 8 genes most closely associated with cancer progression under the condition of matrix stiffening. Among these genes, spindle pole body component 25 homolog (SPC25) was one of the most up-regulated genes in stiff matrix and tumor tissue. Knockdown of SPC25 in H1299 cells using shRNA significantly inhibited cell proliferation with downregulation of the expression of checkpoint protein, Cyclin B1, under the condition of stiff matrix whereas the proliferation rate in soft matrix was not affected by SPC25 silencing. Thus, our findings provide novel key molecules for studying the relationship of extracellular matrix stiffening and cancer progression. Copyright © 2018 Elsevier Inc. All rights reserved.

High-response hybrid quantum dots- 2D conductor phototransistors: recent progress and perspectives

NASA Astrophysics Data System (ADS)

Sablon, Kimberly A.; Sergeev, Andrei; Najmaei, Sina; Dubey, Madan

2017-03-01

Having been inspired by the tremendous progress in material nanoscience and device nanoengineering, hybrid phototransistors combine solution processed colloidal semiconductor quantum dots (QDs) with graphene or two-dimensional (2D) semiconductor materials. Novel detectors demonstrate ultrahigh photoconductive gain, high and selective photoresponse, low noise, and very high responsivity in visible- and near-infrared ranges. The outstanding performance of phototransistors is primarily due to the strong, selective, and size tunable absorption of QDs and fast charge transfer in 2D high mobility conductors. However, the relatively small mobility of QD nanomaterials was a technological barrier, which limited the operating rate of devices. Very recent innovations in detector design and significant progress in QD ligand engineering provide effective tools for further qualitative improvements. This article reviews the recent progress in material science, nanophysics, and device engineering related to hybrid phototransistors. Detectors based on various QD nanomaterials and several 2D conductors are compared, and advantages and disadvantages of various nanomaterials for applications in hybrid phototransistors are identified. We also benchmark the experimental characteristics with model results that establish interrelations and tradeoffs between detector characteristics, such as responsivity, dark and noise currents, the photocarrier lifetime, response, and noise bandwidths. We have shown that the most recent phototransistors demonstrate performance limited by the fundamental generation recombination noise in high gain devices. Interrelation between the dynamic range of the detector and the detector sensitivity is discussed. The review is concluded with a brief discussion of the remaining challenges and possible significant improvements in the performance of hybrid phototransistors.

Analysis of simian virus 40 small t antigen-induced progression of rat F111 cells minimally transformed by large T antigen.

PubMed Central

Zerrahn, J; Deppert, W

1993-01-01

Minimal transformants of rat F111 fibroblasts were established after infection with the large T antigen (large T)-encoding retroviral expression vector pZIPTEX (M. Brown, M. McCormack, K. Zinn, M. Farrell, I. Bikel, and D. Livingston, J. Virol. 60:290-293, 1986). Coexpression of small t antigen (small t) in these cells efficiently led to their progression toward a significantly enhanced transformed phenotype. Small t forms a complex with phosphatase 2A and thereby might influence cellular phosphorylation processes, including the phosphorylation of large T. Since phosphorylation can modulate the transforming activity of large T, we asked whether the phosphorylation status of large T in minimally transformed cells might differ from that of large T in maximally transformed FR(wt648) cells and whether it might be altered by coexpression of small t. We found the phosphate turnover on large T in minimally transformed cells significantly different from that in fully transformed cells. This resulted in underphosphorylation of large T in minimally transformed cells at phosphorylation sites previously shown to be involved in the regulation of the transforming activity of large T. However, coexpression of small t in the minimally transformed cells did not alter the phosphate turnover on large T during progression; i.e., it did not induce a change in the steady-state phosphorylation of large T. This suggests that the helper function of small t during the progression of these cells was not mediated by modulating phosphatase 2A activity toward large T. Images PMID:8382310

Progress in molecular imaging in endoscopy and endomicroscopy for cancer imaging

PubMed Central

Khondee, Supang; Wang, Thomas D.

2014-01-01

Imaging is an essential tool for effective cancer management. Endoscopes are important medical instruments for performing in vivo imaging in hollow organs. Early detection of cancer can be achieved with surveillance using endoscopy, and has been shown to reduce mortality and to improve outcomes. Recently, great advancements have been made in endoscopic instruments, including new developments in optical designs, light sources, optical fibers, miniature scanners, and multimodal systems, allowing for improved resolution, greater tissue penetration, and multispectral imaging. In addition, progress has been made in the development of highly-specific optical probes, allowing for improved specificity for molecular targets. Integration of these new endoscopic instruments with molecular probes provides a unique opportunity for significantly improving patient outcomes and has potential to further improve early detection, image guided therapy, targeted therapy, and personalized medicine. This work summarizes current and evolving endoscopic technologies, and provides an overview of various promising optical molecular probes. PMID:23502247

Quantitative PCR and immunohistochemical analyses of HMGB1 and RAGE expression in canine disseminated histiocytic sarcoma (malignant histiocytosis).

PubMed

Sterenczak, Katharina A; Kleinschmidt, Sven; Wefstaedt, Patrick; Eberle, Nina; Hewicker-Trautwein, Marion; Bullerdiek, Jörn; Nolte, Ingo; Murua Escobar, Hugo

2011-05-01

Disorders of histiocytic origin affecting humans and dogs share various similarities. Canine disseminated histiocytic sarcoma (DHS) (formerly known as malignant histiocytosis) is an aggressive neoplasm of interstitial dendritic cells (DCs). The receptor for glycation end products (RAGE) and the high mobility group box1 protein (HMGB1) have been shown to be required for the maturation and migration of DCs. Thus, deregulation of the expression of these genes could have a major effect on the progression of histiocytic disorders. Neoplastic canine DHS samples and non-neoplastic control samples were analysed immunohistochemically and via real-time PCR. Significant down-regulation of RAGE in the lung tumour samples and down-regulation of HMGB1 in the lung, lymph node and spleen tumour samples were detected compared to their non-neoplastic counterparts. RAGE and HMGB1 expression down-regulation in canine DHS points to a role in the progression of histiocytic disorders.

Recent Progress Towards Predicting Aircraft Ground Handling Performance

NASA Technical Reports Server (NTRS)

Yager, T. J.; White, E. J.

1981-01-01

The significant progress which has been achieved in development of aircraft ground handling simulation capability is reviewed and additional improvements in software modeling identified. The problem associated with providing necessary simulator input data for adequate modeling of aircraft tire/runway friction behavior is discussed and efforts to improve this complex model, and hence simulator fidelity, are described. Aircraft braking performance data obtained on several wet runway surfaces is compared to ground vehicle friction measurements and, by use of empirically derived methods, good agreement between actual and estimated aircraft braking friction from ground vehilce data is shown. The performance of a relatively new friction measuring device, the friction tester, showed great promise in providing data applicable to aircraft friction performance. Additional research efforts to improve methods of predicting tire friction performance are discussed including use of an instrumented tire test vehicle to expand the tire friction data bank and a study of surface texture measurement techniques.

Metamaterial electromagnetic wave absorbers.

PubMed

Watts, Claire M; Liu, Xianliang; Padilla, Willie J

2012-06-19

The advent of negative index materials has spawned extensive research into metamaterials over the past decade. Metamaterials are attractive not only for their exotic electromagnetic properties, but also their promise for applications. A particular branch-the metamaterial perfect absorber (MPA)-has garnered interest due to the fact that it can achieve unity absorptivity of electromagnetic waves. Since its first experimental demonstration in 2008, the MPA has progressed significantly with designs shown across the electromagnetic spectrum, from microwave to optical. In this Progress Report we give an overview of the field and discuss a selection of examples and related applications. The ability of the MPA to exhibit extreme performance flexibility will be discussed and the theory underlying their operation and limitations will be established. Insight is given into what we can expect from this rapidly expanding field and future challenges will be addressed. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of exercise on fitness and cognition in progressive MS: a randomized, controlled pilot trial.

PubMed

Briken, S; Gold, S M; Patra, S; Vettorazzi, E; Harbs, D; Tallner, A; Ketels, G; Schulz, K H; Heesen, C

2014-03-01

Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis (MS). Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans. It may, therefore, be particularly useful for MS patients with pronounced neurodegeneration. To investigate the potential of standardized exercise as a therapeutic intervention for progressive MS, in a randomized-controlled pilot trial. Patients with progressive MS and moderate disability (Expanded Disability Status Scale (EDSS) of 4-6) were randomized to one of three exercise interventions (arm ergometry, rowing, bicycle ergometry) for 8-10 weeks or a waitlist control group. We analyzed the drop-out rate as a measure of feasibility. The primary endpoint of the study was aerobic fitness. Secondary endpoints were walking ability, cognitive function as measured by a neuropsychological test battery, depression and fatigue. A total of 42 patients completed the trial (10.6% drop-out rate). Significant improvements were seen in aerobic fitness. In addition, exercise improved walking ability, depressive symptoms, fatigue and several domains of cognitive function. This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS. Larger exercise studies are needed to confirm the effect on cognition. ISRCTN (trial number 76467492) http://isrctn.org.

Upregulation of long noncoding RNA HOXA-AS3 promotes tumor progression and predicts poor prognosis in glioma

PubMed Central

Wu, Fan; Zhang, Chuanbao; Cai, Jinquan; Yang, Fan; Liang, Tingyu; Yan, Xiaoyan; Wang, Haoyuan; Wang, Wen; Chen, Jing; Jiang, Tao

2017-01-01

Long noncoding RNAs (lncRNAs) have recently emerged as new potentially promising therapeutic targets in many cancers. However, their prognostic value and biological functions associated with glioma remain to be elucidated. Here, High-throughput RNAseq was performed to detect the expression profiles of lncRNAs in 325 human glioma tissues. It was shown that a novel lncRNA HOXA-AS3 was one of the most significantly upregulated lncRNAs in glioma tissues. Quantitative PCR further verified the increased expression of HOXA-AS3 in patient samples and glioma cell lines. Uni and Multivariate Cox regression analysis revealed that HOXA-AS3 was an independent prognostic factor in glioma patients. Gene set enrichment analysis indicated that the gene sets correlated with HOXA-AS3 expression were involved in cell cycle progression and E2F targets. Functionally, HOXA-AS3 silencing resulted in proliferation arrest by altering cell cycle progression and promoting cell apoptosis, and impaired cell migration in glioma cells. Furthermore, the growth-inhibiting effect of HOXA-AS3 knockdown was also demonstrated in Xenograft mouse model. Our results highlight the important role of HOXA-AS3 in glioma progression, and indicate that HOXA-AS3 may be served as a valuable prognostic biomarker for glioma. PMID:28881797

HPV status and favourable outcome in vulvar squamous cancer.

PubMed

Wakeham, Katie; Kavanagh, Kim; Cuschieri, Kate; Millan, David; Pollock, Kevin G; Bell, Sarah; Burton, Kevin; Reed, Nicholas S; Graham, Sheila V

2017-03-01

It is universally accepted that high-risk human papillomavirus (HR-HPV) is the cause of cervical dysplasia and cancer. More recently, it has been shown that HPV is also a marker of clinical outcome in oropharyngeal cancer. However, contemporary information is lacking on both the prevalence of HPV infection in vulvar cancer (VSCC), its precursor lesion, vulvar intraepithelial neoplasia (VIN) and the influence of HPV-status on the prognosis of this malignancy. We have conducted a detailed population-based study to examine rates of progression of VIN to VSCC, type-specific HPV prevalence in vulvar disease and the influence of HPV status on clinical outcome in VSCC. We observed that the age at which women are diagnosed with VSCC is falling and there is a significant time gap between first diagnosis of VIN and progression to invasive disease. HR-HPV infection was detected in 87% (97/112) cases of VIN and 52% cases (32/62) of VSCC. The presence of HR-HPV in squamous intraepithelial lesion was associated with lower rates of progression to invasive cancer (hazard ratio, 0.22, p = 0.001). In the adjusted analysis, HR-HPV was associated with improved progression-free survival of VSCC compared to those with HPV negative tumours (hazard ratio, 0.32, p = 0.02). © 2016 UICC.

Recent progress in the imaging of soil processes at the microscopic scale, and a look ahead

NASA Astrophysics Data System (ADS)

Garnier, Patricia; Baveye, Philippe C.; Pot, Valérie; Monga, Olivier; Portell, Xavier

2016-04-01

Over the last few years, tremendous progress has been achieved in the visualization of soil structures at the microscopic scale. Computed tomography, based on synchrotron X-ray beams or table-top equipment, allows the visualization of pore geometry at micrometric resolution. Chemical and microbiological information obtainable in 2D cuts through soils can now be interpolated, with the support of CT-data, to produce 3-dimensional maps. In parallel with these analytical advances, significant progress has also been achieved in the computer simulation and visualization of a range of physical, chemical, and microbiological processes taking place in soil pores. In terms of water distribution and transport in soils, for example, the use of Lattice-Boltzmann models as well as models based on geometric primitives has been shown recently to reproduce very faithfully observations made with synchrotron X-ray tomography. Coupling of these models with fungal and bacterial growth models allows the description of a range of microbiologically-mediated processes of great importance at the moment, for example in terms of carbon sequestration. In this talk, we shall review progress achieved to date in this field, indicate where questions remain unanswered, and point out areas where further advances are expected in the next few years.

Toxicological and efficacy assessment of post-transition metal (Indium) phthalocyanine for photodynamic therapy in neuroblastoma

PubMed Central

Neagu, Monica; Constantin, Carolina; Tampa, Mircea; Matei, Clara; Lupu, Andreea; Manole, Emilia; Ion, Rodica-Mariana; Fenga, Concettina; Tsatsakis, Aristidis M.

2016-01-01

Metallo-phthalocyanines due to their photophysical characteristics as high yield of triplet state and long lifetimes, appear to be good candidates for photodynamic therapy (PDT). Complexes with diamagnetic metals such as Zn2+, Al3+ Ga3+ and In3+meet such requirements and are recognized as potential PDT agents. Clinically, Photofrin® PDT in neuroblastoma therapy proved in pediatric subjects diagnosed with progressive/recurrent malignant brain tumors increased progression free survival and overall survival outcome. Our study focuses on the dark toxicity testing of a Chloro-Indium-phthalocyanine photosensitizer (In-Pc) upon SH-SY5Y neuroblastoma cell line and its experimental in vitro PDT. Upon testing, In-Pc has shown a relatively high singlet oxygen quantum yield within the cells subjected to PDT (0.553), and 50 μg/mL IC50. Classical toxicological and efficacy assessment were completed with dynamic cellular impedance measurement methodology. Using this technology we have shown that long time incubation of neuroblastoma cell lines in In-Pc (over 5 days) does not significantly hinder cell proliferation when concentration are ≤ 10 μg/mL. When irradiating neuroblastoma cells loaded with non-toxic concentration of In-Pc, 50% of cells entered apoptosis. Transmission electron microscopy has confirmed apoptotic characteristics of cells. Investigating the proliferative capacity of the in vitro treated cells we have shown that cells that “escape” the irradiation protocol, present a reduced proliferative capacity. In conclusion, In-Pc represents another photosensitizer that can display sound PDT properties enhancing neuroblastoma therapy armentarium. PMID:27626486

Toxicological and efficacy assessment of post-transition metal (Indium) phthalocyanine for photodynamic therapy in neuroblastoma.

PubMed

Neagu, Monica; Constantin, Carolina; Tampa, Mircea; Matei, Clara; Lupu, Andreea; Manole, Emilia; Ion, Rodica-Mariana; Fenga, Concettina; Tsatsakis, Aristidis M

2016-10-25

Metallo-phthalocyanines due to their photophysical characteristics as high yield of triplet state and long lifetimes, appear to be good candidates for photodynamic therapy (PDT). Complexes with diamagnetic metals such as Zn2+, Al3+ Ga3+ and In3+meet such requirements and are recognized as potential PDT agents. Clinically, Photofrin® PDT in neuroblastoma therapy proved in pediatric subjects diagnosed with progressive/recurrent malignant brain tumors increased progression free survival and overall survival outcome. Our study focuses on the dark toxicity testing of a Chloro-Indium-phthalocyanine photosensitizer (In-Pc) upon SH-SY5Y neuroblastoma cell line and its experimental in vitro PDT. Upon testing, In-Pc has shown a relatively high singlet oxygen quantum yield within the cells subjected to PDT (0.553), and 50 μg/mL IC50. Classical toxicological and efficacy assessment were completed with dynamic cellular impedance measurement methodology. Using this technology we have shown that long time incubation of neuroblastoma cell lines in In-Pc (over 5 days) does not significantly hinder cell proliferation when concentration are ≤ 10 μg/mL. When irradiating neuroblastoma cells loaded with non-toxic concentration of In-Pc, 50% of cells entered apoptosis. Transmission electron microscopy has confirmed apoptotic characteristics of cells. Investigating the proliferative capacity of the in vitro treated cells we have shown that cells that "escape" the irradiation protocol, present a reduced proliferative capacity. In conclusion, In-Pc represents another photosensitizer that can display sound PDT properties enhancing neuroblastoma therapy armentarium.

Saccharomycotina and Taphrinomycotina – progress in circumscription of genera

USDA-ARS?s Scientific Manuscript database

Much progress has been made in understanding relationships among the yeasts. DNA barcoding (D1/D2, ITS) has provided a rapid means for species identification and phylogenetic analysis of gene sequences has shown that the Ascomycota is comprised of three major lineages, i.e, Saccharomycotina (buddin...

A 7-year follow-up study of obstructive sleep apnoea in healthy elderly: The PROOF cohort study.

PubMed

Sforza, Emilia; Hupin, David; Pichot, Vincent; Barthélémy, Jean Claude; Roche, Frédéric

2017-07-01

Clinical and epidemiological cohort studies have shown that obstructive sleep apnoea (OSA) is a common but largely undiagnosed disorder in senior subjects, where progressive deterioration of the pathology would be expected as a consequence of the ageing processes. Our study examines the longitudinal progression of OSA over a 7-year period in a community-based sample of healthy subjects. The sample consisted of 284 volunteers, aged >65 years (52% women, 48% men) accepting clinical and instrumental follow-up at 7 years. OSA was defined as an apnoea-hypopnoea index (AHI) of ≥15. Between evaluations in the total sample, AHI slightly decreased from 17.8 ± 14 to 16.7 ± 11 with a decrease affecting more the hypopnoea index (P < 0.001) and associated with significant changes (P < 0.001) in all indices of hypoxaemia. While in the non-OSA group there was a slight but significant increase of AHI, a significant AHI decrease was noted in mild-moderate patients (P < 0.01) and a significant rise of nocturnal hypoxaemia in severe OSA patients (P < 0.001). The AHI decrease was not associated with clinical, weight, metabolic and blood pressure changes between the two evaluations; the baseline AHI value being the only factor correlated to the degree of AHI decline. In elderlies, the severity and prevalence of OSA decrease progressively with ageing without effect of factors commonly influencing OSA severity. This trend may support the hypothesis that in healthy elderly, OSA is a phenomenon related to ageing. © 2017 Asian Pacific Society of Respirology.

Decreased expression of 14-3-3 σ, an early event of malignant transformation of respiratory epithelium, also facilitates progression of squamous cell lung cancer

PubMed Central

Sun, Nan; Wu, Yongkai; Huang, Bo; Liu, Qian; Dong, Yinan; Ding, Jianqiao; Liu, Yongyu

2015-01-01

Background It has been shown that 14-3-3 σ serves as a tumor suppressor gene, and is downregulated in various tumor tissues. However, the role of 14-3-3 σ during the initiation and progression of lung squamous cell carcinoma (SqCC) is not well understood. Methods The expression status of 14-3-3 σ in archival tissue samples from 40 lung SqCC patients (36 with normal bronchia, 19 squamous metaplasia, and 17 dysplasia/carcinoma in situ, in their tissue samples) was examined by immunohistochemical analysis. The proliferation rate and tumor formation ability of the H520 cell transfected with 14-3-3 σ was tested with methyl thiazolyl tetrazolium assay and nude mice subcutaneous injection, respectively. Results In the normal bronchial epithelia, 14-3-3 σ was highly expressed, whereas it was significantly decreased in precancerous and cancerous tissues. Compared with matched invasive cancer tissues, the expression level of 14-3-3 σ in squamous metaplasia was significantly higher (P = 0.049), while that in dysplasia/carcinoma in situ showed no significant changes (P = 0.135). Statistical analysis showed that the expression level of 14-3-3 σ in tumor tissue was associated with the differentiation grade of the tumor (P = 0.001) and the prognosis of the patient (P = 0.003). The overexpression of 14-3-3 σ significantly suppressed the proliferation of H520 cells in vitro and in vivo. Conclusion The inactivation of 14-3-3 σ may be a very early event in tumorigenesis and could facilitate the initiation and progression of lung SqCC in a sustainable way. PMID:26557909

COX-derived prostanoid pathways in gastrointestinal cancer development and progression: novel targets for prevention and intervention.

PubMed

Cathcart, Mary-Clare; O'Byrne, Kenneth J; Reynolds, John V; O'Sullivan, Jacintha; Pidgeon, Graham P

2012-01-01

Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE(2), which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA(2) in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD(2) and its metabolite 15d-PGJ2, PGF(1α) and PGI(2). Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity. A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field. Copyright © 2011 Elsevier B.V. All rights reserved.

Keratoconus: an inflammatory disorder?

PubMed Central

Galvis, V; Sherwin, T; Tello, A; Merayo, J; Barrera, R; Acera, A

2015-01-01

Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition. PMID:25931166

An exploratory study into the effect of time-restricted internet access on face-validity, construct validity and reliability of postgraduate knowledge progress testing

PubMed Central

2013-01-01

Background Yearly formative knowledge testing (also known as progress testing) was shown to have a limited construct-validity and reliability in postgraduate medical education. One way to improve construct-validity and reliability is to improve the authenticity of a test. As easily accessible internet has become inseparably linked to daily clinical practice, we hypothesized that allowing internet access for a limited amount of time during the progress test would improve the perception of authenticity (face-validity) of the test, which would in turn improve the construct-validity and reliability of postgraduate progress testing. Methods Postgraduate trainees taking the yearly knowledge progress test were asked to participate in a study where they could access the internet for 30 minutes at the end of a traditional pen and paper test. Before and after the test they were asked to complete a short questionnaire regarding the face-validity of the test. Results Mean test scores increased significantly for all training years. Trainees indicated that the face-validity of the test improved with internet access and that they would like to continue to have internet access during future testing. Internet access did not improve the construct-validity or reliability of the test. Conclusion Improving the face-validity of postgraduate progress testing, by adding the possibility to search the internet for a limited amount of time, positively influences test performance and face-validity. However, it did not change the reliability or the construct-validity of the test. PMID:24195696

Autonomous stress imaging cores: from concept to reality

NASA Astrophysics Data System (ADS)

van der Velden, Stephen; Rajic, Nik; Brooks, Chris; Galea, Steve

2016-04-01

The historical reliance of thermoelastic stress analysis on cooled infrared detection has created significant cost and practical impediments to the widespread use of this powerful full-field stress measurement technique. The emergence of low-cost microbolometers as a practical alternative has allowed for an expansion of the traditional role of thermoelastic stress analysis, and raises the possibility that it may in future become a viable structural health monitoring modality. Experimental results are shown to confirm that high resolution stress imagery can be obtained from an uncooled thermal camera core significantly smaller than any infrared imaging device previously applied to TSA. The paper provides a summary of progress toward the development of an autonomous stress-imaging capability based on this core.

The role of rotors in atrial fibrillation

PubMed Central

Swarup, Vijay; Narayan, Sanjiv M.

2015-01-01

Despite significant advances in our understanding of atrial fibrillation (AF) mechanisms in the last 15 years, ablation outcomes remain suboptimal. A potential reason is that many ablation techniques focus on anatomic, rather than patient-specific functional targets for ablation. Panoramic contact mapping, incorporating phase analysis, repolarization and conduction dynamics, and oscillations in AF rate, overcomes many prior difficulties with mapping AF. This approach provides evidence that the mechanisms sustaining human AF are deterministic, largely due to stable electrical rotors and focal sources in either atrium. Ablation of such sources (Focal Impulse and Rotor Modulation: FIRM ablation) has been shown to improve ablation outcome compared with conventional ablation alone; independent laboratories directly targeting stable rotors have shown similar results. Clinical trials examining the role of stand-alone FIRM ablation are in progress. Looking forward, translating insights from patient-specific mapping to evidence-based guidelines and clinical practice is the next challenge in improving patient outcomes in AF management. PMID:25713729

[Distant mental influence on living organisms].

PubMed

Bonilla, Ernesto

2013-12-01

This article reviews studies of distant mental influence on living organisms, including mental suggestions of sleeping and awakening, mental influence at long distances, mental interactions with remote biological systems, mental effects on physiological activity and the sense of being stared at. Significant effects of distant mental influence have been shown in several randomized controlled trials in humans, animals, plants, bacteria and cells in the laboratory. Although distant mental influence on living organisms appears to contradict our ordinary sense of reality and the laws defined by conventional science, several hypotheses have been proposed to explain the observed effects; they include skeptical, signal transfer, field, multidimensional space/time and quantum mechanics hypotheses. In conclusion, as the progress of physics continues to expand our comprehension of reality, a rational explanation for distant mind-matter interaction will emerge and, as history has shown repeatedly, the supernatural events will evolve into paranormal and then, into normal ones, as the scientific frontiers expand.

Active ingredients of ginger as potential candidates in the prevention and treatment of diseases via modulation of biological activities

PubMed Central

Rahmani, Arshad H; shabrmi, Fahad M Al; Aly, Salah M

2014-01-01

The current mode of treatment based on synthetic drugs is expensive and also causes genetic and metabolic alterations. However, safe and sound mode of treatment is needed to control the diseases development and progression. In this regards, medicinal plant and its constituents play an important role in diseases management via modulation of biological activities. Ginger, the rhizome of the Zingiber officinale, has shown therapeutic role in the health management since ancient time and considered as potential chemopreventive agent. Numerous studies based on clinical trials and animal model has shown that ginger and its constituents shows significant role in the prevention of diseases via modulation of genetic and metabolic activities. In this review, we focused on the therapeutics effects of ginger and its constituents in the diseases management, and its impact on genetic and metabolic activities. PMID:25057339

[Serum level of S100B as a marker of progression of vascular mild cognitive impairment into subcortical vascular dementia and therapy effectiveness].

PubMed

Levada, O A; Traïlin, A V

2012-01-01

We evaluated serum level of S100B in 11 patients with subcortical vascular dementia (SVD) and 19 patients with subcortical vascular mild cognitive impairment (SVMCI). Comparable groups were age-matched (79.18 +/- 7.76 in SVD group, 77.84 +/- 3.83 in SVMCI; P = 0.53). 22 patients were assessed after 1 month therapy. It was shown that the serum S100B level significantly increased--(0.065 +/- 0.020) micro/l (P = 0.0005) in SVD patients comparing to SVMCI ones - (0.043 +/- 0.010) microg/l. S100B level was significantly correlated with the clinical parameters: MMSE performance (r(s) = -0.61), CDR (r(s) = 0.58), attention task (r(s) = -0.46), pseudobulbar syndrome severity (r(s) = 0.37) and walking alteration (r(s)= 0.37). In patients with reduction of S100B level due to therapy (positive dynamics, n = 12) we registered significant improvement of some clinical parameters: MMSE, attention level, walking. In patients with increasing of S100B level (negative dynamics, n = 10) we didn't registered improvement of any clinical parameters. We made the conclusion that the serum level of S100B could be used as marker of progression SVMCI into SVD and therapy effectiveness.

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions*

PubMed Central

Blanco, Mario Andres; Alečković, Maša; Hua, Yuling; Li, Tuo; Wei, Yong; Xu, Zhen; Cristea, Ileana M.; Kang, Yibin

2011-01-01

Metastasis is the deadliest and most poorly understood feature of malignant diseases. Recent work has shown that Metadherin (MTDH) is overexpressed in over 40% of breast cancer patients and promotes metastasis and chemoresistance in experimental models of breast cancer progression. Here we applied mass spectrometry-based screen to identify staphylococcal nuclease domain-containing 1 (SND1) as a candidate MTDH-interacting protein. After confirming the interaction between SND1 and MTDH, we tested the role of SND1 in breast cancer and found that it strongly promotes lung metastasis. SND1 was further shown to promote resistance to apoptosis and to regulate the expression of genes associated with metastasis and chemoresistance. Analyses of breast cancer clinical microarray data indicated that high expression of SND1 in primary tumors is strongly associated with reduced metastasis-free survival in multiple large scale data sets. Thus, we have uncovered SND1 as a novel MTDH-interacting protein and shown that it is a functionally and clinically significant mediator of metastasis. PMID:21478147

Progress in Written Language Bursts, Pauses, Transcription, and Written Composition across Schooling

ERIC Educational Resources Information Center

Alves, Rui A.; Limpo, Teresa

2015-01-01

Research on adult writers has shown that writing proceeds through bursts of transcription activity interspersed by long pauses. Yet few studies have examined how these writing behaviors unfold during early and middle childhood. This study traces the progress of bursts, pauses, transcription, and written composition in Portuguese students from…

Ramipril retards development of aortic valve stenosis in a rabbit model: mechanistic considerations.

PubMed

Ngo, Doan Tm; Stafford, Irene; Sverdlov, Aaron L; Qi, Weier; Wuttke, Ronald D; Zhang, Yuan; Kelly, Darren J; Weedon, Helen; Smith, Malcolm D; Kennedy, Jennifer A; Horowitz, John D

2011-02-01

Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS. The effects of 8 weeks of treatment with either vitamin D₂ at 25,000 IU for 4 days a week alone or in combination with ramipril (0.5 mg·kg⁻¹) on aortic valve structure and function were examined in New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)) and aortic valve:outflow tract flow velocity ratio were utilized to quantify changes in valve structure and function. Treatment with ramipril significantly reduced AV(BS) and improved aortic valve :outflow tract flow velocity ratio. The intravalvular content of the pro-oxidant thioredoxin-interacting protein was decreased significantly with ramipril treatment. Endothelial function, as measured by asymmetric dimethylarginine concentrations and vascular responses to ACh, was improved significantly with ramipril treatment. Ramipril retards the development of AVS, reduces valvular thioredoxin-interacting protein accumulation and limits endothelial dysfunction in this animal model. These findings provide important insights into the mechanisms of AVS development and an impetus for future human studies of AVS retardation using an angiotensin-converting enzyme inhibitor. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Developing and validating a predictive model for stroke progression.

PubMed

Craig, L E; Wu, O; Gilmour, H; Barber, M; Langhorne, P

2011-01-01

Progression is believed to be a common and important complication in acute stroke, and has been associated with increased mortality and morbidity. Reliable identification of predictors of early neurological deterioration could potentially benefit routine clinical care. The aim of this study was to identify predictors of early stroke progression using two independent patient cohorts. Two patient cohorts were used for this study - the first cohort formed the training data set, which included consecutive patients admitted to an urban teaching hospital between 2000 and 2002, and the second cohort formed the test data set, which included patients admitted to the same hospital between 2003 and 2004. A standard definition of stroke progression was used. The first cohort (n = 863) was used to develop the model. Variables that were statistically significant (p < 0.1) on univariate analysis were included in the multivariate model. Logistic regression was the technique employed using backward stepwise regression to drop the least significant variables (p > 0.1) in turn. The second cohort (n = 216) was used to test the performance of the model. The performance of the predictive model was assessed in terms of both calibration and discrimination. Multiple imputation methods were used for dealing with the missing values. Variables shown to be significant predictors of stroke progression were conscious level, history of coronary heart disease, presence of hyperosmolarity, CT lesion, living alone on admission, Oxfordshire Community Stroke Project classification, presence of pyrexia and smoking status. The model appears to have reasonable discriminative properties [the median receiver-operating characteristic curve value was 0.72 (range 0.72-0.73)] and to fit well with the observed data, which is indicated by the high goodness-of-fit p value [the median p value from the Hosmer-Lemeshow test was 0.90 (range 0.50-0.92)]. The predictive model developed in this study contains variables that can be easily collected in practice therefore increasing its usability in clinical practice. Using this analysis approach, the discrimination and calibration of the predictive model appear sufficiently high to provide accurate predictions. This study also offers some discussion around the validation of predictive models for wider use in clinical practice.

Non-DBS DNA Repair Genes Regulate Radiation-induced Cytogenetic Damage Repair and Cell Cycle Progression

NASA Technical Reports Server (NTRS)

Zhang, Ye; Rohde, Larry H.; Emami, Kamal; Casey, Rachael; Wu, Honglu

2008-01-01

Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have shown that genes up-regulated by IR may play important roles in DNA damage repair, the relationship between the regulation of gene expression by IR, particularly genes not known for their roles in DSB repair, and its impact on cytogenetic responses has not been systematically studied. In the present study, the expression of 25 genes selected on the basis of their transcriptional changes in response to IR was individually knocked down by transfection with small interfering RNA in human fibroblast cells. The purpose of this study is to identify new roles of these selected genes on regulating DSB repair and cell cycle progression , as measured in the micronuclei formation and chromosome aberration. In response to IR, the formation of MN was significantly increased by suppressed expression of 5 genes: Ku70 in the DSB repair pathway, XPA in the NER pathway, RPA1 in the MMR pathway, and RAD17 and RBBP8 in cell cycle control. Knocked-down expression of 4 genes (MRE11A, RAD51 in the DSB pathway, SESN1, and SUMO1) significantly inhibited cell cycle progression, possibly because of severe impairment of DNA damage repair. Furthermore, loss of XPA, P21, or MLH1 expression resulted in both significantly enhanced cell cycle progression and increased yields of chromosome aberrations, indicating that these gene products modulate both cell cycle control and DNA damage repair. Most of the 11 genes that affected cytogenetic responses are not known to have clear roles influencing DBS repair. Nine of these 11 genes were up-regulated in cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulate the biological consequences after IR.

Cumulative Significance of Hyporheic Exchange and Biogeochemical Processing in River Networks

NASA Astrophysics Data System (ADS)

Harvey, J. W.; Gomez-Velez, J. D.

2014-12-01

Biogeochemical reactions in rivers that decrease excessive loads of nutrients, metals, organic compounds, etc. are enhanced by hydrologic interactions with microbially and geochemically active sediments of the hyporheic zone. The significance of reactions in individual hyporheic flow paths has been shown to be controlled by the contact time between river water and sediment and the intrinsic reaction rate in the sediment. However, little is known about how the cumulative effects of hyporheic processing in large river basins. We used the river network model NEXSS (Gomez-Velez and Harvey, submitted) to simulate hyporheic exchange through synthetic river networks based on the best available models of network topology, hydraulic geometry and scaling of geomorphic features, grain size, hydraulic conductivity, and intrinsic reaction rates of nutrients and metals in river sediment. The dimensionless reaction significance factor, RSF (Harvey et al., 2013) was used to quantify the cumulative removal fraction of a reactive solute by hyporheic processing. SF scales reaction progress in a single pass through the hyporheic zone with the proportion of stream discharge passing through the hyporheic zone for a specified distance. Reaction progress is optimal where the intrinsic reaction timescale in sediment matches the residence time of hyporheic flow and is less efficient in longer residence time hyporheic flow as a result of the decreasing proportion of river flow that is processed by longer residence time hyporheic flow paths. In contrast, higher fluxes through short residence time hyporheic flow paths may be inefficient because of the repeated surface-subsurface exchanges required to complete the reaction. Using NEXSS we found that reaction efficiency may be high in both small streams and large rivers, although for different reasons. In small streams reaction progress generally is dominated by faster pathways of vertical exchange beneath submerged bedforms. Slower exchange beneath meandering river banks mainly has importance only in large rivers. For solutes entering networks in proportion to water inputs it is the lower order streams that tend to dominate cumulative reaction progress.

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

PubMed

Stewart, A Keith; Rajkumar, S Vincent; Dimopoulos, Meletios A; Masszi, Tamás; Špička, Ivan; Oriol, Albert; Hájek, Roman; Rosiñol, Laura; Siegel, David S; Mihaylov, Georgi G; Goranova-Marinova, Vesselina; Rajnics, Péter; Suvorov, Aleksandr; Niesvizky, Ruben; Jakubowiak, Andrzej J; San-Miguel, Jesus F; Ludwig, Heinz; Wang, Michael; Maisnar, Vladimír; Minarik, Jiri; Bensinger, William I; Mateos, Maria-Victoria; Ben-Yehuda, Dina; Kukreti, Vishal; Zojwalla, Naseem; Tonda, Margaret E; Yang, Xinqun; Xing, Biao; Moreau, Philippe; Palumbo, Antonio

2015-01-08

Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

Antibodies neutralizing hepsin protease activity do not impact cell growth but inhibit invasion of prostate and ovarian tumor cells in culture.

PubMed

Xuan, Jian-Ai; Schneider, Doug; Toy, Pam; Lin, Rick; Newton, Alicia; Zhu, Ying; Finster, Silke; Vogel, David; Mintzer, Bob; Dinter, Harald; Light, David; Parry, Renate; Polokoff, Mark; Whitlow, Marc; Wu, Qingyu; Parry, Gordon

2006-04-01

Hepsin is a type II transmembrane serine protease that is expressed in normal liver, and at lower levels in kidney, pancreas, and testis. Several studies have shown that hepsin mRNA is significantly elevated in most prostate tumors, as well as a significant fraction of ovarian and renal cell carcinomas and hepatomas. Although the overexpression of mRNA in these tumors has been extensively documented, there has been conflicting literature on whether hepsin plays a role in tumor cell growth and progression. Early literature implied a role for hepsin in human tumor cell proliferation, whereas recent studies with a transgenic mouse model for prostate cancer support a role for hepsin in tumor progression and metastases. To evaluate this issue further, we have expressed an activatable form of hepsin, and have generated a set of monoclonal antibodies that neutralize enzyme activity. The neutralizing antibodies inhibit hepsin enzymatic activity in biochemical and cell-based assays. Selected neutralizing and nonneutralizing antibodies were used in cell-based assays with tumor cells to evaluate the effect of antibodies on tumor cell growth and invasion. Neutralizing antibodies failed to inhibit the growth of prostate, ovarian, and hepatoma cell lines in culture. However, potent inhibitory effects of the antibodies were seen on invasion of ovarian and prostate cells in transwell-based invasion assays. These results support a role for hepsin in tumor cell progression but not in primary tumor growth. Consistent with this, immunohistochemical experiments with a mouse monoclonal antibody reveal progressively increased staining of prostate tumors with advanced disease, and in particular, extensive staining of bone metastatic lesions.

Using health games for rehabilitation of patients with infantile cerebral palsy.

PubMed

Lee, Wan-Chen; Reyes-Fernández, Miriam C; Posada-Gómez, Rubén; Juárez-Martínez, Ulises; Martínez-Sibaja, Albino; Alor-Hernández, Giner

2016-08-01

[Purpose] The purposes of this study were to evaluate whether the therapeutic games developed by the study team are significantly effective for upper limb rehabilitation of patients with cerebral palsy and to assess the development of the games and the evolution of patients throughout the therapy sessions. [Subjects and Methods] This study demonstrates the results of using therapeutic games in patients with infantile cerebral palsy. The therapies were performed in 30-minute sessions for about 1 to 4 months. This study shows the progress of five children with cerebral palsy during the sessions. The time it took the children on each road and the times required to complete a task were measured. In addition, the level of difficulty of the games was gradually increased at each session. [Results] Results have shown good progress on the accuracy of the movements and an increase in concentration level during the execution of the games, showing an improvement in the patients' performance by 40-55% faster. [Conclusions] Health games encourage children to comply with therapy. The advantage of the game is that the patient can perform the therapy at home, which could help achieve further progress in patients.

STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model.

PubMed

Yokota, Tsubasa; Omachi, Kohei; Suico, Mary Ann; Kamura, Misato; Kojima, Haruka; Fukuda, Ryosuke; Motomura, Keishi; Teramoto, Keisuke; Kaseda, Shota; Kuwazuru, Jun; Takeo, Toru; Nakagata, Naomi; Shuto, Tsuyoshi; Kai, Hirofumi

2018-02-01

Alport syndrome (AS) is a hereditary, progressive nephritis caused by mutation of type IV collagen. Previous studies have shown that activation of signal transducer and activator of transcription 3 (STAT3) exacerbates other renal diseases, but whether STAT3 activation exacerbates AS pathology is still unknown. Here we aim to investigate the involvement of STAT3 in the progression of AS. Phosphorylated STAT3 expression was assessed by immunoblotting analysis of kidneys and glomeruli of an AS mouse model (Col4a5 G5X mutant). To determine the effect of blocking STAT3 signaling, we treated AS mice with the STAT3 inhibitor stattic (10 mg/kg i.p., three times per week for 10 weeks; n = 10). We assessed the renal function [proteinuria, blood urea nitrogen (BUN), serum creatinine] and analyzed the glomerular injury score, fibrosis and inflammatory cell invasion by histological staining. Moreover, we analyzed the gene expression of nephritis-associated molecules. Phosphorylated STAT3 was upregulated in AS kidneys and glomeruli. Treatment with stattic ameliorated the progressive renal dysfunction, such as increased levels of proteinuria, BUN and serum creatinine. Stattic also significantly suppressed the gene expression levels of renal injury markers (Lcn2, Kim-1), pro-inflammatory cytokines (Il-6, KC), pro-fibrotic genes (Tgf-β, Col1a1, α-Sma) and Mmp9. Stattic treatment decreased the renal fibrosis congruently with the decrease of transforming growth factor beta (TGF-β) protein and increase of antifibrosis-associated markers p-Smad1, 5 and 8, which are negative regulators of TGF-β signaling. STAT3 inhibition significantly ameliorated the renal dysfunction in AS mice. Our finding identifies STAT3 as an important regulator in AS progression and provides a promising therapeutic target for AS. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

[Progress in the prevention of type 2 diabetes].

PubMed

Schernthaner, Guntram

2003-11-28

Type 2 diabetes mellitus is a major health problem associated with excess morbidity and mortality. Defects in the action and/or secretion of insulin are the two major abnormalities leading to development of glucose intolerance. Any intervention in the impaired glucose tolerance phase that reduces resistance to insulin or protects the beta-cells, or both, should prevent or delay progression to diabetes. The natural history of type 2 diabetes includes a preceding period of impaired glucose tolerance (IGT)/impaired fasting glucose (IFG) which provides an opportunity for targeted intervention within large communities. As the prevalence of this metabolic disorder is rapidly increasing and current treatment fails to stabilise the disease in most patients, prevention should be considered as a key objective in the near future. Lifestyle intervention studies have consistently shown that quite modest changes can reduce the progression from IGT to diabetes by 50-60%. The Diabetes Prevention Program (DPP) randomised trial has shown that a combined program of weight loss, improvement of diet and increase of physical exercise lowers the risk for development of type 2 diabetes by 58% compared with placebo. It may, however, not be possible to translate these successful findings to larger cohorts or maintain the lifestyle changes longer term. This has lead to consideration of pharmacotherapy. Benefits have been found for metformin, acarbose and troglitazone. Treatment with metformin was less effective than lifestyle modifications, resulting in an average reduction of risk for development of type 2 diabetes by 31% compared with placebo. Similarly, acarbose in the STOP-NIDDM trial reduced the risk of developing type 2 diabetes in patients with IGT by 25%. Remarkably, cardiovascular event rates, in particular myocardial infarction, were significantly reduced when acarbose was used instead of placebo in subjects with glucose intolerance. The ACE inhibitors captopril (CAPPP) or ramipril (HOPE) and the Angiotensin-II receptor antagonist losartan (LIFE) have been shown to reduce the appearance of diabetes by one third when given to patients with hypertension. Since many hypertensive patients are insulin-resistant and have an increased risk in developing type 2 diabetes, the protective effect of these classes of antihypertensive drugs might be explained by their antiinsulin-resistance effects.

A new approach to the evolution of the blastic crisis from chronic myelocytic leukemia: dynamic interplay of cellular alterations and a changing microenvironment.

PubMed Central

Grossman, Z

1986-01-01

The mechanisms responsible for the massive hyperplasia and for the blastic crisis in chronic myelocytic leukemia are poorly understood. The most generally accepted hypothesis proposes that this progression is due to the development of genetic instability in the leukemic cells. In particular, the two phases of the disease are believed to reflect different, discrete genetic events. Such events remain undefined as yet, and the causal significance of observed genetic aberrations is not clear. An alternative hypothesis is presented here. It is assumed that the feedback interactions adjust the relative probabilities of maturation and replication of the 'committed' as well as the pluripotent cells, and further that mitotic cells at all stages possess considerable phenotypic adaptability; in particular their self-renewal capacity can vary in response to changes in the cellular composition of the tissue even within a conventionally defined compartment. On this basis, it is shown that chronic leukemia can arise and evolve into the blastic crisis from a progressive decline in a single clonal characteristic--inducibility to maturation. It is shown, with the help of mathematical considerations, how an initial hereditable event in an early hemopoietic cell can cause a disturbance of the tissue which feeds back onto the individual members of the clone, resulting in a cascade of dynamic changes which can lead to blast cell dominance. PMID:3458586

Proteomic Analysis of Metabolic Responses to Biofuels and Chemicals in Photosynthetic Cyanobacteria.

PubMed

Sun, T; Chen, L; Zhang, W

2017-01-01

Recent progresses in various "omics" technologies have enabled quantitative measurements of biological molecules in a high-throughput manner. Among them, high-throughput proteomics is a rapidly advancing field that offers a new means to quantify metabolic changes at protein level, which has significantly facilitated our understanding of cellular process, such as protein synthesis, posttranslational modifications, and degradation in responding to environmental perturbations. Cyanobacteria are autotrophic prokaryotes that can perform oxygenic photosynthesis and have recently attracted significant attentions as one promising alternative to traditionally biomass-based "microbial cell factories" to produce green fuels and chemicals. However, early studies have shown that the low tolerance to toxic biofuels and chemicals represented one major hurdle for further improving productivity of the cyanobacterial production systems. To address the issue, metabolic responses and their regulation of cyanobacterial cells to toxic end-products need to be defined. In this chapter, we discuss recent progresses in interpreting cyanobacterial responses to biofuels and chemicals using high-throughput proteomics approach, aiming to provide insights and guidelines on how to enhance tolerance and productivity of biofuels or chemicals in the renewable cyanobacteria systems in the future. © 2017 Elsevier Inc. All rights reserved.

Protein arginine N-methyltransferase 1 promotes the proliferation and metastasis of hepatocellular carcinoma cells.

PubMed

Gou, Qing; He, ShuJiao; Zhou, ZeJian

2017-02-01

Hepatocellular carcinoma is the most common subtype of liver cancer. Protein arginine N-methyltransferase 1 was shown to be upregulated in various cancers. However, the role of protein arginine N-methyltransferase 1 in hepatocellular carcinoma progression remains incompletely understood. We investigated the clinical and functional significance of protein arginine N-methyltransferase 1 in a series of clinical hepatocellular carcinoma samples and a panel of hepatocellular carcinoma cell lines. We performed suppression analysis of protein arginine N-methyltransferase 1 using small interfering RNA to determine the biological roles of protein arginine N-methyltransferase 1 in hepatocellular carcinoma. In addition, the expression of epithelial-mesenchymal transition indicators was verified by western blotting in hepatocellular carcinoma cell lines after small interfering RNA treatment. Protein arginine N-methyltransferase 1 expression was found to be significantly upregulated in hepatocellular carcinoma cell lines and clinical tissues. Moreover, downregulation of protein arginine N-methyltransferase 1 in hepatocellular carcinoma cells by small interfering RNA could inhibit cell proliferation, migration, and invasion in vitro. These results indicate that protein arginine N-methyltransferase 1 may contribute to hepatocellular carcinoma progression and serves as a promising target for the treatment of hepatocellular carcinoma patients.

The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer.

PubMed

Cathcart, Mary-Clare; Reynolds, John V; O'Byrne, Kenneth J; Pidgeon, Graham P

2010-04-01

Prostacyclin synthase and thromboxane synthase signaling via arachidonic acid metabolism affects a number of tumor cell survival pathways such as cell proliferation, apoptosis, tumor cell invasion and metastasis, and angiogenesis. However, the effects of these respective synthases differ considerably with respect to the pathways described. While prostacyclin synthase is generally believed to be anti-tumor, a pro-carcinogenic role for thromboxane synthase has been demonstrated in a variety of cancers. The balance of oppositely-acting COX-derived prostanoids influences many processes throughout the body, such as blood pressure regulation, clotting, and inflammation. The PGI(2)/TXA(2) ratio is of particular interest in-vivo, with the corresponding synthases shown to be differentially regulated in a variety of disease states. Pharmacological inhibition of thromboxane synthase has been shown to significantly inhibit tumor cell growth, invasion, metastasis and angiogenesis in a range of experimental models. In direct contrast, prostacyclin synthase overexpression has been shown to be chemopreventive in a murine model of the disease, suggesting that the expression and activity of this enzyme may protect against tumor development. In this review, we discuss the aberrant expression and known functions of both prostacyclin synthase and thromboxane synthase in cancer. We discuss the effects of these enzymes on a range of tumor cell survival pathways, such as tumor cell proliferation, induction of apoptosis, invasion and metastasis, and tumor cell angiogenesis. As downstream signaling pathways of these enzymes have also been implicated in cancer states, we examine the role of downstream effectors of PGIS and TXS activity in tumor growth and progression. Finally, we discuss current therapeutic strategies aimed at targeting these enzymes for the prevention/treatment of cancer.

Turning science on robust cattle into improved genetic selection decisions.

PubMed

Amer, P R

2012-04-01

More robust cattle have the potential to increase farm profitability, improve animal welfare, reduce the contribution of ruminant livestock to greenhouse gas emissions and decrease the risk of food shortages in the face of increased variability in the farm environment. Breeding is a powerful tool for changing the robustness of cattle; however, insufficient recording of breeding goal traits and selection of animals at younger ages tend to favour genetic change in productivity traits relative to robustness traits. This paper has extended a previously proposed theory of artificial evolution to demonstrate, using deterministic simulation, how choice of breeding scheme design can be used as a tool to manipulate the direction of genetic progress, whereas the breeding goal remains focussed on the factors motivating individual farm decision makers. Particular focus was placed on the transition from progeny testing or mass selection to genomic selection breeding strategies. Transition to genomic selection from a breeding strategy where candidates are selected before records from progeny being available was shown to be highly likely to favour genetic progress in robustness traits relative to productivity traits. This was shown even with modest numbers of animals available for training and when heritability for robustness traits was only slightly lower than that for productivity traits. When transitioning from progeny testing to a genomic selection strategy without progeny testing, it was shown that there is a significant risk that robustness traits could become less influential in selection relative to productivity traits. Augmentations of training populations using genotyped cows and support for industry-wide improvements in phenotypic recording of robustness traits were put forward as investment opportunities for stakeholders wishing to facilitate the application of science on robust cattle into improved genetic selection schemes.

The Educational Progress of Women. Findings from "The Condition of Education 1995."

ERIC Educational Resources Information Center

Smith, Thomas M.

This fifth publication in the series "Findings from 'The Condition of Education'" summarizes educational differences between females and males that research has shown to be related to labor market outcomes. Differences in academic achievement, progression rates, types of courses taken, level of effort, and field of study may all affect the labor…

Year 3 Magnet Schools Assistance Program Annual Progress Report, 2009-10. E&R Report No. 10.09

ERIC Educational Resources Information Center

Brasfield, Jon; Cárdenas, Virginia

2010-01-01

The three Magnet Schools Assistance Program (MSAP) schools: East Garner International Baccalaureate Magnet Middle School (EGMMS), Garner International Baccalaureate Magnet High School (GMHS), and Southeast Raleigh Leadership and Technology Magnet High School (SRMHS) have shown progress on MSAP performance measures during the 3rd year of the grant.…

[Chronic kidney disease and dyslipidaemia].

PubMed

Pascual, Vicente; Serrano, Adalberto; Pedro-Botet, Juan; Ascaso, Juan; Barrios, Vivencio; Millán, Jesús; Pintó, Xavier; Cases, Aleix

Chronic kidney disease (CKD) has to be considered as a high, or even very high risk cardiovascular risk condition, since it leads to an increase in cardiovascular mortality that continues to increase as the disease progresses. An early diagnosis of CKD is required, together with an adequate identification of the risk factors, in order to slow down its progression to more severe states, prevent complications, and to delay, whenever possible, the need for renal replacement therapy. Dyslipidaemia is a factor of the progression of CKD that increases the risk in developing atherosclerosis and its complications. Its proper control contributes to reducing the elevated cardiovascular morbidity and mortality presented by these patients. In this review, an assessment is made of the lipid-lowering therapeutic measures required to achieve to recommended objectives, by adjusting the treatment to the progression of the disease and to the characteristics of the patient. In CKD, it seems that an early and intensive intervention of the dyslipidaemia is a priority before there is a significant decrease in kidney function. Treatment with statins has been shown to be safe and effective in decreasing LDL-Cholesterol, and in the reduction of cardiovascular events in individuals with CKD, or after renal transplant, although there is less evidence in the case of dialysed patients. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

Treg/Th17 balance in stable CAD patients with different stages of coronary atherosclerosis.

PubMed

Potekhina, Alexandra V; Pylaeva, Ekaterina; Provatorov, Sergey; Ruleva, Natalya; Masenko, Valery; Noeva, Elena; Krasnikova, Tatiana; Arefieva, Tatiana

2015-01-01

Objective. Immune processes play a significant role in atherosclerosis plaque progression. Regulatory T cells and T helpers 17 were shown to possess anti- and pro-atherogenic activity, respectively. We aimed to investigate the balance of circulating Treg and Th17 in stable angina patients with different stages of coronary atherosclerosis. Methods. Treg, Th17 and Th1 cell frequencies were studied in 117 patients via direct immunofluorescence staining and flow cytometry. Group 1 had intact coronary arteries. Group 2 and Group 3 had undergone previous coronary stenting; in Group 2 no coronary atherosclerosis progression was found, in Group 3 patients had disease progression in non-invaded coronary arteries. Group 4 had severe coronary atherosclerosis. Results. The frequencies of CD4+CD25highCD127low, CD4+foxp3+, and CD4+IL10 + T cells were decreased, and CD4+IL17 + T cells frequencies were increased in group 4 vs. 1. Treg/Th17 ratios were declined in groups 3 and 4 vs. groups 1 and 2. IL-10 level was lower while hsCRP and sCD25 levels were higher in group 4 vs. 1. Conclusion. We assume that the imbalance in pro- and anti-inflammatory/atherogenic lymphocyte subpopulations is associated with atherosclerosis progression. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

How preserved is episodic memory in behavioral variant frontotemporal dementia?

PubMed

Hornberger, M; Piguet, O; Graham, A J; Nestor, P J; Hodges, J R

2010-02-09

Studies have shown variable memory performance in patients with behavioral variant frontotemporal dementia (bvFTD). Our study investigated whether this variability is due to the admixture of patients with true bvFTD and phenocopy patients. We also sought to compare performance of patients with bvFTD and patients with Alzheimer disease (AD). We analyzed neuropsychological memory performance in patients with a clinical diagnosis of bvFTD divided into those who progressed (n = 50) and those who remained stable (n = 39), patients with AD (n = 64), and healthy controls (n = 64). Patients with progressive bvFTD were impaired on most memory tests to a similar level to that of patients with early AD. Findings from a subset of patients with progressive bvFTD with confirmed FTLD pathology (n = 10) corroborated these findings. By contrast, patients with phenocopy bvFTD performed significantly better than progressors and patients with AD. Logistic regression revealed that patients with bvFTD can be distinguished to a high degree (85%) on the immediate recall score of a word list learning test (Rey Auditory Verbal Learning Test). Our results provide evidence for an underlying memory deficit in "real" or progressive behavioral variant frontotemporal dementia (bvFTD) similar to Alzheimer disease, though the groups differ in orientation scores, with patients with bvFTD being intact. Exclusion solely based on impaired neuropsychological memory performance can potentially lead to an underdiagnosis of FTD.

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

Liao, Xiao-hui; Zhang, Ling, E-mail: lindazhang8508@hotmail.com; Chen, Guo-tao

Tubular epithelial-to-mesenchymal transition (EMT) plays a crucial role in the progression of renal tubular interstitial fibrosis (TIF), which subsequently leads to chronic kidney disease (CKD) and eventually, end-stage renal disease (ESRD). We propose that augmenter of liver regeneration (ALR), a member of the newly discovered ALR/Erv1 protein family shown to ameliorate hepatic fibrosis, plays a similar protective role in renal tubular cells and has potential as a new treatment option for CKD. Here, we showed that recombinant human ALR (rhALR) inhibits EMT in renal tubular cells by antagonizing activation of the transforming growth factor-β1 (TGF-β1) signaling pathway. Further investigation revealedmore » that rhALR suppresses the expression of TGF-β receptor type II (TβR II) and significantly alleviates TGF-β1-induced phosphorylation of Smad2 and nuclear factor-κB (NF-κB). No apparent adverse effects were observed upon the addition of rhALR alone to cells. These findings collectively suggest that ALR plays a role in inhibiting progression of renal tubular EMT, supporting its potential utility as an effective antifibrotic strategy to reverse TIF in CKD. - Highlights: • ALR is involved in the pathological progression of renal EMT in NRK-52E cells. • ALR suppresses the expression of TβRII and the phosphorylation of Smad2 and NF-κB. • ALR plays a role in inhibiting progression of renal tubular EMT.« less

The E3 ligase for metastasis associated 1 protein, TRIM25, is targeted by microRNA-873 in hepatocellular carcinoma.

PubMed

Li, Yu-Hui; Zhong, Ming; Zang, Hong-Liang; Tian, Xiao-Feng

2018-07-01

Tumor metastasis accounts for 90% of all cancer-related deaths. Epithelial to mesenchymal transition (EMT) considered to be centrally important in acquired resistance to chemotherapy and in progression of tumors to secondary organs. One of the important mediators of metastatic progression in hepatocellular carcinoma (HCC) is the metastasis associated protein 1 (MTA-1). We have earlier shown that in the context of HCC and normal liver cell lines, MTA-1 protein is actively stabilized in HCC cell lines and actively degraded in normal liver cells. We have also shown that TRIM25 is the E3 ligase that interacts with and degrades MTA-1 protein. The identity of the factor regulating expression of TRIM25 in normal liver cells and HCC is unknown. In the current work we elucidate that microRNA (miR)- 873 targets TRIM25 in HCC cells. Both metagenomic analysis and quantification of miR-873 and TRIM25 in 25 HCC patients revealed an inverse correlation between the two in HCC patients with high miR-873 and low TRIM25 expression, respectively. The expression pattern was mimicked in the normal liver cells THLE-2 and the HCC cell line, HuH6. In vitro luciferase reporter assays confirmed TRIM25 as the target of miR-873. Transient transfection of HuH6 cells with an anti-miR-873 antagomir significantly decreased both transwell motility in these cells. Furthermore, in in vivo xenograft assays treatment with anti-miR-873 antagomir significantly decreased hepatic nodules formation. Cumulatively, our data indicate that suppression of TRIM25 expression by high levels of miR-873 dictates MTA1 protein upregulation in HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

A review of a novel, Bruton's tyrosine kinase inhibitor, ibrutinib.

PubMed

Lee, Chung-Shien; Rattu, Mohammad A; Kim, Sara S

2016-02-01

Ibrutinib, a Bruton's kinase inhibitor, was granted an accelerated approval by the US Food and Drug Administration in November, 2013, for the treatment of relapsed or refractory mantle cell lymphoma and subsequently for the treatment of relapsed refractory chronic lymphocytic leukemia in February, 2014. In the pivotal phase 2 study of 111 patients with relapsed or refractory mantle cell lymphoma, the overall response rate in patients who received ibrutinib 560 mg daily was 68%. The median progression-free survival was 13.9 months, and the overall survival was 58% at 18 months. In a recently published phase 3 trial (RESONATE) that compared ibrutinib and ofatumumab for the treatment of relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, ibrutinib at the daily dosage of 420 mg demonstrated a significantly higher overall response rate (43% in ibrutinib vs. 4% in ofatumumab) and a significantly improved overall survival at 12 months (90% ibrutinib vs. 81% ofatumumab). Similar clinical benefits were shown regardless of del (17 p). Ibrutinib was well tolerated, and dose-limiting toxicity was not observed. Ibrutinib has shown durable remission, improved progression-free survival and overall survival, and favorable safety profile in indolent B-cell lymphoid malignancies. Ibrutinib, as a monotherapy, is an effective treatment modality as a salvage therapy for treatment of mantle cell lymphoma and chronic lymphocytic leukemia / small lymphocytic lymphoma, particularly in older patients (age ≥70 years) who are not a candidate for intensive chemotherapy and/or those with del (17 p). In patients with chronic lymphocytic leukemia and del (17 p), the current practice guideline recommends ibrutinib as an upfront treatment option. Current on-going trials will further define its role as upfront therapy and/or as a combination therapy in indolent B-cell lymphoid malignancies. © The Author(s) 2014.

Classroom interactions: exploring the practices of high- and low-expectation teachers.

PubMed

Rubie-Davies, Christine M

2007-06-01

Early research exploring teacher expectations concentrated on the dyadic classroom interactions of teachers with individual students. More recent studies have shown whole class factors to have more significance in portraying teachers' expectations. Recently teachers having high or low expectations for all their students have been identified. The aim of the current investigation was to explore whether the classroom exchanges of high- and low-expectation teachers differed substantially and might be considered a mechanism for teachers' expectations. The participants were 12 primary school teachers from eight schools who had been identified as having expectations for their students' learning that were either significantly above or below the children's achievement level. The teachers formed three groups called high-expectation, low-expectation and average-progress teachers. The participants were observed twice in the academic year during half-hour reading lessons. Two people observed each lesson, one completing a structured observation protocol and the other a running record and audiotape. In contrast to the average progress and low expectation teachers, the high-expectation teachers spent more time providing a framework for students' learning, provided their students with more feedback, questioned their students using more higher-order questions, and managed their students' behaviour more positively. There appear to be important differences in the classroom environments for the students of high-expectation, average-progress and low-expectation teachers. The differences apply to both the instructional and socioemotional environments of the classroom. Such disparities may act as mechanisms for teacher expectation effects.

Evaluation of the Medical Academic Community of Bosnia and Herzegovina Based on Scopus Parameters.

PubMed

Masic, Izet

2017-06-01

The academic community of Bosnia and Herzegovina (B&H) is represented by four Academies, which include eminent personalities in the field of medical sciences (Academy of Sciences and Arts of Bosnia and Herzegovina, Department for Medical Sciences (ANUBiH), Academy of Sciences and Arts of the Republika Srpska (ANURS), Croatian Academy of Sciences and Arts in BiH (HAZU B&H), and the Academy of Medical Sciences of Bosnia and Herzegovina (AMNuBiH)). To present scientometric analysis of members of the medical sphere of the ANUBiH, ANURS, HAZU B&H and AMNuBiH, to evaluate members and their scientific rating. The work has an analytical character and presents analysis of the data obtained from the Scopus database. Results are shown through number of cases, percentage, arithmetic mean, standard deviation, median and interquartile range, with Spearman's rank correlation coefficient. The analysis showed a significant correlation between the Academy and the country of origin of the academician. In AMNuBiH and ANUBiH are mainly represented academics originating from Bosnia and Herzegovina, while ANURS, 71.4% of the members, are academics with background from Serbia. There is no significant correlation between the observed parameters (Scopus parameters-number of papers, H index, number of citations) according to memberschip in Academies. By analyzing the correlation between the country of residence, the number of papers, H index and the number of citations, it has been shown that the correlation is significant between the state and the number of papers, but not the other two observed parameters. Criteria for admission to main academic communities are highly questionable, as this analysis showed. Progress in the academic hierarchy must be more stringent, and the criteria must be set to the highest possible level, as this is the only path which leads to progress.

Evaluation of the Medical Academic Community of Bosnia and Herzegovina Based on Scopus Parameters

PubMed Central

Masic, Izet

2017-01-01

Introduction: The academic community of Bosnia and Herzegovina (B&H) is represented by four Academies, which include eminent personalities in the field of medical sciences (Academy of Sciences and Arts of Bosnia and Herzegovina, Department for Medical Sciences (ANUBiH), Academy of Sciences and Arts of the Republika Srpska (ANURS), Croatian Academy of Sciences and Arts in BiH (HAZU B&H), and the Academy of Medical Sciences of Bosnia and Herzegovina (AMNuBiH)). Aim: To present scientometric analysis of members of the medical sphere of the ANUBiH, ANURS, HAZU B&H and AMNuBiH, to evaluate members and their scientific rating. Material and methods: The work has an analytical character and presents analysis of the data obtained from the Scopus database. Results are shown through number of cases, percentage, arithmetic mean, standard deviation, median and interquartile range, with Spearman’s rank correlation coefficient. Results: The analysis showed a significant correlation between the Academy and the country of origin of the academician. In AMNuBiH and ANUBiH are mainly represented academics originating from Bosnia and Herzegovina, while ANURS, 71.4% of the members, are academics with background from Serbia. There is no significant correlation between the observed parameters (Scopus parameters–number of papers, H index, number of citations) according to memberschip in Academies. By analyzing the correlation between the country of residence, the number of papers, H index and the number of citations, it has been shown that the correlation is significant between the state and the number of papers, but not the other two observed parameters. Conclusion: Criteria for admission to main academic communities are highly questionable, as this analysis showed. Progress in the academic hierarchy must be more stringent, and the criteria must be set to the highest possible level, as this is the only path which leads to progress. PMID:28974826

Discussion on the progress and future of satellite communication (Japan)

NASA Technical Reports Server (NTRS)

Ogata, M.; Mizusawa, H.; Irie, K.

1985-01-01

The current status of communications satellite development in Japan is presented. It is shown that beginning with research on satellite communucations in the late 1950's, progress was made in the areas of communications, remote sensing, and technology experimentation. The current status of communication satellites is presented, stressing development in the areas of CFRP construction elements, the use of LSI and MIC circuits, advanced multibeam antenna systems, Ku and Ka band transmission systems, and the shift to small-scale earth stations. Methods for reducing costs and increasing transmission efficiency are shown. The technical specifications of all satellite projects currently under development are given. Users of Japanese communications satellite are presented.

CO2 laser irradiation enhances CaF2 formation and inhibits lesion progression on demineralized dental enamel-in vitro study.

PubMed

Zancopé, Bruna R; Rodrigues, Lívia P; Parisotto, Thais M; Steiner-Oliveira, Carolina; Rodrigues, Lidiany K A; Nobre-dos-Santos, Marinês

2016-04-01

This study evaluated if Carbon dioxide (CO2) (λ 10.6 μm) laser irradiation combined with acidulated phosphate fluoride gel application (APF gel) enhances "CaF2" uptake by demineralized enamel specimens (DES) and inhibits enamel lesion progression. Thus, two studies were conducted and DES were subjected to APF gel combined or not with CO2 laser irradiation (11.3 or 20.0 J/cm(2), 0.4 or 0.7 W) performed before, during, or after APF gel application. In study 1, 165 DES were allocated to 11 groups. Fluoride as "CaF2 like material" formed on enamel was determined in 100 DES (n = 10/group), and the surface morphologies of 50 specimens were evaluated by scanning electron microscopy (SEM) before and after "CaF2" extraction. In study 2, 165 DES (11 groups, n = 15), subjected to the same treatments as in study 1, were further subjected to a pH-cycling model to simulate a high cariogenic challenge. The progression of demineralization in DES was evaluated by cross-sectional microhardness and polarized light microscopy analyses. Laser at 11.3 J/cm(2) applied during APF gel application increased "CaF2" uptake on enamel surface. Laser irradiation and APF gel alone arrested the lesion progression compared with the control (p < 0.05). Areas of melting, fusion, and cracks were observed. CO2 laser irradiation, combined with a single APF application enhanced "CaF2" uptake on enamel surface and a synergistic effect was found. However, regarding the inhibition of caries lesion progression, no synergistic effect could be demonstrated. In conclusion, the results have shown that irradiation with specific laser parameters significantly enhanced CaF2 uptake by demineralized enamel and inhibited lesion progression.

Does cannabidiol have a role in the treatment of schizophrenia?

PubMed

Gururajan, Anand; Malone, Daniel Thomas

2016-10-01

Schizophrenia is a debilitating psychiatric disorder which places a significant emotional and economic strain on the individual and society-at-large. Unfortunately, currently available therapeutic strategies do not provide adequate relief and some patients are treatment-resistant. In this regard, cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, has shown significant promise as a potential antipsychotic for the treatment of schizophrenia. However, there is still considerable uncertainty about the mechanism of action of CBD as well as the brain regions which are thought to mediate its putative antipsychotic effects. We argue that further research on CBD is required to fast-track its progress to the clinic and in doing so, we may generate novel insights into the neurobiology of schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

Recent updates of precision therapy for gastric cancer: Towards optimal tailored management.

PubMed

Joo, Moon Kyung; Park, Jong-Jae; Chun, Hoon Jai

2016-05-21

Signaling pathways of gastric carcinogenesis and gastric cancer progression are being avidly studied to seek optimal treatment of gastric cancer. Among them, hepatocyte growth factor (HGF)/c-MET, phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathways have been widely investigated. Their aberrant expression or mutation has been significantly associated with advanced stage or poor prognosis of gastric cancer. Recently, aberrations of immune checkpoints including programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) have been suggested as an important step in the formation of a microenvironment favorable for gastric cancer. Accomplishments in basic research have led to the development of novel agents targeting these signaling pathways. However, phase III studies of selective anti-HGF/c-MET antibodies and mTOR inhibitor failed to show significant benefits in terms of overall survival and progression-free survival. Few agents directly targeting STAT3 have been developed. However, this target is still critical issue in terms of chemoresistance, and SH2-containing protein tyrosine phosphatase 1 might be a significant link to effectively inhibit STAT3 activity. Inhibition of PD-1/PD-L1 showed durable efficacy in phase I studies, and phase III evaluation is warranted. Therapeutic strategy to concurrently inhibit multiple tyrosine kinases is a reasonable option, however, lapatinib needs to be further evaluated to identify good responders. Regorafenib has shown promising effectiveness in prolonging progression-free survival in a phase II study. In this topic highlight, we review the biologic roles and outcomes of clinical studies targeting these signaling pathways.

Clinical Factors Predicting Detection of T790M Mutation in Rebiopsy for EGFR-Mutant Non-small-cell Lung Cancer.

PubMed

Kawamura, Takahisa; Kenmotsu, Hirotsugu; Omori, Shota; Nakashima, Kazuhisa; Wakuda, Kazushige; Ono, Akira; Naito, Tateaki; Murakami, Haruyasu; Omae, Katsuhiro; Mori, Keita; Tanigawara, Yusuke; Nakajima, Takashi; Ohde, Yasuhisa; Endo, Masahiro; Takahashi, Toshiaki

2018-03-01

T790M, a secondary epidermal growth factor receptor (EGFR) mutation, accounts for approximately 50% of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs). To facilitate the use of third-generation EGFR-TKIs to potentially overcome T790M-mediated resistance, we evaluated the clinical factors influencing the incidence of T790M mutation. We retrospectively screened patients with non-small-cell lung cancer harboring EGFR mutations with progressive disease who were rebiopsied between January 2013 and December 2016. Factors influencing T790M status were evaluated by univariate and multivariate analysis. Among 131 rebiopsied patients for whom EGFR mutation status was available, 58 (44%) had T790M mutations. Patient characteristics at rebiopsy were not significantly different between T790M-positive and -negative groups, except for surgical history (postsurgery recurrence). Total duration of EGFR-TKI treatment before rebiopsy, TKI-free interval, EGFR-TKI treatment history immediately before rebiopsy, continuation of initial EGFR-TKI beyond progressive disease, progression-free survival after initial TKI treatment, and rebiopsy site (other than fluid samples) significantly influenced T790M status. The incidence of T790M mutation was shown by multivariate analysis to be significantly higher in patients with postsurgery recurrence and total duration of EGFR-TKI treatment ≥ 1 year before rebiopsy (odds ratio, 4.2; 95% confidence interval, 1.3-15.7 and odds ratio, 4.4; 95% confidence interval, 1.1-19.8, respectively). Postsurgery recurrence and longer total duration of EGFR-TKI treatment before rebiopsy may represent useful predictive markers for T790M detection. In patients with these clinical factors, rebiopsies are more recommended to detect T790M mutation. Copyright © 2017 Elsevier Inc. All rights reserved.

Ductular reaction in hereditary hemochromatosis: the link between hepatocyte senescence and fibrosis progression.

PubMed

Wood, Marnie J; Gadd, Victoria L; Powell, Lawrie W; Ramm, Grant A; Clouston, Andrew D

2014-03-01

The development of portal fibrosis following the iron loading of hepatocytes is the first stage of fibrogenesis in hereditary hemochromatosis. In other chronic liver diseases it has been shown that a ductular reaction (DR) appears early, correlates with fibrosis progression, and is a consequence of activation of an alternative pathway of hepatocyte replication. This study was designed to investigate the presence of the DR in hemochromatosis and describe its associations. Liver biopsies from 63 C282Y homozygous patients were assessed for hepatic iron concentration (HIC) and graded for iron loading, fibrosis stage, steatosis, and inflammation. Immunostaining allowed quantification of the DR, hepatocyte senescence and proliferation, and analysis incorporated clinical data. Hepatocyte senescence was positively correlated with HIC, serum ferritin, and oxidative stress. A DR was demonstrated and occurred prior to histological fibrosis. HIC, age, hepatocyte senescence and proliferation, portal inflammation, and excessive alcohol consumption all had significant associations with the extent of the DR. In multivariate analysis, iron loading, hepatocyte replicative arrest, and portal inflammation remained independently and significantly associated with the DR. Of factors associated with fibrosis progression, the DR (odds ratio [OR] 10.86 P<0.0001) and the presence of portal inflammation (OR 4.31, P=0.028) remained significant after adjustment for cofactors. The extent of the DR regressed following therapeutic venesection. Iron loading of hepatocytes leads to impaired replication, stimulating the development of the DR in hemochromatosis and this correlates strongly with hepatic fibrosis. Portal inflammation occurs in hemochromatosis and is independently associated with the DR and fibrosis, and thus its role in this disease should be evaluated further. © 2014 by the American Association for the Study of Liver Diseases.

Increasing methylation of the calcitonin gene during disease progression in sequential samples from CML patients.

PubMed

Mills, K I; Guinn, B A; Walsh, V A; Burnett, A K

1996-09-01

In chronic myeloid leukaemia (CML), disease progression from the initial chronic phase to the acute phase or blast crisis has previously been shown to be correlated with progressive increases in hyper-methylation of the calcitonin gene, located at chromosome 11p15. However, sequential studies of individual patients were not performed in these investigations. We have analysed 44 samples from nine patients with typical Philadelphia chromosome positive CML throughout their disease progression to determine the methylation state of the calcitonin gene at these time points. Densitometry was used to quantitate the ratio of the normal 2.0 kb Hpa II fragments, indicating normal methylation status of the gene, compared to the intensity of the abnormal, hyper-methylated, 2.6-3.1 kb Hpa II fragments. We found a gradual increase in the ratio of methylated:unmethylated calcitonin gene during chronic phase with a dramatic rise at blast crisis. Further, the ratio of the abnormal hypermethylated 3.1 kb fragments to the methylated 2.6 kb fragment resulted in the identification of a clonal expansion of abnormally methylated cells. This expansion of cells with hypermethylation of the calcitonin gene during chronic phase was shown to coincide with the presence of a mutation in the p53 gene. The data presented in this study would suggest that an increased methylation status of the calcitonin gene during disease progression may indicate the expansion of abnormal blast cell populations and subsequent progression to blast crisis.

Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors.

PubMed

Roussos, Evanthia T; Wang, Yarong; Wyckoff, Jeffrey B; Sellers, Rani S; Wang, Weigang; Li, Jiufeng; Pollard, Jeffrey W; Gertler, Frank B; Condeelis, John S

2010-01-01

The actin binding protein Mammalian enabled (Mena), has been implicated in the metastatic progression of solid tumors in humans. Mena expression level in primary tumors is correlated with metastasis in breast, cervical, colorectal and pancreatic cancers. Cells expressing high Mena levels are part of the tumor microenvironment for metastasis (TMEM), an anatomical structure that is predictive for risk of breast cancer metastasis. Previously we have shown that forced expression of Mena adenocarcinoma cells enhances invasion and metastasis in xenograft mice. Whether Mena is required for tumor progression is still unknown. Here we report the effects of Mena deficiency on tumor progression, metastasis and on normal mammary gland development. To investigate the role of Mena in tumor progression and metastasis, Mena deficient mice were intercrossed with mice carrying a transgene expressing the polyoma middle T oncoprotein, driven by the mouse mammary tumor virus. The progeny were investigated for the effects of Mena deficiency on tumor progression via staging of primary mammary tumors and by evaluation of morbidity. Stages of metastatic progression were investigated using an in vivo invasion assay, intravital multiphoton microscopy, circulating tumor cell burden, and lung metastases. Mammary gland development was studied in whole mount mammary glands of wild type and Mena deficient mice. Mena deficiency decreased morbidity and metastatic dissemination. Loss of Mena increased mammary tumor latency but had no affect on mammary tumor burden or histologic progression to carcinoma. Elimination of Mena also significantly decreased epidermal growth factor (EGF) induced in vivo invasion, in vivo motility, intravasation and metastasis. Non-tumor bearing mice deficient for Mena also showed defects in mammary gland terminal end bud formation and branching. Deficiency of Mena decreases metastasis by slowing tumor progression and reducing tumor cell invasion and intravasation. Mena deficiency during development causes defects in invasive processes involved in mammary gland development. These findings suggest that functional intervention targeting Mena in breast cancer patients may provide a valuable treatment option to delay tumor progression and decrease invasion and metastatic spread leading to an improved prognostic outcome.

Sporadic Jakob-Creutzfeldt Disease Presenting as Primary Progressive Aphasia

PubMed Central

Johnson, David Y.; Dunkelberger, Diana L.; Henry, Maya; Haman, Aissatou; Greicius, Michael D.; Wong, Katherine; DeArmond, Stephen J.; Miller, Bruce L.; Gorno-Tempini, Maria Luisa; Geschwind, Michael D.

2015-01-01

Objective To report the clinical, neuropsychological, linguistic, imaging, and neuropathological features of a unique case of sporadic Jakob-Creutzfeldt disease in which the patient presented with a logopenic variant of primary progressive aphasia. Design Case report. Setting Large referral center for atypical memory and aging disorders, particularly Jakob-Creutzfeldt disease. Patient Patient presenting with logopenic variant primary progressive aphasia initially thought to be due to Alzheimer disease. Results Despite the long, slow 3.5-year course, the patient was shown to have pathology-proven sporadic Jakob-Creutzfeldt disease. Conclusions These findings expand the differential of primary progressive aphasia to include prion disease. PMID:23400721

Micronutrients, N-Acetyl Cysteine, Probiotics and Prebiotics, a Review of Effectiveness in Reducing HIV Progression

PubMed Central

Hummelen, Ruben; Hemsworth, Jaimie; Reid, Gregor

2010-01-01

Low serum concentrations of micronutrients, intestinal abnormalities, and an inflammatory state have been associated with HIV progression. These may be ameliorated by micronutrients, N-acetyl cysteine, probiotics, and prebiotics. This review aims to integrate the evidence from clinical trials of these interventions on the progression of HIV. Vitamin B, C, E, and folic acid have been shown to delay the progression of HIV. Supplementation with selenium, N-acetyl cysteine, probiotics, and prebiotics has considerable potential, but the evidence needs to be further substantiated. Vitamin A, iron, and zinc have been associated with adverse effects and caution is warranted for their use. PMID:22254046

Effects of episodic future thinking on discounting: Personalized age-progressed pictures improve risky long-term health decisions.

PubMed

Kaplan, Brent A; Reed, Derek D; Jarmolowicz, David P

2016-03-01

Many everyday choices are associated with both delayed and probabilistic outcomes. The temporal attention hypothesis suggests that individuals' decision making can be improved by focusing attention on temporally distal events and implies that environmental manipulations that bring temporally distal outcomes into focus may alter an individual's degree of discounting. One such manipulation, episodic future thinking, has shown to lower discount rates; however, several questions remain about the applicability of episodic future thinking to domains other than delay discounting. The present experiments examine the effects of a modified episodic-future-thinking procedure in which participants viewed age-progressed computer-generated images of themselves and answered questions related to their future, on probability discounting in the context of both a delayed health gain and loss. Results indicate that modified episodic future thinking effectively altered individuals' degree of discounting in the predicted directions and demonstrate the applicability of episodic future thinking to decision making of socially significant outcomes. © 2015 Society for the Experimental Analysis of Behavior.

[Vascular aging, arterial hypertension and physical activity].

PubMed

Schmidt-Trucksäss, A; Weisser, B

2011-11-01

The present review delineates the significance of intima-media-thickness, arterial stiffness and endothelial function for vascular aging. There is profound evidence for an increase in intima-media-thickness and vascular stiffness not only during healthy aging but induced also by cardiovascular risk factors. There is a central role of arterial hypertension for this progression in both structural factors. In addition, both parameters are strongly associated with cardiovascular risk. Endothelial function measured as postischemic flow-mediated vasodilatation is a functional parameter which is decreased both in healthy aging and by cardiovascular risk factors. Physical activity modifies the influence of aging and risk factors on endothelial function. A positive influence of endurance exercise on vascular stiffness and endothelial function has been demonstrated in numerous studies. In long-term studies, regular physical activity has been shown to reduce the progression of intima-media-thickness. Thus, arterial hypertension accelerates vascular aging, while physical activity has a positive influence on a variety of vascular parameters associated with vascular aging. © Georg Thieme Verlag KG Stuttgart · New York.

Role of rasagiline in treating Parkinson's disease: Effect on disease progression.

PubMed

Malaty, Irene A; Fernandez, Hubert H

2009-08-01

Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B) inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson's disease (PD) patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients), and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of "Off", and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily). Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily) and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration.

Pemetrexed in previously treated non-small-cell lung cancer.

PubMed

Rosell, Rafael; Sanchez, Jose Miguel; Taron, Miquel; Moran, Teresa; Ciuraqui, Beatriz; Canela, Mercedes; Felip, Enriqueta; Massuti, Bartomeu; Camps, Carlos

2004-07-01

Several decades of chemotherapy trials in non-small-cell lung cancer (NSCLC) have clearly shown a survival benefit for chemotherapy over best supportive care. However, only short-lived responses are attained, with an average of four cycles of chemotherapy, before tumor progression is observed. Second-line chemotherapy has been demonstrated to improve outcome, with docetaxel (Taxotere) as the predominant cytotoxic drug. A recent randomized trial in second-line NSCLC indicated that the novel drug pemetrexed (Alimta) attained the same response, time to progression, and survival as docetaxel. This finding ushers in a new age in second-line treatment that can be further invigorated by the addition of targeted agents. Accumulated evidence indicates that overexpression of epidermal growth factor receptor and HER2/neu, which occurs frequently in NSCLC, leads to the deregulation of PI3K and MAPK, activating Akt and enhancing chemoresistance. Future clinical trials in NSCLC will include tailored and multitargeted therapy and pemetrexed represents a significant step forward in this direction.

Neuroprotective effects of phytochemicals on dopaminergic neuron cultures.

PubMed

Sandoval-Avila, S; Diaz, N F; Gómez-Pinedo, U; Canales-Aguirre, A A; Gutiérrez-Mercado, Y K; Padilla-Camberos, E; Marquez-Aguirre, A L; Díaz-Martínez, N E

2016-06-21

Parkinson's disease is a progressive neurodegenerative disorder characterised by a loss of dopaminergic neurons in the substantia nigra pars compacta, which results in a significant decrease in dopamine levels and consequent functional motor impairment. Although its aetiology is not fully understood, several pathogenic mechanisms, including oxidative stress, have been proposed. Current therapeutic approaches are based on dopamine replacement drugs; these agents, however, are not able to stop or even slow disease progression. Novel therapeutic approaches aimed at acting on the pathways leading to neuronal dysfunction and death are under investigation. In recent years, such natural molecules as polyphenols, alkaloids, and saponins have been shown to have a neuroprotective effect due to their antioxidant and anti-inflammatory properties. The aim of our review is to analyse the most relevant studies worldwide addressing the benefits of some phytochemicals used in in vitro models of Parkinson's disease. Copyright © 2016 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Cardiac considerations in the operative management of the patient with Duchenne or Becker muscular dystrophy.

PubMed

Cripe, Linda H; Tobias, Joseph D

2013-09-01

Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) is a progressive multisystem neuromuscular disorder. In addition to the skeletal muscle, the myocardium in the DMD/BMD patient is dystrophin deficient which results in a progressive cardiomyopathy. The myopathic myocardium poses significant risk of increased morbidity and mortality at the time of major surgical procedures. Careful attention must be given to the DMD/BMD patient during the intraoperative and postoperative period. Anesthesia selection is critical and anesthetics should be avoided which have been shown to be harmful in this patient population. Preanesthesia assessment should include cardiac consultation and detailed preoperative evaluation. Intraoperative management needs to insure that the weakened myocardium is not compromised by physiologic changes such as hypotension or major fluid shifts. Finally, attention to the cardiac status of the patient must continue into the postoperative period. The surgical care of the DMD/BMD patient requires a multispecialty approach to insure operative success. © 2013 John Wiley & Sons Ltd.

Developing a Domain Theory Defining and Exemplifying a Learning Theory of Progressive Attainments

ERIC Educational Resources Information Center

Bunderson, C. Victor

2011-01-01

This article defines the concept of Domain Theory, or, when educational measurement is the goal, one might call it a "Learning Theory of Progressive Attainments in X Domain". The concept of Domain Theory is first shown to be rooted in validity theory, then the concept of domain theory is expanded to amplify its necessary but long neglected…

Ovarian function's role during cancer cachexia progression in the female mouse.

PubMed

Hetzler, Kimbell L; Hardee, Justin P; LaVoie, Holly A; Murphy, E Angela; Carson, James A

2017-05-01

Cachexia is a debilitating condition that occurs with chronic disease, including cancer; our research has shown that some regulation of cancer cachexia progression is affected by sex differences. The Apc Min/+ mouse is genetically predisposed to develop intestinal tumors; IL-6 signaling and hypogonadism are associated with cachexia severity in the male. This relationship in the female warrants further investigation, as we have shown that the ability of IL-6 to induce cachexia differs between the sexes. Since ovarian reproductive function relies on a complex system of endocrine signaling to affect whole body homeostasis, we examined the relationship between ovarian reproductive function and progression of cancer cachexia in the female Apc Min/+ mouse. Our study of ovarian reproductive function in female Apc Min/+ mice showed disease-related cessation of estrous cycling (acyclicity) in 38% of mice. Acyclicity, including morphological and functional losses and enhanced muscle inflammatory gene expression, was associated with severe cachexia. Interestingly, ovariectomy rescued body weight and muscle mass and function but increased muscle sensitivity to systemic IL-6 overexpression. In conclusion, our results provide evidence for a relationship between ovarian reproductive function and cachexia progression in female Apc Min/+ mice. Copyright © 2017 the American Physiological Society.

Ovarian function’s role during cancer cachexia progression in the female mouse

PubMed Central

Hetzler, Kimbell L.; Hardee, Justin P.; LaVoie, Holly A.; Murphy, E. Angela

2017-01-01

Cachexia is a debilitating condition that occurs with chronic disease, including cancer; our research has shown that some regulation of cancer cachexia progression is affected by sex differences. The ApcMin/+ mouse is genetically predisposed to develop intestinal tumors; IL-6 signaling and hypogonadism are associated with cachexia severity in the male. This relationship in the female warrants further investigation, as we have shown that the ability of IL-6 to induce cachexia differs between the sexes. Since ovarian reproductive function relies on a complex system of endocrine signaling to affect whole body homeostasis, we examined the relationship between ovarian reproductive function and progression of cancer cachexia in the female ApcMin/+ mouse. Our study of ovarian reproductive function in female ApcMin/+ mice showed disease-related cessation of estrous cycling (acyclicity) in 38% of mice. Acyclicity, including morphological and functional losses and enhanced muscle inflammatory gene expression, was associated with severe cachexia. Interestingly, ovariectomy rescued body weight and muscle mass and function but increased muscle sensitivity to systemic IL-6 overexpression. In conclusion, our results provide evidence for a relationship between ovarian reproductive function and cachexia progression in female ApcMin/+ mice. PMID:28292759

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma.

PubMed

Macha, Muzafar A; Batra, Surinder K; Ganti, Apar Kishor

2013-01-01

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC.

Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma

PubMed Central

Macha, Muzafar A; Batra, Surinder K; Ganti, Apar Kishor

2013-01-01

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC. PMID:23940421

Photometry of icy satellites: How important is multiple scattering in diluting shadows?

NASA Technical Reports Server (NTRS)

Buratti, B.; Veverka, J.

1984-01-01

Voyager observations have shown that the photometric properties of icy satellites are influenced significantly by large-scale roughness elements on the surfaces. While recent progress was made in treating the photometric effects of macroscopic roughness, it is still the case that even the most complete models do not account for the effects of multiple scattering fully. Multiple scattering dilutes shadows caused by large-scale features, yet for any specific model it is difficult to calculate the amount of dilution as a function of albedo. Accordingly, laboratory measurements were undertaken using the Cornell Goniometer to evaluate the magnitude of the effect.

The Ree and ɛNd of 40-70 Ma old fish debris from the west-African platform

NASA Astrophysics Data System (ADS)

Grandjean, Patricia; Cappetta, Henri; Albarède, Francis

1988-04-01

REE concentrations and Nd isotopic compositions have been determined in Late Cretaceous-Early Cenozoic fish debris from West African and Israeli platform sediments and show a strong regional control independent of time, except for those from the Northern Morocco. It is suggested that, although diagenetic fluids do not contribute REE's directly to the phosphatic debris, they may significantly change the Ce anomaly and the ɛNd(T) value of the epicontinental seas, which, in turn, control the REE in marine phosphates. It is shown that, over the investigated period, the North Moroccan shelf seawater was progressively flushed by deep North-Atlantic water.

Extracting diagnostic stromal organization features based on intrinsic two-photon excited fluorescence and second-harmonic generation signals

NASA Astrophysics Data System (ADS)

Zhuo, Shuangmu; Chen, Jianxin; Xie, Shusen; Hong, Zhibin; Jiang, Xingshan

2009-03-01

Intrinsic two-photon excited fluorescence (TPEF) and second-harmonic generation (SHG) signals are shown to differentiate between normal and neoplastic human esophageal stroma. It was found that TPEF and SHG signals from normal and neoplastic stroma exhibit different organization features, providing quantitative information about the biomorphology and biochemistry of tissue. By comparing normal with neoplastic stroma, there were significant differences in collagen-related changes, elastin-related changes, and alteration in proportions of matrix molecules, giving insight into the stromal changes associated with cancer progression and providing substantial potential to be applied in vivo to the clinical diagnosis of epithelial precancers and cancers.

ZnO nanoparticles applied to bioimaging and drug delivery.

PubMed

Xiong, Huan-Ming

2013-10-04

The last decade has seen significant achievements in biomedical diagnosis and therapy at the levels of cells and molecules. Nanoparticles with luminescent or magnetic properties are used as detection probes and drug carriers, both in vitro and in vivo. ZnO nanoparticles, due to their good biocompatibility and low cost, have shown promising potential in bioimaging and drug delivery. The recent exciting progress on the biomedical applications of ZnO-based nanomaterials is reviewed here, along with discussions on the advantages and limitations of these advanced materials and suggestions for improving methods. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Next-generation organic photovoltaics based on non-fullerene acceptors

NASA Astrophysics Data System (ADS)

Cheng, Pei; Li, Gang; Zhan, Xiaowei; Yang, Yang

2018-03-01

Over the past three years, a particularly exciting and active area of research within the field of organic photovoltaics has been the use of non-fullerene acceptors (NFAs). Compared with fullerene acceptors, NFAs possess significant advantages including tunability of bandgaps, energy levels, planarity and crystallinity. To date, NFA solar cells have not only achieved impressive power conversion efficiencies of 13-14%, but have also shown excellent stability compared with traditional fullerene acceptor solar cells. This Review highlights recent progress on single-junction and tandem NFA solar cells and research directions to achieve even higher efficiencies of 15-20% using NFA-based organic photovoltaics are also proposed.

Small capillary pumped AMTEC systems

NASA Astrophysics Data System (ADS)

Hunt, Thomas K.; Sievers, Robert K.; Butkiewicz, David A.; Pantolin, Jan E.; Ivanenok, Joseph F.

1993-01-01

Alkali Metal Thermoelectric Converter (AMTEC) systems offer significant potential advantages for space power. Recent experiments have shown that electromagnetic pumps can operate with a negative priming head and so may be suitable for space applications in microgravity (Hunt et al. 1992). Capillary pumped cells offer an alternative approach to microgravity compatibility. We have designed, built, and operated capillary pumped AMTEC cells in various orientations with respect to gravity in order to provide a presumptive demonstration of zero-G capability (Sievers et al. 1992). We report lifetime and performance data for these capillary pumped AMTEC cells. Progress on other issues relating to space flight testing of AMTEC systems is also discussed.

Health Monitoring of Thermal Barrier Coatings by Mid-Infrared Reflectance

NASA Technical Reports Server (NTRS)

Eldridge, J. I.; Spuckler, C. M.; Nesbitt, J. A.; Street, K. W.

2002-01-01

Mid-infrared (MIR) reflectance is shown to be a powerful tool for monitoring the integrity of 8wt% yttria-stabilized zirconia (8YSZ) thermal barrier coatings (TBCs). Because of the translucent nature of plasma-sprayed 8YSZ TBCs, particularly at MIR wavelengths (3 to 5 microns), measured reflectance does not only originate from the TBC surface, but contains strong contributions from internal scattering within the coating as well as reflectance from the underlying TBC/substrate interface. Therefore, changes in MIR reflectance measurements can be used to monitor the progression of TBC delamination. In particular, MIR reflectance is shown to reproducibly track the progression of TBC delamination produced by repeated thermal cycling (to 1163 C) of plasma-sprayed 8YSZ TBCs on Rene N5 superalloy substrates. To understand the changes in MIR reflectance with the progression of a delamination crack network, a four-flux scattering model is used to predict the increase in MIR reflectance produced by the introduction of these cracks.

Bone Scan Index and Progression-free Survival Data for Progressive Metastatic Castration-resistant Prostate Cancer Patients Who Received ODM-201 in the ARADES Multicentre Study.

PubMed

Reza, Mariana; Jones, Robert; Aspegren, John; Massard, Christophe; Mattila, Leena; Mustonen, Mika; Wollmer, Per; Trägårdh, Elin; Bondesson, Eva; Edenbrandt, Lars; Fizazi, Karim; Bjartell, Anders

2016-12-01

ODM-201, a new-generation androgen receptor inhibitor, has shown clinical efficacy in prostate cancer (PCa). Quantitative methods are needed to accurately assess changes in bone as a measurement of treatment response. The Bone Scan Index (BSI) reflects the percentage of skeletal mass a given tumour affects. To evaluate the predictive value of the BSI in metastatic castration-resistant PCa (mCRPC) patients undergoing treatment with ODM-201. From a total of 134 mCRPC patients who participated in the Activity and Safety of ODM-201 in Patients with Progressive Metastatic Castration-resistant Prostate Cancer clinical trial and received ODM-201, we retrospectively selected all those patients who had bone scan image data of sufficient quality to allow for both baseline and 12-wk follow-up BSI-assessments (n=47). We used the automated EXINI bone BSI software (EXINI Diagnostics AB, Lund, Sweden) to obtain BSI data. We used the Cox proportional hazards model and Kaplan-Meier estimates to investigate the association among BSI, traditional clinical parameters, disease progression, and radiographic progression-free survival (rPFS). In the BSI assessments, at follow-up, patients who had a decrease or at most a 20% increase from BSI baseline had a significantly longer time to progression in bone (median not reached vs 23 wk, hazard ratio [HR]: 0.20; 95% confidence interval [CI], 0.07-0.58; p=0.003) and rPFS (median: 50 wk vs 14 wk; HR: 0.35; 95% CI, 0.17-0.74; p=0.006) than those who had a BSI increase >20% during treatment. The on-treatment change in BSI was significantly associated with rPFS in mCRPC patients, and an increase >20% in BSI predicted reduced rPFS. BSI for quantification of bone metastases may be a valuable complementary method for evaluation of treatment response in mCRPC patients. An increase in Bone Scan Index (BSI) was associated with shorter time to disease progression in patients treated with ODM-201. BSI may be a valuable method of complementing treatment response evaluation in patients with advanced prostate cancer. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Pomegranate and Its Components as Alternative Treatment for Prostate Cancer

PubMed Central

Wang, Lei; Martins-Green, Manuela

2014-01-01

Prostate cancer is the second leading cause of cancer deaths in men in the United States. There is a major need for less toxic but yet effective therapies to treat prostate cancer. Pomegranate fruit from the tree Punica granatum has been used for centuries for medicinal purposes and is described as “nature’s power fruit”. Recent research has shown that pomegranate juice (PJ) and/or pomegranate extracts (PE) significantly inhibit the growth of prostate cancer cells in culture. In preclinical murine models, PJ and/or PE inhibit growth and angiogenesis of prostate tumors. More recently, we have shown that three components of PJ, luteolin, ellagic acid and punicic acid together, have similar inhibitory effects on prostate cancer growth, angiogenesis and metastasis. Results from clinical trials are also promising. PJ and/or PE significantly prolonged the prostate specific antigen (PSA) doubling time in patients with prostate cancer. In this review we discuss data on the effects of PJ and PE on prostate cancer. We also discuss the effects of specific components of the pomegranate fruit and how they have been used to study the mechanisms involved in prostate cancer progression and their potential to be used in deterring prostate cancer metastasis. PMID:25158234

Metabolic Impact of Rapamycin (Sirolimus) and B-Estradiol Using Mouse Embryonic Fibroblasts as a Model for Lymphangioleiomyomatosis.

PubMed

Marsh, Katherine M; Schipper, David; Ferng, Alice S; Johnson, Kitsie; Fisher, Julia; Knapp, Shannon; Dicken, Destiny; Khalpey, Zain

2017-08-01

Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease that predominantly affects women of childbearing age. Exogenous rapamycin (sirolimus) has been shown to improve clinical outcomes and was recently approved to treat LAM, whereas estrogen (E 2 ) is implicated in disease progression. No consistent metabolic model currently exists for LAM, therefore wild-type mouse embryonic fibroblasts (MEF +/+) and TSC2 knockout cells (MEF -/-) were used in this study as a model for LAM. Oxygen consumption rates (OCR) and redox potential were measured to determine metabolic state across control cells, MEF +/+ and -/- cells treated with rapamycin (Rapa), and MEF +/+ and -/- cells treated with E 2 . An XF96 extracellular flux analyzer from Seahorse Bioscience ® was used to measure OCR, and a RedoxSYS™ ORP was used to measure redox potential. OCR of MEF -/- cells treated with rapamycin (MEF -/- Rapa) versus MEF -/- control were significantly lower across all conditions. The static oxidation reduction potential of the MEF -/- Rapa group was also lower, approaching significance. The coupling efficiency and ratio of ATP-linked respiration to maximum respiration were statistically lower in MEF -/- Rapa compared to MEF +/+ Rapa. There were no significant metabolic findings across any of the MEF cells treated with E 2 . MEF -/- control cells versus MEF +/+ control cells were not found to significantly differ. MEF cells are thought to be a feasible metabolic model for LAM, which has implications for future pharmacologic and biologic testing.

Analysis of the activation status of Akt, NFkappaB, and Stat3 in human diffuse gliomas.

PubMed

Wang, Huamin; Wang, Hua; Zhang, Wei; Huang, Helen J; Liao, Warren S L; Fuller, Gregory N

2004-08-01

Loss of phosphatase and tensin homolog (PTEN) and amplification of the epidermal growth factor receptor (EGFR) gene contribute to the progression of gliomas. As downstream targets of the PTEN and EGFR signaling pathways, Akt, NFkappaB, and signal transducer and activator of transcription-3 (Stat3) have been shown to play important roles in the control of cell proliferation, apoptosis, and oncogenesis. We examined the activation status of Akt, NFkappaB, and Stat3 in 259 diffuse gliomas using tissue microarrays and immunohistochemistry, and evaluated their association with glioma grade. We observed significant positive correlations between the activation status of Akt and NFkappaB and glioma grade. In contrast, only focal immunoreactivity for phospho-Stat3 was observed in < 9% of high-grade gliomas. In addition, we observed a significant correlation between the activation of Akt and NFkappaB. Functional correlation between Akt activation and the activation of NFkappaB was confirmed in U251MG GBM cells in which inhibition of Akt activation either by stable expression of PTEN or by the PI3-kinase inhibitors, wortmannin and LY294002, led to a concomitant decrease in NFkappaB-binding activity. Thus, our results demonstrate that constitutive activation of Akt and NFkappaB, but not Stat3, contributes significantly to the progression of diffuse gliomas, and activation of Akt may lead to NFkappaB activation in high-grade gliomas.

Fear of progression.

PubMed

Herschbach, Peter; Dinkel, Andreas

2014-01-01

Fear of progression (or fear of recurrence) is an appropriate, rational response to the real threat of cancer and cancer treatments. However, elevated levels of fear of progression can become dysfunctional, affecting well-being, quality of life, and social functioning. Research has shown that fear of progression is one of the most frequent distress symptoms of patients with cancer and with other chronic diseases. As a clear consensus concerning clinically relevant states of fear of progression is currently lacking, it is difficult to provide a valid estimate of the rate of cancer patients who clearly suffer from fear of progression. However, recent systematic reviews suggest that probably 50 % of cancer patients experience moderate to severe fear of progression. Furthermore, many patients express unmet needs in dealing with the fear of cancer spreading. These results underline the necessity to provide effective psychological treatments for clinical levels of fear of progression. A few psychosocial interventions for treating fear of progression have been developed so far. Our own, targeted intervention study showed that dysfunctional fear of progression can be effectively treated with a brief group therapy.

Natural history of moderately dilated tubular ascending aorta: implications for determining the optimal imaging interval.

PubMed

Park, Kay-Hyun; Chung, Suryeun; Kim, Dong Jung; Kim, Jun Sung; Lim, Cheong

2017-05-01

For a moderately dilated ascending aorta (diameter 35-54 mm), current guidelines recommend continuous annual or semi-annual examinations with computed tomography or magnetic resonance imaging. However, few data have shown the yield and benefit of such a protocol. This study aimed to investigate the fate of a moderately dilated ascending aorta and thereby determine the adequate imaging interval. In our institutional database, we identified adult patients having an ascending aortic diameter ≥40 mm in contrast-enhanced computed tomography and follow-up imaging(s) after ≥1 year. Of the 509 patients (mean age 67.2 ± 10.4 years) enrolled in the study, the maximal diameter of the ascending aorta was compared between the first and last images. Also, their medical records were reviewed to investigate the associated illness and clinical events. The mean growth rate of the patients with a 40-44 mm ( n  = 321), 45-49 mm ( n  = 142) and ≥50 mm ( n  = 46) ascending aorta was 0.3 ± 0.5, 0.3 ± 0.5 and 0.7 ± 0.9 mm/year, respectively. During the mean interval of 4.3 ± 2.4 years, significant progression (diameter increase by ≥5 mm) occurred in 3.4, 5.6 and 21.7%, respectively. The 3- to 5-year rates of freedom from significant progression were 99.1%-96.5% (40-44 mm) and 97.8%-96.4% (45-49 mm). In multivariate analysis, initial ascending aortic diameter ≥45 mm and aortic valve regurgitation were significantly associated with significant progression. Acute type A aortic dissection occurred in 5 patients (1%), before the maximal diameter of the ascending aorta reached 55 mm or significant progression was observed. For a moderately dilated ascending aorta not exceeding 45 mm in maximal diameter and stable in the first annual follow-up image, a 3- to 4-year interval would be reasonable before subsequent imaging. More frequent imaging may be warranted in patients with aortic valve insufficiency or with an aortic diameter ≥45 mm. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Targeting BET bromodomain proteins in solid tumors

PubMed Central

Sahai, Vaibhav; Redig, Amanda J.; Collier, Katharine A.; Eckerdt, Frank D.; Munshi, Hidayatullah G.

2016-01-01

There is increasing interest in inhibitors targeting BET (bromodomain and extra-terminal) proteins because of the association between this family of proteins and cancer progression. BET inhibitors were initially shown to have efficacy in hematologic malignancies; however, a number of studies have now shown that BET inhibitors can also block progression of non-hematologic malignancies. In this Review, we summarize the efficacy of BET inhibitors in select solid tumors; evaluate the role of BET proteins in mediating resistance to current targeted therapies; and consider potential toxicities of BET inhibitors. We also evaluate recently characterized mechanisms of resistance to BET inhibitors; summarize ongoing clinical trials with these inhibitors; and discuss potential future roles of BET inhibitors in patients with solid tumors. PMID:27283767

The Use of Individual Growth and Developmental Indicators for Progress Monitoring and Intervention Decision Making in Early Education

ERIC Educational Resources Information Center

Walker, Dale; Carta, Judith J.; Greenwood, Charles R.; Buzhardt, Joseph F.

2008-01-01

Progress monitoring tools have been shown to be essential elements in current approaches to intervention problem-solving models. Such tools have been valuable not only in marking individual children's level of performance relative to peers but also in measuring change in skill level in a way that can be attributed to intervention and development.…

Quantum Manybody Physics with Rydberg Polaritons

DTIC Science & Technology

2016-06-22

report, such as final, technical, interim, memorandum, master’s thesis, progress, quarterly, research , special, group study, etc. 3. DATES COVERED...for public release. Over the course of this grant, we have seen tremendous progress, both theoretically and experimentally , in our control of photonic...shown in multiple stages of construction at left and below, spans three optical tables in two rooms: One for the experimental control system

Following the Mobile Student: Can We Develop the Capacity for a Comprehensive Database To Assess Student Progression? Research Report.

ERIC Educational Resources Information Center

Ewell, Peter T.; Schild, Paula R.; Paulson, Karen

A major problem in measuring student success in postsecondary education is the difficulty in tracking students' progress as they transfer from one institution to another. National studies have shown that more than half of students attend more than one institution in their pursuit of a bachelor's degree. This study examined existing state-level…

Safety and clinical efficacy of everolimus in the treatment of advanced renal cell carcinoma (RCC)

PubMed Central

Shahani, Rohan; Kwan, Kevin G; Kapoor, Anil

2010-01-01

Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies. Recently, there has been a paradigm shift in the management of advanced RCC. New targeted therapies including vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have been developed which have shown promising results in a patient population who otherwise had very few options for treatment. The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients. More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies. Although a survival advantage in phase III trials is seen with everolimus, associated systemic toxicities, while generally well tolerated, are not insignificant. These include mucositis, hyperglycemia, hyperlipidemia, and pneumonitis. Despite the side effects, emerging evidence points to everolimus as the optimal second-line treatment for patients with advanced renal cell carcinoma. PMID:21701620

Ovsiankina's Great Relief: How Supplemental Work during the Weekend May Contribute to Recovery in the Face of Unfinished Tasks.

PubMed

Weigelt, Oliver; Syrek, Christine J

2017-12-20

Unfinished tasks have been identified as a significant job stressor that impairs employee recovery after work. Classic experimental research by Ovsiankina has shown that people tend to resume yet unfinished tasks to satisfy their need for closure. We apply this notion to current working life and examine supplemental work after hours as a means to achieve peace of mind. We investigate how progress towards goal accomplishment through supplemental work may facilitate recovery in terms of psychological detachment, relaxation, autonomy, and mastery experiences. We conducted a week-level diary study among 83 employees over a period of 14 consecutive weeks, which yielded 575 observations in total and 214 matched observations of unfinished tasks, supplemental work during the weekend, progress, and recovery experiences. Unfinished tasks were assessed on Friday. Supplemental work and recovery experiences were assessed on Monday. Multilevel modeling analyses provide evidence that unfinished tasks at the end of the work week are associated with lower levels of detachment at the intraindividual level, tend to relate to lower relaxation, but are unrelated to autonomy and mastery. Progress towards finishing tasks during the weekend alleviates the detrimental effects of unfinished tasks on both kinds of recovery experiences. Supplemental work is negatively linked to detachment, but largely unrelated to the other recovery experiences.

[DIET CHARACTERISTICS IN PATIENTS WITH CHRONIC KIDNEY DISEASE].

PubMed

Bašić-Marković, N; Šutić, I; Popović, B; Marković, R; Vučak, J

2016-12-01

Because of the increasing number of patients, chronic kidney disease (CKD) has become a significant public health problem. As kidney function decreases, it is necessary to introduce certain dietary modifications. The aim was to investigate what is the appropriate approach to diet of CKD patients, which could contribute to slowing down progression of the disease. Dietary recommendations are individual for each patient, but also vary in the same patient depending on the stage of disease progression because special attention must be paid to appropriate intake of macronutrients (protein, carbohydrates and fats), micronutrients (sodium, potassium, calcium, phosphorus, zinc, selenium, various vitamins), and water. In newly diagnosed patients, it is necessary to assess their nutritional status and energy requirements. It has been shown that protein-energy malnutrition, muscle loss and cachexia are strong predictors of mortality in CKD. Comparing different dietary approaches in everyday life of patients suffering from CKD, it was found that the most effective diet is Mediterranean food style. Studies confirm that Mediterranean diet has a preventive effect on renal function and reduces progression of the disease. Preventive measures, correct identification and early intervention can increase survival of patients and improve their quality of life. Mediterranean diet tailored to individual stages of CKD has been confirmed as the best choice in CKD patients.

Role of Renal Urothelium in the Development and Progression of Kidney Disease

PubMed Central

Carpenter, Ashley R.; McHugh, Kirk M.

2016-01-01

The clinical and financial impact of chronic kidney disease (CKD) is significant, while the progression and prognosis of CKD is variable and often poor. Studies using the megabladder (mgb−/−) model of CKD have shown that renal urothelium plays a key role in modulating the early injury responses following the development of congenital obstruction. The aim of this review is to examine the role that urothelium has in normal urinary tract development and pathogenesis. We discuss normal morphology of renal urothelium and then examine the role that uroplakins (Upks) play in its development. Histologic, biochemical and molecular characterization of Upk1bRFP/RFP mice indicated Upk1b expression is essential for normal urinary tract development, apical plaque/AUM formation and differentiation and functional integrity of the renal urothelium. Our studies provide the first evidence Upk1b is directly associated with the development of congenital anomalies of the urinary tract (CAKUT), spontaneous age-dependent hydronephrosis and dysplastic urothelia. These observations demonstrate the importance of proper urothelial differentiation in the normal development and pathogenesis of the urinary tract, and provide a unique working model to test the hypothesis that the complex etiology associated with CKD is dependent upon predetermined genetic susceptibilities that establish pathogenic thresholds for disease initiation and progression. PMID:27115886

Canine Leishmaniasis Progression is Associated with Vitamin D Deficiency.

PubMed

Rodriguez-Cortes, A; Martori, C; Martinez-Florez, A; Clop, A; Amills, M; Kubejko, J; Llull, J; Nadal, J M; Alberola, J

2017-06-13

The relationship between vitamin D deficiency and the risk of suffering from a plethora of health disorders, ranging from autoimmune processes to infectious diseases has been widely described. Nonetheless, the potential role of vitamin D in visceral leishmaniasis remains uncharacterized. In the Mediterranean basin, where the dog is leishmania's main peri-domestic reservoir, control measures against the canine disease have shown beneficial effects on the incidence of human leishmaniasis. In this study, we measured the vitamin D levels in serum samples from a cohort of 68 healthy and disease dogs from a highly endemic area and we have also studied the relationship of these levels with parasitological and immunological parameters. The sick dogs presented significantly lower (P < 0.001) vitamin D levels (19.6 ng/mL) than their non-infected (31.8 ng/mL) and the asymptomatic counterparts (29.6 ng/mL). In addition, vitamin D deficiency correlated with several parameters linked to leishmaniasis progression. However, there was no correlation between vitamin D levels and the Leishmania-specific cellular immune response. Moreover, both the leishmanin skin test and the IFN-γ levels displayed negative correlations with serological, parasitological and clinical signs. Further studies to determine the functional role of vitamin D on the progression and control of canine leishmaniasis are needed.

Physiological Aβ Concentrations Produce a More Biomimetic Representation of the Alzheimer's Disease Phenotype in iPSC Derived Human Neurons.

PubMed

Berry, Bonnie J; Smith, Alec S T; Long, Christopher J; Martin, Candace C; Hickman, James J

2018-05-22

Alzheimer's disease (AD) is characterized by slow, progressive neurodegeneration leading to severe neurological impairment, but current drug development efforts are limited by the lack of robust, human-based disease models. Amyloid-β (Aβ) is known to play an integral role in AD progression as it has been shown to interfere with neurological function. However, studies into AD pathology commonly apply Aβ to neurons for short durations at nonphysiological concentrations to induce an exaggerated dysfunctional phenotype. Such methods are unlikely to elucidate early stage disease dysfunction, when treatment is still possible, since damage to neurons by these high concentrations is extensive. In this study, we investigated chronic, pathologically relevant Aβ oligomer concentrations to induce an electrophysiological phenotype that is more representative of early AD progression compared to an acute high-dose application in human cortical neurons. The high, acute oligomer dose resulted in severe neuronal toxicity as well as upregulation of tau and phosphorylated tau. Chronic, low-dose treatment produced significant functional impairment without increased cell death or accumulation of tau protein. This in vitro phenotype more closely mirrors the status of early stage neural decline in AD pathology and could provide a valuable tool to further understanding of early stage AD pathophysiology and for screening potential therapeutic compounds.

Neo-epitope Peptides as Biomarkers of Disease Progression for Muscular Dystrophies and Other Myopathies

PubMed Central

Arvanitidis, A.; Henriksen, K.; Karsdal, M.A.; Nedergaard, A.

2016-01-01

For several decades, serological biomarkers of neuromuscular diseases as dystrophies, myopathies and myositis have been limited to routine clinical biochemistry panels. Gauging the pathological progression is a prerequisite for proper treatment and therefore identifying accessible, easy to monitor biomarkers that can predict the disease progression would be an important advancement. Most muscle diseases involve accelerated muscle fiber degradation, inflammation, fatty tissue substitution and/or fibrosis. All these pathological traits have been shown to give rise to serological peptide biomarkers in other tissues, underlining the potential application of existing biomarkers of such traits in muscle disorders. A significant quantity of tissue is involved in these pathological mechanisms alongside with qualitative changes in protein turnover in myofibrillar, extra-cellular matrix and immunological cell protein fractions accompanied by alterations in body fluids. We propose that protein and peptides can leak out of the afflicted muscles and can be of use in diagnosis, prediction of pathology trajectory and treatment efficacy. Proteolytic cleavage systems are especially modulated during a range of muscle pathologies, thereby giving rise to peptides that are differentially released during disease manifestation. Therefore, we believe that pathology-specific post-translational modifications like cleavages can give rise to neoepitope peptides that may represent a promising class of peptides for discovery of biomarkers pertaining to neuromuscular diseases. PMID:27854226

Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

PubMed Central

Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

2004-01-01

The term “prion” was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word “prion” has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the “mad cow” crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

Optimizing clinical benefit with targeted treatment in mRCC: "Tumor growth rate" as an alternative clinical endpoint.

PubMed

Milella, Michele

2016-06-01

Tumor growth rate (TGR), usually defined as the ratio between the slope of tumor growth before the initiation of treatment and the slope of tumor growth during treatment, between the nadir and disease progression, is a measure of the rate at which tumor volume increases over time. In patients with metastatic renal cell carcinoma (mRCC), TGR has emerged as a reliable alternative parameter to allow a quantitative and dynamic evaluation of tumor response. This review presents evidence on the correlation between TGR and treatment outcomes and discusses the potential role of this tool within the treatment scenario of mRCC. Current evidence, albeit of retrospective nature, suggests that TGR might represent a useful tool to assess whether treatment is altering the course of the disease, and has shown to be significantly associated with progression-free survival and overall survival. Therefore, TGR may represent a valuable endpoint for clinical trials evaluating new molecularly targeted therapies. Most importantly, incorporation of TGR in the assessment of individual patients undergoing targeted therapies may help clinicians decide if a given agent is no longer able to control disease growth and whether continuing therapy beyond RECIST progression may still produce clinical benefit. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Rapamycin alleviates brain edema after focal cerebral ischemia reperfusion in rats.

PubMed

Guo, Wei; Feng, Guoying; Miao, Yanying; Liu, Guixiang; Xu, Chunsheng

2014-06-01

Brain edema is a major consequence of cerebral ischemia reperfusion. However, few effective therapeutic options are available for retarding the brain edema progression after cerebral ischemia. Recently, rapamycin has been shown to produce neuroprotective effects in rats after cerebral ischemia reperfusion. Whether rapamycin could alleviate this brain edema injury is still unclear. In this study, the rat stroke model was induced by a 1-h left transient middle cerebral artery occlusion using an intraluminal filament, followed by 48 h of reperfusion. The effects of rapamycin (250 μg/kg body weight, intraperitoneal; i.p.) on brain edema progression were evaluated. The results showed that rapamycin treatment significantly reduced the infarct volume, the water content of the brain tissue and the Evans blue extravasation through the blood-brain barrier (BBB). Rapamycin treatment could improve histological appearance of the brain tissue, increased the capillary lumen space and maintain the integrity of BBB. Rapamycin also inhibited matrix metalloproteinase 9 (MMP9) and aquaporin 4 (AQP4) expression. These data imply that rapamycin could improve brain edema progression after reperfusion injury through maintaining BBB integrity and inhibiting MMP9 and AQP4 expression. The data of this study provide a new possible approach for improving brain edema after cerebral ischemia reperfusion by administration of rapamycin.

Recent progress in advanced optical materials based on gadolinium aluminate garnet (Gd3Al5O12)

PubMed Central

Li, Ji-Guang; Sakka, Yoshio

2015-01-01

This review article summarizes the recent achievements in stabilization of the metastable lattice of gadolinium aluminate garnet (Gd3Al5O12, GAG) and the related developments of advanced optical materials, including down-conversion phosphors, up-conversion phosphors, transparent ceramics, and single crystals. Whenever possible, the materials are compared with their better known YAG and LuAG counterparts to demonstrate the merits of the GAG host. It is shown that novel emission features and significantly improved luminescence can be attained for a number of phosphor systems with the more covalent GAG lattice and the efficient energy transfer from Gd3+ to the activator. Ce3+ doped GAG-based single crystals and transparent ceramics are also shown to simultaneously possess the advantages of high theoretical density, fast scintillation decay, and high light yields, and hold great potential as scintillators for a wide range of applications. The unresolved issues are also pointed out. PMID:27877750

Simulation of alternate hohlraum shapes for improved inner beam propagation in indirectly-driven ICF implosions

NASA Astrophysics Data System (ADS)

Robey, H. F.; Berzak Hopkins, L. F.

2017-10-01

Recent indirectly-driven ICF experiments performed on the National Ignition Facility have shown that the propagation of the inner beam cones is impeded late in the laser pulse by the growth of a gold bubble, which is initiated at the location where the outer beams hit the hohlraum wall and which expands radially inward into the hohlraum as the implosion progresses. Late in time, this gold bubble intercepts a significant portion of the inner beams reducing the available energy reaching the waist of the hohlraum and affecting the implosion symmetry. Integrated hohlraum simulations of alternate hohlraum shapes using HYDRA are performed to explore options for reducing the impact of the gold bubble on inner beam propagation. The simulations are based on recent NIF implosions using High-Density Carbon (HDC) ablators, which have shown good performance, but which could benefit from improved inner beam propagation. This work was performed under the auspices of the Lawrence Livermore National Security, LLC, (LLNS) under Contract No. DE-AC52-07NA27344.

Recent progress in advanced optical materials based on gadolinium aluminate garnet (Gd3Al5O12)

NASA Astrophysics Data System (ADS)

Li, Ji-Guang; Sakka, Yoshio

2015-02-01

This review article summarizes the recent achievements in stabilization of the metastable lattice of gadolinium aluminate garnet (Gd3Al5O12, GAG) and the related developments of advanced optical materials, including down-conversion phosphors, up-conversion phosphors, transparent ceramics, and single crystals. Whenever possible, the materials are compared with their better known YAG and LuAG counterparts to demonstrate the merits of the GAG host. It is shown that novel emission features and significantly improved luminescence can be attained for a number of phosphor systems with the more covalent GAG lattice and the efficient energy transfer from Gd3+ to the activator. Ce3+ doped GAG-based single crystals and transparent ceramics are also shown to simultaneously possess the advantages of high theoretical density, fast scintillation decay, and high light yields, and hold great potential as scintillators for a wide range of applications. The unresolved issues are also pointed out.

In vivo imaging of the dynamics of different variants of EGFR in glioblastomas.

PubMed

Shah, Khalid

2011-01-01

A number of altered pathways in cancer cells depend on growth factor receptors. The amplification/alteration of the epidermal growth factor receptor (EGFR) has been shown to play a significant role in enhancing tumor burden in a number of tumors, including malignant glioblastomas (GBM). To dissect the role of EGFR expression in tumor progression in mouse models of cancer and ultimately evaluate targeted therapies, it is necessary to visualize the dynamics of EGFR in real time in vivo. Non-invasive imaging based on quantitative and qualitative changes in light emission by fluorescent and bioluminescent markers offers a huge potential to facilitate drug development. Multiple approaches could be used to follow a molecular target or pathway with the fusion of a bioluminescent-fluorescent marker. This unit describes a protocol for simultaneously imaging EGFR activity and progression of GBM in a mouse model. Human glioma cells transduced with lentiviral vectors bearing different combinations of fluorescent and bioluminescent proteins either fused to EGFR or expressed alone can be grown as monolayers and maintained over several passages. The unit begins with a method for transducing glioma cells with lentiviral vectors for stable expression of these fluorescent and bioluminescent markers in vitro, followed by transplantation of engineered glioma cells in mice, and, finally, sequential bioluminescent imaging of EGFR expression and GBM progression in mice. The protocol details characterization of engineered glioma cells in culture, surgical preparation, craniotomy, cell implantation, animal recovery, and imaging procedures to study kinetics of EGFR expression and GBM progression.

Recent Progress on Systems and Synthetic Biology Approaches to Engineer Fungi As Microbial Cell Factories.

PubMed

Amores, Gerardo Ruiz; Guazzaroni, María-Eugenia; Arruda, Letícia Magalhães; Silva-Rocha, Rafael

2016-04-01

Filamentous fungi are remarkable organisms naturally specialized in deconstructing plant biomass and this feature has a tremendous potential for biofuel production from renewable sources. The past decades have been marked by a remarkable progress in the genetic engineering of fungi to generate industry-compatible strains needed for some biotech applications. In this sense, progress in this field has been marked by the utilization of high-throughput techniques to gain deep understanding of the molecular machinery controlling the physiology of these organisms, starting thus the Systems Biology era of fungi. Additionally, genetic engineering has been extensively applied to modify wellcharacterized promoters in order to construct new expression systems with enhanced performance under the conditions of interest. In this review, we discuss some aspects related to significant progress in the understating and engineering of fungi for biotechnological applications, with special focus on the construction of synthetic promoters and circuits in organisms relevant for industry. Different engineering approaches are shown, and their potential and limitations for the construction of complex synthetic circuits in these organisms are examined. Finally, we discuss the impact of engineered promoter architecture in the single-cell behavior of the system, an often-neglected relationship with a tremendous impact in the final performance of the process of interest. We expect to provide here some new directions to drive future research directed to the construction of high-performance, engineered fungal strains working as microbial cell factories.

Serum Bilirubin and Disease Progression in Mild COPD

PubMed Central

Apperley, Scott; Park, Hye Yun; Holmes, Daniel T.; Wise, Robert A.; Connett, John E.

2015-01-01

BACKGROUND: COPD is a chronic inflammatory disorder associated with oxidative stress. Serum bilirubin has potent antioxidant actions, and higher concentrations have been shown to protect against oxidative stress. The relation between serum bilirubin and COPD progression is unknown. METHODS: Serum bilirubin was measured in 4,680 smokers aged 35 to 60 years old with mild to moderate airflow limitation. The relationship of serum bilirubin to postbronchodilator FEV1 and rate of FEV1 decline over 3 to 9 years was determined using regression modeling. Total and disease-specific mortality were also ascertained. RESULTS: Serum bilirubin was positively related to FEV1 (P < .001). Serum bilirubin was also negatively related to the annual decline in FEV1 when adjusted for baseline demographics, pack-years smoked, and baseline measures of lung function (P = .01). Additionally, serum bilirubin was negatively associated with risk of death from coronary heart disease (P = .03); however, the relationships between bilirubin and other mortality end points were not statistically significant (P > .05). CONCLUSIONS: Bilirubin is inversely related to COPD disease severity and progression. Higher serum bilirubin concentration was associated with a higher FEV1 and less annual decline in FEV1. Bilirubin was also associated with less coronary heart disease mortality. These data support the hypothesis that bilirubin has a protective effect on COPD disease progression, possibly through its antioxidant actions. Bilirubin may prove useful as an easily accessible and readily available blood-based COPD biomarker. PMID:25539285

Plasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure.

PubMed

Dickinson, Brent A; Semus, Hillary M; Montgomery, Rusty L; Stack, Christianna; Latimer, Paul A; Lewton, Steven M; Lynch, Joshua M; Hullinger, Thomas G; Seto, Anita G; van Rooij, Eva

2013-06-01

Recent studies have shown that microRNAs (miRNAs), besides being potent regulators of gene expression, can additionally serve as circulating biomarkers of disease. The aim of this study is to determine if plasma miRNAs can be used as indicators of disease progression or therapeutic efficacy in hypertension-induced heart disease. In order to define circulating miRNAs that change during hypertension-induced heart failure and that respond to therapeutic treatment, we performed miRNA arrays on plasma RNA from hypertensive rats that show signs of heart failure. Array analysis indicated that approximately one-third of the miRNAs on the array are detectable in plasma. Quantitative real-time polymerase chain reaction (PCR) analysis for a selected panel of miRNAs indicated that circulating levels of miR-16, miR-20b, miR-93, miR-106b, miR-223, and miR-423-5p were significantly increased in response to hypertension-induced heart failure, while this effect was blunted in response to treatment with antimiR-208a as well as an ACE inhibitor. Moreover, treatment with antimiR-208a resulted in a dramatic increase in one miRNA, miR-19b. A time course study indicated that several of these miRNA changes track with disease progression. Circulating levels of miRNAs are responsive to therapeutic interventions and change during the progression of hypertension-induced heart disease.

Scientific progress: Knowledge versus understanding.

PubMed

Dellsén, Finnur

2016-04-01

What is scientific progress? On Alexander Bird's epistemic account of scientific progress, an episode in science is progressive precisely when there is more scientific knowledge at the end of the episode than at the beginning. Using Bird's epistemic account as a foil, this paper develops an alternative understanding-based account on which an episode in science is progressive precisely when scientists grasp how to correctly explain or predict more aspects of the world at the end of the episode than at the beginning. This account is shown to be superior to the epistemic account by examining cases in which knowledge and understanding come apart. In these cases, it is argued that scientific progress matches increases in scientific understanding rather than accumulations of knowledge. In addition, considerations having to do with minimalist idealizations, pragmatic virtues, and epistemic value all favor this understanding-based account over its epistemic counterpart. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biomechanics of far cortical locking.

PubMed

Bottlang, Michael; Feist, Florian

2011-02-01

The development of far cortical locking (FCL) was motivated by a conundrum: locked plating constructs provide inherently rigid stabilization, yet they should facilitate biologic fixation and secondary bone healing that relies on flexible fixation to stimulate callus formation. Recent studies have confirmed that the high stiffness of standard locked plating constructs can suppress interfragmentary motion to a level that is insufficient to reliably promote secondary fracture healing by callus formation. Furthermore, rigid locking screws cause an uneven stress distribution that may lead to stress fracture at the end screw and stress shielding under the plate. This review summarizes four key features of FCL constructs that have been shown to enhance fixation and healing of fractures: flexible fixation, load distribution, progressive stiffening, and parallel interfragmentary motion. Specifically, flexible fixation provided by FCL reduces the stiffness of a locked plating construct by 80% to 88% to actively promote callus proliferation similar to an external fixator. Load is evenly distributed between FCL screws to mitigate stress risers at the end screw. Progressive stiffening occurs by near cortex support of FCL screws and provides additional support under elevated loading. Finally, parallel interfragmentary motion by the S-shaped flexion of FCL screws promotes symmetric callus formation. In combination, these features of FCL constructs have been shown to induce more callus and to yield significantly stronger and more consistent healing compared with standard locked plating constructs. As such, FCL constructs function as true internal fixators by replicating the biomechanical behavior and biologic healing response of external fixators.

Bitter gourd (Momordica charantia) as a rich source of bioactive components to combat cancer naturally: Are we on the right track to fully unlock its potential as inhibitor of deregulated signaling pathways.

PubMed

Farooqi, Ammad Ahmad; Khalid, Sumbul; Tahir, Fatima; Sabitaliyevich, Uteuliev Yerzhan; Yaylim, Ilhan; Attar, Rukset; Xu, Baojun

2018-05-10

Research over decades has progressively explored pharmacological actions of bitter gourd (Momordica charantia). Biologically and pharmacologically active molecules isolated from M. charantia have shown significant anti-cancer activity in cancer cell lines and xenografted mice. In this review spotlight was set on the bioactive compounds isolated from M. charantia that effectively inhibited cancer development and progression via regulation of protein network in cancer cells. We summarize most recent high-quality research work in cancer cell lines and xenografted mice related to tumor suppressive role-play of M. charantia and its bioactive compounds. Although M. charantia mediated health promoting, anti-diabetic, hepatoprotective, anti-inflammatory effects have been extensively investigated, there is insufficient information related to regulation of signaling networks by bioactive molecules obtained from M. charantia in different cancers. M. charantia has been shown to modulate AKT/mTOR/p70S6K signaling, p38MAPK-MAPKAPK-2/HSP-27 pathway, cell cycle regulatory proteins and apoptosis-associated proteins in different cancers. However, still there are visible knowledge gaps related to the drug targets in different cancers because we have not yet developed comprehensive understanding of the M. charantia mediated regulation of signal transduction pathways. To explore these questions, experimental platforms are needed that can prove to be helpful in getting a step closer to personalized medicine. Copyright © 2018 Elsevier Ltd. All rights reserved.

Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression.

PubMed

Ibrahim, Ashraf E K; Arends, Mark J; Silva, Ana-Luisa; Wyllie, Andrew H; Greger, Liliana; Ito, Yoko; Vowler, Sarah L; Huang, Tim H-M; Tavaré, Simon; Murrell, Adele; Brenton, James D

2011-04-01

Although aberrant methylation of key genes in the progression of colorectal neoplasia has been reported, no model-based analysis of the incremental changes through the intermediate adenoma stage has been described. In addition, the biological drivers for these methylation changes have yet to be defined. Linear mixed-effects modelling was used in this study to understand the onset and patterns of the methylation changes of SFRP2, IGF2 DMR0, H19, LINE-1 and a CpG island methylator phenotype (CIMP) marker panel, and they were correlated with DNA methyltransferase 3B (DNMT3B) levels of expression in a sample set representative of colorectal neoplastic progression. Methylation of the above CpG islands was measured using quantitative pyrosequencing assays in 261 tissue samples. This included a prospective collection of 44 colectomy specimens with concurrent normal mucosa, adenoma and invasive cancer tissues. Tissue microarrays from a subset of 64 cases were used for immunohistochemical analysis of DNMT3B expression. It is shown that the onset and pattern of methylation changes during colorectal neoplastic progression are locus dependent. The CIMP marker RUNX3 was the earliest CpG island showing significant change, followed by the CIMP markers NEUROG1 and CACNA1G at the hyperplastic polyp stage. SFRP2 and IGF2 DMR0 showed significant methylation changes at the adenomatous polyp stage, followed by the CIMP markers CDKN2A and hMLH1 at the adenocarcinoma stage. DNMT3B levels of immunohistochemical expression increased significantly (p < 0.001) from normal to hyperplastic and from adenomatous polyps to carcinoma samples. DNMT3B expression correlated positively with SFRP2 methylation (r = 0.42, p < 0.001, 95% CI 0.25 to 0.56), but correlated negatively with IGF2 DMR0 methylation (r = 0.26, p = 0.01, 95% CI -0.45 to -0.05). A subset of the CIMP panel (NEUROG1, CACNA1G and CDKN2A) positively correlated with DNMT3B levels of expression (p < 0.05). Hierarchical epigenetic alterations occur at transition points during colorectal neoplastic progression. These cumulative changes are closely correlated with a gain of DNMT3B expression, suggesting a causal relationship.

Developing and Validating a Predictive Model for Stroke Progression

PubMed Central

Craig, L.E.; Wu, O.; Gilmour, H.; Barber, M.; Langhorne, P.

2011-01-01

Background Progression is believed to be a common and important complication in acute stroke, and has been associated with increased mortality and morbidity. Reliable identification of predictors of early neurological deterioration could potentially benefit routine clinical care. The aim of this study was to identify predictors of early stroke progression using two independent patient cohorts. Methods Two patient cohorts were used for this study – the first cohort formed the training data set, which included consecutive patients admitted to an urban teaching hospital between 2000 and 2002, and the second cohort formed the test data set, which included patients admitted to the same hospital between 2003 and 2004. A standard definition of stroke progression was used. The first cohort (n = 863) was used to develop the model. Variables that were statistically significant (p < 0.1) on univariate analysis were included in the multivariate model. Logistic regression was the technique employed using backward stepwise regression to drop the least significant variables (p > 0.1) in turn. The second cohort (n = 216) was used to test the performance of the model. The performance of the predictive model was assessed in terms of both calibration and discrimination. Multiple imputation methods were used for dealing with the missing values. Results Variables shown to be significant predictors of stroke progression were conscious level, history of coronary heart disease, presence of hyperosmolarity, CT lesion, living alone on admission, Oxfordshire Community Stroke Project classification, presence of pyrexia and smoking status. The model appears to have reasonable discriminative properties [the median receiver-operating characteristic curve value was 0.72 (range 0.72–0.73)] and to fit well with the observed data, which is indicated by the high goodness-of-fit p value [the median p value from the Hosmer-Lemeshow test was 0.90 (range 0.50–0.92)]. Conclusion The predictive model developed in this study contains variables that can be easily collected in practice therefore increasing its usability in clinical practice. Using this analysis approach, the discrimination and calibration of the predictive model appear sufficiently high to provide accurate predictions. This study also offers some discussion around the validation of predictive models for wider use in clinical practice. PMID:22566988

Transuranic solid waste management programs. Progress report, July--December 1975

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

Not Available

1976-09-01

Progress is reported for three transuranic solid waste management programs funded at the Los Alamos Scientific Laboratory (LASL) by the Energy Research and Development Administration (ERDA) Division of Fuel Cycle and Production (NFCP). Under the Transuranic Waste Research and Development Program, continued studies have shown the potential attractiveness of fiber drums as an acceptable substitute for the current mild steel storage containers. Various fire retardants have been evaluated, with one indicating significant ability to inhibit fire propagation. Continued radiolysis studies, under laboratory and field conditions, continue to reaffirm earlier LASL results indicating no significant hazard from radiolytic reactions, assuming nomore » change in current allowable loadings. Care must be exercised to differentiate between radiolytic and chemical reactions. Other efforts have identified a modification of chemical processing to reduce the amounts of plutonium requiring retrievable storage. Studies are also in progress to enhance the sensitivity of the LASL MEGAS assay system. The Transuranic-Contaminated Solid Waste Treatment Development Facility building was 72 percent complete as of December 31, 1975, which is in accord with the existing schedule. Procurement of process components is also on schedule. Certain modifications to the facility have been made, and various pre-facility experiments on waste container handling and processing have been completed. The program for the Evaluation of Transuranic-Contaminated Radioactive Waste Disposal Areas continued development of various computer modules for simulation of radionuclide transport within the biosphere. In addition, program staff contributed to an ERDA document on radioactive waste management through the preparation of a report on burial of radioactive waste at ERDA-contractor and commercial sites.« less

GD2-targeted immunotherapy and potential value of circulating microRNAs in neuroblastoma.

PubMed

Gholamin, Sharareh; Mirzaei, Hamed; Razavi, Seyed-Mostafa; Hassanian, Seyed Mahdi; Saadatpour, Leila; Masoudifar, Aria; ShahidSales, Soodabeh; Avan, Amir

2018-02-01

Neuroblastoma (NB) with various clinical presentation is a known childhood malignancy. Despite significant progress in treatment of NB afflicted patients, high risk disease is usually associated with poor outcome, resulting in long-term survival of less that 50%. Known as a disease most commonly originated form the nerve roots, the variants involved in NB imitation and progression remain to be elucidated. The outcome of low to intermediate risk disease is favorable whereas the high risk NB disease with dismal prognosis, positing the necessity of novel approaches for early detection and prognostication of advanced disease. Tailored immunotherapy approaches have shown significant improvement in high-risk NB patients. It has found a link between Gangliosides and progression of NB. The vast majority of neuroblastoma tumors express elevated levels of GD2, opening new insight into using anti-GD2 drugs as potential treatments for NBs. Implication of anti-GD2 monoclonal antibodies for treatment of high risk NBs triggers further investigation to unearth novel biomarkers as prognostic and response biomarker to guide additional multimodal tailored treatment approaches. A growing body of evidence supports the usefulness of miRNAs to evaluate high risk NBs response to anti-GD2 drugs and further prevent drug-related toxicities in refractory or recurrent NBs. miRNAs and circulating proteins in body fluids (plasma and serum) present as potential biomarkers in early detection of NBs. Here, we summarize various biomarkers involved in diagnosis, prognosis and response to treatment in patients with NB. We further attempted to overview prognostic biomarkers in response to treatment with anti-GD2 drugs. © 2017 Wiley Periodicals, Inc.

Chemotactic Cues for NOTCH1-Dependent Leukemia

PubMed Central

Piovan, Erich; Tosello, Valeria; Amadori, Alberto; Zanovello, Paola

2018-01-01

The NOTCH signaling pathway is a conserved signaling cascade that regulates many aspects of development and homeostasis in multiple organ systems. Aberrant activity of this signaling pathway is linked to the initiation and progression of several hematological malignancies, exemplified by T-cell acute lymphoblastic leukemia (T-ALL). Interestingly, frequent non-mutational activation of NOTCH1 signaling has recently been demonstrated in B-cell chronic lymphocytic leukemia (B-CLL), significantly extending the pathogenic significance of this pathway in B-CLL. Leukemia patients often present with high-blood cell counts, diffuse disease with infiltration of the bone marrow, secondary lymphoid organs, and diffusion to the central nervous system (CNS). Chemokines are chemotactic cytokines that regulate migration of cells between tissues and the positioning and interactions of cells within tissue. Homeostatic chemokines and their receptors have been implicated in regulating organ-specific infiltration, but may also directly and indirectly modulate tumor growth. Recently, oncogenic NOTCH1 has been shown to regulate infiltration of leukemic cells into the CNS hijacking the CC-chemokine ligand 19/CC-chemokine receptor 7 chemokine axis. In addition, a crucial role for the homing receptor axis CXC-chemokine ligand 12/CXC-chemokine receptor 4 has been demonstrated in leukemia maintenance and progression. Moreover, the CCL25/CCR9 axis has been implicated in the homing of leukemic cells into the gut, particularly in the presence of phosphatase and tensin homolog tumor suppressor loss. In this review, we summarize the latest developments regarding the role of NOTCH signaling in regulating the chemotactic microenvironmental cues involved in the generation and progression of T-ALL and compare these findings to B-CLL. PMID:29666622

Second-harmonic generation scattering directionality predicts tumor cell motility in collagen gels

NASA Astrophysics Data System (ADS)

Burke, Kathleen A.; Dawes, Ryan P.; Cheema, Mehar K.; Van Hove, Amy; Benoit, Danielle S. W.; Perry, Seth W.; Brown, Edward

2015-05-01

Second-harmonic generation (SHG) allows for the analysis of tumor collagen structural changes throughout metastatic progression. SHG directionality, measured through the ratio of the forward-propagating to backward-propagating signal (F/B ratio), is affected by collagen fibril diameter, spacing, and disorder of fibril packing within a fiber. As tumors progress, these parameters evolve, producing concurrent changes in F/B. It has been recently shown that the F/B of highly metastatic invasive ductal carcinoma (IDC) breast tumors is significantly different from less metastatic tumors. This suggests a possible relationship between the microstructure of collagen, as measured by the F/B, and the ability of tumor cells to locomote through that collagen. Utilizing in vitro collagen gels of different F/B ratios, we explored the relationship between collagen microstructure and motility of tumor cells in a "clean" environment, free of the myriad cells, and signals found in in vivo. We found a significant relationship between F/B and the total distance traveled by the tumor cell, as well as both the average and maximum velocities of the cells. Consequently, one possible mechanism underlying the observed relationship between tumor F/B and metastatic output in IDC patient samples is a direct influence of collagen structure on tumor cell motility.

How MMPs Impact Bone Responses to Metastatic Prostate Cancer

DTIC Science & Technology

2010-02-01

13. SUPPLEMENTARY NOTES 14. ABSTRACT Using an animal model of prostate tumor progression in the bone we have previously shown that MMPs...in osteolytic or osteoblastic responses between wild type and MMP-9 deficient animals were detected by Faxitron, CT, SPECT and histomorphometry...as the ‘vicious cycle’ (4). Using an animal model of 2 tumor progression in the bone, we have previously identified a group of enzymes known as

Downregulation of feline sarcoma-related protein inhibits cell migration, invasion and epithelial-mesenchymal transition via the ERK/AP-1 pathway in bladder urothelial cell carcinoma.

PubMed

Hu, Xudong; Zhang, Zhiqiang; Liang, Zhaofeng; Xie, Dongdong; Zhang, Tao; Yu, Dexin; Zhong, Caiyun

2017-02-01

Feline sarcoma-related protein (Fer) is a nuclear and cytoplasmic non-receptor protein tyrosine kinase and Fer overexpression is associated with various biological processes. However, the clinicopathological characteristics and molecular mechanisms of Fer expression in bladder urothelial cell carcinoma (UCC) have yet to be elucidated. The present study demonstrated that Fer was significantly upregulated in bladder UCC tissues and cell lines. A clinicopathological analysis suggested that Fer expression was significantly associated with tumor stage, histological grade and lymph node status, and Fer expression was a prognostic factor for overall survival in a multivariate analysis. Furthermore, small interfering RNA (siRNA) was used to silence the expression of the Fer gene in human bladder UCC T24 cells, and was shown to significantly reduce the migration and invasion of the cells. It was also observed that Fer-siRNA caused the T24 cells to acquire an epithelial cobblestone phenotype, and was able to reverse the epithelial-mesenchymal transition of the cells. Subsequently, Fer-knockdown was shown to deactivate the extracellular signal-regulated kinase/activator protein-1 signaling pathway in T24 cells. These results indicated, for the first time, that Fer has a critical role in bladder UCC progression and may be a potential therapeutic target for bladder UCC metastasis.

Downregulation of GLUT4 contributes to effective intervention of estrogen receptor-negative/HER2-overexpressing early stage breast disease progression by lapatinib

PubMed Central

Acharya, Sunil; Xu, Jia; Wang, Xiao; Jain, Shalini; Wang, Hai; Zhang, Qingling; Chang, Chia-Chi; Bower, Joseph; Arun, Banu; Seewaldt, Victoria; Yu, Dihua

2016-01-01

Tamoxifen and aromatase inhibitors (AIs) have shown efficacy in prevention of estrogen receptor-positive (ER+) breast cancer; however, there exists no proven prevention strategy for estrogen receptor-negative (ER-) breast cancer. Up to 40% of ER- breast cancers have human epidermal growth factor receptor 2 overexpression (HER2+), suggesting HER2 signaling might be a good target for chemoprevention for certain ER- breast cancers. Here, we tested the feasibility of the HER2-targeting agent lapatinib in prevention and/or early intervention of an ER-/HER2+ early-stage breast disease model. We found that lapatinib treatment forestalled the progression of atypical ductal hyperplasia (ADH)-like acini to ductal carcinoma in situ (DCIS)-like acini in ER-/HER2+ human mammary epithelial cells (HMECs) in 3D culture. Mechanistically, we found that inhibition of HER2/Akt signaling by lapatinib led to downregulation of GLUT4 and a reduced glucose uptake in HER2-overexpressing cells, resulting in decreased proliferation and increased apoptosis of these cells in 3D culture. Additionally, our data suggest that HER2-driven glycolytic metabolic dysregulation in ER-/HER2+ HMECs might promote early-stage breast disease progression, which can be reversed by lapatinib treatment. Furthermore, low-dose lapatinib treatment, starting at the early stages of mammary grand transformation in the MMTV-neu* mouse model, significantly delayed mammary tumor initiation and progression, extended tumor-free survival, which corresponded to effective inhibition of HER2/Akt signaling and downregulation of GLUT4 in vivo. Taken together, our results indicate that lapatinib, through its inhibition of key signaling pathways and tumor-promoting metabolic events, is a promising agent for the prevention/early intervention of ER-/HER2+ breast cancer progression. PMID:27293993

Illness Progression as a Function of Independent and Accumulating Poor Prognosis Factors in Outpatients With Bipolar Disorder in the United States

PubMed Central

Altshuler, Lori L.; Leverich, Gabriele S.; Nolen, Willem A.; Kupka, Ralph; Grunze, Heinz; Frye, Mark A.; Suppes, Trisha; McElroy, Susan L.; Keck, Paul E.; Rowe, Mike

2014-01-01

Objective: Many patients with bipolar disorder in the United States experience a deteriorating course of illness despite naturalistic treatment in the community. We examined a variety of factors associated with this pattern of illness progression. Method: From 1995 to 2002, we studied 634 adult outpatients with bipolar disorder (mean age of 40 years) emanating from 4 sites in the United States. Patients gave informed consent and completed a detailed questionnaire about demographic, vulnerability, and course-of-illness factors and indicated whether their illness had shown a pattern of increasing frequency or severity of manic or depressive episodes. Fifteen factors previously linked in the literature to a poor outcome were examined for their relationship to illness progression using Kruskal-Wallis test, followed by a 2-sample Wilcoxon rank sum (Mann-Whitney) test, χ2, and logistical regression. Results: All of the putative poor prognosis factors occurred with a high incidence, and, with the exception of obesity, were significantly (P < .05) associated with illness progression. These factors included indicators of genetic and psychosocial risk and loss of social support, early onset, long delay to first treatment, anxiety and substance abuse comorbidity, rapid cycling in any year, and the occurrence of more than 20 prior episodes prior to entering the network. A greater number of factors were linearly associated with the likelihood of a progressively worsening course. Conclusions: Multiple genetic, psychosocial, and illness factors were associated with a deteriorating course of bipolar disorder from onset to study entry in adulthood. The identification of these factors provides important targets for earlier and more effective therapeutic intervention in the hope of achieving a more benign course of bipolar disorder. PMID:25834764

Effect of Adolescent Cigarette Smoking on Adulthood Substance Use and Abuse: The Mediating Role of Educational Attainment

PubMed Central

Strong, Carol; Juon, Hee-Soon; Ensminger, Margaret E.

2018-01-01

Background Even though the association between cigarette smoking and later substance use has been shown, there is still no compelling evidence that demonstrates the long-term effects in a high drug using community in African Americans. Few studies have examined the mediating mechanisms of the effect of adolescent cigarette smoking on the drug progression pathway. Objectives We examined the long-term influence of adolescent smoking on later illegal drug use in a cohort of urban African Americans, and the mediating role of educational attainment in the drug progression pathway. Methods The study used a longitudinal dataset from the Woodlawn Project that followed 1,242 African Americans from 1966–1967 (at age 6–7) through 2002–2003 (at age 42–43). We used the propensity score matching method to find a regular and a nonregular adolescent smoking group that had similar childhood characteristics; we used the matched sample to assess the association between adolescent smoking and drug progression, and the mediating role of educational attainment. Results Adolescent regular smokers showed significantly higher odds of using marijuana, cocaine, and heroin, having alcohol abuse problems and any drug dependence, and abuse problems in adulthood. We found that educational attainment mediated most of the drug progression pathway, including cigarette smoking, marijuana, cocaine and heroin use, and drug dependence or abuse problems in adulthood, but not alcohol abuse. Conclusions More focus needs to be put on high school dropout and development of interventions in community settings for African Americans to alter the pathway for drug progression for adolescents who use cigarettes regularly. PMID:26787191

CAA for Jet Noise Physics: Issues and Recent Progress

NASA Technical Reports Server (NTRS)

Mankbadi, Reda

2001-01-01

Dr. Mankbadi summarized recent CAA results. Examples of the effect of various boundary condition schemes on the computed acoustic field, for a point source in a uniform flow, were shown. Solutions showing the impact of inflow excitations on the result were also shown. Results from a large eddy simulation, using a fourth-order MacCormack scheme with a Smagorinsky sub-grid turbulence model, were shown for a Mach 2.1 unheated jet. The results showed that the results were free from spurious modes. Results were shown for a Mach 1.4 jet using LES in the near field and the Kirchhoff method for the far field. Predicted flow field characteristics were shown to be in good agreement with data and predicted far field directivities were shown to be in qualitative agree with experimental measurements.

Detection Progress of Selected Drugs in TLC

PubMed Central

Pyka, Alina

2014-01-01

This entry describes applications of known indicators and dyes as new visualizing reagents and various visualizing systems as well as photocatalytic reactions and bioautography method for the detection of bioactive compounds including drugs and compounds isolated from herbal extracts. Broadening index, detection index, characteristics of densitometric band, modified contrast index, limit of detection, densitometric visualizing index, and linearity range of detected compounds were used for the evaluation of visualizing effects of applied visualizing reagents. It was shown that visualizing effect depends on the chemical structure of the visualizing reagent, the structure of the substance detected, and the chromatographic adsorbent applied. The usefulness of densitometry to direct detection of some drugs was also shown. Quoted papers indicate the detection progress of selected drugs investigated by thin-layer chromatography (TLC). PMID:24551853

Color Doppler imaging of the retrobulbar circulation in progressive glaucoma optic neuropathy.

PubMed

Magureanu, Marineta; Stanila, Adriana; Bunescu, Liviu Valentin; Armeanu, Cristina

2016-01-01

It is known that elevated intraocular pressure (IOP) is the primary risk factor for glaucoma. Recently, more and more evidences have shown that the vascular deficit also plays an important role in the pathogenesis and progressions of glaucomatous optic neuropathy. This issue is backed up by glaucomatous optic neuropathy (GON) cases drug compensated in which the progression of the disease in one or both eyes is ascertained despite a normal and relatively constant IOP. The present study evaluated the hemodynamic parameters in the retrobulbar circulation in patients with progressive glaucomatous optic neuropathy in one eye, who received compensated medication. The hemodynamic parameters (PSV, EDV, IR) were measured by using color Doppler ultrasound and progression was evaluated by a repeated automated perimetry. The obtained values were statistically analyzed and compared with those obtained for the stable eye.

Laser-induced fluorescence spectroscopy for improved chemical analysis

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

Gelbwachs, J.A.

1983-09-01

This report summarizes the progress achieved over the past five years in the laser-induced fluorescence spectroscopy (LIFS) for improved chemical analysis program. Our initial efforts yielded significantly lower detection limits for trace elemental analysis by the use of both cw and pulsed laser excitations. New methods of LIFS were developed that were shown to overcome many of the traditional limitations to LIFS techniques. LIFS methods have been applied to yield fundamental scientific data that further the understanding of forces between atoms and other atoms and molecules. In recent work, two-photon ionization was combined with LIFS and applied, for the firstmore » time, to the study of energy transfer in ions.« less

[Autologous bone marrow transplantation in intestinal carcinoma].

PubMed

Sebesta, C; Tiefengraber, E; Kier, P; Ruckser, R; Habertheuer, K H; Schmid, A; Hinterberger, W

1995-01-01

Although adjuvant chemotherapy has made some progress in the treatment of colorectal cancer, chemotherapy of metastatic disease remains disappointing. Autologous bone marrow or stem cell transplantation following supralethal chemotherapy is presently not of major significance in tumors of the intestine. The registry of the EBMT (European Cooperative Group for Blood and Marrow Transplantation) contains at March 1993 a total of 2085 cases of autotransplants for solid tumors, of which only 19 were performed for disseminated gastrointestinal cancer (15 gastric, 4 colon). It remains to be shown, whether the presently poor results can be improved upon inclusion of lymphokine-activated killer cells (LAK-cells) by use of cytokine combinations or by the use of tumor infiltrating lymphocytes (TIL) post transplantation.

Off-farm applications of solar energy in agriculture

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

Berry, R.E.

1980-01-01

Food processing applications make up almost all present off-farm studies of solar energy in agriculture. Research, development and demonstration projects on solar food processing have shown significant progress over the past 3 years. Projects have included computer simulation and mathematical models, hardware and process development for removing moisture from horticultural or animal products, integration of energy conservation with solar energy augmentation in conventional processes, and commercial scale demonstrations. The demonstration projects include solar heated air for drying prunes and raisins, soy beans and onions/garlic; and solar generated steam for orange juice pasteurization. Several new and planned projects hold considerable promisemore » for commerical exploitation in future food processes.« less

Augmentation of the Pullout Repair of a Medial Meniscus Posterior Root Tear by Arthroscopic Centralization.

PubMed

Koga, Hideyuki; Watanabe, Toshifumi; Horie, Masafumi; Katagiri, Hiroki; Otabe, Koji; Ohara, Toshiyuki; Katakura, Mai; Sekiya, Ichiro; Muneta, Takeshi

2017-08-01

The meniscus roots are critical for meniscus function in preserving correct knee kinematics and avoiding meniscus extrusion and, consequently, in the progression of osteoarthritis. Several techniques exist for medial meniscus posterior root tear repair; however, current surgical techniques have been proved to fail to reduce meniscus extrusion, which has been shown to be associated with development of osteoarthritis, although significant improvements in the postoperative clinical findings have been achieved. This Technical Note describes an arthroscopic technique for the medial meniscus posterior root tear in which a pullout repair is augmented by a centralization technique to restore and maintain the medial meniscus function by efficiently reducing meniscus extrusion.

Mitochondrial catalase suppresses naturally occurring lung cancer in old mice.

PubMed

Ge, Xuang; Pettan-Brewer, Christina; Morton, John; Carter, Katrina; Fatemi, Sy; Rabinovitch, Peter; Ladiges, Warren C

2015-01-01

Lung cancer is generally difficult to detect until the late stages of disease, when it is much more difficult to treat because of the more aggressive and invasive behavior. Advanced lung cancer is much more common in older adults making it even more challenging to treat. Adenocarcinoma belongs to a category of non-small cell lung cancers, which comprise up to 40% of all lung cancers, and about half of these have an activating K-ras mutation. Because treatment relapses are common, more effective unconventional treatment and prevention methods are needed. In this regard, the antioxidant enzyme catalase targeted to mitochondria (mCAT) has been shown to delay aging and cancer in mice, and the progression of transgenic oncogene and syngeneic tumors was suppressed, helping support the notion that attenuation of mitochondria-generated hydrogen peroxide signaling is associated with an antitumor effect. In order to determine if mCAT has any effect on naturally occurring lung cancer of the adenocarcinoma type in old mice, the tumor incidence and progression were examined in the lungs of old mCAT transgenic and wild-type (WT) mice with a CB6F1 (Balb/c X C57BL/6) background. CB6F1 mice with a WT genotype were found to have a high incidence of adenomas at 24 months of age, which progressed to adenocarcinomas at 32 months of age. CB6F1 mice with the mCAT genotype had significantly reduced incidence and severity of lung tumors at both ages. Fibroblasts isolated from the lungs of old mCAT mice, but not WT mice, were shown to secrete soluble factors that inhibited lung tumor cell growth suggesting that stromal fibroblasts play a role in mediating the antitumor effects of mCAT. The aged CB6F1 mouse, with its high incidence of K-ras mutant lung cancer, is an excellent model to further study the anticancer potential of mitochondria-targeted therapy.

Mitochondrial catalase suppresses naturally occurring lung cancer in old mice

PubMed Central

Ge, Xuang; Pettan-Brewer, Christina; Morton, John; Carter, Katrina; Fatemi, Sy; Rabinovitch, Peter; Ladiges, Warren C.

2015-01-01

Lung cancer is generally difficult to detect until the late stages of disease, when it is much more difficult to treat because of the more aggressive and invasive behavior. Advanced lung cancer is much more common in older adults making it even more challenging to treat. Adenocarcinoma belongs to a category of non-small cell lung cancers, which comprise up to 40% of all lung cancers, and about half of these have an activating K-ras mutation. Because treatment relapses are common, more effective unconventional treatment and prevention methods are needed. In this regard, the antioxidant enzyme catalase targeted to mitochondria (mCAT) has been shown to delay aging and cancer in mice, and the progression of transgenic oncogene and syngeneic tumors was suppressed, helping support the notion that attenuation of mitochondria-generated hydrogen peroxide signaling is associated with an antitumor effect. In order to determine if mCAT has any effect on naturally occurring lung cancer of the adenocarcinoma type in old mice, the tumor incidence and progression were examined in the lungs of old mCAT transgenic and wild-type (WT) mice with a CB6F1 (Balb/c X C57BL/6) background. CB6F1 mice with a WT genotype were found to have a high incidence of adenomas at 24 months of age, which progressed to adenocarcinomas at 32 months of age. CB6F1 mice with the mCAT genotype had significantly reduced incidence and severity of lung tumors at both ages. Fibroblasts isolated from the lungs of old mCAT mice, but not WT mice, were shown to secrete soluble factors that inhibited lung tumor cell growth suggesting that stromal fibroblasts play a role in mediating the antitumor effects of mCAT. The aged CB6F1 mouse, with its high incidence of K-ras mutant lung cancer, is an excellent model to further study the anticancer potential of mitochondria-targeted therapy. PMID:26400209

Gene editing of the extra domain A positive fibronectin in various tumors, amplified the effects of CRISPR/Cas system on the inhibition of tumor progression.

PubMed

Lv, Wan-Qi; Wang, Hai-Cheng; Peng, Jing; Wang, Yi-Xiang; Jiang, Jiu-Hui; Li, Cui-Ying

2017-12-01

The low efficiency of clustered, regularly interspaced, palindromic repeats-associated Cas (CRISPR/Cas) system editing genes in vivo limits the application. A components of the extracellular matrix (ECM), the extra domain A positive fibronectin (EDA+FN), may be a target for CRISPR/Cas system for the pro-oncogenic effects. The exclusion of EDA exon would alter the microenvironment and inhibit tumor progression, even the frequency of gene editing is still limited. The pro-oncogenic effects were confirmed by the exclusion of EDA exon from the fibronectin gene, as illustrated by the down-regulated proliferation, migration and invasion of CNE-2Z or SW480 cells (P<0.05). Furthermore, although the efficacy of EDA exon knockout through CRISPR/Cas system was shown to be low in vivo , the EDA+FN protein levels decrease obviously, inhibiting the tumor growth rate significantly (P<0.05), which was accompanied by a decrease in Ki-67 expression and microvessel numbers, and increased E-cadherin or decreased Vimentin expression (P<0.05). Human nasopharyngeal carcinoma cell line CNE-2Z, and the colorectal carcinoma cell line SW480 were transfected with CRISPR/Cas9 plasmids targeting EDA exon. The effects of the exclusion of EDA on the cell proliferation, motility and epithelial-mesenchymal transition (EMT) were investigated, and the western blot and real-time PCR were performed to analyze the underlying mechanisms. Furthermore, CRISPR/Cas9 plasmids were injected into xenograft tumors to knockout EDA exon in vivo , and tumor growth, cell proliferation, EMT rate, or vascularization were investigated using western blot, PCR and immunohistochemistry. CRISPR/Cas system targeting ECM components was shown to be an effective method for the inhibition of tumor progression, as these paracrine or autocrine molecules are necessary for various tumor cells. This may represent a novel strategy for overcoming the drug evasion or resistance, in addition, circumventing the low efficiency of CRISPR/Cas system in vivo .

Recovery of antigen-specific T cell responses from dogs infected with Leishmania (L.) infantum by use of vaccine associated TLR-agonist adjuvant.

PubMed

Schaut, Robert G; Grinnage-Pulley, Tara L; Esch, Kevin J; Toepp, Angela J; Duthie, Malcolm S; Howard, Randall F; Reed, Steven G; Petersen, Christine A

2016-10-17

Visceral leishmaniasis (VL), caused by infection with the obligate intracellular protozoan parasite Leishmania infantum, is a fatal disease of dogs and humans. Protection against VL requires a T helper 1 (Th1) skewed CD4 + T response, but despite this knowledge, there are currently no approved-to-market vaccines for humans and only three veterinary-use vaccines globally. As VL progresses from asymptomatic to symptomatic, L. infantum-specific interferon gamma (IFNγ) driven-Th1 responses become dampened and a state of immune exhaustion established. T cell exhaustion and other immunoregulatory processes, starting during asymptomatic disease, are likely to hinder vaccine-induced responses if vaccine is administered to infected, but asymptomatic and seronegative, individuals. In this study we evaluated how immune exhaustion, shown previously by our group to worsen in concert with VL progression, effected the capacity of vaccine candidate antigen/toll-like receptor (TLR) agonist combinations to promote protective CD4 + T cell responses during progressive VL. In conjunction with Th1 responses, we also evaluated concomitant stimulation of immune-balanced IL-10 regulatory cytokine production by these vaccine products in progressive VL canine T cells. Vaccine antigen L111f in combination with TLR agonists significantly recovered CD4 + T cell IFNγ intracellular production in T cells from asymptomatic VL dogs. Vaccine antigen NS with TLR agonists significantly recovered CD4 + T cell production in both endemic control and VL dogs. Combinations of TLR agonists and vaccine antigens overcame L. infantum induced cellular exhaustion, allowing robust Th1 CD4 + T cell responses from symptomatic dogs that previously had dampened responses to antigen alone. Antigen-agonist adjuvants can be utilized to promote more robust vaccine responses from infected hosts in endemic areas where vaccination of asymptomatic, L. infantum-infected animals is likely. Copyright © 2016. Published by Elsevier Ltd.

Prognostic significance of β2-adrenergic receptor expression in malignant melanoma.

PubMed

Shimizu, Akira; Kaira, Kyoichi; Mori, Keita; Kato, Madoka; Shimizu, Kimihiro; Yasuda, Masahito; Takahashi, Ayumi; Oyama, Tetsunari; Asao, Takayuki; Ishikawa, Osamu

2016-05-01

Recent studies cite β2-adrenergic receptor (β2AR) antagonists as novel therapeutic agents for melanoma, as they may reduce the disease progression. The β2AR has shown to be expressed in malignant melanoma. However, it remains unclear whether the β2AR expression has a clinical and pathological significance in patients with cutaneous malignant melanoma. We herein conducted a clinicopathological study to investigate the protein expression of β2AR in malignant melanoma of the skin and its prognostic significance. One hundred thirty-three patients with surgically resected cutaneous malignant melanoma were evaluated. Tumor sections were stained by immunohistochemistry for β2AR, Ki-67, the microvessel density (MVD) determined by CD34, and p53. β2AR was highly expressed in 44.4 % (59 out of 133) of the patients. The expression of β2AR was significantly associated with the tumor thickness, ulceration, T factor, N factor, disease stage, tumor size, cell proliferation (Ki-67), and MVD (CD34). Using Spearman's rank test, the β2AR expression was correlated with Ki-67 (r = 0.278; 95 % CI, 0.108 to 0.432; P = 0.001), CD34 (r = 0.445; 95 %CI, 0.293 to 0.575; P < 0.001), and the tumor size (r = 0.226; 95 % CI, 0.053 to 0.386; P = 0.008). Using a univariate analysis, the tumor thickness, ulceration, disease stage, β2AR, Ki-67, and CD34 had a significant relationship with the overall and progression-free survivals. A multivariable analysis confirmed that β2AR was an independent prognostic factor for predicting a poor overall survival (HR 1.730; 95 % CI 1.221-2.515) and progression-free survival (HR 1.576; 95 % CI 1.176-2.143) of malignant melanoma of the skin. β2AR can serve as a promising prognostic factor for predicting a worse outcome after surgical treatment and may play an important role in the development and aggressiveness of malignant melanoma.

EEG low-resolution brain electromagnetic tomography (LORETA) in Huntington's disease.

PubMed

Painold, Annamaria; Anderer, Peter; Holl, Anna K; Letmaier, Martin; Saletu-Zyhlarz, Gerda M; Saletu, Bernd; Bonelli, Raphael M

2011-05-01

Previous studies have shown abnormal electroencephalography (EEG) in Huntington's disease (HD). The aim of the present investigation was to compare quantitatively analyzed EEGs of HD patients and controls by means of low-resolution brain electromagnetic tomography (LORETA). Further aims were to delineate the sensitivity and utility of EEG LORETA in the progression of HD, and to correlate parameters of cognitive and motor impairment with neurophysiological variables. In 55 HD patients and 55 controls a 3-min vigilance-controlled EEG (V-EEG) was recorded during midmorning hours. Power spectra and intracortical tomography were computed by LORETA in seven frequency bands and compared between groups. Spearman rank correlations were based on V-EEG and psychometric data. Statistical overall analysis by means of the omnibus significance test demonstrated significant (p < 0.01) differences between HD patients and controls. LORETA theta, alpha and beta power were decreased from early to late stages of the disease. Only advanced disease stages showed a significant increase in delta power, mainly in the right orbitofrontal cortex. Correlation analyses revealed that a decrease of alpha and theta power correlated significantly with increasing cognitive and motor decline. LORETA proved to be a sensitive instrument for detecting progressive electrophysiological changes in HD. Reduced alpha power seems to be a trait marker of HD, whereas increased prefrontal delta power seems to reflect worsening of the disease. Motor function and cognitive function deteriorate together with a decrease in alpha and theta power. This data set, so far the largest in HD research, helps to elucidate remaining uncertainties about electrophysiological abnormalities in HD.

[Research progress on molecular genetics of male homosexuality].

PubMed

Tu, Dan; Xu, Ruiwei; Zhao, Guanglu; Wang, Binbin; Feng, Tiejian

2016-08-01

Sexual orientation is influenced by both environmental factors and biological factors. Family and twin studies have shown that genetic factors play an important role in the formation of male homosexuality. Genome-wide scan also revealed candidate chromosomal regions which may be associated with male homosexuality, but so far no clearly related genes have been found. This article reviews the progress of relevant studies and candidate genes which are related to male homosexuality.

Role of macropore flow in the transport of Escherichia coli cells in undisturbed cores of a brown leached soil.

PubMed

Martins, Jean M F; Majdalani, Samer; Vitorge, Elsa; Desaunay, Aurélien; Navel, Aline; Guiné, Véronique; Daïan, Jean François; Vince, Erwann; Denis, Hervé; Gaudet, Jean Paul

2013-02-01

The objective of this work was to evaluate the transport of Escherichia coli cells in undisturbed cores of a brown leached soil collected at La Côte St André (France). Two undisturbed soil cores subjected to repeated injections of bacterial cells and/or bromide tracer were used to investigate the effect of soil hydrodynamics and ionic strength on cell mobility. Under the tested experimental conditions, E. coli cells were shown to be transported at the water velocity (retardation factor close to 1) and their retention appeared almost insensitive to water flow and ionic strength variations, both factors being known to control bacterial transport in model saturated porous media. In contrast, E. coli breakthrough curves evolved significantly along with the repetition of the cell injections in each soil core, with a progressive acceleration of their transport. The evolution of E. coli cells BTCs was shown to be due to the evolution of the structure of soil hydraulic pathways caused by the repeated water infiltrations and drainage as may occur in the field. This evolution was demonstrated through mercury intrusion porosimetry (MIP) performed on soil aggregates before and after the repeated infiltrations of bacteria. MIP revealed a progressive and important reduction of the soil aggregate porosity, n, that decreased from approximately 0.5 to 0.3, along with a decrease of the soil percolating step from 27 to 2 μm. From this result a clear compaction of soil aggregates was evidenced that concerned preferentially the pores larger than 2 μm equivalent diameter, i.e. those allowing bacterial cell passage. Since no significant reduction of the global soil volume was observed at the core scale, this aggregate compaction was accompanied by macropore formation that became progressively the preferential hydraulic pathway in the soil cores, leading to transiently bi-modal bacterial BTCs. The evolution of the soil pore structure induced a modification of the main hydrodynamic processes, evolving from a matrix-dominant transfer of water and bacteria to a macropore-dominant transfer. This work points out the importance of using undisturbed natural soils to evaluate the mobility of bacteria in the field, since the evolving hydrodynamic properties of soils appeared to dominate most physicochemical factors.

Effects of lines of progress and semilogarithmic charts on ratings of charted data

PubMed Central

Bailey, Donald B.

1984-01-01

The extent to which interrater agreement and ratings of significance on both changes in level and trend are affected by lines of progress and semilogarithmic charts was investigated. Thirteen graduate students rated four sets of charts, each set containing 19 phase changes. Set I data were plotted on equal interval charts. In Set II a line of progress was drawn through each phase on each chart. In Set III data points were replotted on semilogarithmic charts. In Set IV a line of progress was drawn through each phase of each Set III chart. A significant main effect on interrater agreement was found for lines of progress as well as a significant 2-way interaction between lines of progress and change type. Three main effects (chart type, lines of progress, and type of change) and a significant 3-way interaction were found for ratings of significance. Implications of these data for visual analysis of charted data are discussed. PMID:16795676

Reduced m6A mRNA methylation is correlated with the progression of human cervical cancer

PubMed Central

Kong, Beihua; Song, Chen; Cong, Jianglin; Hou, Jianqing; Wang, Shaoguang

2017-01-01

The m6A mRNA methylation involves in mRNA splicing, degradation and translation. Recent studies have revealed that reduced m6A mRNA methylation might promote cancer development. However, the role of m6A mRNA methylation in cervical cancer development remains unknown. Therefore, we investigated the role of m6A methylation in cervical cancer in the current study. We first evaluated the m6A mRNA methylation level in 286 pairs of cervical cancer samples and their adjacent normal tissues by dot blot assay. Then the role of m6A on patient survival rates and cervical cancer progression were assessed. The m6A level was significantly reduced in the cervical cancer when comparing with the adjacent normal tissue. The m6A level reduction was significantly correlated with the FIGO stage, tumor size, differentiation, lymph invasion and cancer recurrence. It was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with cervical cancer. Reducing m6A level via manipulating the m6A regulators expression promoted cervical cancer cell proliferation. And increasing m6A level significantly suppressed tumor development both in vitro and in vivo. Our results showed that the reduced m6A level is tightly associated with cervical cancer development and m6A mRNA methylation might be a potential therapeutic target in cervical cancer. PMID:29228737

ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma

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

Ungerer, Christopher; Doberstein, Kai; Buerger, Claudia

2010-10-22

Research highlights: {yields} Strong ADAM15 expression is found in normal melanocytes. {yields} ADAM15 expression is significantly downregulated in patients with melanoma metastasis. {yields} TGF-{beta} can downregulate ADAM15 expression in melanoma cells. {yields} Overexpression of ADAM15 in melanoma cells inhibits migration, proliferation and invasion of melanoma cells. {yields} Conclusion: ADAM15 represents an tumor suppressor protein in melanoma. -- Abstract: In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far.more » In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma. We further demonstrate that IFN-{gamma} and TGF-{beta} downregulate ADAM15 protein levels in melanoma cells. To investigate the role of ADAM15 in melanoma progression, we overexpressed ADAM15 in melanoma cells. Importantly, overexpression of ADAM15 in melanoma cells reduced the migration, invasion and the anchorage dependent and independent cell growth of melanoma cells. In summary, the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma.« less

High expression of B7-H6 in human glioma tissues promotes tumor progression.

PubMed

Jiang, Tianwei; Wu, Wei; Zhang, Huasheng; Zhang, Xiangsheng; Zhang, Dingding; Wang, Qiang; Huang, Lei; Wang, Ye; Hang, Chunhua

2017-06-06

B7-H6, a new member of B7-family ligand, also known as NCR3LG1, plays an important role in NK cells mediated immune responses. Many studies have shown that it is highly expressed in various human cancers, and its expression levels are significantly associated with cancer patients' clinicopathological parameters and postoperative prognoses. But, still the exact role of B7-H6 expression in human glioma remains elusive. In the present study, we have characterized the B7-H6 expression in the human glioma tissues as well as glioma cell lines, U87 and U251. We observed that B7-H6 was highly expressed in the human glioma tissues, and its expression was significantly associated with cancer progression. By using the RNA interference technology, we successfully ablated B7-H6 expression in human glioma cell lines to further study its contribution towards various biological features of this malignancy. Our study identified that the B7-H6 knockdown in U87 and U251 glioma cells significantly suppressed cell proliferation, migration, invasion, and enhanced apoptosis along with induction of cell cycle arrest. It thus suggested that B7-H6 play an important role in the regulation of the biological behavior of these glioma cells. However, the detailed mechanism of B7-H6 mediated regulation of glioma cancer cell transformation and its prognostic value merits further investigation.

Effect of vitamin C supplementation on lipid profile, serum uric acid, and ascorbic acid in children on hemodialysis.

PubMed

El Mashad, Ghada Mohamed; ElSayed, Hanan M; Nosair, Nahla A

2016-01-01

Children with end-stage renal disease (ESRD) suffer from dyslipidemia and hyperuricemia that might play a causal role in the progression of cardiovascular disease (CVD). The aim of the study is to assess the effects of Vitamin C supplementation on uric acid, ascorbic acid, and serum lipid levels among children on hemodialysis (HD). This prospective study was conducted in the pediatric nephrology unit at Menoufia University Hospital. The study included a total of 60 children with ESRD on maintenance HD therapy. They were divided into two groups: Group I (supplemented group, n = 30) received intravenous Vitamin C supplementation and Group II (control, n = 30) received placebo (intravenous saline) for three months. The results are shown as a mean ± standard deviation. Statistical evaluation was performed by SPSS software (version 11.5) using paired t-test. After supplementation with Vitamin C, the serum Vitamin C and high-density lipoprotein levels increased significantly with a significant reduction in the levels of serum uric acid, cholesterol, low-density lipoproteins, and triglyceride at the end of the study period. No significant changes were observed in the control group. Vitamin C can serve as a useful urate lowering medicine in HD patients to avoid complications of hyperuricemia. Furthermore, it had favorable effects on the lipid profile. This improvement can be considered as a preventive strategy in the progression of CVD in HD patients. Vitamin C supplementation improves ascorbic acid deficiency in these patients.

Mars aqueous chemistry experiment

NASA Technical Reports Server (NTRS)

Clark, Benton C.; Mason, Larry W.

1994-01-01

Mars Aqueous Chemistry Experiment (MACE) is designed to conduct a variety of measurements on regolith samples, encompassing mineral phase analyses, chemical interactions with H2O, and physical properties determinations. From these data, much can be learned or inferred regarding the past weathering environment, the contemporaneous soil micro-environments, and the general chemical and physical state of the Martian regolith. By analyzing both soil and duricrust samples, the nature of the latter may become more apparent. Sites may be characterized for comparative purposes and criteria could be set for selection of high priority materials on future sample return missions. The second year of the MACE project has shown significant progress in two major areas. MACE Instrument concept definition is a baseline design that has been generated for the complete MACE instrument, including definition of analysis modes, mass estimates and thermal model. The design includes multiple reagent reservoirs, 10 discrete analysis cells, sample manipulation capability, and thermal control. The MACE Measurement subsystems development progress is reported regarding measurement capabilities for aqueous ion sensing, evolved gas sensing, solution conductivity measurement, reagent addition (titration) capabilities, and optical sensing of suspended particles.

First indications demonstrating the preventive effects of NZ-419, a novel intrinsic antioxidant, on the initiation and/or progression of chronic renal failure in rats.

PubMed

Ienaga, Kazuharu; Mikami, Hiroki; Yokozawa, Takako

2009-07-01

The concentration of NZ-419 (5-hydroxy-1-methylimidazolidine-2,4-dione), an intrinsic antioxidant, has been shown to increase in the sera of animals and patients with chronic renal failure (CRF). This is the first report that orally administered exogenous NZ-419 prevents the initiation and/or progression of CRF in rats using an adenine-loaded model. After 24 d of adenine loading, there was a ca. 90% decrease in creatinine clearance (C(Cr)) in the control rats. Treatment with NZ-419 from the beginning significantly inhibited the decrease in C(Cr) and also the increase in serum creatinine (sCr). Bio-markers for in vivo hydroxyl radicals, the serum methylguanidine (sMG) level, and sMG/sCr molar ratio, not only in serum but also in the urine, kidney, liver, and muscle indicated that NZ-419 inhibited the increase in oxidative stress induced by CRF in rats. An increase of guanidinosuccinic acid, an another bio-marker of oxidative stress, was also inhibited with NZ-419.

Checkpoint inhibition for advanced mucosal melanoma.

PubMed

Thierauf, Julia; Veit, Johannes A; Hess, Jochen; Treiber, Nicolai; Lisson, Catharina; Weissinger, Stephanie E; Bommer, Martin; Hoffmann, Thomas K

2017-04-01

Whereas anti-PD-1 therapy has demonstrated a significant and durable response against advanced cutaneous melanoma, conventional chemotherapies have shown only minor benefit against advanced mucosal melanoma. To investigate the efficacy of anti-PD-1 therapy in a small cohort of patients with mucosal melanoma of the head and neck. We analysed five patients with mucosal melanoma of the head and neck who received nivolumab or pembrolizumab, at an advanced stage. Expression of PD-L1 and PD-1 in all tumour samples was evaluated immunohistochemically. All patients received at least two cycles of nivolumab or pembrolizumab. The most severe adverse events were categorised as CTCAE (common terminology criteria for adverse events) Grade 2. All patients showed progressive disease after restaging at three and six months, and no partial or complete response was observed. Immunohistochemical staining demonstrated PD-L1 expression in less than 5% of tumour cells. Systemic therapy with either nivolumab or pembrolizumab showed no clinical response, however, tumour progression was identified in all patients using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune-related response criteria (irRC) to evaluate tumour response.

Progress towards measuring the Rydberg Constant Using Circular Rydberg Atoms in an Intensity-Modulated Optical Lattice

NASA Astrophysics Data System (ADS)

Ramos, Andira; Moore, Kaitlin; Raithel, Georg

2015-05-01

Recent significant disagreement with the previously established size of the proton demonstrates a need to reconsider the current value of the Rydberg constant, the effects of the nuclear charge distribution and QED in hydrogen-like atoms. An experiment is in progress to obtain a measurement of the Rydberg constant by studying circular Rydberg atoms, which exhibit very small QED shifts and electron wavefunctions which do not overlap with the nucleus. Cold Rydberg atoms are trapped using a ponderomotive potential. To drive the transitions, a novel type of spectroscopy is used which utilizes an optical-lattice field that is intensity-modulated at the frequencies of atomic transitions. The method is free of typical spectroscopic selection rules and has been shown to drive transitions up to fifth order. Combined with optical Rydberg-atom trapping, the method enables the measurement of narrow, sub-THz transitions between long-lived circular Rydberg levels. Energy shifts affecting this precision measurement will also be discussed. This work is suported by NSF, NIST and NASA grants.

Arsenite inhibits mitotic division and perturbs spindle dynamics in HeLa S3 cells.

PubMed

Huang, S C; Lee, T C

1998-05-01

Arsenical compounds, known to be human carcinogens, were shown to disturb cell cycle progression and induce cytogenetic alterations in a variety of cell systems. We report here that a 24 h treatment of arsenite induced mitotic accumulation in human cell lines. HeLa S3 and KB cells were most susceptible: 35% of the total cell population was arrested at the mitotic stage after treatment with 5 microM sodium arsenite in HeLa S3 cells and after 10 microM in KB cells. Under a microscope, we observed abnormal mitotic figures in arsenite-arrested mitotic cells, including deranged chromosome congression, elongated polar distance of mitotic spindle, and enhanced microtubule immunofluorescence. The spindle microtubules of arsenite-arrested mitotic cells were more resistant to nocodazole-induced dissolution than those of control mitotic cells. According to turbidity assay, arsenite at concentrations below 100 microM significantly enhanced polymerization of tubulins. Since spindle dynamics play a crucial role in mitotic progression, our results suggest that arsenite-induced mitotic arrest may be due to arsenite's effects on attenuation of spindle dynamics.

Dynamic and Progressive Control of DNA Origami Conformation by Modulating DNA Helicity with Chemical Adducts.

PubMed

Chen, Haorong; Zhang, Hanyu; Pan, Jing; Cha, Tae-Gon; Li, Shiming; Andréasson, Joakim; Choi, Jong Hyun

2016-05-24

DNA origami has received enormous attention for its ability to program complex nanostructures with a few nanometer precision. Dynamic origami structures that change conformation in response to environmental cues or external signals hold great promises in sensing and actuation at the nanoscale. The reconfiguration mechanism of existing dynamic origami structures is mostly limited to single-stranded hinges and relies almost exclusively on DNA hybridization or strand displacement. Here, we show an alternative approach by demonstrating on-demand conformation changes with DNA-binding molecules, which intercalate between base pairs and unwind DNA double helices. The unwinding effect modulates the helicity mismatch in DNA origami, which significantly influences the internal stress and the global conformation of the origami structure. We demonstrate the switching of a polymerized origami nanoribbon between different twisting states and a well-constrained torsional deformation in a monomeric origami shaft. The structural transformation is shown to be reversible, and binding isotherms confirm the reconfiguration mechanism. This approach provides a rapid and reversible means to change DNA origami conformation, which can be used for dynamic and progressive control at the nanoscale.

Mars aqueous chemistry experiment

NASA Astrophysics Data System (ADS)

Clark, Benton C.; Mason, Larry W.

1994-06-01

Mars Aqueous Chemistry Experiment (MACE) is designed to conduct a variety of measurements on regolith samples, encompassing mineral phase analyses, chemical interactions with H2O, and physical properties determinations. From these data, much can be learned or inferred regarding the past weathering environment, the contemporaneous soil micro-environments, and the general chemical and physical state of the Martian regolith. By analyzing both soil and duricrust samples, the nature of the latter may become more apparent. Sites may be characterized for comparative purposes and criteria could be set for selection of high priority materials on future sample return missions. The second year of the MACE project has shown significant progress in two major areas. MACE Instrument concept definition is a baseline design that has been generated for the complete MACE instrument, including definition of analysis modes, mass estimates and thermal model. The design includes multiple reagent reservoirs, 10 discrete analysis cells, sample manipulation capability, and thermal control. The MACE Measurement subsystems development progress is reported regarding measurement capabilities for aqueous ion sensing, evolved gas sensing, solution conductivity measurement, reagent addition (titration) capabilities, and optical sensing of suspended particles.

Role of rasagiline in treating Parkinson’s disease: Effect on disease progression

PubMed Central

Malaty, Irene A; Fernandez, Hubert H

2009-01-01

Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B) inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson’s disease (PD) patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson’s Disease Outpatients), and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of “Off”, and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily). Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily) and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration. PMID:19753135

INEL BNCT Research Program Annual Report 1993

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

Venhuizen, J.R.

1994-08-01

This report is a summary of the progress and research produced for the Idaho National Engineering Laboratory Boron Neutron Capture Therapy Research Program for calendar year 1993. Contributions from all the principal investigators are included, covering chemistry (pituitary tumor studies, boron drug development including liposomes, lipoproteins, and carboranylalanine derivatives), pharmacology (murine screenings, toxicity testing, boron drug analysis), physics (radiation dosimetry software, neutron beam and filter design, neutron beam measurement dosimetry), and radiation biology (tissue and efficacy studies of small and large animal models). Information on the potential toxicity of borocaptate sodium and boronophenylalanine is presented. Results of 21 spontaneous-tumor-bearing dogsmore » that have been treated with boron neutron capture therapy at the Brookhaven National Laboratory are updated. Boron-containing drug purity verification is discussed in some detail. Advances in magnetic resonance imaging of boron in vivo are discussed. Several boron-carrying drugs exhibiting good tumor uptake are described. Significant progress in the potential of treating pituitary tumors is presented. Measurement of the epithermal-neutron flux of the Petten (The Netherlands) High Flux Reactor beam (HFB11B), and comparison to predictions are shown.« less

Autoantibodies against AT1 and α1-adrenergic receptors predict arterial stiffness progression in normotensive subjects over a 5-year period.

PubMed

Li, Gang; Cao, Zhe; Wu, Xiao-Wei; Wu, Hui-Kun; Ma, Yi; Wu, Bin; Wang, Wei-Qing; Cheng, Jian; Zhou, Zi-Hua; Tu, Yuan-Chao

2017-12-15

Arterial stiffness is an independent indicator of cardiovascular risk. Autoantibodies (AAs) against angiotensin AT 1 receptor (AT 1 -AAs) and α 1 -adrenergic receptor (α 1 -AAs) are important in the pathogenesis of hypertension. We identified the types of AT 1 -AAs and α 1 -AAs in normotensive subjects, with the aim of determining whether these antibodies predict aortic stiffness progression. Carotid-femoral pulse wave velocity (cf-PWV) was used to measure aortic stiffness. Overall, 816 subjects (71% of those invited) underwent a medical examination and evaluation of aortic stiffness. The types of AT 1 -AAs and α 1 -AAs were measured at baseline. Meanwhile, plasma renin, angiotensin II (Ang II), and norepinephrine (NE) concentrations were measured at baseline and follow-up. Baseline mean cf-PWV was 9.90 ± 0.84 m/s and follow-up was 10.51 ± 1.12 m/s. The annualized ΔPWV was 0.12 ± 0.08 m/s/year. At the end of follow-up, 129 normotensive subjects developed hypertension and 144 subjects had PWV progression. After adjustment for covariates, AA type was independently associated with ΔPWV, annualized ΔPWV, and abnormal PWV. In our study, the risk of developing hypertension (RR =2.028, 95% CI: 1.227-3.351, P =0.006) and PWV progression (RR =2.910, 95% CI: 1.612-5.253, P <0.001) in AA-positive subjects was significantly higher than that in AA-negative subjects. Receiver operating characteristic (ROC) curve showed AA had an identify power to discriminate subjects with or without PWV and hypertension progression. We have shown for the first time that the types of A 1 -AAs and α 1 -AAs are independent predictors for aortic stiffness progression in normotensive subjects. Our data collectively support the utility of these AAs as potential markers of aortic stiffness. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Physical activity and cancer prevention : pathways and targets for intervention.

PubMed

Rogers, Connie J; Colbert, Lisa H; Greiner, John W; Perkins, Susan N; Hursting, Stephen D

2008-01-01

The prevalence of obesity, an established epidemiological risk factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Modulation of energy balance, via increased physical activity, has been shown in numerous comprehensive epidemiological reviews to reduce cancer risk. Unfortunately, the effects and mechanistic targets of physical activity interventions on the carcinogenesis process have not been thoroughly characterized. Studies to date suggest that exercise can exert its cancer-preventive effects at many stages during the process of carcinogenesis, including both tumour initiation and progression. As discussed in this review, exercise may be altering tumour initiation events by modifying carcinogen activation, specifically by enhancing the cytochrome P450 system and by enhancing selective enzymes in the carcinogen detoxification pathway, including, but not limited to, glutathione-S-transferases. Furthermore, exercise may reduce oxidative damage by increasing a variety of anti-oxidant enzymes, enhancing DNA repair systems and improving intracellular protein repair systems. In addition to altering processes related to tumour initiation, exercise may also exert a cancer-preventive effect by dampening the processes involved in the promotion and progression stages of carcinogenesis, including scavenging reactive oxygen species (ROS); altering cell proliferation, apoptosis and differentiation; decreasing inflammation; enhancing immune function; and suppressing angiogenesis. A paucity of data exists as to whether exercise may be working as an anti-promotion strategy via altering ROS in initiated or preneoplastic models; therefore, no conclusions can be made about this possible mechanism. The studies directly examining cell proliferation and apoptosis have shown that exercise can enhance both processes, which is difficult to interpret in the context of carcinogenesis. Studies examining the relationship between exercise and chronic inflammation suggest that exercise may reduce pro-inflammatory mediators and reduce the state of low-grade, chronic inflammation. Additionally, exercise has been shown to enhance components of the innate immune response (i.e. macrophage and natural killer cell function). Finally, only a limited number of studies have explored the relationship between exercise and angiogenesis; therefore, no conclusions can be made currently about the role of exercise in the angiogenesis process as it relates to tumour progression. In summary, exercise can alter biological processes that contribute to both anti-initiation and anti-progression events in the carcinogenesis process. However, more sophisticated, detailed studies are needed to examine each of the potential mechanisms contributing to an exercise-induced decrease in carcinogenesis in order to determine the minimum dose, duration and frequency of exercise needed to yield significant cancer-preventive effects, and whether exercise can be used prescriptively to reverse the obesity-induced physiological changes that increase cancer risk.

Light intensity affects RNA silencing of a transgene in Nicotiana benthamiana plants.

PubMed

Kotakis, Christos; Vrettos, Nicholas; Kotsis, Dimitrios; Tsagris, Mina; Kotzabasis, Kiriakos; Kalantidis, Kriton

2010-10-12

Expression of exogenous sequences in plants is often suppressed through one of the earliest described RNA silencing pathways, sense post-transcriptional gene silencing (S-PTGS). This type of suppression has made significant contributions to our knowledge of the biology of RNA silencing pathways and has important consequences in plant transgenesis applications. Although significant progress has been made in recent years, factors affecting the stability of transgene expression are still not well understood. It has been shown before that the efficiency of RNA silencing in plants is influenced by various environmental factors. Here we report that a major environmental factor, light intensity, significantly affects the induction and systemic spread of S-PTGS. Moreover, we show that photoadaptation to high or low light intensity conditions differentially affects mRNA levels of major components of the RNA silencing machinery. Light intensity is one of the previously unknown factors that affect transgene stability at the post-transcriptional level. Our findings demonstrate an example of how environmental conditions could affect RNA silencing.

[Research progress of relationship between diabetes and intestinal epithelial tight junction barrier and intervetion of berberine].

PubMed

Qin, Xin; Dong, Hui; Lu, Fu-Er

2016-06-01

Intestinal tight junction is an important part of the small intestinal mucosa barrier. It plays a very significant role in maintaining the intestinal mucosal permeability and integrity, preventing the bacterial endotoxin and toxic macromolecular substances into the body so as to keep a stable internal environment. Numerous studies have shown that intestinal mucosal barrier dysfunction is closely related to the development of diabetes. Therefore, protecting intestinal tight junction and maintaining the mucosal barrier have great significance in the prevention and treatment of diabetes. The effect of berberine in diabetes treatment is obvious. However, the pharmacological study found that the bioavailability of berberine is extremely low. Some scholars put forward that the major site of pharmaceutical action of berberine might be in the gut. Studies have shown that berberine could regulate the intestinal flora and intestinal hormone secretion, protect the intestinal barrier, inhibit the absorption of glucose, eliminate the intestinal inflammation and so on. Recently studies have found that the hypoglycemic effect of berberine is likely to relate with the influence on intestinal tight junction and the protection of mucosal barrier. Here is the review about the association between intestinal tight junction barrier dysfunction and diabetes, and the related hypoglycemic mechanism of berberine. Copyright© by the Chinese Pharmaceutical Association.

Naproxcinod shows significant advantages over naproxen in the mdx model of Duchenne Muscular Dystrophy.

PubMed

Miglietta, Daniela; De Palma, Clara; Sciorati, Clara; Vergani, Barbara; Pisa, Viviana; Villa, Antonello; Ongini, Ennio; Clementi, Emilio

2015-08-22

In dystrophin-deficient muscles of Duchenne Muscular Dystrophy (DMD) patients and the mdx mouse model, nitric oxide (NO) signalling is impaired. Previous studies have shown that NO-donating drugs are beneficial in dystrophic mouse models. Recently, a long-term treatment (9 months) of mdx mice with naproxcinod, an NO-donating naproxen, has shown a significant improvement of the dystrophic phenotype with beneficial effects present throughout the disease progression. It remains however to be clearly dissected out which specific effects are due to the NO component compared with the anti-inflammatory activity associated with naproxen. Understanding the contribution of NO vs the anti-inflammatory effect is important, in view of the potential therapeutic perspective, and this is the final aim of this study. Five-week-old mdx mice received either naproxcinod (30 mg/kg) or the equimolar dose of naproxen (20 mg/kg) in the diet for 6 months. Control mdx mice were used as reference. Treatments (or vehicle for control groups) were administered daily in the diet. For the first 3 months the study was performed in sedentary animals, then all mice were subjected to exercise until the sixth month. Skeletal muscle force was assessed by measuring whole body tension in sedentary animals as well as in exercised mice and resistance to fatigue was measured after 3 months of running exercise. At the end of 6 months of treatment, animals were sacrificed for histological analysis and measurement of naproxen levels in blood and skeletal muscle. Naproxcinod significantly ameliorated skeletal muscle force and resistance to fatigue in sedentary as well as in exercised mice, reduced inflammatory infiltrates and fibrosis deposition in both cardiac and diaphragm muscles. Conversely, the equimolar dose of naproxen showed no effects on fibrosis and improved muscle function only in sedentary mice, while the beneficial effects in exercised mice were lost demonstrating a limited and short-term effect. In conclusion, this study shows that NO donation may have an important role, in addition to anti-inflammatory activity, in slowing down the progression of the disease in the mdx mouse model therefore positioning naproxcinod as a promising candidate for treatment of DMD.

Intraarticularly-Injected Mesenchymal Stem Cells Stimulate Anti-Inflammatory Molecules and Inhibit Pain Related Protein and Chondrolytic Enzymes in a Monoiodoacetate-Induced Rat Arthritis Model

PubMed Central

Ichiseki, Toru; Shimasaki, Miyako; Ueda, Yoshimichi; Tsuchiya, Masanobu; Souma, Daisuke; Kaneuji, Ayumi; Kawahara, Norio

2018-01-01

Persistent inflammation is well known to promote the progression of arthropathy. mesenchymal stem cells (MSCs) have been shown to possess anti-inflammatory properties and tissue differentiation potency. Although the experience so far with the intraarticular administration of mesenchymal stem cell (MSC) to induce cartilage regeneration has been disappointing, MSC implantation is now being attempted using various surgical techniques. Meanwhile, prevention of osteoarthritis (OA) progression and pain control remain important components of the treatment of early-stage OA. We prepared a shoulder arthritis model by injecting monoiodoacetate (MIA) into a rat shoulder, and then investigated the intraarticular administration of MSC from the aspects of the cartilage protective effect associated with their anti-inflammatory property and inhibitory effect on central sensitization of pain. When MIA was administered in this rat shoulder arthritis model, anti-Calcitonin Gene Related Peptide (CGRP) was expressed in the joint and C5 spinal dorsal horn. Moreover, expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), a marker of joint cartilage injury, was similarly elevated following MIA administration. When MSC were injected intraarticularly after MIA, the expression of CGRP in the spinal dorsal horn was significantly deceased, indicating suppression of the central sensitization of pain. The expression of ADAMTS 5 in joint cartilage was also significantly inhibited by MSC administration. In contrast, a significant increase in the expression of TNF-α stimulated gene/protein 6 (TSG-6), an anti-inflammatory and cartilage protective factor shown to be produced and secreted by MSC intraarticularly, was found to extend to the cartilage tissue following MSC administration. In this way, the intraarticular injection of MSC inhibited the central sensitization of pain and increased the expression of the anti-inflammatory and cartilage protective factor TSG-6. As the least invasive conservative strategies possible are desirable in the actual clinical setting, the intraarticular administration of MSC, which appears to be effective for the treatment of pain and cartilage protection in early-stage arthritis, may achieve these aims. PMID:29315262

Delayed Onset and Reduced Cognitive Deficits through Pre-Conditioning with 3-Nitropropionic Acid is Dependent on Sex and CAG Repeat Length in the R6/2 Mouse Model of Huntington's Disease.

PubMed

Skillings, Elizabeth A; Morton, A Jennifer

2016-01-01

Impairments in energy metabolism are implicated in Huntington's disease (HD) pathogenesis. Reduced levels of the mitochondrial enzyme succinate dehydrogenase (SDH), the main element of complex II, are observed post mortem in the brains of HD patients, and energy metabolism defects have been identified in both presymptomatic and symptomatic HD patients. Chemical preconditioning with 3-nitropropionic acid (3-NP), an irreversible inhibitor of SDH, has been shown to increase tolerance against experimental hypoxia in both heart and brain. Here we studied the effect of chronic preconditioning in the R6/2 mouse model of HD using mice carrying CAG repeat lengths of either 250 or 400 repeats. Both are transgenic fragment models, with 250CAG mice having a more rapid disease progression than 400CAG mice. Low doses of 3-NP (24 mg/kg) were administered via the drinking water and the effect on phenotype progression and cognition function assessed. After 3-NP treatment there were significant improvements in all aspects of the behavioural phenotype, apart from body weight, with timing and magnitude of improvements dependent on both CAG repeat length and sex. Specifically, a delay in the deterioration of general health (as shown by delayed onset of glycosuria and increased survival) was seen in both male and female 400CAG mice and in female 250CAG mice and was consistent with improved appearance of 3-NP treated R6/2 mice. Male 250CAG mice showed improvements but these were short term, and 3-NP treatment eventually had deleterious effects on their survival rate. When cognitive performance of 250CAG mice was assessed using a two-choice discrimination touchscreen task, we found that female mice showed significant improvements. Together, our results support the idea that energy metabolism contributes to the pathogenesis of HD, and suggest that improving energy deficits might be a therapeutically useful target.

Proinflammatory adipokine leptin mediates disinfection byproduct bromodichloromethane-induced early steatohepatitic injury in obesity

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

Das, Suvarthi; Kumar, Ashutosh; Seth, Ratanesh Kumar

Today's developed world faces a major public health challenge in the rise in the obese population and the increased incidence in fatty liver disease. There is a strong association among diet induced obesity, fatty liver disease and development of nonalcoholic steatohepatitis but the environmental link to disease progression remains unclear. Here we demonstrate that in obesity, early steatohepatitic lesions induced by the water disinfection byproduct bromodichloromethane are mediated by increased oxidative stress and leptin which act in synchrony to potentiate disease progression. Low acute exposure to bromodichloromethane (BDCM), in diet-induced obesity produced oxidative stress as shown by increased lipid peroxidation,more » protein free radical and nitrotyrosine formation and elevated leptin levels. Exposed obese mice showed histopathological signs of early steatohepatitic injury and necrosis. Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and TNF-α levels. Co-incubation of leptin and BDCM caused Kupffer cell activation as shown by increased MCP-1 release and NADPH oxidase membrane assembly, a phenomenon that was decreased in Kupffer cells isolated from leptin receptor knockout mice. In obese mice that were BDCM-exposed, livers showed a significant increase in Kupffer cell activation marker CD68 and, increased necrosis as assessed by levels of isocitrate dehydrogenase, events that were decreased in the absence of leptin or its receptor. In conclusion, our results show that exposure to the disinfection byproduct BDCM in diet-induced obesity augments steatohepatitic injury by potentiating the effects of leptin on oxidative stress, Kupffer cell activation and cell death in the liver. - Highlights: ► BDCM acute exposure sensitizes liver to increased free radical stress in obesity. ► BDCM-induced higher leptin contributes to early steatohepatitic lesions. ► Increased leptin mediates protein radical and 3-nitrotyrosine formation. ► BDCM exposure in obesity activates Kupffer cells and NADPH oxidase. ► BDCM/leptin synergy promotes necrotic cell-death and augments steatohepatitis.« less

Influence of 1α, 25-dihydroxyvitamin D3 [1, 25(OH)2D3] on the expression of Sox 9 and the transient receptor potential vanilloid 5/6 ion channels in equine articular chondrocytes.

PubMed

Hdud, Ismail M; Loughna, Paul T

2014-01-01

Sox 9 is a major marker of chondrocyte differentiation. When chondrocytes are cultured in vitro they progressively de-differentiate and this is associated with a decline in Sox 9 expression. The active form of vitamin D, 1, 25 (OH)2D3 has been shown to be protective of cartilage in both humans and animals. In this study equine articular chondrocytes were grown in culture and the effects of 1, 25 (OH)2D3 upon Sox 9 expression examined. The expression of the transient receptor potential vanilloid (TRPV) ion channels 5 and 6 in equine chondrocytes in vitro, we have previously shown, is inversely correlated with de-differentiation. The expression of these channels in response to 1, 25 (OH)2D3 administration was therefore also examined. The active form of vitamin D (1, 25 (OH)2D3) when administered to cultured equine chondrocytes at two different concentrations significantly increased the expression of Sox 9 at both. In contrast 1, 25 (OH)2D3 had no significant effect upon the expression of either TRPV 5 or 6 at either the protein or the mRNA level. The increased expression of Sox 9, in equine articular chondrocytes in vitro, in response to the active form of vitamin D suggests that this compound could be utilized to inhibit the progressive de-differentiation that is normally observed in these cells. It is also supportive of previous studies indicating that 1α, 25-dihydroxyvitamin D3 can have a protective effect upon cartilage in animals in vivo. The previously observed correlation between the degree of differentiation and the expression levels of TRPV 5/6 had suggested that these ion channels may have a direct involvement in, or be modulated by, the differentiation process in vitro. The data in the present study do not support this.

Self-efficacy: a means of identifying problems in nursing education and career progress.

PubMed

Harvey, V; McMurray, N

1994-10-01

Two nursing self-efficacy scales (academic and clinical) were developed and refined for use in identifying problems in progress in undergraduate nurses. Emergent factors within each scale contained items representing important aspects of nursing education. Both measures showed good internal consistency, test-retest reliability, and construct validity. Sensitivity to content and focus of tuition at time of completion was shown with some changes in factor structure over samples of first year nursing students. Academic self-efficacy (but not clinical self-efficacy) was predictive of course withdrawal. Applications to nursing education, progress in pursuing a nursing career and attrition are discussed.

The NASA Juncture Flow Experiment: Goals, Progress, and Preliminary Testing (Invited)

NASA Technical Reports Server (NTRS)

Rumsey, Christopher L.; Neuhart, Danny H.; Kegerise, Michael A.

2016-01-01

NASA has been working toward designing and conducting a juncture flow experiment on a wing-body aircraft configuration. The experiment is planned to provide validation-quality data for CFD that focuses on the onset and progression of a separation bubble near the wing-body juncture trailing edge region. This paper describes the goals and purpose of the experiment. Although currently considered unreliable, preliminary CFD analyses of several different configurations are shown. These configurations have been subsequently tested in a series of "risk-reduction" wind tunnel tests, in order to help down-select to a final configuration that will attain the desired flow behavior. The risk-reduction testing at the higher Reynolds number has not yet been completed (at the time of this writing), but some results from one of the low-Reynolds-number experiments are shown.

Prevention of Age-Related Macular Degeneration.

PubMed

Singh, Niharika; Srinivasan, Sangeetha; Muralidharan, Vinata; Roy, Rupak; V, Jayprakash; Raman, Rajiv

2017-01-01

Age-related macular degeneration (AMD) compromises quality of life. However, the available therapeutic options are limited. This has led to the identification of modifiable risk factors to prevent the development or alter the natural course and prognosis of AMD. The identification and modification of risk factors has the potential for greater public health impact on reducing morbidity from AMD. Likewise, identifying the imaging clues and genetic clues could serve as a guide to recognizing the propensity for progression to severe and end stages of the disease. Several attempts, both successful and unsuccessful, have been made for interventions that could delay the progression of AMD. Of these, pharmacological interventions have shown promising results. The Age-Related Eye Disease Study 1 and 2 have shown the beneficial role of antioxidants in a selected group of patients. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

Structural Covariance of the Default Network in Healthy and Pathological Aging

PubMed Central

Turner, Gary R.

2013-01-01

Significant progress has been made uncovering functional brain networks, yet little is known about the corresponding structural covariance networks. The default network's functional architecture has been shown to change over the course of healthy and pathological aging. We examined cross-sectional and longitudinal datasets to reveal the structural covariance of the human default network across the adult lifespan and through the progression of Alzheimer's disease (AD). We used a novel approach to identify the structural covariance of the default network and derive individual participant scores that reflect the covariance pattern in each brain image. A seed-based multivariate analysis was conducted on structural images in the cross-sectional OASIS (N = 414) and longitudinal Alzheimer's Disease Neuroimaging Initiative (N = 434) datasets. We reproduced the distributed topology of the default network, based on a posterior cingulate cortex seed, consistent with prior reports of this intrinsic connectivity network. Structural covariance of the default network scores declined in healthy and pathological aging. Decline was greatest in the AD cohort and in those who progressed from mild cognitive impairment to AD. Structural covariance of the default network scores were positively associated with general cognitive status, reduced in APOEε4 carriers versus noncarriers, and associated with CSF biomarkers of AD. These findings identify the structural covariance of the default network and characterize changes to the network's gray matter integrity across the lifespan and through the progression of AD. The findings provide evidence for the large-scale network model of neurodegenerative disease, in which neurodegeneration spreads through intrinsically connected brain networks in a disease specific manner. PMID:24048852

Nutritional Approaches to Achieve Weight Loss in Nonalcoholic Fatty Liver Disease123

PubMed Central

Hsu, Christine C; Ness, Erik; Kowdley, Kris V

2017-01-01

Nonalcoholic fatty liver disease (NAFLD) can range in spectrum from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is characterized by lipotoxicity, hepatocellular ballooning, and inflammation and can progress to cirrhosis. Weight loss is the cornerstone treatment for NAFLD and NASH. Various randomized controlled trials have shown that weight loss of ≥5–10% leads to significant improvements in hepatic steatosis. Diets high in sodium and fructose have been implicated in the pathogenesis of NAFLD. Although some clinical studies suggest that an isocaloric high-fructose diet does not worsen NAFLD, these clinical studies are often short in duration. More recently, the Dietary Approaches to Stop Hypertension diet, a sodium-restricted diet, has been associated with less prevalence of NAFLD and has been shown to improve NAFLD. In addition, the Mediterranean diet has been promising in improving hepatic steatosis, and a larger randomized controlled trial is currently enrolling subjects. For those who are unable to pursue weight loss through dietary approaches, bariatric surgery has been shown to improve hepatic steatosis and steatohepatitis. This method has been variable in improving hepatic fibrosis. In conclusion, weight loss is crucial to the improvement of NAFLD and NASH, and patients should attempt various diets in an attempt to achieve weight loss. PMID:28298270

Nutritional Approaches to Achieve Weight Loss in Nonalcoholic Fatty Liver Disease.

PubMed

Hsu, Christine C; Ness, Erik; Kowdley, Kris V

2017-03-01

Nonalcoholic fatty liver disease (NAFLD) can range in spectrum from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is characterized by lipotoxicity, hepatocellular ballooning, and inflammation and can progress to cirrhosis. Weight loss is the cornerstone treatment for NAFLD and NASH. Various randomized controlled trials have shown that weight loss of ≥5-10% leads to significant improvements in hepatic steatosis. Diets high in sodium and fructose have been implicated in the pathogenesis of NAFLD. Although some clinical studies suggest that an isocaloric high-fructose diet does not worsen NAFLD, these clinical studies are often short in duration. More recently, the Dietary Approaches to Stop Hypertension diet, a sodium-restricted diet, has been associated with less prevalence of NAFLD and has been shown to improve NAFLD. In addition, the Mediterranean diet has been promising in improving hepatic steatosis, and a larger randomized controlled trial is currently enrolling subjects. For those who are unable to pursue weight loss through dietary approaches, bariatric surgery has been shown to improve hepatic steatosis and steatohepatitis. This method has been variable in improving hepatic fibrosis. In conclusion, weight loss is crucial to the improvement of NAFLD and NASH, and patients should attempt various diets in an attempt to achieve weight loss. © 2017 American Society for Nutrition.

Impacts of fresh lime juice and peel on atherosclerosis progression in an animal model.

PubMed

Boshtam, Maryam; Asgary, Sedigheh; Moshtaghian, Jamal; Naderi, Gholamali; Jafari-Dinani, Narges

2013-11-01

The main protective role of antioxidants in the progression of atherosclerosis has been shown in some studies. Therefore, this project evaluated the effects of Citrus aurantifolia (Christm) juice and peel on antioxidant activity and atherosclerosis progression in rabbits receiving a hypercholesterolemic diet. Forty white New Zealand male rabbits were randomly allocated to four groups. All groups were on hypercholesterolemic diet for two months. While the first group was considered as the hypercholesterolemic control, groups 2 and 3 (intervention groups) received 5 ml/day lime juice and 1 g/day dried lime peel powder, respectively. Group 4 was fed a normal diet (normal control). Before and after the study, weight was measured and a fasting blood specimen was taken from the rabbits. Serum lipids analyses and antioxidant activity evaluations were then performed. The rabbits' aorta and coronary arteries were separated and the presence of fatty streaks was studied. Comparing to the hypercholesterolemic control group (-25.2 ± 7.0), only the plasma total antioxidant capacity change was significantly more in rabbits supplemented with lime juice (16.3 ± 14.7) and peel (8.6 ± 7.1) (P = 0.008). The presence of fatty streaks in coronary arteries and aorta of the intervention groups [juice (0.2 ± 0.01); peel (0.0 ± 0.00)] was significantly decreased compared to the hypercholesterolemic control group (1.2 ± 0.4) (P < 0.001). Based on our findings, Citrus aurantifolia peel and juice increase plasma antioxidant capacity in rabbits, and can thus prevent or decelerate the process of atherogenesis. However, lime peel is more effective than lime juice.

Markers of activated inflammatory cells correlate with severity of liver damage in children with nonalcoholic fatty liver disease.

PubMed

De Vito, Rita; Alisi, Anna; Masotti, Andrea; Ceccarelli, Sara; Panera, Nadia; Citti, Arianna; Salata, Michele; Valenti, Luca; Feldstein, Ariel E; Nobili, Valerio

2012-07-01

Concomitantly to the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children. NAFLD encompasses a spectrum of histological damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), with possible progression to cirrhosis. There is growing evidence that the immune system plays a pivotal role in the initiation and progression to NASH but the cellular nature of the hepatic inflammation is still unknown. The present study includes 34 children with biopsy-proven NAFLD. Liver damage was evaluated by the NAFLD activity score (NAS), and the inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3 and CD163 which are markers of leukocytes, T cells and activated Kupffer cells/macrophages, respectively. Our results have shown that CD45+ (P<0.0001) and CD163+ (P<0.0001) cells were markedly increased in children with severe histological activity (NAS≥5) compared to children with lower activity (NAS<5), whereas CD3+ cells were significantly lower (P<0.01) in children with severe histological activity. There was a significant association between the numbers of CD45+, CD3+ and CD163+ cells, regarding both the portal tract and liver lobule, and the severity of steatosis, ballooning and fibrosis (P<0.01). These data suggest that the severity and composition of the inflammatory infiltrate correlate with steatosis and the severity of disease in children with NAFLD. Moreover, a decrease in CD3+ cells may be involved in the pathogenesis of liver damage. Future studies should evaluate whether it can predict the progression of liver disease independently of established histological scores.

Stimulation of ganglionated plexus attenuates cardiac neural remodeling and heart failure progression in a canine model of acute heart failure post-myocardial infarction.

PubMed

Luo, Da; Hu, Huihui; Qin, Zhiliang; Liu, Shan; Yu, Xiaomei; Ma, Ruisong; He, Wenbo; Xie, Jing; Lu, Zhibing; He, Bo; Jiang, Hong

2017-12-01

Heart failure (HF) is associated with autonomic dysfunction. Vagus nerve stimulation has been shown to improve cardiac function both in HF patients and animal models of HF. The purpose of this present study is to investigate the effects of ganglionated plexus stimulation (GPS) on HF progression and autonomic remodeling in a canine model of acute HF post-myocardial infarction. Eighteen adult mongrel male dogs were randomized into the control (n=8) and GPS (n=10) groups. All dogs underwent left anterior descending artery ligation followed by 6-hour high-rate (180-220bpm) ventricular pacing to induce acute HF. Transthoracic 2-dimensional echocardiography was performed at different time points. The plasma levels of norepinephrine, B-type natriuretic peptide (BNP) and Ang-II were measured using ELISA kits. C-fos and nerve growth factor (NGF) proteins expressed in the left stellate ganglion as well as GAP43 and TH proteins expressed in the peri-infarct zone were measured using western blot. After 6h of GPS, the left ventricular end-diastolic volume, end-systolic volume and ejection fraction showed no significant differences between the 2 groups, but the interventricular septal thickness at end-systole in the GPS group was significantly higher than that in the control group. The plasma levels of norepinephrine, BNP, Ang-II were increased 1h after myocardial infarction while the increase was attenuated by GPS. The expression of c-fos and NGF proteins in the left stellate ganglion as well as GAP43 and TH proteins in cardiac peri-infarct zone in GPS group were significantly lower than that in control group. GPS inhibits cardiac sympathetic remodeling and attenuates HF progression in canines with acute HF induced by myocardial infarction and ventricular pacing. Copyright © 2017 Elsevier B.V. All rights reserved.

Increased expression of c-Ski as a co-repressor in transforming growth factor-beta signaling correlates with progression of esophageal squamous cell carcinoma.

PubMed

Fukuchi, Minoru; Nakajima, Masanobu; Fukai, Yasuyuki; Miyazaki, Tatsuya; Masuda, Norihiro; Sohda, Makoto; Manda, Ryokuhei; Tsukada, Katsuhiko; Kato, Hiroyuki; Kuwano, Hiroyuki

2004-03-01

Transforming growth factor-beta (TGF-beta) regulates cell growth inhibition, and inactivation of the TGF-beta signaling pathway contributes to tumor development. In our previous study, altered expression of TGF-beta, TGF-beta-specific receptors and Smad4 was shown to correlate with tumor progression in esophageal squamous cell carcinoma (SCC). These components, however, were maintained normally in some patients with esophageal SCC. In our study, the mechanism by which aggressive esophageal SCC maintains these components was investigated, with particular emphasis on the participation of c-Ski and SnoN as transcriptional co-repressors in TGF-beta signaling. Immunohistochemistry for c-Ski and SnoN was carried out on surgical specimens obtained from 80 patients with esophageal SCC. The expression of c-Ski and SnoN was also studied in 6 established cell lines derived from esophageal SCC and compared to an immortalized human esophageal cell line by Western blotting. High levels of expression of c-Ski, detected immunohistologically, were found to correlate with depth of invasion (p = 0.0080) and pathologic stage (p = 0.0447). There was, however, no significant correlation between expression of SnoN and clinicopathologic characteristics. A significant correlation between c-Ski and TGF-beta expression was observed. Moreover, in patients with TGF-beta negative expression, the survival rates of patients with c-Ski positive expression were significantly lower than those of patients with c-Ski negative expression (p = 0.0486). c-Ski was expressed at a high level in 5 of 6 cell lines derived from esophageal SCC compared to immortalized esophageal keratinocytes. Furthermore, the cyclin-dependent kinase (CDK) inhibitor, p21 that was up-regulated by TGF-beta signaling was expressed at a low level in the 5 cell lines. The expression of c-Ski protein as a transcriptional co-repressor in TGF-beta signaling seems to be correlated with tumor progression of esophageal SCC. Copyright 2003 Wiley-Liss, Inc.

Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18.

PubMed

Xu, Xiaohui; Song, Cheng; Chen, Zhihua; Yu, Chenxiao; Wang, Yi; Tang, Yiting; Luo, Judong

2018-01-01

The purpose of this study was to investigate the effect of human antigen R (HuR) downregulation and the potential target genes of HuR on the progression of esophageal squamous cell carcinoma (ESCC). In this study, a proteomics assay was used to detect the expression of proteins after HuR downregulation, and a luciferase assay was used to detect the potential presence of a HuR binding site on the 3'-untranslated region (3'-UTR) of interleukin 18 (IL-18). In addition, colony formation assay, MTT, EdU incorporation assay, Western blot, flow cytometry, immunohistochemistry, transwell invasion assay, and wound healing assay were used. In the present study, we found that the expression of both HuR protein and mRNA levels were higher in tumor tissues than in the adjacent tissues. HuR downregulation significantly suppressed cell proliferation. In addition, the metastasis of esophageal cancer cells was inhibited, while the expression of E-cadherin was increased and the expression of matrix metalloproteinase (MMP) 2, MMP9, and vimentin was decreased after HuR knockdown. Moreover, silencing of HuR disturbed the cell cycle of ESCC cells mainly by inducing G1 arrest. Furthermore, proteomics analysis showed that downregulation of HuR in TE-1 cells resulted in 100 upregulated and 122 downregulated proteins, including IL-18 as a significantly upregulated protein. The expression of IL-18 was inversely regulated by HuR. IL-18 expression was decreased in ESCC tissues, and exogenous IL-18 significantly inhibited the proliferation and metastasis of ESCC cells. The 3'-UTR of IL-18 harbored a HuR binding site, as shown by an in vitro luciferase assay. HuR plays an important role in the progression of esophageal carcinoma by targeting IL-18, which may be a potential therapeutic target for the treatment of ESCC.

Progressive Hemifacial Atrophy and Linear Scleroderma En Coup de Sabre: A Spectrum of the Same Disease?

PubMed

Khamaganova, Irina

2017-01-01

Similar clinical and histhopathological features in progressive hemifacial atrophy and linear scleroderma en coup de sabre are well known. Trauma may predispose to the development of both diseases. The lack of association with anti-Borrelia antibodies was shown in both cases as well. The otolaryngological and endocrine disorders may be associated findings in both diseases. However, there are certain differences in neurological and ophthalmological changes in the diseases.

Progressive Hemifacial Atrophy and Linear Scleroderma En Coup de Sabre: A Spectrum of the Same Disease?

PubMed Central

Khamaganova, Irina

2018-01-01

Similar clinical and histhopathological features in progressive hemifacial atrophy and linear scleroderma en coup de sabre are well known. Trauma may predispose to the development of both diseases. The lack of association with anti-Borrelia antibodies was shown in both cases as well. The otolaryngological and endocrine disorders may be associated findings in both diseases. However, there are certain differences in neurological and ophthalmological changes in the diseases. PMID:29445726

The Role of ERG and CXCR4 in Prostate Cancer Progression

DTIC Science & Technology

2012-06-01

cells. CXCR4 is a chemokine receptor that has been shown to function as a key receptor for homing of circulating tumor cells to secondary sites...T., Cordon -Cardo, C., Gerald, W., and Pandolfi, P. P. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the...be exon 0, which when included in the fusion is found to be associated with less aggressive behavior and therefore more favorab le prognosis

Preventing Myopia.

PubMed

Lagrèze, Wolf A; Schaeffel, Frank

2017-09-04

Nearsightedness (myopia) has become more common around the world recently, mainly because of changes in visual, educational, and recreational behavior. The question arises how the risk of myopia and its progression can be reduced. This would lessen the prevalence and severity of myopia and also lower the risk of secondary diseases that impair visual acuity. The PubMed/Medline database was selectively searched for pertinent literature. The risk of myopia is lowered by exposure to daylight and increased by activities performed at short visual distances (close-up work). A person with little exposure to daylight has a fivefold risk of developing myopia, which can rise as high as a 16-fold risk if that person also performs close-up work. Two meta-analyses and a large randomized clinical trial from Asia have shown that the progression of myopia over two years of observation can be lessened by up to 0.71 diopters by the administration of atropine eye drops in a concentration that has practically no serious side effects. At higher doses, myopia progresses more severely than in the placebo group after the cessation of therapy. This is an off-label treatment. A weaker effect on progression has been shown for multifocal optical corrections that include both a distance correction and a correction for near vision. Effective pharmacological and optical measures are now available to lessen the progression of myopia. The increasing prevalence of myopia should motivate pediatricians, parents, and schools to pay attention to risk factors such as close-up work and lack of daylight exposure, particularly in view of the increased use of digital media.

Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer.

PubMed

Peters, Solange; Camidge, D Ross; Shaw, Alice T; Gadgeel, Shirish; Ahn, Jin S; Kim, Dong-Wan; Ou, Sai-Hong I; Pérol, Maurice; Dziadziuszko, Rafal; Rosell, Rafael; Zeaiter, Ali; Mitry, Emmanuel; Golding, Sophie; Balas, Bogdana; Noe, Johannes; Morcos, Peter N; Mok, Tony

2017-08-31

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .).

Study of the areas and thicknesses of mesiobucal root canals prepared by three endodontic techniques.

PubMed

Constante, Isa Geralda Teixeira; Davidowicz, Harry; Barletta, Fernando Branco; de Moura, Abilio Albuquerque Maranhão

2007-01-01

The purpose of this study was to compare, in vitro, by means of computerized analysis of digital radiographic images, the anatomic alterations produced in the mandibular molar tooth dentinal walls of mesiobucal canals with severe curvature by three different endodontic techniques: Progressive Preparation, Staged and Serial Preparation. A selection was made of 45 extracted, human, mandibular molars, with root curvatures greater than 25 degrees. They were divided into three groups for every technique studied, which were then sub-divided into three sub-groups in accordance with the position of the curvature along the root: cervical, median or apical. After access surgery and tooth length determination, the canals were filled with 100% Barium Sulphate radiological contrast and the teeth were then radiographed with a direct digital radiography system, using a special apparatus capable of keeping the samples in the same spatial position during the different radiographic takes. After the above-mentioned endodontic techniques had been performed, the teeth were again filled with Barium sulphate and were also radiographed under the same previously mentioned conditions. The pre- and post-operative digital images were then analyzed in two computerized programs, AutoCAD 2004 and CorelDraw 10, to assess, respectively, the areas and the horizontal alterations which occurred in the internal and external walls of the root canals. The results indicated that although no significant differences among the techniques were shown in the statistical analysis, in a descriptive analysis the Progressive Preparation technique was shown to be more regular, uniform and effective.

Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine

PubMed Central

Moudra, Alena; Hubackova, Sona; Machalova, Veronika; Vancurova, Marketa; Bartek, Jiri; Reinis, Milan; Hodny, Zdenek; Jonasova, Anna

2016-01-01

ABSTRACT Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis frequently progressing into acute myeloid leukemia (AML), with emerging evidence implicating aberrant bone marrow (BM) microenvironment and inflammation-related changes. 5-azacytidine (5-AC) represents standard MDS treatment. Besides inhibiting DNA/RNA methylation, 5-AC has been shown to induce DNA damage and apoptosis in vitro. To provide insights into in vivo effects, we assessed the proinflammatory cytokines alterations during MDS progression, cytokine changes after 5-AC, and contribution of inflammatory comorbidities to the cytokine changes in MDS patients. We found that IL8, IP10/CXCL10, MCP1/CCL2 and IL27 were significantly elevated and IL12p70 decreased in BM of MDS low-risk, high-risk and AML patients compared to healthy donors. Repeated sampling of the high-risk MDS patients undergoing 5-AC therapy revealed that the levels of IL8, IL27 and MCP1 in BM plasma were progressively increasing in agreement with in vitro experiments using several cancer cell lines. Moreover, the presence of inflammatory diseases correlated with higher levels of IL8 and MCP1 in low-risk but not in high-risk MDS. Overall, all forms of MDS feature a deregulated proinflammatory cytokine landscape in the BM and such alterations are further augmented by therapy of MDS patients with 5-AC. PMID:27853634

Knockdown of long non-coding RNA TP73-AS1 inhibits osteosarcoma cell proliferation and invasion through sponging miR-142.

PubMed

Yang, Guangling; Song, Ruipeng; Wang, Limin; Wu, Xuejian

2018-07-01

Long non-coding RNA P73 antisense RNA 1 T (lncRNA TP73-AS1) has been shown to involve in the progression of numerous tumors. Nevertheless, the expression as well as the functional mechanisms of TP73-AS1 in osteosarcoma (OS) are still largely unknown. This study aimed to explore the roles and underlying mechanism of TP73-AS1 in OS progression. In thye present study, TP73-AS1 expression was significantly increased in OS tissues and cell lines. High TP73-AS1 expression was associated with poor overall survival of OS patients. TP73-AS1 knockdown suppressed OS cells proliferation and invasion in vitro as well as tumor growth in vivo. Furthermore, we identified that miR-142 could act as a direct target for TP73-AS1 and miR-142 inhibition reversed the suppression of OS cells proliferation and invasion induced by TP73-AS1 knockdown. In addition, we showed that TP73-AS1 could function as a sponge of miR-142 to positively regulate Rac1 in OS cells. Thus, our data suggested that TP73-AS1 served as an oncogenic lncRNA in OS progression, and could be regarded as an efficient therapeutic target in the treatment of OS. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Licorice infusion: Chemical profile and effects on the activation and the cell cycle progression of human lymphocytes

PubMed Central

Cheel, José; Onofre, Gabriela; Vokurkova, Doris; Tůmová, Lenka; Neugebauerová, Jarmila

2010-01-01

A licorice infusion (LI) and its major constituents were investigated for their capacity to stimulate the activation and the cell cycle progression of human lymphocytes, measured by the CD69 expression and DNA content, respectively. The chemical profile of LI was determined by high-performance liquid chromatography-diode array detection (HPLC-DAD). Results: Two major components of LI were identified as liquiritin (1) and glycyrrhizin (2); total flavones and flavonols were shown as its minor constituents. The LI (100-800 μg/ml) stimulated the expression of CD69 on lymphocytes in a concentration-independent manner. Values of the activation index (AI) of total lymphocytes treated with LI (100-800 μg/ml) did not differ significantly among them (P < 0.05), but were 50% lower than the AI value exhibited by cells treated with phytohemagglutinin (PHA). The LI showed a similar effect on T cells, but on a lower scale. Compounds 1 and 2 (12-100 μg/ml) did not stimulate the CD69 expression on lymphocytes. The LI, 1 and 2 showed no meaningful effect on cell cycle progression of lymphocytes. The experimental data indicates that LI stimulates the activation of lymphocytes as a result of a proliferation-independent process. This finding suggests that LI could be considered as a potential specific immune stimulator. PMID:20548933

Evaluating the predictive power of multivariate tensor-based morphometry in Alzheimer's disease progression via convex fused sparse group Lasso

NASA Astrophysics Data System (ADS)

Tsao, Sinchai; Gajawelli, Niharika; Zhou, Jiayu; Shi, Jie; Ye, Jieping; Wang, Yalin; Lepore, Natasha

2014-03-01

Prediction of Alzheimers disease (AD) progression based on baseline measures allows us to understand disease progression and has implications in decisions concerning treatment strategy. To this end we combine a predictive multi-task machine learning method1 with novel MR-based multivariate morphometric surface map of the hippocampus2 to predict future cognitive scores of patients. Previous work by Zhou et al.1 has shown that a multi-task learning framework that performs prediction of all future time points (or tasks) simultaneously can be used to encode both sparsity as well as temporal smoothness. They showed that this can be used in predicting cognitive outcomes of Alzheimers Disease Neuroimaging Initiative (ADNI) subjects based on FreeSurfer-based baseline MRI features, MMSE score demographic information and ApoE status. Whilst volumetric information may hold generalized information on brain status, we hypothesized that hippocampus specific information may be more useful in predictive modeling of AD. To this end, we applied Shi et al.2s recently developed multivariate tensor-based (mTBM) parametric surface analysis method to extract features from the hippocampal surface. We show that by combining the power of the multi-task framework with the sensitivity of mTBM features of the hippocampus surface, we are able to improve significantly improve predictive performance of ADAS cognitive scores 6, 12, 24, 36 and 48 months from baseline.

Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection.

PubMed

Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

2015-09-03

Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation.

Ovsiankina’s Great Relief: How Supplemental Work during the Weekend May Contribute to Recovery in the Face of Unfinished Tasks

PubMed Central

Syrek, Christine J.

2017-01-01

Unfinished tasks have been identified as a significant job stressor that impairs employee recovery after work. Classic experimental research by Ovsiankina has shown that people tend to resume yet unfinished tasks to satisfy their need for closure. We apply this notion to current working life and examine supplemental work after hours as a means to achieve peace of mind. We investigate how progress towards goal accomplishment through supplemental work may facilitate recovery in terms of psychological detachment, relaxation, autonomy, and mastery experiences. We conducted a week-level diary study among 83 employees over a period of 14 consecutive weeks, which yielded 575 observations in total and 214 matched observations of unfinished tasks, supplemental work during the weekend, progress, and recovery experiences. Unfinished tasks were assessed on Friday. Supplemental work and recovery experiences were assessed on Monday. Multilevel modeling analyses provide evidence that unfinished tasks at the end of the work week are associated with lower levels of detachment at the intraindividual level, tend to relate to lower relaxation, but are unrelated to autonomy and mastery. Progress towards finishing tasks during the weekend alleviates the detrimental effects of unfinished tasks on both kinds of recovery experiences. Supplemental work is negatively linked to detachment, but largely unrelated to the other recovery experiences. PMID:29261139

Longitudinal changes in MRI markers in a reversible unilateral ureteral obstruction mouse model: preliminary experience.

PubMed

Haque, Muhammad E; Franklin, Tammy; Bokhary, Ujala; Mathew, Liby; Hack, Bradley K; Chang, Anthony; Puri, Tipu S; Prasad, Pottumarthi V

2014-04-01

To evaluate longitudinal changes in renal oxygenation and diffusion measurements in a model of reversible unilateral ureteral obstruction (rUUO) which has been shown to induce chronic renal functional deficits in a strain dependent way. C57BL/6 mice show higher degree of functional deficit compared with BALB/c mice. Because hypoxia and development of fibrosis are associated with chronic kidney diseases and are responsible for progression, we hypothesized that MRI measurements would be able to monitor the longitudinal changes in this model and will show strain dependent differences in response. Here blood oxygenation level dependent (BOLD) and diffusion MRI measurements were performed at three time points over a 30 day period in mice with rUUO. The studies were performed on a 4.7T scanner with the mice anesthetized with isoflurane before UUO, 2 and 28 days postrelease of 6 days of obstruction. We found at the early time point (∼2 days after releasing the obstruction), the relative oxygenation in C57Bl/6 mice were lower compared with BALB/c. Diffusion measurements were lower at this time point and reached statistical significance in BALB/c These methods may prove valuable in better understanding the natural progression of kidney diseases and in evaluating novel interventions to limit progression. Copyright © 2013 Wiley Periodicals, Inc.

Molecular Mechanisms of Prostate Cancer Progression

DTIC Science & Technology

2003-01-01

other drugs ( novobiocin and related hsp90 inhibitors have been shown to bind to the N-ter- coumarins) that are reported to target hsp90 are now be...undesirable for an indirect method of telomerase inhibition (data not shown). However, radicicol, which binds in the ATP- binding pocket of hsp90 and...compounds (e.g. novobiocin ) to block chaperone function using a totally different mechanism of hsp90 inhbition, as well as innovative genetic approaches

Silencing the myotrophin gene by RNA interference leads to the regression of cardiac hypertrophy.

PubMed

Gupta, Sudhiranjan; Maitra, Ratan; Young, Dave; Gupta, Anasuya; Sen, Subha

2009-08-01

Myotrophin-induced activation of NF-kappaB has been shown to be associated with cardiac hypertrophy (CH) that progresses to heart failure (HF). In the present study, we examined the cause-and-effect relationship between myotrophin and NF-kappaB activation using small hairpin RNA (shRNA) against myotrophin both in vitro (using neonatal rat myocytes) and in vivo [using myotrophin transgenic (Myo-Tg) mice, which overexpress myotrophin in the heart, develop CH, and gradually progress to HF]. Among several lentiviral vectors expressing myotrophin shRNAs, L-sh-109 showed the best silencing effect at both the mRNA (155.3 +/- 5.9 vs. 32.5 +/- 5.5, P < 0.001) and protein levels associated with a significant reduction of atrial natriuretic factor (ANF) and NF-kappaB. In vivo, when L-sh-109 was delivered directly into the hearts of 10-wk-old Myo-Tg mice, we observed a significant regression of cardiac mass (8.0 vs. 5.7 mg/g, P < 0.001) and myotrophin gene expression (54.5% over untreated Myo-Tg mice, P < 0.001) associated with a reduction in ANF and NF-kappaB signaling components. Our data suggest that using RNA interference to silence the myotrophin gene prevents NF-kappaB activation, associated with an attenuation of CH. This strategy could be an excellent therapeutic means for the treatment of CH and HF.

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

PubMed Central

Montagnani Marelli, Marina; Marzagalli, Monica; Moretti, Roberta M.; Beretta, Giangiacomo; Casati, Lavinia; Comitato, Raffaella; Gravina, Giovanni L.; Festuccia, Claudio; Limonta, Patrizia

2016-01-01

Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma. PMID:27461002

Self-controlled learning benefits: exploring contributions of self-efficacy and intrinsic motivation via path analysis.

PubMed

Ste-Marie, Diane M; Carter, Michael J; Law, Barbi; Vertes, Kelly; Smith, Victoria

2016-09-01

Research has shown learning advantages for self-controlled practice contexts relative to yoked (i.e., experimenter-imposed) contexts; yet, explanations for this phenomenon remain relatively untested. We examined, via path analysis, whether self-efficacy and intrinsic motivation are important constructs for explaining self-controlled learning benefits. The path model was created using theory-based and empirically supported relationships to examine causal links between these psychological constructs and physical performance. We hypothesised that self-efficacy and intrinsic motivation would have greater predictive power for learning under self-controlled compared to yoked conditions. Participants learned double-mini trampoline progressions, and measures of physical performance, self-efficacy and intrinsic motivation were collected over two practice days and a delayed retention day. The self-controlled group (M = 2.04, SD = .98) completed significantly more skill progressions in retention than their yoked counterparts (M = 1.3, SD = .65). The path model displayed adequate fit, and similar significant path coefficients were found for both groups wherein each variable was predominantly predicted by its preceding time point (e.g., self-efficacy time 1 predicts self-efficacy time 2). Interestingly, the model was not moderated by group; thus, failing to support the hypothesis that self-efficacy and intrinsic motivation have greater predictive power for learning under self-controlled relative to yoked conditions.

New scoring methodology improves the sensitivity of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) in clinical trials.

PubMed

Verma, Nishant; Beretvas, S Natasha; Pascual, Belen; Masdeu, Joseph C; Markey, Mia K

2015-11-12

As currently used, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) has low sensitivity for measuring Alzheimer's disease progression in clinical trials. A major reason behind the low sensitivity is its sub-optimal scoring methodology, which can be improved to obtain better sensitivity. Using item response theory, we developed a new scoring methodology (ADAS-CogIRT) for the ADAS-Cog, which addresses several major limitations of the current scoring methodology. The sensitivity of the ADAS-CogIRT methodology was evaluated using clinical trial simulations as well as a negative clinical trial, which had shown an evidence of a treatment effect. The ADAS-Cog was found to measure impairment in three cognitive domains of memory, language, and praxis. The ADAS-CogIRT methodology required significantly fewer patients and shorter trial durations as compared to the current scoring methodology when both were evaluated in simulated clinical trials. When validated on data from a real clinical trial, the ADAS-CogIRT methodology had higher sensitivity than the current scoring methodology in detecting the treatment effect. The proposed scoring methodology significantly improves the sensitivity of the ADAS-Cog in measuring progression of cognitive impairment in clinical trials focused in the mild-to-moderate Alzheimer's disease stage. This provides a boost to the efficiency of clinical trials requiring fewer patients and shorter durations for investigating disease-modifying treatments.

[Nocturnal spasmodic cough in the infant. Evolution after antireflux treatment].

PubMed

Dordal, M T; Baltazar, M A; Roca, I; Marques, L; Server, M T; Botoy, J

1994-02-01

Several studies have shown the relationship between gastro-oesophageal reflux, bronchial asthma and chronic nocturnal cough and this should not be neglected, particularly in patients who present an unfavourable development in spite of conventional treatment. For diagnosis of gastroesophageal reflux, amongst other investigations, esophageal gammagraphy of swallowing, that detects alterations in the mobility of the oesophagus, secondary to a possible oesophagitis. The objective of this study was to evaluate the clinical progress and gammagraphy of a group of children with chronic predominantly nocturnal cough (with or without bronchial asthma) with initially pathological esophageal gammagraphy, after three months of treatment with gastrokinetic drugs (cisapride against domperidone) and postural dietetic limits, in comparison with a reference group who, although having followed the limits in question had not received the pharmacological treatment. From the clinical viewpoint, cough disappeared in 64.5% of cases without significant statistical differences between the two groups. Gammagraphy became normal in 20/55 cases, improved in 10/55 cases and was unchanged in 25/55. Although there was no significant difference, gammagraphy development was better in children who received domperidone. The agreement between clinical progress and gammagraphy was 60% with a large number of false positives in the gammagraphy. We believe that the simple introduction of the postural-dietetic measures may improve the clinical control in the type of patients who present with a chronic nocturnally predominant cough that does not yield to conventional treatment.

Predictive factors for structural remission using abatacept: results from the ABROAD study.

PubMed

Murakami, Kosaku; Sekiguchi, Masahiro; Hirata, Shintaro; Fujii, Takao; Matsui, Kiyoshi; Morita, Satoshi; Ohmura, Koichiro; Kawahito, Yutaka; Nishimoto, Norihiro; Mimori, Tsuneyo; Sano, Hajime

2018-05-29

To investigate the effect of abatacept (ABA) on preventing joint destruction in biological disease-modifying anti-rheumatic drug (bDMARD)-naïve rheumatoid arthritis (RA) patients in real-world clinical practice. RA patients were collected from the ABROAD (ABatacept Research Outcomes as a First-line Biological Agent in the Real WorlD) study cohort. They had moderate or high disease activity and were treated with ABA as a first-line bDMARD. Radiographic change between baseline and 1 year after ABA treatment was assessed with the van der Heijde's modified total Sharp score (mTSS). Predictive factors for structural remission (St-REM), defined as ΔmTSS ≤0.5/year, were determined. Among 118 patients, 81 (67.5%) achieved St-REM. Disease duration <3 years (odds ratio (OR) = 3.152, p = 0.007) and slower radiographic progression (shown as "baseline mTSS/year <3", OR = 3.727, p = 0.004) were independently significant baseline predictive factors for St-REM irrespective of age and sex. St-REM prevalence increased significantly if clinical remission based on the Simplified Disease Activity Index was achieved at least once until 24 weeks after ABA treatment. Shorter disease duration, smaller radiographic progression at baseline, and rapid clinical response were predictive factors for sustained St-REM after ABA therapy in bDMARD-naïve RA patients.

Future directions in bladder cancer immunotherapy: towards adaptive immunity

PubMed Central

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed. PMID:26860539

Future directions in bladder cancer immunotherapy: towards adaptive immunity.

PubMed

Smith, Sean G; Zaharoff, David A

2016-01-01

The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed.

An application specific integrated circuit based multi-anode microchannel array readout system

NASA Technical Reports Server (NTRS)

Smeins, Larry G.; Stechman, John M.; Cole, Edward H.

1991-01-01

Size reduction of two new multi-anode microchannel array (MAMA) readout systems is described. The systems are based on two analog and one digital application specific integrated circuits (ASICs). The new readout systems reduce volume over previous discrete designs by 80 percent while improving electrical performance on virtually every significant parameter. Emphasis is made on the packaging used to achieve the volume reduction. Surface mount technology (SMT) is combined with modular construction for the analog portion of the readout. SMT reliability concerns and the board area impact of MIL SPEC SMT components is addressed. Package selection for the analog ASIC is discussed. Future sytems will require even denser packaging and the volume reduction progression is shown.

Characterization of a 1,4-{beta}-D-glucan synthase from Dictyostelium discoideum. Progress report, May 1990--January 1992

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

Blanton, R.L.

1992-01-15

Various aspects of research concerning Dictyostelium discoideum are presented. The initial focus of this project was upon: the characterization of potential probes for the cellulose synthase (antibody and nucleic acid), the determination of the cultural induction conditions of cellulose synthesis, the solubilization of the enzyme activity, the development of a non-inhibitory disruption buffer, the generation and isolation of mutant strains deficient in cellulose synthesis, and the development of the capability to determine the degree of polymerization of the in vitro product. I have briefly summarized our most significant findings with only selected data sets being shown in this report inmore » the interest of brevity.« less

Nanoparticle-mediated drug delivery for treating melanoma

PubMed Central

Mundra, Vaibhav; Li, Wei; Mahato, Ram I

2015-01-01

Melanoma originated from melanocytes is the most aggressive type of skin cancer with limited treatment options. New targeted therapeutic options with the discovery of BRAF and MEK inhibitors have shown significant survival benefits. Despite the recent progress, development of chemoresistance and systemic toxicity remains a challenge for treating metastatic melanoma. While the response from the first line of treatment against melanoma using dacarbazine remains only 5–10%, the prolonged use of targeted therapy against mutated oncogene BRAF develops chemoresistance. In this review, we will discuss the nanoparticle-based strategies for encapsulation and conjugation of drugs to the polymer for maximizing their tumor distribution through enhanced permeability and retention effect. We will also highlight photodynamic therapy and design of melanoma-targeted nanoparticles. PMID:26244818

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study.

PubMed

Dreyling, Martin; Jurczak, Wojciech; Jerkeman, Mats; Silva, Rodrigo Santucci; Rusconi, Chiara; Trneny, Marek; Offner, Fritz; Caballero, Dolores; Joao, Cristina; Witzens-Harig, Mathias; Hess, Georg; Bence-Bruckler, Isabelle; Cho, Seok-Goo; Bothos, John; Goldberg, Jenna D; Enny, Christopher; Traina, Shana; Balasubramanian, Sriram; Bandyopadhyay, Nibedita; Sun, Steven; Vermeulen, Jessica; Rizo, Aleksandra; Rule, Simon

2016-02-20

Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma. Janssen Research & Development, LLC. Copyright © 2016 Elsevier Ltd. All rights reserved.

The beneficial effects of massage therapy for insomnia in postmenopausal women.

PubMed

Hachul, H; Oliveira, D S; Bittencourt, L R A; Andersen, M L; Tufik, S

2014-06-01

With increases life expectancy, the incidence of undesirable manifestations of menopause has increased as well. The effects of lost ovarian function include progressive decrease in estradiol secretion, trophic changes in the breast, vasomotor symptoms, anxiety, depression, and sleep disorders. Insomnia, which has physiological consequences and can result in a loss of quality of life, is prevalent in women after menopause. Hormone therapy has been widely used to reduce menopausal symptoms, but its use in recent years has been questioned because of the reported risks of cardiovascular events and increased incidence of tumors. This controversy has generated significant interest in non-hormonal treatments among both physicians and patients. Our previous research has shown a positive effect of massage therapy on menopausal symptoms. We explored the hypothesis that massage therapy would produce beneficial effects in postmenopausal women through inflammatory and immunological changes. Recent results from self-report questionnaires have shown improvements in sleep pattern and quality of life following massage therapy. These findings demonstrate the effectiveness of massage therapy for the treatment of postmenopausal symptoms, particularly insomnia, and indicate that it is a promising line of research.

Measuring topographies from conventional SEM acquisitions.

PubMed

Shi, Qiwei; Roux, Stéphane; Latourte, Félix; Hild, François; Loisnard, Dominique; Brynaert, Nicolas

2018-04-27

The present study extends the stereoscopic imaging principle for estimating the surface topography to two orientations, namely, normal to the electron beam axis and inclined at 70° as suited for EBSD analyses. In spite of the large angle difference, it is shown that the topography can be accurately determined using regularized global Digital Image Correlation. The surface topography is compared to another estimate issued from a 3D FIB-SEM procedure where the sample surface is first covered by a Pt layer, and its initial topography is progressively revealed from successive FIB-milling. These two methods are successfully compared on a 6% strained steel specimen in an in situ mechanical test. This analysis is supplemented by a third approach estimating the change of topography from crystal rotations as measured from successive EBSD images. This last technique ignores plastic deformation, and thus only holds in an elastic regime. For the studied example, despite the large plastic flow, it is shown that crystal rotation already accounts for a significant part of the deformation-induced topography. Copyright © 2018 Elsevier B.V. All rights reserved.

Ischemic tolerance in pre-myelinated white matter: the role of astrocyte glycogen in brain pathology.

PubMed

Fern, Robert

2015-06-01

In isolated white matter, ischemic tolerance changes dramatically in the period immediately before the onset of myelination. In the absence of an extrinsic energy source, postnatal day 0 to 2 (P0 to P2) white matter axons are here shown to maintain excitability for over twice as long as axons >P2, a differential that was dependent on glycogen metabolism. Prolonged withdrawal of extrinsic energy supply tended to spare axons in zones around astrocytes, which are shown to be the sole repository for glycogen particles in developing white matter. Analysis of mitochondrial volume fraction revealed that neither axons nor astrocytes had a low metabolic rate in neonatal white matter, while oligodendroglia at older ages had an elevated metabolism. The astrocyte population is established early in neural development, and exhibits reduced cell density as maturation progresses and white matter expands. The findings show that this event establishes the necessary conditions for ischemia sensitivity in white matter and indicates that astrocyte proximity may be significant for the survival of neuronal elements in conditions associated with compromised energy supply.

Management of Locally Advanced Cancer Cervix an Indian Perspective.

PubMed

Singh, J K; Chauhan, Richa

2015-01-01

Cervical cancer has a major impact on the lives of Indian women with an estimated 122, 844 new cases of cervical cancer in the year 2012. About 80% of these cases present in a locally advanced stage leading to high morbidity and mortality. Because of lack of public awareness and infrastructure for screening and early detection in developing countries, this late presentation is likely to continue in the coming years. Radiation therapy has been the treatment of choice for patients with locally advanced cancer cervix. Many clinical trials and meta-analyses have shown a significant improvement in overall and progression-free survival with decreased local and distant recurrences with the use of concurrent chemotherapy with radiation. Most of these trials have been done in women from developed countries where the patient and disease profile are entirely different from ours. Recently, few trials from India have also shown promising results in locally advanced cancer cervix with concurrent chemoradiotherapy but toxicities remain a major concern. Further exploration is required for the use of concurrent chemo radiation prior to incorporating it into routine clinical practice.

Thermal barrier coating life prediction model development, phase 1

NASA Technical Reports Server (NTRS)

Demasi, Jeanine T.; Ortiz, Milton

1989-01-01

The objective of this program was to establish a methodology to predict thermal barrier coating (TBC) life on gas turbine engine components. The approach involved experimental life measurement coupled with analytical modeling of relevant degradation modes. Evaluation of experimental and flight service components indicate the predominant failure mode to be thermomechanical spallation of the ceramic coating layer resulting from propagation of a dominant near interface crack. Examination of fractionally exposed specimens indicated that dominant crack formation results from progressive structural damage in the form of subcritical microcrack link-up. Tests conducted to isolate important life drivers have shown MCrAlY oxidation to significantly affect the rate of damage accumulation. Mechanical property testing has shown the plasma deposited ceramic to exhibit a non-linear stress-strain response, creep and fatigue. The fatigue based life prediction model developed accounts for the unusual ceramic behavior and also incorporates an experimentally determined oxide rate model. The model predicts the growth of this oxide scale to influence the intensity of the mechanic driving force, resulting from cyclic strains and stresses caused by thermally induced and externally imposed mechanical loads.

Genistein and daidzein: different molecular effects on prostate cancer.

PubMed

Adjakly, Mawussi; Ngollo, Marjolaine; Boiteux, Jean-Paul; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

2013-01-01

Diet is believed to play an important role in cancer. It has been revealed by epidemiological studies that Asian populations, who consume phytoestrogens in large amounts, have a lower incidence of prostate cancer in comparison with the Western world, where consumption of soy is lower. Genistein and daidzein, the soy phytoestrogens most widely studied, are believed to be potent anticancer agents and have been shown to possess anticancer properties. It has been shown that these compounds inhibit the growth of cancer cells through the modulation of genes controlling cell-cycle progression. Genistein inhibits the activation of the kappa light polypeptide gene enhancer in B-cells (NF-κB), signaling pathway, which is implicated in the balance between cell survival and programmed cell death (apoptosis). Antioxidant and antiangiogenesis properties of genistein have been also described. Soy isoflavones are also implicated in reversion of epigenetic events observed in prostate cancer. Significant advances have been made for understanding how soy isoflavones are implicated in protection against prostate cancer. However, more studies are needed to better-understand and elucidate all pathways mobilized by genistein and daidzein, in order to fully exploit their anticancer properties.

The beneficial effects of massage therapy for insomnia in postmenopausal women☆

PubMed Central

Hachul, H.; Oliveira, D.S.; Bittencourt, L.R.A.; Andersen, M.L.; Tufik, S.

2014-01-01

With increases life expectancy, the incidence of undesirable manifestations of menopause has increased as well. The effects of lost ovarian function include progressive decrease in estradiol secretion, trophic changes in the breast, vasomotor symptoms, anxiety, depression, and sleep disorders. Insomnia, which has physiological consequences and can result in a loss of quality of life, is prevalent in women after menopause. Hormone therapy has been widely used to reduce menopausal symptoms, but its use in recent years has been questioned because of the reported risks of cardiovascular events and increased incidence of tumors. This controversy has generated significant interest in non-hormonal treatments among both physicians and patients. Our previous research has shown a positive effect of massage therapy on menopausal symptoms. We explored the hypothesis that massage therapy would produce beneficial effects in postmenopausal women through inflammatory and immunological changes. Recent results from self-report questionnaires have shown improvements in sleep pattern and quality of life following massage therapy. These findings demonstrate the effectiveness of massage therapy for the treatment of postmenopausal symptoms, particularly insomnia, and indicate that it is a promising line of research. PMID:26483913

PubMed Central

DE LOS ANGELES BEYTÍA, MARIA; VRY, JULIA; KIRSCHNER, JANBERND

2012-01-01

Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3,600-6,000 newborn males. It is manifested by the absence of the dystrophin protein in muscle fibres, which causes progressive damage leading to death in the third decade of life. The only medication so far shown to be effective in delaying the progression of this illness are corticosteroids, which have been shown to increase muscle strength in randomised controlled studies; long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction, dilated cardiomyopathy and scoliosis. Several potential drugs are now being investigated. Genetic therapy, involving the insertion of a dystrophin gene through a vector, has proven effective in animals but not humans. Currently under clinical study is Ataluren, a molecule that binds with ribosomes and may allow the insertion of an aminoacid in the premature termination codon, and exon-skipping, which binds with RNA and excludes specific sites of RNA splicing, producing a dystrophin that is smaller but functional. There are also studies attempting to modulate other muscular proteins, such as myostatin and utrophin, to reduce symptoms. This paper does not address cardiomyopathy treatment in DMD patients. PMID:22655510

Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina

PubMed Central

Damiani, Devid; Alexander, John J; O'Rourke, Jason R; McManus, Mike; Jadhav, Ashutosh P; Cepko, Constance L; Hauswirth, William W; Harfe, Brian D; Strettoi, Enrica

2009-01-01

MicroRNAs (miRNAs) are small, highly conserved molecules that have been shown to regulate the expression of genes by binding to specific target mRNAs. Dicer, an RNase III endonuclease, is essential for the production and function of mature miRNAs and removal of Dicer has been shown to disrupt many developmental processes. In this report, Dicer was removed specifically from the retina using a floxed Dicer conditional allele and the retinal Chx10Cre transgene. Retinal Dicer knockout mice displayed a reproducible inability to respond to light. In addition, morphological defects were observed with the formation of photoreceptor rosettes at P16 which progressed to more general cellular disorganization and widespread degeneration of retinal cell types as the animals aged. This was accompanied by concomitant decrease in both scotopic and photopic ERG responses. Interestingly, removing a single allele of Dicer resulted in ERG deficits throughout life but not to morphological abnormalities. Northern blot analysis of Dicer depleted retinas showed a decrease in several microRNAs. The observation that progressive retinal degeneration occurred upon removal of Dicer raises the possibility that miRNAs are involved in retinal neurodegenerative disorders. PMID:18463241

The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH).

PubMed

Gandaglia, Giorgio; Briganti, Alberto; Gontero, Paolo; Mondaini, Nicola; Novara, Giacomo; Salonia, Andrea; Sciarra, Alessandro; Montorsi, Francesco

2013-08-01

Several different stimuli may induce chronic prostatic inflammation, which in turn would lead to tissue damage and continuous wound healing, thus contributing to prostatic enlargement. Patients with chronic inflammation and benign prostatic hyperplasia (BPH) have been shown to have larger prostate volumes, more severe lower urinary tract symptoms (LUTS) and a higher probability of acute urinary retention than their counterparts without inflammation. Chronic inflammation could be a predictor of poor response to BPH medical treatment. Thus, the ability to identify patients with chronic inflammation would be crucial to prevent BPH progression and develop target therapies. Although the histological examination of prostatic tissue remains the only available method to diagnose chronic inflammation, different parameters, such as prostatic calcifications, prostate volume, LUTS severity, storage and prostatitis-like symptoms, poor response to medical therapies and urinary biomarkers, have been shown to be correlated with chronic inflammation. The identification of patients with BPH and chronic inflammation might be crucial in order to develop target therapies to prevent BPH progression. In this context, clinical, imaging and laboratory parameters might be used alone or in combination to identify patients that harbour chronic prostatic inflammation. © 2013 BJU International.

Induction of acute hepatic injury by endotoxin in mice.

PubMed

Xie, Guo-Qi; Jiang, Jian-Xin; Chen, Yong-Hua; Liu, Da-Wei; Zhu, Pei-Fang; Wang, Zheng-Guo

2002-11-01

To investigate the changes of scavenger receptor (SR) and CD14 in Kupffer cells in endotoxemia in order to uncover the mechanism of the liver to turn a defense organ into effector one in sepsis. Mouse models of endotoxemia of different severity were reproduced by injection of different doses of lipopolysaccharide (LPS) via the tail vein. The expression of SR and CD14 in the liver was assayed by immunohistochemistry and was subsequently analyzed with an image analysis system. The levels of TNF-alpha and IL-6 in liver tissue were determined with ELISA. The expression of SR in the liver in the high-dose group was markedly decreased one hour after injection of LPS, and also in the low-dose group at 3 hours. The expression of SR in the liver in the two groups was shown to be progressively decreased with the time prolonged. There was significant difference in average optical density (OD) values of SR between the two groups. The expression of CD14 in the two groups was shown to be significantly increased one hour after injection of LPS, and more significantly with the time prolonged. But there was no significant difference in OD values of CD14 between the two groups. The contents of intrahepatic proinflammatory mediators TNF-alpha, IL-6, ALT and TBIL were significantly increased after injection of LPS. Correlation analysis revealed that the changes of TNF-alpha, IL-6, ALT, and TBIL were negatively correlated with the expression of SR, and positively with the expression of CD14. The up-regulation of CD14 expression and down-regulation of SR expression on Kupffer cells might be one of the important mechanisms for the conversion of Kupffer cells from immune defensive to inflammatory response cells in acute hepatic injury.

Mammary Gland Tumor Development in Transgenic Mice Overexpressing Different Isoforms of the CDP/Cux Transcription Factor

DTIC Science & Technology

2009-03-01

tumors and in uterine leiomyomas , suggesting that these proteins play a key role in tumor development and progression. My project consisted in... leiomyomas , suggesting that these proteins could play a key role in tumor development and progression (6, 7). I have also previoulsly shown that...and p110 are involved in cancer development. The p110 and p75 isoforms are overexpressed in primary human tumors, such as in uterine leiomyomas and

Substrate Induced Conformational Studies of the Hormone Binding Domain of the Human Estrogen Receptor by Fluorine NMR

DTIC Science & Technology

1998-07-01

the progression of breast cancer and the estrogen receptor (ER) has been implicated in reproductive cancers . Our laboratory would like to understand how...function. ൖ. SUBJECT TERMS 15. NUMBER OF PAGES Breast Cancer 41 16. PRICE CODE 17. SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION OF THIS 19...production of estrogen or estrogen like materials. Estrogen has been shown to be involved in the progression of breast cancer and the estrogen receptor (ER

Organoids: Modelling polycystic kidney disease

NASA Astrophysics Data System (ADS)

Romagnani, Paola

2017-11-01

Cysts were generated from organoids in vitro and the removal of adherent cues was shown to play a key role in polycystic kidney disease progression. These cysts resembled those of diseased tissue phenotypically and were capable of remodelling their microenvironment.

Bad phosphorylation as a target of inhibition in oncology.

PubMed

Bui, Ngoc-Linh-Chi; Pandey, Vijay; Zhu, Tao; Ma, Lan; Basappa; Lobie, Peter E

2018-02-28

Bcl-2 agonist of cell death (BAD) is a BH3-only member of the Bcl-2 family which possesses important regulatory function in apoptosis. BAD has also been shown to possess many non-apoptotic functions closely linked to cancer including regulation of glycolysis, autophagy, cell cycle progression and immune system development. Interestingly, BAD can be either pro-apoptotic or pro-survival depending on the phosphorylation state of three specific serine residues (human S75, S99 and S118). Expression of BAD and BAD phosphorylation patterns have been shown to influence tumor initiation and progression and play a predictive role in disease prognosis, drug response and chemosensitivity in various cancers. This review aims to summarize the current evidence on the functional role of BAD phosphorylation in human cancer and evaluate the potential utility of modulating BAD phosphorylation in cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Relationship between progression of visual field defect and intraocular pressure in primary open-angle glaucoma.

PubMed

Naito, Tomoko; Yoshikawa, Keiji; Mizoue, Shiro; Nanno, Mami; Kimura, Tairo; Suzumura, Hirotaka; Shiraga, Fumio

2015-01-01

To analyze the relationship between intraocular pressure (IOP) and the progression of visual field defects in Japanese primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG) patients. The subjects of the study were patients undergoing treatment for POAG or NTG who had performed visual field tests at least ten times with a Humphrey field analyzer (Swedish interactive thresholding algorithm standard, C30-2 program). The progression of visual field defects was defined by a significantly negative value of the mean deviation slope at the final visual field test during the follow-up period. The relationships between the progression of visual field defects and IOP, as well as other clinical factors, were retrospectively analyzed. A total of 156 eyes of 156 patients were included in the analysis. Significant progression of visual field defects was observed in 70 eyes of 70 patients (44.9%), while no significant progression was evident in 86 eyes of 86 patients (55.1%). The eyes with visual field defect progression had significantly lower baseline IOP (P<0.05), as well as significantly lower IOP reduction rate (P<0.01). The standard deviation of IOP values during follow-up was significantly greater in the eyes with visual field defect progression than in eyes without (P<0.05). Reducing IOP is thought to be useful for Japanese POAG or NTG patients to suppress the progression of visual field defects. In NTG, IOP management should take into account not only achieving the target IOP, but also minimizing the fluctuation of IOP during follow-up period.

Somatostatin Analogues according to Ki67 index in neuroendocrine tumours: an observational retrospective-prospective analysis from real life

PubMed Central

Faggiano, Antongiulio; Carratù, Anna Chiara; Guadagno, Elia; Tafuto, Salvatore; Tatangelo, Fabiana; Riccardi, Ferdinando; Mocerino, Carmela; Palmieri, Giovannella; Damiano, Vincenzo; Siciliano, Roberta; Leo, Silvana; Mauro, Annamaria; Tozzi, Lucia Franca; Battista, Claudia; De Rosa, Gaetano; Colao, Annamaria

2016-01-01

Somatostatin analogues (SSAs) have shown limited and variable antiproliferative effects in neuroendocrine tumours (NETs). Whether tumour control by SSAs depends on grading based on the 2010 WHO NET classification is still unclear. The aim of this study is to evaluate the efficacy of long-acting SSAs in NETs according to Ki67 index. An observational Italian multicentre study was designed to collect data in patients with gastro-entero-pancreatic or thoracic NETs under SSA treatment. Both retrospective and prospective data were included and they were analysed in line with Ki67 index, immunohistochemically evaluated in tumour samples and graded according to WHO classification (G1 = Ki67 index 0-2%, G2 = Ki67 index 3-20%, G3 = Ki67 index > 20%). Among 601 patients with NET, 140 with a histologically confirmed gastro-entero-pancreatic or thoracic NET or NET with unknown primary were treated with lanreotide autogel or octreotide LAR. An objective tumour response was observed in 11%, stability in 58% and progression in 31%. Objective response and tumour stability were not significantly different between G1 and G2 NETs. Progression free survival was longer but not significantly different in G1 than G2 NETs (median: 89 vs 43 months, p = 0.15). The median PFS was significantly longer in NETs showing Ki67 < 5% than in those showing Ki67 ≥5% (89 vs 35 months, p = 0.005). SSA therapy shows significant antiproliferative effects in well differentiated low/intermediate-proliferating NETs, not only G1 but also in G2 type. A Ki67 index of 5% seems to work better than 3% to select the best candidates for SSA therapy. PMID:26701729

Somatostatin analogues according to Ki67 index in neuroendocrine tumours: an observational retrospective-prospective analysis from real life.

PubMed

Faggiano, Antongiulio; Carratù, Anna Chiara; Guadagno, Elia; Tafuto, Salvatore; Tatangelo, Fabiana; Riccardi, Ferdinando; Mocerino, Carmela; Palmieri, Giovannella; Damiano, Vincenzo; Siciliano, Roberta; Leo, Silvana; Mauro, Annamaria; Tozzi, Lucia Franca; Battista, Claudia; De Rosa, Gaetano; Colao, Annamaria

2016-02-02

Somatostatin analogues (SSAs) have shown limited and variable antiproliferative effects in neuroendocrine tumours (NETs). Whether tumour control by SSAs depends on grading based on the 2010 WHO NET classification is still unclear. The aim of this study is to evaluate the efficacy of long-acting SSAs in NETs according to Ki67 index. An observational Italian multicentre study was designed to collect data in patients with gastro-entero-pancreatic or thoracic NETs under SSA treatment. Both retrospective and prospective data were included and they were analysed in line with Ki67 index, immunohistochemically evaluated in tumour samples and graded according to WHO classification (G1 = Ki67 index 0-2%, G2 = Ki67 index 3-20%, G3 = Ki67 index > 20%). Among 601 patients with NET, 140 with a histologically confirmed gastro-entero-pancreatic or thoracic NET or NET with unknown primary were treated with lanreotide autogel or octreotide LAR. An objective tumour response was observed in 11%, stability in 58% and progression in 31%. Objective response and tumour stability were not significantly different between G1 and G2 NETs. Progression free survival was longer but not significantly different in G1 than G2 NETs (median: 89 vs 43 months, p = 0.15). The median PFS was significantly longer in NETs showing Ki67 < 5% than in those showing Ki67 ≥ 5% (89 vs 35 months, p = 0.005). SSA therapy shows significant antiproliferative effects in well differentiated low/intermediate-proliferating NETs, not only G1 but also in G2 type. A Ki67 index of 5% seems to work better than 3% to select the best candidates for SSA therapy.

PROGRESSIVE COLLAPSE TESTING OF RELOCATABLE TROOP BARRACKS

DTIC Science & Technology

2017-06-02

sight at many U.S. and coalition bases worldwide. Cost effective, readily available , and robust, CONEX containers can be stacked and connected together...three stories high constructed with CONEX containers in a 3 × 3 × 2 grid as shown in Figure 3. The column loss locations investigated are shown in...Lackland Air Force Base, Texas available to the general public, including foreign AFCEC Public Affairs Office at Joint Base San AFCEC-CX-TY-TR-2017-0018

Chemoprevention of esophageal squamous cell carcinoma

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

Stoner, Gary D.; Wang Lishu; Chen Tong

2007-11-01

Esophageal squamous cell carcinoma (SCC) is responsible for approximately one-sixth of all cancer-related mortality worldwide. This malignancy has a multifactorial etiology involving several environmental, dietary and genetic factors. Since esophageal cancer has often metastasized at the time of diagnosis, current treatment modalities offer poor survival and cure rates. Chemoprevention offers a viable alternative that could well be effective against the disease. Clinical investigations have shown that primary chemoprevention of this disease is feasible if potent inhibitory agents are identified. The Fischer 344 (F-344) rat model of esophageal SCC has been used extensively to investigate the biology of the disease, andmore » to identify chemopreventive agents that could be useful in human trials. Multiple compounds that inhibit tumor initiation by esophageal carcinogens have been identified using this model. These include several isothiocyanates, diallyl sulfide and polyphenolic compounds. These compounds influence the metabolic activation of esophageal carcinogens resulting in reduced genetic (DNA) damage. Recently, a few agents have been shown to inhibit the progression of preneoplastic lesions in the rat esophagus into tumors. These agents include inhibitors of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF) and c-Jun [a component of activator protein-1 (AP-1)]. Using a food-based approach to cancer prevention, we have shown that freeze-dried berry preparations inhibit both the initiation and promotion/progression stages of esophageal SCC in F-344 rats. These observations have led to a clinical trial in China to evaluate the ability of freeze-dried strawberries to influence the progression of esophageal dysplasia to SCC.« less

Activation of the Nrf2-ARE Pathway in Hepatocytes Protects Against Steatosis in Nutritionally Induced Non-alcoholic Steatohepatitis in Mice

PubMed Central

Lee, Lung-Yi; Köhler, Ulrike A.; Zhang, Li; Roenneburg, Drew; Werner, Sabine; Johnson, Jeffrey A.; Foley, David P.

2014-01-01

Oxidative stress is implicated in the development of non-alcoholic steatohepatitis (NASH). The Nrf2-antioxidant response element pathway protects cells from oxidative stress. Studies have shown that global Nrf2 deficiency hastens the progression of NASH. The purpose of this study was to determine whether long-term hepatocyte-specific activation of Nrf2 mitigates NASH progression. Transgenic mice expressing a constitutively active Nrf2 construct in hepatocytes (AlbCre+/caNrf2+) and littermate controls were generated. These mice were fed standard or methionine-choline-deficient (MCD) diet, a diet used to induce NASH development in rodents. After 28 days of MCD dietary feeding, mice developed significant increases in steatosis, inflammation, oxidative stress, and HSC activation compared with those mice on standard diet. AlbCre+/caNrf2+ animals had significantly decreased serum transaminases and reduced steatosis when compared with the AlbCre+/caNrf2− animals. This significant reduction in steatosis was associated with increased expression of genes involved in triglyceride export (MTTP) and β-oxidation (CPT2). However, there were no differences in the increased oxidative stress, inflammation, and HSC activation from MCD diet administration between the AlbCre+/caNrf2− and AlbCre+/caNrf2+ animals. We conclude that hepatocyte-specific activation of Nrf2-mediated gene expression decreased hepatocellular damage and steatosis in a dietary model of NASH. However, hepatocyte-specific induction of Nrf2-mediated gene expression alone is insufficient to mitigate inflammation, oxidative stress, and HSC activation in this nutritional NASH model. PMID:25294219

Advances in retinal imaging for diabetic retinopathy and diabetic macular edema.

PubMed

Tan, Colin Siang Hui; Chew, Milton Cher Yong; Lim, Louis Wei Yi; Sadda, Srinivas R

2016-01-01

Diabetic retinopathy and diabetic macular edema (DME) are leading causes of blindness throughout the world, and cause significant visual morbidity. Ocular imaging has played a significant role in the management of diabetic eye disease, and the advent of advanced imaging modalities will be of great value as our understanding of diabetic eye diseases increase, and the management options become increasingly varied and complex. Color fundus photography has established roles in screening for diabetic eye disease, early detection of progression, and monitoring of treatment response. Fluorescein angiography (FA) detects areas of capillary nonperfusion, as well as leakage from both microaneurysms and neovascularization. Recent advances in retinal imaging modalities complement traditional fundus photography and provide invaluable new information for clinicians. Ultra-widefield imaging, which can be used to produce both color fundus photographs and FAs, now allows unprecedented views of the posterior pole. The pathologies that are detected in the periphery of the retina have the potential to change the grading of disease severity, and may be of prognostic significance to disease progression. Studies have shown that peripheral ischemia may be related to the presence and severity of DME. Optical coherence tomography (OCT) provides structural detail of the retina, and the quantitative and qualitative features are useful in the monitoring of diabetic eye disease. A relatively recent innovation, OCT angiography, produces images of the fine blood vessels at the macula and optic disc, without the need for contrast agents. This paper will review the roles of each of these imaging modalities for diabetic eye disease.

Advances in retinal imaging for diabetic retinopathy and diabetic macular edema

PubMed Central

Tan, Colin Siang Hui; Chew, Milton Cher Yong; Lim, Louis Wei Yi; Sadda, Srinivas R

2016-01-01

Diabetic retinopathy and diabetic macular edema (DME) are leading causes of blindness throughout the world, and cause significant visual morbidity. Ocular imaging has played a significant role in the management of diabetic eye disease, and the advent of advanced imaging modalities will be of great value as our understanding of diabetic eye diseases increase, and the management options become increasingly varied and complex. Color fundus photography has established roles in screening for diabetic eye disease, early detection of progression, and monitoring of treatment response. Fluorescein angiography (FA) detects areas of capillary nonperfusion, as well as leakage from both microaneurysms and neovascularization. Recent advances in retinal imaging modalities complement traditional fundus photography and provide invaluable new information for clinicians. Ultra-widefield imaging, which can be used to produce both color fundus photographs and FAs, now allows unprecedented views of the posterior pole. The pathologies that are detected in the periphery of the retina have the potential to change the grading of disease severity, and may be of prognostic significance to disease progression. Studies have shown that peripheral ischemia may be related to the presence and severity of DME. Optical coherence tomography (OCT) provides structural detail of the retina, and the quantitative and qualitative features are useful in the monitoring of diabetic eye disease. A relatively recent innovation, OCT angiography, produces images of the fine blood vessels at the macula and optic disc, without the need for contrast agents. This paper will review the roles of each of these imaging modalities for diabetic eye disease. PMID:26953028

Polymer microarray technology for stem cell engineering

PubMed Central

Coyle, Robert; Jia, Jia; Mei, Ying

2015-01-01

Stem cells hold remarkable promise for applications in tissue engineering and disease modeling. During the past decade, significant progress has been made in developing soluble factors (e.g., small molecules and growth factors) to direct stem cells into a desired phenotype. However, the current lack of suitable synthetic materials to regulate stem cell activity has limited the realization of the enormous potential of stem cells. This can be attributed to a large number of materials properties (e.g., chemical structures and physical properties of materials) that can affect stem cell fate. This makes it challenging to design biomaterials to direct stem cell behavior. To address this, polymer microarray technology has been developed to rapidly identify materials for a variety of stem cell applications. In this article, we summarize recent developments in polymer array technology and their applications in stem cell engineering. Statement of significance Stem cells hold remarkable promise for applications in tissue engineering and disease modeling. In the last decade, significant progress has been made in developing chemically defined media to direct stem cells into a desired phenotype. However, the current lack of the suitable synthetic materials to regulate stem cell activities has been limiting the realization of the potential of stem cells. This can be attributed to the number of variables in material properties (e.g., chemical structures and physical properties) that can affect stem cells. Polymer microarray technology has shown to be a powerful tool to rapidly identify materials for a variety of stem cell applications. Here we summarize recent developments in polymer array technology and their applications in stem cell engineering. PMID:26497624

Analysis of Social and Genetic Factors Influencing Heterosexual Transmission of HIV within Serodiscordant Couples in the Henan Cohort

PubMed Central

Zhang, Yilei; Li, Jie; Ma, Xuejun; Li, Ning; Wang, Qi; Xue, Xiujuan; Luo, Le; Li, Zizhao; Ring, Huijun Z.; Ring, Brian Z.; Su, Li

2015-01-01

There is considerable variability between individuals in susceptibility to infection by human immunodeficiency virus (HIV). Many social, clinical and genetic factors are known to contribute to the likelihood of HIV transmission, but there is little consensus on the relative importance and potential interaction of these factors. Additionally, recent studies of several variants in chemokine receptors have identified alleles that may be predictive of HIV transmission and disease progression; however the strengths and directions of the associations of these genetic markers with HIV transmission have markedly varied between studies. To better identify factors that predict HIV transmission in a Chinese population, 180 cohabiting serodiscordant couples were enrolled for study by the Henan Center for Disease Prevention and Control, and transmission and progression of HIV infection were regularly measured. We found that anti-retroviral therapy, education level, and condom use were the most significant factors in determining likelihood of HIV transmission in this study. We also assessed ten variants in three genes (CXCL12, CCR2, and CCR5) that have been shown to influence HIV transmission. We found two tightly linked variants in CCR2 and CCR5, rs1799864 and rs1800024, have a significant positive association with transmission as recessive models (OR>10, P value=0.011). Mixed effects models showed that these genetic variants both retained significance when assessed with either treatment or condom use. These markers of transmission susceptibility may therefore serve to help stratify individuals by risk for HIV transmission. PMID:26068906

The progressive nature of concentration camp syndrome in former prisoners of Nazi concentration camps--Not just history, but the important issue of contemporary medicine.

PubMed

Jabłoński, Robert; Rosińczuk, Joanna; Leszek, Jerzy; Uchmanowicz, Izabella; Panaszek, Bernard

2016-04-01

Constant stress, slave labor, tortures, and starvation all affected the health of concentration camp prisoners, contributing to multimorbidities, increased mortality and accelerated development of chronic illnesses, what we have shown in an earlier publication. The interrelated somatic and psychological symptoms gave rise to concentration camp syndrome (KZ-syndrome), which has many features of PTSD, occurring frequently nowadays. The paper attempts at assessing the influence of concentration camp conditions on functional disorders in each system of the human body, occurring in KZ-syndrome, and at demonstrating the progressive nature of the syndrome. A retrospective assessment of the former prisoners' health after 5 and 30 years following their leaving camps was performed based on medical records and surveys. The materials included 250 former prisoners who underwent medical examination in 1950, i.e. 5 years after leaving the camp, of whom 120 former prisoners survived and were examined and surveyed in 1975, i.e. 30 years after leaving the camp. KZ-syndrome was shown to occur in 58.8% of former prisoners 5 years after leaving the camp, and in 77.5% after 30 years (p < 0.001), which confirms the syndrome's chronic and progressive nature. Pathological sequels of internment in concentration camps, in the form of KZ-syndrome, were observed in most former prisoners. Over time, the number of morbidities and the intensity of symptoms increased, which indicates that the syndrome has a chronic and progressive nature. KZ-syndrome is a multi-organ disorder, with numerous chronic comorbidities exacerbating the progression. Copyright © 2015 Elsevier Ltd. All rights reserved.

Amyotrophic lateral sclerosis immunoglobulins increase Ca2+ currents in a motoneuron cell line.

PubMed

Mosier, D R; Baldelli, P; Delbono, O; Smith, R G; Alexianu, M E; Appel, S H; Stefani, E

1995-01-01

The sporadic form of amyotrophic lateral sclerosis (ALS) is an idiopathic and eventually lethal disorder causing progressive degeneration of cortical and spinal motoneurons. Recent studies have shown that the majority of patients with sporadic ALS have serum antibodies that bind to purified L-type voltage-gated calcium channels and that antibody titer correlates with the rate of disease progression. Furthermore, antibodies purified from ALS patient sera have been found to alter the physiologic function of voltage-gated calcium channels in nonmotoneuron cell types. Using whole-cell patch-clamp techniques, immunoglobulins purified from sera of 5 of 6 patients with sporadic ALS are now shown to increase calcium currents in a hybrid motoneuron cell line, VSC4.1. These calcium currents are blocked by the polyamine funnel-web spider toxin FTX, which has previously been shown to block Ca2+ currents and evoked transmitter release at mammalian motoneuron terminals. These data provide additional evidence linking ALS to an autoimmune process and suggest that antibody-induced increases in calcium entry through voltage-gated calcium channels may occur in motoneurons in this disease, with possible deleterious effects in susceptible neurons.

Curcumin slows osteoarthritis progression and relieves osteoarthritis-associated pain symptoms in a post-traumatic osteoarthritis mouse model.

PubMed

Zhang, Zhuo; Leong, Daniel J; Xu, Lin; He, Zhiyong; Wang, Angela; Navati, Mahantesh; Kim, Sun J; Hirsh, David M; Hardin, John A; Cobelli, Neil J; Friedman, Joel M; Sun, Hui B

2016-06-03

Curcumin has been shown to have chondroprotective potential in vitro. However, its effect on disease and symptom modification in osteoarthritis (OA) is largely unknown. This study aimed to determine whether curcumin could slow progression of OA and relieve OA-related pain in a mouse model of destabilization of the medial meniscus (DMM). Expression of selected cartilage degradative-associated genes was evaluated in human primary chondrocytes treated with curcumin and curcumin nanoparticles and assayed by real-time PCR. The mice subjected to DMM surgery were orally administered curcumin or topically administered curcumin nanoparticles for 8 weeks. Cartilage integrity was evaluated by Safranin O staining and Osteoarthritis Research Society International (OARSI) score, and by immunohistochemical staining of cleaved aggrecan and type II collagen, and levels of matrix metalloproteinase (MMP)-13 and ADAMTS5. Synovitis and subchondral bone thickness were scored based on histologic images. OA-associated pain and symptoms were evaluated by von Frey assay, and locomotor behavior including distance traveled and rearing. Both curcumin and nanoparticles encapsulating curcumin suppressed mRNA expression of pro-inflammatory mediators IL-1β and TNF-α, MMPs 1, 3, and 13, and aggrecanase ADAMTS5, and upregulated the chondroprotective transcriptional regulator CITED2, in primary cultured chondrocytes in the absence or presence of IL-1β. Oral administration of curcumin significantly reduced OA disease progression, but showed no significant effect on OA pain relief. Curcumin was detected in the infrapatellar fat pad (IPFP) following topical administration of curcumin nanoparticles on the skin of the injured mouse knee. Compared to vehicle-treated controls, topical treatment led to: (1) reduced proteoglycan loss and cartilage erosion and lower OARSI scores, (2) reduced synovitis and subchondral plate thickness, (3) reduced immunochemical staining of type II collagen and aggrecan cleavage epitopes and numbers of chondrocytes positive for MMP-13 and ADAMTS5 in the articular cartilage, and (4) reduced expression of adipokines and pro-inflammatory mediators in the IPFP. In contrast to oral curcumin, topical application of curcumin nanoparticles relieved OA-related pain as indicated by reduced tactile hypersensitivity and improved locomotor behavior. This study provides the first evidence that curcumin significantly slows OA disease progression and exerts a palliative effect in an OA mouse model.

Serum TK levels in CLL identify Binet stage A patients within biologically defined prognostic subgroups most likely to undergo disease progression.

PubMed

Matthews, Christine; Catherwood, Mark A; Morris, T C M; Kettle, Paul J; Drake, Mary B; Gilmore, William S; Alexander, H Denis

2006-10-01

Serum thymidine kinase (TK) levels have been shown to be correlated with survival in many malignancies, including chronic lymphocytic leukaemia (CLL). This study was designed to investigate associations between TK levels and other prognostic markers, in newly and previously diagnosed Binet stage A patients. Furthermore, the use of serum TK measurement to identify subcategories of disease within those defined by IgV(H) mutational status, gene usage and chromosomal aberrations was investigated. Ninety-one CLL patients were enrolled. Serum TK levels were measured using a radioenzyme assay. IgV(H) mutational status and V(H) gene usage were determined using BIOMED-2 primers and protocol. Recurring chromosomal abnormalities were detected by interphase fluorescent in situ hybridisation (FISH). Flow cytometry and reverse transcriptase polymerase chain reaction (RT-PCR) determined CD38 and Zap-70 expression, respectively. Significantly higher serum TK levels were found in IgV(H) unmutated, compared with IgV(H) mutated, patients (P < 0.001). Elevated TK levels were also found in patients with CD38 and Zap-70 positivity (P = 0.004, P < 0.001, respectively), short lymphocyte doubling time (LDT) (P = 0.044) and poor or intermediate prognosis chromosomal aberrations (P < 0.001). A TK level of >8.5 U/L best identified patients with progressive disease. Elevated TK levels could identify patients categorised, at diagnosis, into good prognosis subgroups by the various biological markers (mutated IgV(H), good prognosis chromosomal aberrations, Zap-70(-) and CD38(-)) who subsequently showed disease progression. Additionally, patients with V(H)3-21 gene usage showed high TK levels, irrespective of mutational status, and serum TK measurement retained predictive power as disease progressed in all subcategories studied.

Pirfenidone for Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis

PubMed Central

Venegas, Carmen; Arenas, Alex; Rada, Gabriel

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. In the last decades pirfenidone an anti-inflammatory and anti-fibrotic agent has shown benefit in inhibit collagen production and has also demonstrated benefit in decline progression in IPF in physiological outcomes as Forced vital capacity (FVC), in clinical outcomes such as progression free survival (PFS) and a benefit in mortality but no in clinically relevant outcomes as exacerbations or worsening of IPF. Methods: We conducted a systematic review to evaluate the effectiveness of physiological and clinical outcomes of pirfenidone compared to placebo in IPF. We performed a search with no language restriction. Two researchers performed literature search, quality assessment, data extraction and analysis. And was performed a summary of findings table following the GRADE approach. Results: We included 5 RCTs (Randomized controlled trials) in analysis. The meta-analysis resulted in a decrease in all cause-mortality (RR 0.52 IC 0.32–0.88) and IPF related mortality (RR 0.32 IC 0.14–0.75); other outcomes evaluated were worsening of IPF (RR 0.64 IC 0.50–0.83) and acute exacerbation (RR: 0.72 IC 0.30–1.66 respectively). Also there was a decrease in progression free survival (PFS) (RR 0.83 IC 0.74–0.92) compared to placebo. Conclusions: We observed significant differences in physiologic and clinically relevant outcomes such as reduction in all-cause mortality, IPF related mortality, worsening and exacerbation of IPF and PFS. So pirfenidone treatment should be considered not only for its benefits in pulmonary function tests but also by its clinically relevant outcomes. PMID:26308723

Inflammation disrupts the LDL receptor pathway and accelerates the progression of vascular calcification in ESRD patients.

PubMed

Liu, Jing; Ma, Kun Ling; Gao, Min; Wang, Chang Xian; Ni, Jie; Zhang, Yang; Zhang, Xiao Liang; Liu, Hong; Wang, Yan Li; Liu, Bi Cheng

2012-01-01

Chronic inflammation plays a crucial role in the progression of vascular calcification (VC). This study was designed to investigate whether the low-density lipoprotein receptor (LDLr) pathway is involved in the progression of VC in patients with end-stage renal disease (ESRD) during inflammation. Twenty-eight ESRD patients were divided into control and inflamed groups according to plasma C-reactive protein (CRP) level. Surgically removed tissues from the radial arteries of patients receiving arteriovenostomy were used in the experiments. The expression of tumour necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1) of the radial artery were increased in the inflamed group. Hematoxylin-eosin and alizarin red S staining revealed parallel increases in foam cell formation and calcium deposit formation in continuous cross-sections of radial arteries in the inflamed group compared to the control, which were closely correlated with increased LDLr, sterol regulatory element binding protein-2 (SREBP-2), bone morphogenetic proteins-2 (BMP-2), and collagen I protein expression, as shown by immunohistochemical and immunofluorescent staining. Confocal microscopy confirmed that inflammation enhanced the translocation of the SREBP cleavage-activating protein (SCAP)/SREBP-2 complex from the endoplasmic reticulum to the Golgi, thereby activating LDLr gene transcription. Inflammation increased alkaline phosphatase protein expression and reduced α-smooth muscle actin protein expression, contributing to the conversion of the vascular smooth muscle cells in calcified vessels from the fibroblastic to the osteogenic phenotype; osteogenic cells are the main cellular components involved in VC. Further analysis showed that the inflammation-induced disruption of the LDLr pathway was significantly associated with enhanced BMP-2 and collagen I expression. Inflammation accelerated the progression of VC in ESRD patients by disrupting the LDLr pathway, which may represent a novel mechanism involved in the progression of both VC and atherosclerosis.

NO 2 oxidation reactivity and burning mode of diesel particulates

DOE PAGES

Strzelec, Andrea; Vander Wal, Randy L.; Thompson, Thomas N.; ...

2016-03-24

The NO 2 oxidation kinetics and burning mode for diesel particulate from light-duty and medium-duty engines fueled with either ultra low sulfur diesel or soy methyl ester biodiesel blends have been investigated and are shown to be significantly different from oxidation by O 2. Oxidation kinetics were measured using a flow-through packed bed microreactor for temperature programmed reactions and isothermal differential pulsed oxidation reactions. The burning mode was evaluated using the same reactor system for flowing BET specific surface area measurements and HR-TEM with fringe analysis to evaluate the nanostructure of the nascent and partially oxidized particulates. The low activationmore » energy measured, specific surface area progression with extent of oxidation, HR-TEM images and difference plots of fringe length and tortuosity paint a consistent picture of higher reactivity for NO 2, which reacts indiscriminately immediately upon contact with the surface, leading to the Zone I or shrinking core type oxidation. In comparison, O 2 oxidation is shown to have relatively lower reactivity, preferentially attacking highly curved lamella, which are more reactive due to bond strain, and short lamella, which have a higher proportion of more reactive edge sites. Furthermore, this preferential oxidation leads to Zone II type oxidation, where solid phase diffusion of oxygen via pores contributes significantly to slowing the overall oxidation rate, by comparison.« less

Randomized controlled trial of exercise interventions to improve sleep quality and daytime sleepiness in individuals with multiple sclerosis: A pilot study.

PubMed

Siengsukon, Catherine F; Aldughmi, Mayis; Kahya, Melike; Bruce, Jared; Lynch, Sharon; Ness Norouzinia, Abigail; Glusman, Morgan; Billinger, Sandra

2016-01-01

Nearly 70% of individuals with multiple sclerosis (MS) experience sleep disturbances. Increasing physical activity in people with MS has been shown to produce a moderate improvement in sleep quality, and exercise has been shown to improve sleep quality in non-neurologically impaired adults. The purpose of this pilot randomized controlled trial study was to examine the effect of two exercise interventions on sleep quality and daytime sleepiness in individuals with MS. Twenty-eight individuals with relapsing-remitting or secondary progressive MS were randomized into one of two 12-week exercise interventions: a supervised, moderate-intensity aerobic exercise (AE) program or an unsupervised, low-intensity walking and stretching (WS) program. Only individuals who were ≥ 70% compliant with the programs were included in analysis ( n  = 12 AE; n  = 10 WS). Both groups demonstrated a moderate improvement in sleep quality, although only the improvement by the WS group was statistically significant. Only the AE group demonstrated a significant improvement in daytime sleepiness. Change in sleep quality and daytime sleepiness was not correlated with disease severity or with change in cardiovascular fitness, depression, or fatigue. The mechanisms for improvement in sleep quality and daytime sleepiness need further investigation, but may be due to introduction of zeitgebers to improve circadian rhythm.

Model studies on the role of moist convection as a mechanism for interaction between the mesoscales

NASA Technical Reports Server (NTRS)

Waight, Kenneth T., III; Song, J. Aaron; Zack, John W.; Price, Pamela E.

1991-01-01

A three year research effort is described which had as its goal the development of techniques to improve the numerical prediction of cumulus convection on the meso-beta and meso-gamma scales. Two MESO models are used, the MASS (mesoscale) and TASS (cloud scale) models. The primary meteorological situation studied is the 28-29 Jun. 1986 Cooperative Huntsville Meteorological Experiment (COHMEX) study area on a day with relatively weak large scale forcing. The problem of determining where and when convection should be initiated is considered to be a major problem of current approaches. Assimilation of moisture data from satellite, radar, and surface data is shown to significantly improve mesoscale simulations. The TASS model is shown to reproduce some observed mesoscale features when initialized with 3-D observational data. Convection evolution studies center on comparison of the Kuo and Fritsch-Chappell cumulus parameterization schemes to each other, and to cloud model results. The Fritsch-Chappell scheme is found to be superior at about 30 km resolution, while the Kuo scheme does surprisingly well in simulating convection down to 10 km in cases where convergence features are well-resolved by the model grid. Results from MASS-TASS interaction experiments are presented and discussed. A discussion of the future of convective simulation is given, with the conclusion that significant progress is possible on several fronts in the next few years.

Cell-free microRNAs as diagnostic, prognostic, and predictive biomarkers for lung cancer.

PubMed

Zandberga, Elīna; Kozirovskis, Viktors; Ābols, Artūrs; Andrējeva, Diāna; Purkalne, Gunta; Linē, Aija

2013-04-01

Lung cancer is the most common cancer worldwide, accounting for over 1.37 million deaths annually. The clinical outcome and management of lung cancer patients could be substantially improved by the implementation of non-invasive biomarker assays for the early detection, prognosis as well as prediction and monitoring of treatment response. MicroRNAs (miRNAs) have been implicated in the regulation of virtually all signaling circuits within a cell and their dysregulation has been shown to play an essential role in the development and progression of cancer. Recently, miRNAs were found to be released into the circulation and to exist there in a remarkably stable form. Furthermore, various cancers were shown to leave specific miRNA fingerprints in the blood of patients suggesting that cell-free miRNAs could serve as non-invasive biomarkers for the detection or monitoring of cancer and putative therapeutic targets. Since that, a considerable effort has been devoted to decode the information carried by circulating miRNAs. In the current review, we give an insight into the mechanisms of miRNA release into the bloodstream, their putative functional significance and systematically review the studies focused on the identification of cell-free miRNAs with the diagnostic, prognostic, and predictive significance in lung cancer and discuss their potential clinical utility. Copyright © 2012 Wiley Periodicals, Inc.

Mycobacterium smegmatis proteoliposome induce protection in a murine progressive pulmonary tuberculosis model.

PubMed

Tirado, Yanely; Puig, Alina; Alvarez, Nadine; Borrero, Reinier; Aguilar, Alicia; Camacho, Frank; Reyes, Fatima; Fernandez, Sonsire; Perez, Jose Luis; Acevedo, Reynaldo; Mata Espinoza, Dulce; Payan, Jorge Alberto Barrios; Garcia, Maria de Los A; Kadir, Ramlah; Sarmiento, María E; Hernandez-Pando, Rogelio; Norazmi, Mohd-Nor; Acosta, Armando

2016-12-01

Tuberculosis (TB) remains an important cause of mortality and morbidity. The TB vaccine, BCG, is not fully protective against the adult form of the disease and is unable to prevent its transmission although it is still useful against severe childhood TB. Hence, the search for new vaccines is of great interest. In a previous study, we have shown that proteoliposomes obtained from Mycobacterium smegmatis (PLMs) induced cross reactive humoral and cellular response against Mycobacterium tuberculosis (Mtb) antigens. With the objective to evaluate the protective capability of PLMs, a murine model of progressive pulmonary TB was used. Animals immunized with PLMs with and without alum (PLMs/PLMsAL respectively) showed protection compared to non-immunized animals. Mice immunized with PLMsAL induced similar protection as that of BCG. Animals immunized with BCG, PLMs and PLMsAL showed a significant decrease in tissue damage (percentage of pneumonic area/lung) compared to non-immunized animals, with a more prominent effect in BCG vaccinated mice. The protective effect of the administration of PLMs in mice supports its future evaluation as experimental vaccine candidate against Mtb. Copyright © 2016 Elsevier Ltd. All rights reserved.

Acquisition of Real-Time Operation Analytics for an Automated Serial Sectioning System

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

Madison, Jonathan D.; Underwood, O. D.; Poulter, Gregory A.

Mechanical serial sectioning is a highly repetitive technique employed in metallography for the rendering of 3D reconstructions of microstructure. While alternate techniques such as ultrasonic detection, micro-computed tomography, and focused ion beam milling have progressed much in recent years, few alternatives provide equivalent opportunities for comparatively high resolutions over significantly sized cross-sectional areas and volumes. To that end, the introduction of automated serial sectioning systems has greatly heightened repeatability and increased data collection rates while diminishing opportunity for mishandling and other user-introduced errors. Unfortunately, even among current, state-of-the-art automated serial sectioning systems, challenges in data collection have not been fullymore » eradicated. Therefore, this paper highlights two specific advances to assist in this area; a non-contact laser triangulation method for assessment of material removal rates and a newly developed graphical user interface providing real-time monitoring of experimental progress. Furthermore, both are shown to be helpful in the rapid identification of anomalies and interruptions, while also providing comparable and less error-prone measures of removal rate over the course of these long-term, challenging, and innately destructive characterization experiments.« less

Antimicrobial graphene family materials: Progress, advances, hopes and fears.

PubMed

Lukowiak, Anna; Kedziora, Anna; Strek, Wieslaw

2016-10-01

Graphene-based materials have become very popular bionanotechnological instruments in the last few years. Since 2010, the graphene family materials have been recognized as worthy of attention due to its antimicrobial properties. Functionalization of graphene (or rather graphene oxide) surface creates the possibilities to obtain efficient antimicrobial agents. In this review, progress and advances in this field in the last few years are described and discussed. Special attention is devoted to materials based on graphene oxide in which specifically selected components significantly modify biological activity of this carbon structure. Short introduction concerns the physicochemical properties of the graphene family materials. In the section on antimicrobial properties, proposed mechanisms of activity against microorganisms are given showing enhanced action of nanocomposites also under light irradiation (photoinduced activity). Another important feature, i.e. toxicity against eukaryotic cells, is presented with up-to-date data. Taking into account all the information on the properties of the described materials and usefulness of the graphene family as antimicrobial agents, hopes and fears concerning their application are discussed. Finally, some examples of promising usage in medicine and other fields, e.g. in phytobiology and water remediation, are shown. Copyright © 2016 Elsevier B.V. All rights reserved.

Acquisition of Real-Time Operation Analytics for an Automated Serial Sectioning System

DOE PAGES

Madison, Jonathan D.; Underwood, O. D.; Poulter, Gregory A.; ...

2017-03-22

Mechanical serial sectioning is a highly repetitive technique employed in metallography for the rendering of 3D reconstructions of microstructure. While alternate techniques such as ultrasonic detection, micro-computed tomography, and focused ion beam milling have progressed much in recent years, few alternatives provide equivalent opportunities for comparatively high resolutions over significantly sized cross-sectional areas and volumes. To that end, the introduction of automated serial sectioning systems has greatly heightened repeatability and increased data collection rates while diminishing opportunity for mishandling and other user-introduced errors. Unfortunately, even among current, state-of-the-art automated serial sectioning systems, challenges in data collection have not been fullymore » eradicated. Therefore, this paper highlights two specific advances to assist in this area; a non-contact laser triangulation method for assessment of material removal rates and a newly developed graphical user interface providing real-time monitoring of experimental progress. Furthermore, both are shown to be helpful in the rapid identification of anomalies and interruptions, while also providing comparable and less error-prone measures of removal rate over the course of these long-term, challenging, and innately destructive characterization experiments.« less

Identification of first-stage labor arrest by electromyography in term nulliparous women after induction of labor.

PubMed

Vasak, Blanka; Graatsma, Elisabeth M; Hekman-Drost, Elske; Eijkemans, Marinus J; Schagen van Leeuwen, Jules H; Visser, Gerard H A; Jacod, Benoit C

2017-07-01

Worldwide induction and cesarean delivery rates have increased rapidly, with consequences for subsequent pregnancies. The majority of intrapartum cesarean deliveries are performed for failure to progress, typically in nulliparous women at term. Current uterine registration techniques fail to identify inefficient contractions leading to first-stage labor arrest. An alternative technique, uterine electromyography has been shown to identify inefficient contractions leading to first-stage arrest of labor in nulliparous women with spontaneous onset of labor at term. The objective of this study was to determine whether this finding can be reproduced in induction of labor. Uterine activity was measured in 141 nulliparous women with singleton term pregnancies and a fetus in cephalic position during induced labor. Electrical activity of the myometrium during contractions was characterized by its power density spectrum. No significant differences were found in contraction characteristics between women with induced labor delivering vaginally with or without oxytocin and women with arrested labor with subsequent cesarean delivery. Uterine electromyography shows no correlation with progression of labor in induced labor, which is in contrast to spontaneous labor. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

Modeling Aerodynamically Generated Sound of Helicopter Rotors

NASA Technical Reports Server (NTRS)

Brentner, Kenneth S.; Farassat, F.

2002-01-01

A great deal of progress has been made in the modeling of aerodynamically generated sound of rotors over the past decade. Although the modeling effort has focused on helicopter main rotors, the theory is generally valid for a wide range of rotor configurations. The Ffowcs Williams Hawkings (FW-H) equation has been the foundation for much of the development. The monopole and dipole source terms of the FW-H equation account for the thickness and loading noise, respectively. Bladevortex-interaction noise and broadband noise are important types of loading noise, hence much research has been directed toward the accurate modeling of these noise mechanisms. Both subsonic and supersonic quadrupole noise formulations have been developed for the prediction of high-speed impulsive noise. In an effort to eliminate the need to compute the quadrupole contribution, the FW-H equation has also been utilized on permeable surfaces surrounding all physical noise sources. Comparisons of the Kirchhoff formulation for moving surfaces with the FW-H equation have shown that the Kirchhoff formulation for moving surfaces can give erroneous results for aeroacoustic problems. Finally, significant progress has been made incorporating the rotor noise models into full vehicle noise prediction tools.

Basophils and allergic inflammation

PubMed Central

Siracusa, Mark C.; Kim, Brian S.; Spergel, Jonathan M.; Artis, David

2013-01-01

Basophils were discovered by Paul Ehrlich in 1879 and represent the least abundant granulocyte population in mammals. The relative rarity of basophils and their phenotypic similarities with mast cells resulted in this cell lineage being historically overlooked, both clinically and experimentally. However, recent studies in humans and murine systems have shown that basophils perform non-redundant effector functions and significantly contribute to the development and progression of TH2 cytokine-mediated inflammation. Although the potential functions of murine and human basophils have provoked some controversy, recent genetic approaches indicate that basophils can migrate into lymphoid tissues and, in some circumstances, cooperate with other immune cells to promote optimal TH2 cytokine responses in vivo. This article provides a brief historical perspective on basophil-related research and discusses recent studies that have identified previously unappreciated molecules and pathways that regulate basophil development, activation and function in the context of allergic inflammation. Further, we highlight the unique effector functions of basophils and discuss their contributions to the development and pathogenesis of allergic inflammation in human disease. Finally, we discuss the therapeutic potential of targeting basophils in preventing or alleviating the development and progression of allergic inflammation. PMID:24075190

Caffeic acid, tyrosol and p-coumaric acid are potent inhibitors of 5-S-cysteinyl-dopamine induced neurotoxicity.

PubMed

Vauzour, David; Corona, Giulia; Spencer, Jeremy P E

2010-09-01

Parkinson's disease is characterized by a progressive and selective loss of dopaminergic neurons in the substantia nigra. Recent investigations have shown that conjugates such as the 5-S-cysteinyl-dopamine, possess strong neurotoxicity and may contribute to the underlying progression of the disease pathology. Although the neuroprotective actions of flavonoids are well reported, that of hydroxycinnamates and other phenolic acids is less established. We show that the hydroxycinnamates caffeic acid and p-coumaric acid, the hydroxyphenethyl alcohol, tyrosol, and a Champagne wine extract rich in these components protect neurons against injury induced by 5-S-cysteinyl-dopamine in vitro. The protection induced by these polyphenols was equal to or greater than that observed for the flavonoids, (+)-catechin, (-)-epicatechin and quercetin. For example, p-coumaric acid evoked significantly more protection at 1muM (64.0+/-3.1%) than both (-)-epicatechin (46.0+/-4.1%, p<0.05) and (+)-catechin (13.1+/-3.0%, p<0.001) at the same concentration. These data indicate that hydroxycinnamates, phenolic acids and phenolic alcohol are also capable of inducing neuroprotective effects to a similar extent to that seen with flavonoids. Copyright © 2010. Published by Elsevier Inc.

Microneedles for intradermal and transdermal delivery

PubMed Central

Tuan-Mahmood, Tuan-Mazlelaa; McCrudden, Maeliosa T.C.; Torrisi, Barbara M.; McAlister, Emma; Garland, Martin J; Singh, Thakur Raghu Raj; Donnelly, Ryan F

2014-01-01

The formidable barrier properties of the uppermost layer of the skin, the stratum corneum impose significant limitations for successful systemic delivery of a broad range of therapeutic molecules, particularly macromolecules and genetic material. Microneedle delivery has been proposed as a strategy to breach the SC barrier function in order to facilitate effective transport of molecules across the skin. This strategy involves the use of micron sized needles fabricated from different materials and using different geometries to create transient aqueous conduits across the skin. Microneedles in isolation, or in combination with other enhancing strategies, have been shown to dramatically enhance the skin permeability of numerous therapeutic molecules including biopharmaceuticals either in vitro, ex vivo or in vivo. Progress in the areas of microneedle design, development and manufacture have proven promising in terms of the potential use of this emerging delivery method in clinical applications such as insulin delivery, transcutaneous immunisations and cutaneous gene delivery. This review article focuses on recent and potential future developments in microneedle technologies. This will include the detailing of progress made in microneedle design, an exploration of the challenges faced in this field and potential forward strategies to embrace the exploitation of microneedle methodologies, while considering the inherent safety aspects of such therapeutic tools. PMID:23680534

Comparison of minichromosome maintenance proteins (MCM-3, MCM-7) and metallothioneins (MT-I/II, MT-III) expression in relation to clinicopathological data in ovarian cancer.

PubMed

Kobierzycki, Christopher; Pula, Bartosz; Skiba, Mateusz; Jablonska, Karolina; Latkowski, Krzysztof; Zabel, Maciej; Nowak-Markwitz, Ewa; Spaczynski, Marek; Kedzia, Witold; Podhorska-Okolow, Marzena; Dziegiel, Piotr

2013-12-01

Despite great progress in the understanding of ovarian cancer biology, clinicopathological data (i.e. grade, stage, histological type and residual disease after surgery) seem to be the most important prognostic factors. The present study aimed to investigate the relationship between expression of minichromosome maintenance proteins (MCM-3, MCM-7), metallothioneins (MT-I/II, MT-III), and Ki-67 in 103 ovarian cancer cases, mostly of the serous histological type. Statistical analysis revealed strong positive correlations in the expression of MCM-3 vs. Ki-67 (r=0.492), MCM-7 vs. Ki-67 (r=0.651), and MCM-3 vs. MCM-7 (r=0.515) (all p<0.0001). The Kruskal-Wallis test showed an association of increased expression of MCM-3 and Ki-67 with increasing grade of histological malignancy (p=0.0011, p=0.029, respectively). Regarding clinical progression, cytoplasmic MT-I/II expression was significantly higher in more advanced disease stages (III+IV vs. I+II; p=0.0247). Due to the correlations shown here, the determination of MCM proteins as proliferation markers of ovarian cancer, should be strongly considered.

Progress in catalytic ignition fabrication and modeling : fabrication part 1.

DOT National Transportation Integrated Search

2012-06-01

Previous engine testing with Catalytic Plasma Torch (CPT) technology at the University of Idaho has shown promising results in : the reduction of NOx and CO emissions. Because this technology is not yet well characterized, past research has indicated...

O-GlcNAcylation: A New Cancer Hallmark?

PubMed

Fardini, Yann; Dehennaut, Vanessa; Lefebvre, Tony; Issad, Tarik

2013-01-01

O-linked N-acetylglucosaminylation (O-GlcNAcylation) is a reversible post-translational modification consisting in the addition of a sugar moiety to serine/threonine residues of cytosolic or nuclear proteins. Catalyzed by O-GlcNAc-transferase (OGT) and removed by O-GlcNAcase, this dynamic modification is dependent on environmental glucose concentration. O-GlcNAcylation regulates the activities of a wide panel of proteins involved in almost all aspects of cell biology. As a nutrient sensor, O-GlcNAcylation can relay the effects of excessive nutritional intake, an important cancer risk factor, on protein activities and cellular functions. Indeed, O-GlcNAcylation has been shown to play a significant role in cancer development through different mechanisms. O-GlcNAcylation and OGT levels are increased in different cancers (breast, prostate, colon…) and vary during cell cycle progression. Modulating their expression or activity can alter cancer cell proliferation and/or invasion. Interestingly, major oncogenic factors have been shown to be directly O-GlcNAcylated (p53, MYC, NFκB, β-catenin…). Furthermore, chromatin dynamics is modulated by O-GlcNAc. DNA methylation enzymes of the Tet family, involved epigenetic alterations associated with cancer, were recently found to interact with and target OGT to multi-molecular chromatin-remodeling complexes. Consistently, histones are subjected to O-GlcNAc modifications which regulate their function. Increasing number of evidences point out the central involvement of O-GlcNAcylation in tumorigenesis, justifying the attention received as a potential new approach for cancer treatment. However, comprehension of the underlying mechanism remains at its beginnings. Future challenge will be to address directly the role of O-GlcNAc-modified residues in oncogenic-related proteins to eventually propose novel strategies to alter cancer development and/or progression.

Genetic polymorphism in paraoxonase is a risk factor for childhood focal segmental glomerulosclerosis.

PubMed

Frishberg, Y; Toledano, H; Becker-Cohen, R; Feigin, E; Halle, D

2000-12-01

Focal segmental glomerulosclerosis (FSGS) is an important cause of end-stage renal failure (ESRF) in children. Our previous studies have shown that Arab children in Israel have a worse prognosis compared with Jewish patients despite similar clinical presentation and management. Progression of proteinuric glomerular diseases has been associated with alterations in lipid metabolism, and similarities have been drawn between the mechanisms underlying atherosclerosis and glomerulosclerosis. Paraoxonase (PON) is a high-density lipoprotein (HDL)-associated enzyme involved in preventing the oxidation of low-density lipoprotein (LDL), and an association has been shown between two genetic polymorphisms in PON1 and the risk of coronary artery disease. The aim of this study was to determine the frequency of these genetic polymorphisms in PON1 in Arab and Jewish children with FSGS and to determine any association with severity of outcome. Forty-seven children (21 Arab and 26 Jewish) with biopsy-proven FSGS and 274 healthy controls of matching ethnic origin were studied. The glutamine (A)-192-arginine (B) and the methionine (M)-55-leucine (L) polymorphisms were analyzed. The frequency of the A allele was similar in patients and controls (0.68 versus 0.71), as was that of the L allele (0.63 versus 0.6). When subgroups were analyzed, the prevalence of the LL genotype in Arab patients was significantly greater than in Jewish patients (57.1% versus 26.9%, P: < 0.05) and Arab controls (57.1% versus 28.9%, P: < 0.03). A trend in association was found between homozygosity for the L allele and progression of renal disease in Arab children. Homozygosity for the L allele is a risk factor for developing FSGS in Arab children and may be associated with a worse prognosis.

Anemia as a risk factor for chronic kidney disease.

PubMed

Iseki, K; Kohagura, K

2007-11-01

Chronic kidney disease (CKD) is an important and leading cause of end-stage renal disease (ESRD) and moreover, plays a role in the morbidity and mortality due to cardiovascular disease, infection, and cancer. Anemia develops during the early stages of CKD and is common in patients with ESRD. Anemia is an important cause of left ventricular hypertrophy and congestive heart failure. Correction of anemia by erthyropoiesis-stimulating agent (ESA) has been shown to improve survival in patients with congestive heart failure. Anemia is counted as one of the non-conventional risk factors associated with CKD. Hypoxia is one of the common mechanisms of CKD progression. Treatment by ESA is expected to improve quality of life, survival, and prevent the CKD progression. Several clinical studies have shown the beneficial effects of anemia correction on renal outcomes. However, recent prospective trials both in ESRD and in CKD stages 3 and 4 failed to confirm the beneficial effects of correcting anemia on survival. Similarly, treatment of other risk factors such as hyperlipidemia by statin showed no improvement in the survival of dialysis patients. Given the high prevalence of anemia in ESRD and untoward effects of anemia in CKD stages 3 and 4, appropriate and timely intervention on renal anemia using ESA is required for practicing nephrologists and others involved in the care of high-risk population. Lessons from the recent studies are to correct renal anemia (hemoglobin <10 g/dl not hemoglobin > or =13 g/dl). Early intervention for renal anemia is a part of the treatment option in the prevention clinic. In this study, clinical significance of anemia management in patients with CKD is discussed.

O-GlcNAcylation: A New Cancer Hallmark?

PubMed Central

Fardini, Yann; Dehennaut, Vanessa; Lefebvre, Tony; Issad, Tarik

2013-01-01

O-linked N-acetylglucosaminylation (O-GlcNAcylation) is a reversible post-translational modification consisting in the addition of a sugar moiety to serine/threonine residues of cytosolic or nuclear proteins. Catalyzed by O-GlcNAc-transferase (OGT) and removed by O-GlcNAcase, this dynamic modification is dependent on environmental glucose concentration. O-GlcNAcylation regulates the activities of a wide panel of proteins involved in almost all aspects of cell biology. As a nutrient sensor, O-GlcNAcylation can relay the effects of excessive nutritional intake, an important cancer risk factor, on protein activities and cellular functions. Indeed, O-GlcNAcylation has been shown to play a significant role in cancer development through different mechanisms. O-GlcNAcylation and OGT levels are increased in different cancers (breast, prostate, colon…) and vary during cell cycle progression. Modulating their expression or activity can alter cancer cell proliferation and/or invasion. Interestingly, major oncogenic factors have been shown to be directly O-GlcNAcylated (p53, MYC, NFκB, β-catenin…). Furthermore, chromatin dynamics is modulated by O-GlcNAc. DNA methylation enzymes of the Tet family, involved epigenetic alterations associated with cancer, were recently found to interact with and target OGT to multi-molecular chromatin-remodeling complexes. Consistently, histones are subjected to O-GlcNAc modifications which regulate their function. Increasing number of evidences point out the central involvement of O-GlcNAcylation in tumorigenesis, justifying the attention received as a potential new approach for cancer treatment. However, comprehension of the underlying mechanism remains at its beginnings. Future challenge will be to address directly the role of O-GlcNAc-modified residues in oncogenic-related proteins to eventually propose novel strategies to alter cancer development and/or progression. PMID:23964270

Loss of DLK expression in WI-38 human diploid fibroblasts induces a senescent-like proliferation arrest

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

Daviau, Alex; Couture, Jean-Philippe; Blouin, Richard, E-mail: Richard.Blouin@USherbrooke.ca

Highlights: {yields} Role of DLK in cell proliferation. {yields} Modulation of DLK expression during cell cycle progression. {yields} DLK knockdown induces proliferation arrest and senescence. {yields} DLK-depleted cells display loss of cyclin D1 and up-regulation of p21. {yields} DLK participates in cell proliferation by modulating cell cycle regulator expression. -- Abstract: DLK, a serine/threonine kinase that functions as an upstream activator of the mitogen-activated protein kinase (MAPK) pathways, has been shown to play a role in development, cell differentiation, apoptosis and neuronal response to injury. Interestingly, recent studies have shown that DLK may also be required for cell proliferation, althoughmore » little is known about its specific functions. To start addressing this issue, we studied how DLK expression is modulated during cell cycle progression and what effect DLK depletion has on cell proliferation in WI-38 fibroblasts. Our results indicate that DLK protein levels are low in serum-starved cells, but that serum addition markedly stimulated it. Moreover, RNA interference experiments demonstrate that DLK is required for ERK activity, expression of the cell cycle regulator cyclin D1 and proliferation of WI-38 cells. DLK-depleted cells also show a senescent phenotype as revealed by senescence-associated galactosidase activity and up-regulation of the senescence pathway proteins p53 and p21. Consistent with a role for p53 in this response, inhibition of p53 expression by RNA interference significantly alleviated senescence induced by DLK knockdown. Together, these findings indicate that DLK participates in cell proliferation and/or survival, at least in part, by modulating the expression of cell cycle regulatory proteins.« less

Suppression of Coronary Atherosclerosis by Helix B Surface Peptide, a Nonerythropoietic, Tissue-Protective Compound Derived from Erythropoietin

PubMed Central

Ueba, Hiroto; Shiomi, Masashi; Brines, Michael; Yamin, Michael; Kobayashi, Tsutomu; Ako, Junya; Momomura, Shin-ichi; Cerami, Anthony; Kawakami, Masanobu

2013-01-01

Erythropoietin (EPO), a type I cytokine originally identified for its critical role in hematopoiesis, has been shown to have nonhematopoietic, tissue-protective effects, including suppression of atherosclerosis. However, prothrombotic effects of EPO hinder its potential clinical use in nonanemic patients. In the present study, we investigated the antiatherosclerotic effects of helix B surface peptide (HBSP), a nonerythropoietic, tissue-protective compound derived from EPO, by using human umbilical vein endothelial cells (HUVECs) and human monocytic THP-1 cells in vitro and Watanabe heritable hyperlipidemic spontaneous myocardial infarction (WHHLMI) rabbits in vivo. In HUVECs, HBSP inhibited apoptosis (≈70%) induced by C-reactive protein (CRP), a direct mediator of atherosclerosis. By using a small interfering RNA approach, Akt was shown to be a key molecule in HBSP-mediated prevention of apoptosis. HBSP also attenuated CRP-induced production of tumor necrosis factor (TNF)-α and matrix metalloproteinase-9 in THP-1 cells. In the WHHLMI rabbit, HBSP significantly suppressed progression of coronary atherosclerotic lesions as assessed by mean cross-sectional stenosis (HBSP 21.3 ± 2.2% versus control peptide 38.0 ± 2.7%) and inhibited coronary artery endothelial cell apoptosis with increased activation of Akt. Furthermore, TNF-α expression and the number of M1 macrophages and M1/M2 macrophage ratio in coronary atherosclerotic lesions were markedly reduced in HBSP-treated animals. In conclusion, these data demonstrate that HBSP suppresses coronary atherosclerosis, in part by inhibiting endothelial cell apoptosis through activation of Akt and in association with decreased TNF-α production and modified macrophage polarization in coronary atherosclerotic lesions. Because HBSP does not have the prothrombotic effects of EPO, our study may provide a novel therapeutic strategy that prevents progression of coronary artery disease. PMID:23648638

Pretreatment ADC histogram analysis is a predictive imaging biomarker for bevacizumab treatment but not chemotherapy in recurrent glioblastoma.

PubMed

Ellingson, B M; Sahebjam, S; Kim, H J; Pope, W B; Harris, R J; Woodworth, D C; Lai, A; Nghiemphu, P L; Mason, W P; Cloughesy, T F

2014-04-01

Pre-treatment ADC characteristics have been shown to predict response to bevacizumab in recurrent glioblastoma multiforme. However, no studies have examined whether ADC characteristics are specific to this particular treatment. The purpose of the current study was to determine whether ADC histogram analysis is a bevacizumab-specific or treatment-independent biomarker of treatment response in recurrent glioblastoma multiforme. Eighty-nine bevacizumab-treated and 43 chemotherapy-treated recurrent glioblastoma multiformes never exposed to bevacizumab were included in this study. In all patients, ADC values in contrast-enhancing ROIs from MR imaging examinations performed at the time of recurrence, immediately before commencement of treatment for recurrence, were extracted and the resulting histogram was fitted to a mixed model with a double Gaussian distribution. Mean ADC in the lower Gaussian curve was used as the primary biomarker of interest. The Cox proportional hazards model and log-rank tests were used for survival analysis. Cox multivariate regression analysis accounting for the interaction between bevacizumab- and non-bevacizumab-treated patients suggested that the ability of the lower Gaussian curve to predict survival is dependent on treatment (progression-free survival, P = .045; overall survival, P = .003). Patients with bevacizumab-treated recurrent glioblastoma multiforme with a pretreatment lower Gaussian curve > 1.2 μm(2)/ms had a significantly longer progression-free survival and overall survival compared with bevacizumab-treated patients with a lower Gaussian curve < 1.2 μm(2)/ms. No differences in progression-free survival or overall survival were observed in the chemotherapy-treated cohort. Bevacizumab-treated patients with a mean lower Gaussian curve > 1.2 μm(2)/ms had a significantly longer progression-free survival and overall survival compared with chemotherapy-treated patients. The mean lower Gaussian curve from ADC histogram analysis is a predictive imaging biomarker for bevacizumab-treated, not chemotherapy-treated, recurrent glioblastoma multiforme. Patients with recurrent glioblastoma multiforme with a mean lower Gaussian curve > 1.2 μm(2)/ms have a survival advantage when treated with bevacizumab.

Barrett’s esophagus in 2016: From pathophysiology to treatment

PubMed Central

Martinucci, Irene; de Bortoli, Nicola; Russo, Salvatore; Bertani, Lorenzo; Furnari, Manuele; Mokrowiecka, Anna; Malecka-Panas, Ewa; Savarino, Vincenzo; Savarino, Edoardo; Marchi, Santino

2016-01-01

Esophageal complications caused by gastroesophageal reflux disease (GERD) include reflux esophagitis and Barrett’s esophagus (BE). BE is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). The carcinogenic sequence may progress through several steps, from normal esophageal mucosa through BE to EAC. A recent advent of functional esophageal testing (particularly multichannel intraluminal impedance and pH monitoring) has helped to improve our knowledge about GERD pathophysiology, including its complications. Those findings (when properly confirmed) might help to predict BE neoplastic progression. Over the last few decades, the incidence of EAC has continued to rise in Western populations. However, only a minority of BE patients develop EAC, opening the debate regarding the cost-effectiveness of current screening/surveillance strategies. Thus, major efforts in clinical and research practice are focused on new methods for optimal risk assessment that can stratify BE patients at low or high risk of developing EAC, which should improve the cost effectiveness of screening/surveillance programs and consequently significantly affect health-care costs. Furthermore, the area of BE therapeutic management is rapidly evolving. Endoscopic eradication therapies have been shown to be effective, and new therapeutic options for BE and EAC have emerged. The aim of the present review article is to highlight the status of screening/surveillance programs and the current progress of BE therapy. Moreover, we discuss the recent introduction of novel esophageal pathophysiological exams that have improved the knowledge of the mechanisms linking GERD to BE. PMID:27158534

Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus.

PubMed

Tsagareli, Merab G; Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz

2011-01-01

Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

BCL2 expression in CD105 positive neoangiogenic cells and tumor progression in angioimmunoblastic T-cell lymphoma.

PubMed

Ratajczak, Philippe; Leboeuf, Christophe; Wang, Li; Brière, Josette; Loisel-Ferreira, Irmine; Thiéblemont, Catherine; Zhao, Wei-Li; Janin, Anne

2012-06-01

The angiogenic microenvironment has been known to be a component of angioimmunoblastic T-cell lymphoma since its initial characterization. We have shown that angioimmunoblastic T-cell lymphoma endothelial cells produce vascular endothelial growth factor-A (VEGFA), and participate in lymphoma progression. In squamous cell carcinoma, endothelial BCL2 expression induces a crosstalk with tumor cells through VEGFA, a major mediator of tumoral angiogenesis. In the present study, we analyzed BCL2 and VEGFA in 30 angioimmunoblastic T-cell lymphomas, using triple immunofluorescence to identify protein coexpression in well-characterized lymphoma cells and microenvironment neoangiogenic endothelial cells. Using quantitative real-time PCR, we assessed mRNA expression levels in laser-microdissected endothelial and lymphoma cells. In lymphoma cells, as in endothelial cells, BCL2 and VEGFA proteins were coexpressed. BCL2 was expressed only in neoangiogenic CD34(+)CD105(+) endothelial cells. In laser-microdissected cells, mRNA studies showed a significant relationship between BCL2 and VEGFA levels in CD34(+) endothelial cells, but not in CD3(+)CD10(+)lymphoma cells, or in CD34(+) endothelial cells from lymph node hyperplasia. Further study showed that, in AITL, BCL2 mRNA levels in CD34(+)CD105(+) neoangiogenic endothelial cells also correlated with microvessel density, International Prognostic Index, Ann Arbor stage, bone marrow involvement and elevated LDH. BCL2 expression by CD105(+) neoangiogenic endothelial cells is related to tumor progression in angioimmunoblastic T-cell lymphoma.

Sensory-motor problems in Autism

PubMed Central

Whyatt, Caroline; Craig, Cathy

2013-01-01

Despite being largely characterized as a social and cognitive disorder, strong evidence indicates the presence of significant sensory-motor problems in Autism Spectrum Disorder (ASD). This paper outlines our progression from initial, broad assessment using the Movement Assessment Battery for Children (M-ABC2) to subsequent targeted kinematic assessment. In particular, pronounced ASD impairment seen in the broad categories of manual dexterity and ball skills was found to be routed in specific difficulties on isolated tasks, which were translated into focused experimental assessment. Kinematic results from both subsequent studies highlight impaired use of perception-action coupling to guide, adapt and tailor movement to task demands, resulting in inflexible and rigid motor profiles. In particular difficulties with the use of temporal adaption are shown, with “hyperdexterity” witnessed in ballistic movement profiles, often at the cost of spatial accuracy and task performance. By linearly progressing from the use of a standardized assessment tool to targeted kinematic assessment, clear and defined links are drawn between measureable difficulties and underlying sensory-motor assessment. Results are specifically viewed in-light of perception-action coupling and its role in early infant development suggesting that rather than being “secondary” level impairment, sensory-motor problems may be fundamental in the progression of ASD. This logical and systematic process thus allows a further understanding into the potential root of observable motor problems in ASD; a vital step if underlying motor problems are to be considered a fundamental aspect of autism and allow a route of non-invasive preliminary diagnosis. PMID:23882194

Spatial distribution of early red lesions is a risk factor for development of vision-threatening diabetic retinopathy.

PubMed

Ometto, Giovanni; Assheton, Phil; Calivá, Francesco; Chudzik, Piotr; Al-Diri, Bashir; Hunter, Andrew; Bek, Toke

2017-12-01

Diabetic retinopathy is characterised by morphological lesions related to disturbances in retinal blood flow. It has previously been shown that the early development of retinal lesions temporal to the fovea may predict the development of treatment-requiring diabetic maculopathy. The aim of this study was to map accurately the area where lesions could predict progression to vision-threatening retinopathy. The predictive value of the location of the earliest red lesions representing haemorrhages and/or microaneurysms was studied by comparing their occurrence in a group of individuals later developing vision-threatening diabetic retinopathy with that in a group matched with respect to diabetes type, age, sex and age of onset of diabetes mellitus who did not develop vision-threatening diabetic retinopathy during a similar observation period. The probability of progression to vision-threatening diabetic retinopathy was higher in a circular area temporal to the fovea, and the occurrence of the first lesions in this area was predictive of the development of vision-threatening diabetic retinopathy. The calculated peak value showed that the risk of progression was 39.5% higher than the average. There was no significant difference in the early distribution of lesions in participants later developing diabetic maculopathy or proliferative diabetic retinopathy. The location of early red lesions in diabetic retinopathy is predictive of whether or not individuals will later develop vision-threatening diabetic retinopathy. This evidence should be incorporated into risk models used to recommend control intervals in screening programmes for diabetic retinopathy.

Bone marrow mesenchymal stem cells promote head and neck cancer progression through Periostin-mediated phosphoinositide 3-kinase/Akt/mammalian target of rapamycin.

PubMed

Liu, Chuanxia; Feng, Xiaoxia; Wang, Baixiang; Wang, Xinhua; Wang, Chaowei; Yu, Mengfei; Cao, Guifen; Wang, Huiming

2018-03-01

Bone marrow mesenchymal stem cells (BMMSC) have been shown to be recruited to the tumor microenvironment and exert a tumor-promoting effect in a variety of cancers. However, the molecular mechanisms related to the tumor-promoting effect of BMMSC on head and neck cancer (HNC) are not clear. In this study, we investigated Periostin (POSTN) and its roles in the tumor-promoting effect of BMMSC on HNC. In vitro analysis of HNC cells cultured in BMMSC-conditioned media (MSC-CM) showed that MSC-CM significantly promoted cancer progression by enhancing cell proliferation, migration, epithelial-mesenchymal transformation (EMT), and altering expression of cell cycle regulatory proteins and inhibition of apoptosis. Moreover, MSC-CM promoted the expression of POSTN and POSTN promoted HNC progression through the activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. In a murine model of HNC, we found that BMMSC promoted tumor growth, invasion, metastasis and enhanced the expression of POSTN and EMT in tumor tissues. Clinical sample analysis further confirmed that the expression of POSTN and N-cadherin were correlated with pathological grade and lymph node metastasis of HNC. In conclusion, this study indicated that BMMSC promoted proliferation, invasion, survival, tumorigenicity and migration of head and neck cancer through POSTN-mediated PI3K/Akt/mTOR activation. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Molecular pathogenesis and clinical consequences of iron overload in liver cirrhosis.

PubMed

Sikorska, Katarzyna; Bernat, Agnieszka; Wroblewska, Anna

2016-10-01

The liver, as the main iron storage compartment and the place of hepcidin synthesis, is the central organ involved in maintaining iron homeostasis in the body. Excessive accumulation of iron is an important risk factor in liver disease progression to cirrhosis and hepatocellular carcinoma. Here, we review the literature on the molecular pathogenesis of iron overload and its clinical consequences in chronic liver diseases. PubMed was searched for English-language articles on molecular genesis of primary and secondary iron overload, as well as on their association with liver disease progression. We have also included literature on adjuvant therapeutic interventions aiming to alleviate detrimental effects of excessive body iron load in liver cirrhosis. Excess of free, unbound iron induces oxidative stress, increases cell sensitivity to other detrimental factors, and can directly affect cellular signaling pathways, resulting in accelerated liver disease progression. Diagnosis of liver cirrhosis is, in turn, often associated with the identification of a pathological accumulation of iron, even in the absence of genetic background of hereditary hemochromatosis. Iron depletion and adjuvant therapy with antioxidants are shown to cause significant improvement of liver functions in patients with iron overload. Phlebotomy can have beneficial effects on liver histology in patients with excessive iron accumulation combined with compensated liver cirrhosis of different etiology. Excessive accumulation of body iron in liver cirrhosis is an important predictor of liver failure and available data suggest that it can be considered as target for adjuvant therapy in this condition.

Enzyme replacement therapy of Fabry disease.

PubMed

Clarke, Joe T R; Iwanochko, R Mark

2005-08-01

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of the enzyme alpha-galactosidase A and results in pain, progressive renal impairment, cardiomyopathy, and cerebrovascular disease. The results of two major randomized, double-blind, placebo-controlled clinical trials and open-label extensions have shown that replacement of the deficient enzyme with either of two preparations of recombinant human alpha-galactosidase A, agalsidase-alfa, and agalsidase-beta is safe. Biweekly i.v. infusions of 0.2 mg/kg of agalsidase-alfa were associated with a significant decrease in pain and stabilization of renal function. Biweekly infusions of 1 mg/kg of agalsidase-beta were associated with virtually complete clearing of accumulated glycolipid substrate from renal and cutaneous capillary endothelial cells. Several smaller, open-label studies, along with observations made in the course of monitoring large numbers of patients on enzyme replacement therapy, indicated that treatment stabilizes renal function and produces significant improvements in myocardial mass and function. Treatment of Fabry disease by enzyme replacement has a significant impact on at least some serious complications of the disease.

Abrupt Decline in the Arctic Winter Sea Ice Cover

NASA Technical Reports Server (NTRS)

Comiso, Josefino C.

2007-01-01

Maximum ice extents in the Arctic in 2005 and 2006 have been observed to be significantly lower (by about 6%) than the average of those of previous years starting in 1979. Since the winter maxima had been relatively stable with the trend being only about -1.5% per decade (compared to about -10% per decade for the perennial ice area), this is a significant development since signals from greenhouse warming are expected to be most prominent in winter. Negative ice anomalies are shown to be dominant in 2005 and 2006 especially in the Arctic basin and correlated with winds and surface temperature anomalies during the same period. Progressively increasing winter temperatures in the central Arctic starting in 1997 is observed with significantly higher rates of increase in 2005 and 2006. The Atlantic Oscillation (AO) indices correlate weakly with the sea ice and surface temperature anomaly data but may explain the recent shift in the perennial ice cover towards the western region. Results suggest that the trend in winter ice is finally in the process of catching up with that of the summer ice cover.

Effects of a dolphin interaction program on children with autism spectrum disorders – an exploratory research

PubMed Central

2012-01-01

Background Interaction programs involving dolphins and patients with various pathologies or developmental disorders (e.g., cerebral palsy, intellectual impairment, autism, atopic dermatitis, post-traumatic stress disorder, depression) have stimulated interest in their beneficial effects and therapeutic potential. However, the true effects observed in different clinical and psycho-educational setups are still controversial. Results An evaluation protocol consisting of the Childhood Autism Rating Scale (CARS), Psychoeducational Profile-Revised (PEP-R), Autism Treatment Evaluation Checklist (ATEC), Theory of Mind Tasks (ToM Tasks) and a custom-made Interaction Evaluation Grid (IEG) to evaluate behavioural complexity during in-pool interactions was applied to 10 children diagnosed with Autism Spectrum Disorders. The ATEC, ToM Tasks and CARS results show no benefits of the dolphin interaction program. Interestingly, the PEP-R suggests some statistically significant effects on ‘Overall development score’, as well as on their ‘Fine motor development’, ‘Cognitive performance’ and ‘Cognitive verbal development’. Also, a significant evolution in behavioural complexity was shown by the IEG. Conclusions This study does not support significant developmental progress resulting from the dolphin interaction program. PMID:22537536

Connective tissue growth factor (CTGF) and cancer progression.

PubMed

Chu, Chia-Yu; Chang, Cheng-Chi; Prakash, Ekambaranellore; Kuo, Min-Liang

2008-11-01

Connective tissue growth factor (CTGF) is a member of the CCN family of secreted, matrix-associated proteins encoded by immediate early genes that play various roles in angiogenesis and tumor growth. CCN family proteins share uniform modular structure which mediates various cellular functions such as regulation of cell division, chemotaxis, apoptosis, adhesion, motility, angiogenesis, neoplastic transformation, and ion transport. Recently, CTGF expression has been shown to be associated with tumor development and progression. There is growing body of evidence that CTGF may regulate cancer cell migration, invasion, angiogenesis, and anoikis. In this review, we will highlight the influence of CTGF expression on the biological behavior and progression of various cancer cells, as well as its regulation on various types of protein signals and their mechanisms.

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1DeltaE9 mouse model of Alzheimer's disease.

PubMed

Toledo, E M; Inestrosa, N C

2010-03-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid-beta-peptide (Abeta) and synaptic alterations. Treatment with lithium has been shown to provide neuroprotection against several insults, including protection against Abeta neurotoxicity in vitro. Rosiglitazone, a peroxisome proliferator activated receptor-gamma agonist, has been shown to attenuate Abeta-peptide neurotoxic effects, including the inflammatory response of microglia and astrocytes. Both types of drugs activate Wnt signaling, a pathway that has been shown to be related to AD. In this study, a double transgenic mouse model, which coexpresses APPswe and the exon 9 deletion of the presenilin 1 (PSEN1) gene, was used to examine, in vivo, the effect of lithium and rosiglitazone on Abeta neurotoxicity. Mice were tested for spatial memory, and their brain samples were used for histochemical and biochemical analysis. In this study, we report that both drugs significantly reduced (1) spatial memory impairment induced by amyloid burden; (2) Abeta aggregates and Abeta oligomers; and (3) astrocytic and microglia activation. They also prevented changes in presynaptic and postsynaptic marker proteins. Finally, both drugs activate Wnt signaling shown by the increase in beta-catenin and by the inhibition of the glycogen synthase kinase-3beta. We conclude that lithium and rosiglitazone, possibly by the activation of the Wnt signaling pathway, reduce various AD neuropathological markers and may be considered as potential therapeutic agents against the disease.

Programmed death-1 & its ligands: promising targets for cancer immunotherapy.

PubMed

Shrimali, Rajeev K; Janik, John E; Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N

2015-01-01

Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit.

Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms.

PubMed

Epperly, Ted; Dunay, Megan A; Boice, Jack L

2017-06-15

Alzheimer disease comprises a syndrome of progressive cognitive and functional decline. Treatments should target cognitive and functional symptoms. Cholinesterase inhibitors, memantine, and a combination of a cholinesterase inhibitor and memantine have produced statistically significant but clinically small delays in various domains of cognitive and functional decline in select patients with Alzheimer disease. Vitamin E has been shown to delay functional decline in patients with mild to moderate Alzheimer disease, especially when taken in combination with a cholinesterase inhibitor. Structured programs of physical exercise improve physical function and reduce rates of neuropsychiatric symptoms in patients with mild to severe Alzheimer disease. Cognitive stimulation programs show benefit in maintenance of cognitive function and improved self-reported quality of life in patients with mild to moderate Alzheimer disease.

Oak Ridge National Laboratory Site Sustainability Plan with FY 2016 Performance Data

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

Nichols, Teresa A.; Lapsa, Melissa Voss

Campus sustainability is part of an ongoing process of modernization at Oak Ridge National Laboratory (ORNL). Initiated in 2002, it grew to include the Sustainable Campus Initiative (SCI) as of 2008. The SCI embodies a diversity of areas, reflecting the multifaceted nature of sustainability and the resulting need for a holistic approach, by tapping ORNL’s multiplatform science and technology expertise in a pathway critical in catalyzing change and shaping the Laboratory’s future. The past year has shown significant progress for the SCI as well as for sustainable development at large, with the 21st Session of the Conference of the Partiesmore » (COP21) in Paris setting a new pace and direction for worldwide mitigation of climate change in the coming decades.« less

Telerehabilitation for patients with heart failure.

PubMed

Tousignant, Michel; Mampuya, Warner Mbuila

2015-02-01

Heart failure is a chronic and progressive condition that is associated with high morbidity and mortality rates. Even though cardiac rehabilitation (CR) has been shown to be beneficial to heart failure patients, only a very small proportion of them will actually be referred and eventually participate. The low participation rate is due in part to accessibility and travel difficulties. Telerehabilitation is a new approach in the rehabilitation field that allows patients to receive a complete rehabilitation program at home in a safe manner and under adequate supervision. We believe that by increasing accessibility to CR, telerehabilitation programs will significantly improve heart failure patients' functional capacity and quality of life. However, it is crucial to provide policy makers with evidence-based data on cardiac telerehabilitation if we want to see its successful implementation in heart failure patients.

Structural insight into RNA recognition motifs: versatile molecular Lego building blocks for biological systems.

PubMed

Muto, Yutaka; Yokoyama, Shigeyuki

2012-01-01

'RNA recognition motifs (RRMs)' are common domain-folds composed of 80-90 amino-acid residues in eukaryotes, and have been identified in many cellular proteins. At first they were known as RNA binding domains. Through discoveries over the past 20 years, however, the RRMs have been shown to exhibit versatile molecular recognition activities and to behave as molecular Lego building blocks to construct biological systems. Novel RNA/protein recognition modes by RRMs are being identified, and more information about the molecular recognition by RRMs is becoming available. These RNA/protein recognition modes are strongly correlated with their biological significance. In this review, we would like to survey the recent progress on these versatile molecular recognition modules. Copyright © 2012 John Wiley & Sons, Ltd.

[Amyloidosis: Up-to-date].

PubMed

Magy-Bertrand, N

2016-08-01

Amyloidosis is mainly a systemic disease belonging to protein-folding diseases. The past 10 years have shown significant progress in typing and the clinical management of amyloidosis, in the identification of novel prognostic markers for risk-stratification, and also in the development of new therapeutic agents. Biological molecular techniques are now able to type amyloidosis which were unidentified. Cardiac MRI and biomarkers allow a precise risk-stratification, especially in AL amyloidosis. If necessary, this prognostic evaluation may lead to rapid changes in the chemotherapy treatment. Emerging treatments rely on biotherapies, gene therapy, immunotherapy and blocking analogous agents. They give hope about an increase of survival of patients with systemic amyloidosis. Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

[Management of localized, locally advanced and metastatic pancreatic adenocarcinoma].

PubMed

Delpero, Jean-Robert; Turrini, Olivier; Raoul, Jean-Luc

2015-03-01

Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy. The prognosis is extremely poor because PDAC is usually a systemic disease at diagnosis. All stages, the survival does not exceed 5% at 5 years. However 15% of PDAC can be resected and today a margin-negative resection followed by adjuvant chemotherapy remains the only potential for a prolonged survival. Postoperative mortality had significantly decreased and the benefit of postoperative adjuvant chemotherapy has been clearly shown. Substantial progress has been made in the field of palliative chemotherapy by introducing new chemotherapy regimens (FOLFIRINOX [folinic acid, 5-fluorouracil, irinotecan and oxaliplatin] and gemcitabine/nab-paclitaxel), when the patient's performance status allows the use of these drugs. The role of radiation therapy remains controversial.

A look backward and forward in the regulatory and treatment history of multiple myeloma: Approval of novel-novel agents, new drug development, and longer patient survival.

PubMed

Kazandjian, Dickran; Landgren, Ola

2016-12-01

The past decade has seen significant advances in our understanding and treatment of multiple myeloma (MM) and its precursor diseases. These advances include gains in knowledge of the underlying pathobiology including molecular and cellular prognostic factors for disease progression. In parallel we have witnessed the availability of novel therapeutics. Together these advances have translated into improvements in long-term clinical benefit and survival in MM. Indeed, it has been shown that patients diagnosed in the last decade have experienced almost doubling of median survival time. We aim to review and give further insight into drug development and novel drug approvals that have revolutionized the treatment of MM. Published by Elsevier Inc.

Nailfold capillaroscopy in Buerger's disease: A useful tool?

PubMed

Guidelli, Giacomo Maria; Bardelli, Marco; Fioravanti, Antonella; Selvi, Enrico

2014-06-01

Thromboangiitis obliterans (TAO, or Buerger's disease) is a rare inflammatory vasculitis that commonly involves small and medium-sized arteries of the extremities of tobacco smokers between the ages of 25 and 50 years. Although the diagnosis is based on the clinical picture and angiographic findings, we studied the microvascular involvement by nailfold capillaroscopy. We evaluated by nailfold capillaroscopy 2 patients with Buerger's disease, at baseline and after 6 months of tobacco discontinuation and therapy with prostanoids. Both patients presented similar capillaroscopic abnormalities, resembling a scleroderma-like pattern. The microvascular rearrangement was significantly reduced after 6 months of evaluation. The capillaroscopic abnormalities shown in the two patients could be related to thromboangiitis obliterans, and nailfold capillaroscopy could be a useful tool to evaluate disease progression and the response to treatment.

Nailfold capillaroscopy in Buerger’s disease: A useful tool?

PubMed Central

Guidelli, Giacomo Maria; Bardelli, Marco; Fioravanti, Antonella; Selvi, Enrico

2014-01-01

Thromboangiitis obliterans (TAO, or Buerger’s disease) is a rare inflammatory vasculitis that commonly involves small and medium-sized arteries of the extremities of tobacco smokers between the ages of 25 and 50 years. Although the diagnosis is based on the clinical picture and angiographic findings, we studied the microvascular involvement by nailfold capillaroscopy. We evaluated by nailfold capillaroscopy 2 patients with Buerger’s disease, at baseline and after 6 months of tobacco discontinuation and therapy with prostanoids. Both patients presented similar capillaroscopic abnormalities, resembling a scleroderma-like pattern. The microvascular rearrangement was significantly reduced after 6 months of evaluation. The capillaroscopic abnormalities shown in the two patients could be related to thromboangiitis obliterans, and nailfold capillaroscopy could be a useful tool to evaluate disease progression and the response to treatment. PMID:27708881

Improving patient outcomes to targeted therapies in melanoma.

PubMed

Eroglu, Zeynep; Smalley, Keiran S M; Sondak, Vernon K

2016-06-01

The arrival of targeted therapies has led to significant improvements in clinical outcomes for patients with BRAFV600 mutated advanced melanoma over the past five years. In several clinical trials, BRAF and MEK inhibitors have shown improvement in progression free and overall survival, along with much higher tumor response rates in comparison to chemotherapy, with the combination of these drugs superior to monotherapy. These agents are also being tested in earlier-stage patients, in addition to alternative dosing regimens and in combinations with other therapeutics. Efforts are also ongoing to expand the success found with targeted therapies to other subtypes of melanoma, including NRAS and c-kit mutated melanomas, uveal melanomas, and BRAF/NRAS wild type melanomas. Expert Commentary: We aim to provide an overview of clinical outcomes with targeted therapies in melanoma patients.

Pt/SnO2-based CO-oxidation catalysts for long-life closed-cycle CO2 lasers

NASA Technical Reports Server (NTRS)

Schryer, David R.; Upchurch, Billy T.; Hess, Robert V.; Wood, George M.; Sidney, Barry D.; Miller, Irvin M.; Brown, Kenneth G.; Vannorman, John D.; Schryer, Jacqueline; Brown, David R.

1990-01-01

Noble-metal/tin-oxide based catalysts such as Pt/SnO2 have been shown to be good catalysts for the efficient oxidation of CO at or near room temperature. These catalysts require a reductive pretreatment and traces of hydrogen or water to exhibit their full activity. Addition of Palladium enhances the activity of these catalysts with about 15 to 20 percent Pt, 4 percent Pd, and the balance SnO2 being an optimum composition. Unfortunately, these catalysts presently exhibit significant decay due in part to CO2 retention, probably as a bicarbonate. Research on minimizing the decay in activity of these catalysts is currently in progress. A proposed mechanism of CO oxidation on Pt/SnO2-based catalysts has been developed and is discussed.

Space, Atmospheric, and Terrestrial Radiation Environments

NASA Technical Reports Server (NTRS)

Barth, Janet L.; Dyer, C. S.; Stassinopoulos, E. G.

2003-01-01

The progress on developing models of the radiation environment since the 1960s is reviewed with emphasis on models that can be applied to predicting the performance of microelectronics used in spacecraft and instruments. Space, atmospheric, and ground environments are included. It is shown that models must be adapted continually to account for increased understanding of the dynamics of the radiation environment and the changes in microelectronics technology. The IEEE Nuclear and Space Radiation Effects Conference is a vital forum to report model progress to the radiation effects research community.

Enzalutamide in metastatic prostate cancer before chemotherapy.

PubMed

Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana E; Loriot, Yohann; Sternberg, Cora N; Higano, Celestia S; Iversen, Peter; Bhattacharya, Suman; Carles, Joan; Chowdhury, Simon; Davis, Ian D; de Bono, Johann S; Evans, Christopher P; Fizazi, Karim; Joshua, Anthony M; Kim, Choung-Soo; Kimura, Go; Mainwaring, Paul; Mansbach, Harry; Miller, Kurt; Noonberg, Sarah B; Perabo, Frank; Phung, De; Saad, Fred; Scher, Howard I; Taplin, Mary-Ellen; Venner, Peter M; Tombal, Bertrand

2014-07-31

Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

Reductions in Radiographic Progression in Early Rheumatoid Arthritis Over Twenty-Five Years: Changing Contribution From Rheumatoid Factor in Two Multicenter UK Inception Cohorts.

PubMed

Carpenter, Lewis; Norton, Sam; Nikiphorou, Elena; Jayakumar, Keeranur; McWilliams, Daniel F; Rennie, Kirsten L; Dixey, Josh; Kiely, Patrick; Walsh, David Andrew; Young, Adam

2017-12-01

To assess the 5-year progression of erosions and joint space narrowing (JSN) and their associations with rheumatoid factor (RF) status in 2 large, multicenter, early rheumatoid arthritis cohorts, spanning 25 years. Radiographic joint damage was recorded using the Sharp/van der Heijde (SHS) method in the Early Rheumatoid Arthritis Study (ERAS), 1986-2001, and the Early Rheumatoid Arthritis Network (ERAN), 2002-2013. Mixed-effects negative binomial regression estimated changes in radiographic damage over 5 years, including erosions and JSN, separately. RF, along with age, sex, and baseline markers of disease activity were controlled for. A total of 1,216 patients from ERAS and 446 from ERAN had radiographic data. Compared to ERAS, ERAN patients had a lower mean total SHS score at baseline (ERAN 6.2 versus ERAS 10.5; P < 0.001) and mean annual rate of change (ERAN 2.5 per year versus ERAS 6.9 per year; P < 0.001). Seventy-four percent of ERAS and 27% of ERAN patients progressed ≥5 units. Lower scores at baseline in ERAN were largely driven by reductions in JSN (ERAS 3.9 versus ERAN 1.2; P < 0.001), along with erosions (ERAS 1.9 versus ERAN 0.8; P < 0.001). RF was associated with greater progression in each cohort, but the absolute difference in mean annual rate of change for RF-positive patients was substantially higher for ERAS (RF positive 8.6 versus RF negative 5.1; P < 0.001), relative to ERAN (RF positive 2.0 versus RF negative 1.9; P = 0.855). Radiographic progression was shown to be significantly reduced between the 2 cohorts, and was associated with lower baseline damage and other factors, including changes in early disease-modifying antirheumatic drug use. The impact of RF status as a prognostic marker of clinically meaningful change in radiographic progression has markedly diminished in the context of more modern treatment. © 2017, American College of Rheumatology.

Progression of initially mild hepatic fibrosis in patients with chronic hepatitis C infection.

PubMed

Williams, M J; Lang-Lenton, M

2011-01-01

A significant number of patients with chronic hepatitis C infection have minimal fibrosis at presentation. Although the short-term outlook for such patients is good, there are limited data available on long-term progression. We assessed the risk of fibrosis progression in 282 patients with chronic hepatitis C with Ishak stage 0 or 1 fibrosis on initial liver biopsy. Progression of fibrosis stage occurred in 118 patients (42%) over a median interval of 52.5 months. Thirteen (5%) progressed to severe (Ishak stage 4 or more) fibrosis. Progression was significantly associated with both age at initial biopsy [odds ratio (OR) for progression of 1.31 per 10 year increase in age] and median alanine transaminase (ALT) levels during follow-up (OR of 1.06 per 10 IU/L increase). There was no significant association with gender, histological inflammatory grade, hepatic steatosis or body mass index. We conclude that hepatitis C with initially mild fibrosis does progress in a substantial proportion of patients and should not be viewed as a benign disease. Early antiviral therapy should be considered in older patients and those with high ALT levels.

Computer-assisted upper extremity training using interactive biking exercise (iBikE) platform.

PubMed

Jeong, In Cheol; Finkelstein, Joseph

2012-01-01

Upper extremity exercise training has been shown to improve clinical outcomes in different chronic health conditions. Arm-operated bicycles are frequently used to facilitate upper extremity training however effective use of these devices at patient homes is hampered by lack of remote connectivity with clinical rehabilitation team, inability to monitor exercise progress in real time using simple graphical representation, and absence of an alert system which would prevent exertion levels exceeding those approved by the clinical rehabilitation team. We developed an interactive biking exercise (iBikE) platform aimed at addressing these limitations. The platform uses a miniature wireless 3-axis accelerometer mounted on a patient wrist that transmits the cycling acceleration data to a laptop. The laptop screen presents an exercise dashboard to the patient in real time allowing easy graphical visualization of exercise progress and presentation of exercise parameters in relation to prescribed targets. The iBikE platform is programmed to alert the patient when exercise intensity exceeds the levels recommended by the patient care provider. The iBikE platform has been tested in 7 healthy volunteers (age range: 26-50 years) and shown to reliably reflect exercise progress and to generate alerts at pre-setup levels. Implementation of remote connectivity with patient rehabilitation team is warranted for future extension and evaluation efforts.

A Critical Review on the Effect of Docosahexaenoic Acid (DHA) on Cancer Cell Cycle Progression.

PubMed

Newell, Marnie; Baker, Kristi; Postovit, Lynne M; Field, Catherine J

2017-08-17

Globally, there were 14.1 million new cancer diagnoses and 8.2 million cancer deaths in 2012. For many cancers, conventional therapies are limited in their successes and an improved understanding of disease progression is needed in conjunction with exploration of alternative therapies. The long chain polyunsaturated fatty acid, docosahexaenoic acid (DHA), has been shown to enhance many cellular responses that reduce cancer cell viability and decrease proliferation both in vitro and in vivo. A small number of studies suggest that DHA improves chemotherapy outcomes in cancer patients. It is readily incorporated into cancer cell membranes and, as a result there has been considerable research regarding cell membrane initiated events. For example, DHA has been shown to mediate the induction of apoptosis/reduction of proliferation in vitro and in vivo. However, there is limited research into the effect of DHA on cell cycle regulation in cancer cells and the mechanism(s) by which DHA acts are not fully understood. The purpose of the current review is to provide a critical examination of the literature investigating the ability of DHA to stall progression during different cell cycle phases in cancer cells, as well as the consequences that these changes may have on tumour growth, independently and in conjunction with chemotherapy.

Stem cells as the root of pancreatic ductal adenocarcinoma

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

Balic, Anamaria; Dorado, Jorge; Alonso-Gomez, Mercedes

2012-04-01

Emerging evidence suggests that stem cells play a crucial role not only in the generation and maintenance of different tissues, but also in the development and progression of malignancies. For the many solid cancers, it has now been shown that they harbor a distinct subpopulation of cancer cells that bear stem cell features and therefore, these cells are termed cancer stem cells (CSC) or tumor-propagating cells. CSC are exclusively tumorigenic and essential drivers for tumor progression and metastasis. Moreover, it has been shown that pancreatic ductal adenocarcinoma does not only contain one homogeneous population of CSC rather than diverse subpopulationsmore » that may have evolved during tumor progression. One of these populations is called migrating CSC and can be characterized by CXCR4 co-expression. Only these cells are capable of evading the primary tumor and traveling to distant sites such as the liver as the preferred site of metastatic spread. Clinically even more important, however, is the observation that CSC are highly resistant to chemo- and radiotherapy resulting in their relative enrichment during treatment and rapid relapse of disease. Many laboratories are now working on the further in-depth characterization of these cells, which may eventually allow for the identification of their Achilles heal and lead to novel treatment modalities for fighting this deadly disease.« less

A Boolean Network Model of Nuclear Receptor Mediated Cell Cycle Progression

EPA Science Inventory

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad range of cellular processes. Hormones, lipids and xenobiotics have been shown to activate NRs with a range of consequences on development, metabolism, oxidative stress, apoptosis, and prolif...

A Boolean Network Model of Nuclear Receptor Mediated Cell Cycle Progression (S)

EPA Science Inventory

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad range of cellular processes. Hormones, lipids and xenobiotics have been shown to activate NRs with a range of consequences on development, metabolism, oxidative stress, apoptosis, and prolif...

Early Lung Cancer Detection via Global Protein Modification Profiles

DTIC Science & Technology

2013-12-01

Increased DNMT1 protein expression has also been shown to play a critical role in the malignant progression of hepatocellular carcinoma (HCC) and be a...the Malignant Potential and Poor Prognosis of Human Hepatocellular Carcinomas , Int. J. Cancer, 105:527-532.

Ultrasound screening of periarticular soft tissue abnormality around metal-on-metal bearings.

PubMed

Nishii, Takashi; Sakai, Takashi; Takao, Masaki; Yoshikawa, Hideki; Sugano, Nobuhiko

2012-06-01

Although metal hypersensitivity or pseudotumors are concerns for metal-on-metal (MoM) bearings, detailed pathologies of patterns, severity, and incidence of periprosthetic soft tissue lesions are incompletely understood. We examined the potential of ultrasound for screening of periarticular soft tissue lesions around MoM bearings. Ultrasound examinations were conducted in 88 hips (79 patients) with MoM hip resurfacings or MoM total hip arthroplasties with a large femoral head. Four qualitative ultrasound patterns were shown, including normal pattern in 69 hips, joint-expansion pattern in 11 hips, cystic pattern in 5 hips, and mass pattern in 3 hips. Hips with the latter 3 abnormal patterns showed significantly higher frequency of clinical symptoms, without significant differences of sex, duration of implantation, head sizes, and cup abduction/anteversion angles, compared with hips with normal pattern. Ultrasound examination provides sensitive screening of soft tissue reactions around MoM bearings and may be useful in monitoring progression and defining treatment for periarticular soft tissue abnormalities. Copyright © 2012 Elsevier Inc. All rights reserved.

RGC32 induces epithelial-mesenchymal transition by activating the Smad/Sip1 signaling pathway in CRC.

PubMed

Wang, Xiao-Yan; Li, Sheng-Nan; Zhu, Hui-Fang; Hu, Zhi-Yan; Zhong, Yan; Gu, Chuan-Sha; Chen, Shi-You; Liu, Teng-Fei; Li, Zu-Guo

2017-05-04

Response gene to complement 32 (RGC32) is a transcription factor that regulates the expression of multiple genes involved in cell growth, viability and tissue-specific differentiation. However, the role of RGC32 in tumorigenesis and tumor progression in colorectal cancer (CRC) has not been fully elucidated. Here, we showed that the expression of RGC32 was significantly up-regulated in human CRC tissues versus adjacent normal tissues. RGC32 expression was significantly correlated with invasive and aggressive characteristics of tumor cells, as well as poor survival of CRC patients. We also demonstrated that RGC32 overexpression promoted proliferation, migration and tumorigenic growth of human CRC cells in vitro and in vivo. Functionally, RGC32 facilitated epithelial-mesenchymal transition (EMT) in CRC via the Smad/Sip1 signaling pathway, as shown by decreasing E-cadherin expression and increasing vimentin expression. In conclusion, our findings suggested that overexpression of RGC32 facilitates EMT of CRC cells by activating Smad/Sip1 signaling.

“Wine-Dark Sea” in an Organic Flow Battery: Storing Negative Charge in 2,1,3-Benzothiadiazole Radicals Leads to Improved Cyclability

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

Duan, Wentao; Huang, Jinhua; Kowalski, Jeffrey A.

Redox-active organic materials (ROMs) have shown great promise for redox flow battery applications but generally encounter limited cycling efficiency and stability at relevant redox material concentrations in nonaqueous systems. Here we report a new heterocyclic organic anolyte molecule, 2,1,3-benzothiadiazole, that has high solubility, a low redox potential, and fast electrochemical kinetics. Coupling it with a benchmark catholyte ROM, the nonaqueous organic flow battery demonstrated significant improvement in cyclable redox material concentrations and cell efficiencies compared to the state-of-the-art nonaqueous systems. Especially, this system produced exceeding cyclability with relatively stable efficiencies and capacities at high ROM concentrations (>0.5 M), which ismore » ascribed to the highly delocalized charge densities in the radical anions of 2,1,3-benzothiadiazole, leading to good chemical stability. As a result, this material development represents significant progress toward promising next-generation energy storage.« less

Impact of conventional fractionated RT to pelvic lymph nodes and dose-escalated hypofractionated RT to prostate gland using IMRT treatment delivery in high-risk prostate cancer

NASA Astrophysics Data System (ADS)

Pervez, Nadeem

Prostate cancer is the most common cancer among Canadian men. The standard treatment in high-risk category is radical radiation, with androgen suppression treatment (AST). Significant disease progression is reported despite this approach. Radiation dose escalation has been shown to improve disease-free survival; however, it results in higher toxicities. Hypofractionated radiation schedules (larger dose each fraction in shorter overall treatment time) are expected to deliver higher biological doses. A hypofractionated scheme was used in this study to escalate radiation doses with AST. Treatment was well tolerated acutely. Early results of self-administered quality of life reported by patients shows a decrease in QOL which is comparable to other treatment schedules. Significant positional variation of the prostate was observed during treatment. Therefore, we suggest daily target verification to avoid a target miss. Initial late effects are reasonable and early treatment outcomes are promising. Longer follow-up is required for full outcomes assessments.

African swine fever virus serotype-specific proteins are significant protective antigens for African swine fever.

PubMed

Burmakina, G; Malogolovkin, A; Tulman, E R; Zsak, L; Delhon, G; Diel, D G; Shobogorov, N M; Morgunov, Yu P; Morgunov, S Yu; Kutish, G F; Kolbasov, D; Rock, D L

2016-07-01

African swine fever (ASF) is an emerging disease threat for the swine industry worldwide. No ASF vaccine is available and progress is hindered by lack of knowledge concerning the extent of ASFV strain diversity and the viral antigens conferring type-specific protective immunity in pigs. Available data from vaccination/challenge experiments in pigs indicate that ASF protective immunity may be haemadsorption inhibition (HAI) serotype-specific. Recently, we have shown that two ASFV proteins, CD2v (EP402R) and C-type lectin (EP153R), are necessary and sufficient for mediating HAI serological specificity (Malogolovkin et al., 2015).. Here, using ASFV inter-serotypic chimeric viruses and vaccination/challenge experiments in pigs, we demonstrate that serotype-specific CD2v and/or C-type lectin proteins are important for protection against homologous ASFV infection. Thus, these viral proteins represent significant protective antigens for ASFV that should be targeted in future vaccine design and development. Additionally, these data support the concept of HAI serotype-specific protective immunity.

Progress in Desensitization of the Highly HLA Sensitized Patient.

PubMed

Jordan, S C; Choi, J; Kahwaji, J; Vo, A

2016-04-01

The presence of HLA antibodies remains a significant and often impenetrable barrier to kidney transplantation, leading to increased morbidity and mortality for patients remaining on long-term dialysis. In recent years, a number of new approaches have been developed to overcome these barriers. Intravenous immunoglobulin (IVIG) remains the lynchpin of HLA desensitization therapy and has been shown in a prospective, randomized, placebo-controlled trial to improve transplantation rates. In addition, IVIG used in low doses with plasma exchange is a reliable protocol for desensitization. Another significant advancement was the addition of rituximab (anti-B-cell therapy) to IVIG and plasma exchange-based desensitization. This approach has significantly improved rates of transplantation and outcomes. There is limited experience with bortezomib (anti-plasma cell therapy) and eculizumab (complement inhibition) for desensitization. However, recent data from a completed trial of eculizumab failed to show a significant benefit for prevention of antibody-mediated rejection compared with standard therapy plus placebo, and bortezomib produced inconsistent results. There is a growing interest in developing new therapeutic agents for desensitization. Newer approaches that address antibody reduction with B-cell depletion are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy.

PubMed

Qu, Xiao; Wu, Zhinan; Dong, Wei; Zhang, Tiehong; Wang, Liguang; Pang, Zhaofei; Ma, Wei; Du, Jiajun

2017-04-25

Prognostic studies of insulin-like growth factor-1 receptor(IGF-1R) inhibitors in cancer therapy had promising results in infratests, which exhibited that IGF-1R signalling was crucial in cancer cells growth. However, the conclusion of later clinical trials revealed a dim future for IGF-1R inhibitors to treat cancer. We conducted this analysis to figure out how IGF-1R inhibitors acted in clinical cancer therapy. We searched up-to-date studies about the single agent of IGF-1R inhibitors or combination with other therapies in solid tumor. Five IGF-1R anti-agents were involved. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS). 17studies were enrolled. The results was not significant in overall survival (I2=37.1%, P=0.080, HR=1.08, 95% CI=0.97-1.21) and in progression-free survival (I2=0.0%, P=0.637, HR=1.05, 95% CI=0.98-1.12). OS for dalotuzumab, breast cancer, colorectal cancer, and PFS for prostate cancer even indicated harmful effects. So far, anti-IGF-1R mono-antibodies did not make significant differences in solid tumor prognosis. On the contrary, pessimistic effects were shown in the dalotuzumab, breast cancer, colorectal cancer and prostate cancer subgroups. Further studies of IGF-1R anti-agents were needed, but unwarranted in unselected patients by predictive biomarkers.

The effect of cigarette smoking on human seminal parameters, sperm chromatin structure and condensation.

PubMed

Mostafa, R M; Nasrallah, Y S; Hassan, M M; Farrag, A F; Majzoub, A; Agarwal, A

2018-04-01

Considerable debate still exists regarding the effects of cigarette smoking on male fertility. This work aimed to explore effects of cigarette smoking on semen parameters and DNA fragmentation on 95 infertile patients who were divided into infertile male nonsmokers (45) and infertile male smokers (50). Smokers were subdivided according to a number of cigarettes smoked per day into mild (≤10), moderate (11-20) and heavy smokers (≥21). Semen analysis, sperm chromatin condensation integrity with aniline blue staining and sperm viability were compared between the study groups. A significant decrease has been shown in sperm count (p = .006), progressive motility (p = <.001), percentage of normal forms (p = <.001) and viability (p = .002) between infertile nonsmoker and infertile smokers. The percentage of abnormal sperm chromatin condensation was significantly higher in smokers compared to nonsmokers (p = <.001). A linear correlation was detected between the extent of cigarette smoking and the degree of worsening in progressive motility (p = .001), total motility (p < .001), viability (p < .001) and normal morphology (p < .001). These results indicate that cigarette smoking has detrimental effects on semen parameters. It negatively affected all conventional semen parameters in addition to sperm chromatin condensation and sperm viability. These abnormalities were also proportional to the number of cigarettes smoked per day and to the duration of smoking. © 2017 Blackwell Verlag GmbH.

Extracellular matrix composition and rigidity regulate invasive behavior and response to PDT in 3D pancreatic tumor models

NASA Astrophysics Data System (ADS)

Cramer, Gwendolyn; El-Hamidi, Hamid; Jafari, Seyedehrojin; Jones, Dustin P.; Celli, Jonathan P.

2016-03-01

The composition and mechanical compliance of the extracellular matrix (ECM) have been shown to serve as regulators of tumor growth and invasive behavior. These effects may be particularly relevant in tumors of the pancreas, noted for a profound desmoplastic reaction and an abundance of stroma rich in ECM. In view of recent progress in the clinical implementation of photodynamic therapy (PDT) for pancreatic tumors, in this report we examine how ECM composition and rheological properties impact upon invasive behavior and response to PDT in 3D multicellular pancreatic tumor spheroids in ECM environments with characterized rheological properties. Tumor spheroids were cultured initially in attachment-free conditions to form millimeter-sized spheroids that were transplanted into reconstituted ECM microenvironments (Matrigel and Type I Collagen) that were characterized using bulk oscillatory shear rheology. Analysis of growth behavior shows that the soft collagen ECM promoted growth and extensive invasion and this microenvironment was used in subsequent assessment of PDT and chemotherapy response. Evaluation of treatment response revealed that primary tumor nodule growth is inhibited more effectively with PDT, while verteporfin PDT response is significantly enhanced in the ECM-infiltrating populations that are non-responsive to oxaliplatin chemotherapy. This finding is potentially significant, suggesting the potential for PDT to target these clinically problematic invasive populations that are associated with aggressive metastatic progression and chemoresistance. Experiments to further validate and identify the mechanistic basis of this observation are ongoing.

Impact of induction treatment before autologous stem cell transplantation on long-term outcome in patients with newly diagnosed multiple myeloma.

PubMed

Gassiot, Susanna; Motlló, Cristina; Llombart, Inuska; Morgades, Mireia; González, Yolanda; Garcia-Caro, Montse; Ribera, Josep-Maria; Oriol, Albert

2017-06-01

Clinical trials for patients with multiple myeloma (MM) using novel agent (NA)-based regimens before autologous stem cell transplantation (SCT) have shown improvement in response rates and progression-free survival (PFS); however they have failed to identify a significant overall survival (OS) benefit. The aim of this study was to analyze the potential impact of initial induction on the feasibility and outcome of subsequent treatment lines in a real clinical practice setting. Patients with consecutive MM <70 years of age diagnosed between 1999 and 2009 were prospectively registered and classified as having received conventional chemotherapy induction regimens with new agents available at relapse (CC cohort, 89 patients) or as treated with NAs upfront (NA cohort, 65 patients). Patients in the NA cohort demonstrated a superior median PFS (2.8 years vs 1.6 years, P=.03) and also a median PFS from diagnosis to second progression (5.2 years vs 2.7 years, P=.003). After a median follow-up of 7 years, clear differences in OS were observed (7.97 years in NA cohort compared to 3.35 years in CC cohort, P<.001). New agent-based first-line induction treatments provide benefits in both PFS and beyond that point, contributing to a significant improvement in OS. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cellular regeneration strategies for macular degeneration: past, present and future.

PubMed

Chichagova, Valeria; Hallam, Dean; Collin, Joseph; Zerti, Darin; Dorgau, Birthe; Felemban, Majed; Lako, Majlinda; Steel, David H

2018-05-01

Despite considerable effort and significant therapeutic advances, age-related macular degeneration (AMD) remains the commonest cause of blindness in the developed world. Progressive late-stage AMD with outer retinal degeneration currently has no proven treatment. There has been significant interest in the possibility that cellular treatments may slow or reverse visual loss in AMD. A number of modes of action have been suggested, including cell replacement and rescue, as well as immune modulation to delay the neurodegenerative process. Their appeal in this enigmatic disease relate to their generic, non-pathway-specific effects. The outer retina in particular has been at the forefront of developments in cellular regenerative therapies being surgically accessible, easily observable, as well as having a relatively simple architecture. Both the retinal pigment epithelium (RPE) and photoreceptors have been considered for replacement therapies as both sheets and cell suspensions. Studies using autologous RPE, and to a lesser extent, foetal retina, have shown proof of principle. A wide variety of cell sources have been proposed with pluripotent stem cell-derived cells currently holding the centre stage. Recent early-phase trials using these cells for RPE replacement have met safety endpoints and hinted at possible efficacy. Animal studies have confirmed the promise that photoreceptor replacement, even in a completely degenerated outer retina may restore some vision. Many challenges, however, remain, not least of which include avoiding immune rejection, ensuring long-term cellular survival and maximising effect. This review provides an overview of progress made, ongoing studies and challenges ahead.

Effective Skin Cancer Treatment by Topical Co-delivery of Curcumin and STAT3 siRNA Using Cationic Liposomes.

PubMed

Jose, Anup; Labala, Suman; Ninave, Kunal Manoj; Gade, Sudeep Kumar; Venuganti, Venkata Vamsi Krishna

2018-01-01

The aim of the present study was to evaluate the effectiveness of iontophoretic co-delivery of curcumin and anti-STAT3 siRNA using cationic liposomes against skin cancer. Curcumin was encapsulated in DOTAP-based cationic liposomes and then complexed with STAT3 siRNA. This nanocomplex was characterized for the average particle size, zeta-potential, and encapsulation efficiency. The cell viability studies in B16F10 mouse melanoma cells have shown that the co-delivery of curcumin and STAT3 siRNA significantly (p < 0.05) inhibited the cancer cell growth compared with either liposomal curcumin or STAT3 siRNA alone. The curcumin-loaded liposomes were able to penetrate up to a depth of 160 μm inside the skin after iontophoretic (0.47 mA/cm 2 ) application. The in vivo efficacy studies were performed in the mouse model of melanoma skin cancer. Co-administration of the curcumin and STAT3 siRNA using liposomes significantly (p < 0.05) inhibited the tumor progression as measured by tumor volume and tumor weight compared with either liposomal curcumin or STAT3 siRNA alone. Furthermore, the iontophoretic administration of curcumin-loaded liposome-siRNA complex showed similar effectiveness in inhibiting tumor progression and STAT3 protein suppression compared with intratumoral administration. Taken together, cationic liposomes can be utilized for topical iontophoretic co-delivery of small molecule and siRNA for effective treatment of skin diseases.

Cancer-related anorexia/cachexia syndrome and oxidative stress: an innovative approach beyond current treatment.

PubMed

Mantovani, Giovanni; Madeddu, Clelia; Macciò, Antonio; Gramignano, Giulia; Lusso, Maria Rita; Massa, Elena; Astara, Giorgio; Serpe, Roberto

2004-10-01

Cancer-related anorexia/cachexia syndrome and oxidative stress play a key role in the progression and outcome of neoplastic disease. On the basis of our previously published studies and clinical experience, we have developed an innovative approach consisting of diet with high polyphenol content (400 mg), p.o. pharmaconutritional support enriched with n - 3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) 2 cans (237 mL each) per day, medroxiprogesterone acetate 500 mg/d, antioxidant treatment with alpha-lipoic acid 300 mg/d plus carbocysteine lysine salt 2.7 g/d plus vitamin E 400 mg/d plus vitamin A 30,000 IU/d plus vitamin C 500 mg/d, and selective cyclooxygenase-2 inhibitor Celecoxib 200 mg/d. The treatment is administered for 16 weeks. The following variables are evaluated: (a) clinical variables (stage and Eastern Cooperative Oncology Group performance status); (b) nutritional variables (lean body mass, appetite, and resting energy expenditure); (c) laboratory variables (serum levels of proinflammatory cytokines, C-reactive protein, and leptin and blood levels of reactive oxygen species and antioxidant enzymes); and (d) quality of life variables (European Organization for Research and Treatment of Cancer QLQ-C30, EQ-5Dindex, and EQ-5DVAS). A phase II nonrandomized study has been designed to enroll 40 patients with advanced cancer at different sites with symptoms of cancer-related anorexia/cachexia syndrome and oxidative stress. As of January 2004, 28 patients have been enrolled: 25 patients were evaluable and 14 of them have completed the treatment (20 patients have completed 2 months of treatment). As for clinical response, five patients improved, three patients remained unchanged, and six patients worsened. The Eastern Cooperative Oncology Group performance status (grade) 1 remained unchanged. As for nutritional/functional variables, the lean body mass increased significantly at 2 and 4 months. As for laboratory variables, reactive oxygen species decreased significantly and proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha decreased significantly. As for quality of life, it comprehensively improved after treatment. The treatment has been shown to be effective for clinical response, increase of lean body mass, decrease of reactive oxygen species and proinflammatory cytokines, and improvement of quality of life. The treatment has been shown to be safe with good compliance of patients. The study is in progress (14 further patients will be included).

Different patterns of longitudinal brain and spinal cord changes and their associations with disability progression in NMO and MS.

PubMed

Liu, Yaou; Duan, Yunyun; Huang, Jing; Ren, Zhuoqiong; Liu, Zheng; Dong, Huiqing; Weiler, Florian; Hahn, Horst K; Shi, Fu-Dong; Butzkueven, Helmut; Barkhof, Frederik; Li, Kuncheng

2018-01-01

To investigate the longitudinal spinal cord and brain changes in neuromyelitis optica (NMO) and multiple sclerosis (MS) and their associations with disability progression. We recruited 28 NMO, 22 MS, and 20 healthy controls (HC), who underwent both spinal cord and brain MRI at baseline. Twenty-five NMO and 20 MS completed 1-year follow-up. Baseline spinal cord and brain lesion loads, mean upper cervical cord area (MUCCA), brain, and thalamus volume and their changes during a 1-year follow-up were measured and compared between groups. All the measurements were also compared between progressive and non-progressive groups in NMO and MS. MUCCA decreased significantly during the 1-year follow-up in NMO not in MS. Percentage brain volume changes (PBVC) and thalamus volume changes in MS were significantly higher than NMO. MUCCA changes were significantly different between progressive and non-progressive groups in NMO, while baseline brain lesion volume and PBVC were associated with disability progression in MS. MUCCA changes during 1-year follow-up showed association with clinical disability in NMO. Spinal cord atrophy changes were associated with disability progression in NMO, while baseline brain lesion load and whole brain atrophy changes were related to disability progression in MS. • Spinal cord atrophy progression was observed in NMO. • Spinal cord atrophy changes were associated with disability progression in NMO. • Brain lesion and atrophy were related to disability progression in MS.

Control landscapes are almost always trap free: a geometric assessment

NASA Astrophysics Data System (ADS)

Russell, Benjamin; Rabitz, Herschel; Wu, Re-Bing

2017-05-01

A proof is presented that almost all closed, finite dimensional quantum systems have trap free (i.e. free from local optima) landscapes for a large and physically general class of circumstances, which includes qubit evolutions in quantum computing. This result offers an explanation for why gradient-based methods succeed so frequently in quantum control. The role of singular controls is analyzed using geometric tools in the case of the control of the propagator, and thus in the case of observables as well. Singular controls have been implicated as a source of landscape traps. The conditions under which singular controls can introduce traps, and thus interrupt the progress of a control optimization, are discussed and a geometrical characterization of the issue is presented. It is shown that a control being singular is not sufficient to cause control optimization progress to halt, and sufficient conditions for a trap free landscape are presented. It is further shown that the local surjectivity (full rank) assumption of landscape analysis can be refined to the condition that the end-point map is transverse to each of the level sets of the fidelity function. This mild condition is shown to be sufficient for a quantum system’s landscape to be trap free. The control landscape is shown to be trap free for all but a null set of Hamiltonians using a geometric technique based on the parametric transversality theorem. Numerical evidence confirming this analysis is also presented. This new result is the analogue of the work of Altifini, wherein it was shown that controllability holds for all but a null set of quantum systems in the dipole approximation. These collective results indicate that the availability of adequate control resources remains the most physically relevant issue for achieving high fidelity control performance while also avoiding landscape traps.

Progression from Mild Cognitive Impairment to Alzheimer's disease: effects of gender, butyrylcholinesterase genotype and rivastigmine treatment

PubMed Central

Ferris, Steven; Nordberg, Agneta; Soininen, Hilkka; Darreh-Shori, Taher; Lane, Roger

2014-01-01

Objective Evaluate the influence of gender and butyrylcholinesterase (BuChE) genotype on incidence of progression to AD, rate of cognitive and functional decline, and response to rivastigmine treatment in mild cognitive impairment (MCI) subjects. Methods This retrospective exploratory analysis from a 3–4 year, randomized, placebo-controlled study of rivastigmine in MCI subjects included participants who consented to pharmacogenetic testing. Results Of 1018 total patients, 490 (253 [52%] female) were successfully genotyped for BuChE. In subjects receiving placebo, the BuChE wt/wt genotype was associated with a statistically significantly higher rate of progression to AD and functional decline in women, compared with men with the BuChE wt/wt genotype. In subjects with a BuChE-K allele receiving placebo, incidence of progression to AD and rate of functional decline were not significantly different by gender, however cognitive decline was significantly faster in men. Statistically significant benefits of rivastigmine treatment on progression to AD, functional decline, ventricular volume expansion, whole brain atrophy and white matter loss were evident in female BuChE wt/wt. Conclusion Gender appears to differentially influence the type of decline in MCI subjects according to BuChE genotype, with more rapid progression of cognitive decline in male BuChE-K, and more rapid progression to AD and functional decline in female BuChE wt/wt. Cognitive decline in male BuChE-K and functional decline and progression to AD in female BuChE wt/wt were significantly attenuated by rivastigmine. Rivastigmine treatment also significantly reduced ventricular expansion, whole brain atrophy rate and white matter loss in female BuChE wt/wt, suggesting a possible disease-modifying effect. PMID:19617863

Education, Technical Progress, and Economic Growth: The Case of Taiwan.

ERIC Educational Resources Information Center

Lin, T.-C.

2003-01-01

Investigates the effect of education and the role of technical progress on economic growth in Taiwan from 1965-2000. Finds that education has a positive and significant effect on growth, but the role of technical progress does not appear to be extraordinarily important. Furthermore, no markedly significant relationships exist between capital and…

The Role of Endoplasmic Reticulum Stress in Diabetic Nephropathy.

PubMed

Fan, Ying; Lee, Kyung; Wang, Niansong; He, John Cijiang

2017-03-01

Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease (ESRD) worldwide. Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a major role in the development and progression of DN. Recent findings suggested that many attributes of DN, such as hyperglycemia, proteinuria, and increased advanced glycation end products and free fatty acids, can all trigger unfolded protein response (UPR) in kidney cells. Herein, we review the current knowledge on the role of ER stress in the setting of kidney injury with a specific emphasis on DN. As maladaptive ER stress response caused by excessively prolonged UPR will eventually cause cell death and increase kidney injury, several ER stress inhibitors have been shown to improve DN in animal models, albeit blocking both adaptive and maladaptive UPR. More recently, reticulon-1A (RTN1A), an ER-associated protein, was shown to be increased in both human and mouse diabetic kidneys. Its expression correlates with the progression of DN, and its polymorphisms are associated with kidney disease in people with diabetes. Increased RTN1A expression heightened the ER stress response and renal cell apoptosis, and conversely reduced RTN1A in renal cells decreased apoptosis and ameliorated kidney injury and DN progression, suggesting that RTN1A may be a novel target to specifically restrain the maladaptive UPR. These findings suggest that ER stress response in renal cells is a key driver of progression of DN and that the inhibition of the unchecked ER stress response in DN, such as by inhibition of RTN1A function, may be a promising therapeutic approach against DN.

Characterization and Modulation of Proteins Involved in SM Vesication

DTIC Science & Technology

2005-05-01

shown to be the major etiological factor leading to the precancerous stage of actinic keratosis (AK) and to induction and progression of skin cancers...representing a transient regression-prone precancerous stage equivalent to actinic keratosis . To further examine which caspases are apical and

Intra-articular Implantation of Mesenchymal Stem Cells, Part 2

PubMed Central

Kraeutler, Matthew J.; Mitchell, Justin J.; Chahla, Jorge; McCarty, Eric C.; Pascual-Garrido, Cecilia

2017-01-01

Knee osteoarthritis (OA) after partial or total meniscectomy is a prevalent issue that patients must face. Various methods of replacing meniscal tissue have been studied to avoid this progression, including meniscal allograft transplantation, meniscal scaffolds, and synthetic meniscus replacement. Studies have shown that meniscal scaffolds may improve symptoms but have not been shown to prevent progression of OA. Recently, mesenchymal stem cells (MSCs) have been proposed as a possible biological therapy for meniscal regeneration. Several animal studies and 1 human study have evaluated the effect of transplanting MSCs into the knee joint after partial meniscectomy. The purpose of this review was to assess the outcomes of intra-articular transplantation of MSCs on meniscal regeneration in animals and humans after partial meniscectomy. Limited results from animal studies suggest that there is some potential for intra-articular injection of MSCs for the regeneration of meniscal tissue. However, further studies are necessary to determine the quality of regenerated meniscal tissue through histological and biomechanical testing. PMID:28203596

Two faces of Hippo: activate or suppress the Hippo pathway in cancer.

PubMed

Cao, Jingwen; Huang, Wenlong

2017-11-01

The Hippo pathway has generated considerable interest in recent years because of its involvement in several key hallmarks of cancer progression and metastasis. Research on the Hippo signaling pathway in cancer has been used to determine the activity of yes-associated protein (YAP) in tumorigenesis and disease progression. Previous studies have shown that the Hippo pathway can be used as a target to inhibit YAP activity and is a viable treatment for cancer. However, more studies are required to further advance our understanding of the Hippo signaling pathway in cancer. It has been shown that knockout of serine/threonine-kinases LATS1/2 in the Hippo pathway suppresses cancer immunity in mice. In addition, suppression of the oncogene YAP could contribute toward cancer immune therapy. Therefore, regulation of Hippo signaling can be an attractive alternative strategy for cancer treatment. This review will provide a summary of currently known compounds that activate or suppress the Hippo pathway.

The morality of attitudes toward nanotechnology: about God, techno-scientific progress, and interfering with nature

NASA Astrophysics Data System (ADS)

Vandermoere, Frederic; Blanchemanche, Sandrine; Bieberstein, Andrea; Marette, Stephan; Roosen, Jutta

2010-02-01

Using survey data, we examine public attitudes toward and awareness of nanotechnology in Germany ( N = 750). First, it is shown that a majority of the people are still not familiar with nanotechnology. In addition, diffusion of information about nanotechnology thus far mostly seems to reach men and people with a relative higher educational background. Also, pro-science and technology views are positively related with nanotech familiarity. Results further show that a majority of the people have an indifferent, ambiguous, or non-attitude toward nanotechnology. Multinomial logit analyses further reveal that nanotech familiarity is positively related with people's attitudes. In addition, it is shown that traditional religiosity is unrelated to attitudes and that individual religiosity is weakly related to nanotechnology attitudes. However, moral covariates other than religiosity seem of major importance. In particular, our results show that more negative views on technological and scientific progress as well as more holistic views about the relation between people and the environment increase the likelihood of having a negative attitude toward nanotechnology.

ATXN2 with intermediate-length CAG/CAA repeats does not seem to be a risk factor in hereditary spastic paraplegia.

PubMed

Nielsen, Troels Tolstrup; Svenstrup, Kirsten; Budtz-Jørgensen, Esben; Eiberg, Hans; Hasholt, Lis; Nielsen, Jørgen E

2012-10-15

Hereditary spastic paraplegia (HSP) confines a group of heterogeneous neurodegenerative disorders characterized by progressive spasticity and lower limb weakness. Age of onset is highly variable even in familial cases with known mutations suggesting that the disease is modulated by other yet unknown parameters. Although progressive gait disturbances, lower limb spasticity and extensor plantar responses are hallmarks of HSP these characteristics are also found in other neurodegenerative disorders, e.g. amytrophic lateral sclerosis (ALS). HSP has been linked to ALS and frontotemporal degeneration with motor neuron disease (FTD-MND), since TDP-43 positive inclusions have recently been found in an HSP subtype, and TDP-43 are found in abundance in pathological inclusions of both ALS and FTD-MND. Furthermore, ataxin-2 (encoded by the gene ATXN2), a polyglutamine containing protein elongated in spinocerebellar ataxia type 2, has been shown to be a modulator of TDP-43 induced toxicity in ALS animal and cell models. Finally, it has been shown that ATXN2 with non-pathogenic intermediate-length CAG/CAA repeat elongations (encoding the polyglutamine tract) is a genetic risk factor of ALS. Considering the similarities in the disease phenotype and the neuropathological link between ALS and HSP we hypothesized that intermediate-length CAG/CAA repeats in ATXN2 could be a modulator of HSP. We show that in a cohort of 181 HSP patients 4.9 % of the patients had intermediate-length CAG/CAA repeats in ATXN2 which was not significantly different from the frequencies in a Danish control cohort or in American and European control populations. However, the mean age of onset was significantly lower in HSP patients with intermediate-length CAG/CAA repeats in ATXN2 compared to patients with normal length repeats. Based on these results we conclude that ATXN2 is most likely not a risk factor of HSP, whereas it might serve as a modulator of age of onset. Copyright © 2012 Elsevier B.V. All rights reserved.

A Study of the Effects of Electrode Number and Decoding Algorithm on Online EEG-Based BCI Behavioral Performance

PubMed Central

Meng, Jianjun; Edelman, Bradley J.; Olsoe, Jaron; Jacobs, Gabriel; Zhang, Shuying; Beyko, Angeliki; He, Bin

2018-01-01

Motor imagery–based brain–computer interface (BCI) using electroencephalography (EEG) has demonstrated promising applications by directly decoding users' movement related mental intention. The selection of control signals, e.g., the channel configuration and decoding algorithm, plays a vital role in the online performance and progressing of BCI control. While several offline analyses report the effect of these factors on BCI accuracy for a single session—performance increases asymptotically by increasing the number of channels, saturates, and then decreases—no online study, to the best of our knowledge, has yet been performed to compare for a single session or across training. The purpose of the current study is to assess, in a group of forty-five subjects, the effect of channel number and decoding method on the progression of BCI performance across multiple training sessions and the corresponding neurophysiological changes. The 45 subjects were divided into three groups using Laplacian Filtering (LAP/S) with nine channels, Common Spatial Pattern (CSP/L) with 40 channels and CSP (CSP/S) with nine channels for online decoding. At the first training session, subjects using CSP/L displayed no significant difference compared to CSP/S but a higher average BCI performance over those using LAP/S. Despite the average performance when using the LAP/S method was initially lower, but LAP/S displayed improvement over first three sessions, whereas the other two groups did not. Additionally, analysis of the recorded EEG during BCI control indicates that the LAP/S produces control signals that are more strongly correlated with the target location and a higher R-square value was shown at the fifth session. In the present study, we found that subjects' average online BCI performance using a large EEG montage does not show significantly better performance after the first session than a smaller montage comprised of a common subset of these electrodes. The LAP/S method with a small EEG montage allowed the subjects to improve their skills across sessions, but no improvement was shown for the CSP method. PMID:29681792

A Study of the Effects of Electrode Number and Decoding Algorithm on Online EEG-Based BCI Behavioral Performance.

PubMed

Meng, Jianjun; Edelman, Bradley J; Olsoe, Jaron; Jacobs, Gabriel; Zhang, Shuying; Beyko, Angeliki; He, Bin

2018-01-01

Motor imagery-based brain-computer interface (BCI) using electroencephalography (EEG) has demonstrated promising applications by directly decoding users' movement related mental intention. The selection of control signals, e.g., the channel configuration and decoding algorithm, plays a vital role in the online performance and progressing of BCI control. While several offline analyses report the effect of these factors on BCI accuracy for a single session-performance increases asymptotically by increasing the number of channels, saturates, and then decreases-no online study, to the best of our knowledge, has yet been performed to compare for a single session or across training. The purpose of the current study is to assess, in a group of forty-five subjects, the effect of channel number and decoding method on the progression of BCI performance across multiple training sessions and the corresponding neurophysiological changes. The 45 subjects were divided into three groups using Laplacian Filtering (LAP/S) with nine channels, Common Spatial Pattern (CSP/L) with 40 channels and CSP (CSP/S) with nine channels for online decoding. At the first training session, subjects using CSP/L displayed no significant difference compared to CSP/S but a higher average BCI performance over those using LAP/S. Despite the average performance when using the LAP/S method was initially lower, but LAP/S displayed improvement over first three sessions, whereas the other two groups did not. Additionally, analysis of the recorded EEG during BCI control indicates that the LAP/S produces control signals that are more strongly correlated with the target location and a higher R-square value was shown at the fifth session. In the present study, we found that subjects' average online BCI performance using a large EEG montage does not show significantly better performance after the first session than a smaller montage comprised of a common subset of these electrodes. The LAP/S method with a small EEG montage allowed the subjects to improve their skills across sessions, but no improvement was shown for the CSP method.

Cytogenetic Response to Ionizing Radiation Exposure in Human Fibroblasts with Suppressed Expression of Non-DSB Repair Genes

NASA Technical Reports Server (NTRS)

Zhang, Ye; Rohde, Larry H.; Emami, Kamal; Hammond, Dianne; Mehta, Satish K.; Jeevarajan, Antony S.; Pierson, Duane L.; Wu, Honglu

2009-01-01

Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have shown that genes up-regulated by IR may play important roles in DNA damage repair, the relationship between the regulation of gene expression by IR, particularly genes not known for their roles in double-strand break (DSB) repair, and its impact on cytogenetic responses has not been well studied. The purpose of this study is to identify new roles of IR inducible genes in radiation-induced chromosome aberrations and micronuclei formation. In the study, the expression of 25 genes selected on the basis of their transcriptional changes in response to IR was individually knocked down by small interfering RNA in human fibroblast cells. Frequencies of micronuclei (MN) formation and chromosome aberrations were measured to determine the efficiency of cytogenetic repair, and the fraction of bi-nucleated cells in the MN analysis was used as a marker for cell cycle progression. In response to gamma radiation, the formation of MN was significantly increased by suppressed expression of five genes: Ku70 (DSB repair pathway), XPA (nucleotide excision repair pathway), RPA1 (mismatch repair pathway), RAD17 and RBBP8 (cell cycle control). Knocked-down expression of four genes (MRE11A, RAD51 in the DSB pathway, SESN1, and SUMO1) significantly inhibited cell cycle progression, possibly because of severe impairment of DNA damage repair. Moreover, decreased XPA, p21, or MLH1 expression resulted in both significantly enhanced cell cycle progression and increased yields of chromosome aberrations, indicating that these gene products modulate both cell cycle control and DNA damage repair. Nine of these eleven genes, whose knock-down expression affected cytogenetic repair, were up-regulated in cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulate IR-induced biological consequences. Furthermore, eight non-DBS repair genes showed involvement in regulating DSB repair, indicating that successful DSB repair requires both DSB repair mechanisms and non-DSB repair systems.

MicroRNA-211-5p suppresses tumour cell proliferation, invasion, migration and metastasis in triple-negative breast cancer by directly targeting SETBP1.

PubMed

Chen, Liang-Liang; Zhang, Zhou-Jing; Yi, Zhan-Bo; Li, Jian-Jun

2017-06-27

Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer in women globally. This subtype often has early and high recurrence rates, resulting in poor survival, partially due to lack of targeted therapies. To date, the detailed molecular mechanisms underlying TNBC progression are unclear. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyse the expression and function of a metastasis-associated miRNA named miR-211-5p in TNBC. MiRNA array analysis was performed to search for metastasis-associated miRNAs in TNBC. The miR-211-5p expression in tumour tissues, adjacent non-tumourous breast tissues of TNBC patients and cell lines were evaluated by real-time PCR. The protein expression levels were analysed by western blot, immunohistochemistry and in situ hybridisation. Luciferase reporter assays were employed to validate the target of miR-211-5p. The effect of miR-211-5p on TNBC progression was investigated in vitro and in vivo. MiR-211-5p was significantly downregulated in TNBC, and its expression level was associated with overall survival in TNBC. The expression of miR-211-5p suppressed TNBC cell proliferation, invasion, migration and metastasis in vitro and in vivo. Furthermore, SETBP1 was identified as a target of miR-211-5p. Through gain-of-function and loss-of-function studies, SETBP1 was shown to significantly affect colony and cell number in vitro. Enforced expression of miR-211-5p inhibited the expression of SETBP1 significantly and the restoration of SETBP1 expression reversed the inhibitory effects of miR-211-5p on TNBC cell proliferation and metastasis. These findings collectively demonstrate a tumour suppressor role of miR-211-5p in TNBC progression by targeting SETBP1, suggesting that miR-211-5p could serve as a potential prognostic biomarker and therapeutic target for TNBC.

Smart wearable body sensors for patient self-assessment and monitoring.

PubMed

Appelboom, Geoff; Camacho, Elvis; Abraham, Mickey E; Bruce, Samuel S; Dumont, Emmanuel Lp; Zacharia, Brad E; D'Amico, Randy; Slomian, Justin; Reginster, Jean Yves; Bruyère, Olivier; Connolly, E Sander

2014-01-01

Innovations in mobile and electronic healthcare are revolutionizing the involvement of both doctors and patients in the modern healthcare system by extending the capabilities of physiological monitoring devices. Despite significant progress within the monitoring device industry, the widespread integration of this technology into medical practice remains limited. The purpose of this review is to summarize the developments and clinical utility of smart wearable body sensors. We reviewed the literature for connected device, sensor, trackers, telemonitoring, wireless technology and real time home tracking devices and their application for clinicians. Smart wearable sensors are effective and reliable for preventative methods in many different facets of medicine such as, cardiopulmonary, vascular, endocrine, neurological function and rehabilitation medicine. These sensors have also been shown to be accurate and useful for perioperative monitoring and rehabilitation medicine. Although these devices have been shown to be accurate and have clinical utility, they continue to be underutilized in the healthcare industry. Incorporating smart wearable sensors into routine care of patients could augment physician-patient relationships, increase the autonomy and involvement of patients in regards to their healthcare and will provide for novel remote monitoring techniques which will revolutionize healthcare management and spending.

Blood-brain barrier and its function during inflammation and autoimmunity.

PubMed

Sonar, Sandip Ashok; Lal, Girdhari

2018-05-01

The blood-brain barrier (BBB) is an important physiologic barrier that separates CNS from soluble inflammatory mediators and effector immune cells from peripheral circulation. The optimum function of the BBB is necessary for the homeostasis, maintenance, and proper neuronal function. The clinical and experimental findings have shown that BBB dysfunction is an early hallmark of various neurologic disorders ranging from inflammatory autoimmune, neurodegenerative, and traumatic diseases to neuroinvasive infections. Significant progress has been made in the understanding of the regulation of BBB function under homeostatic and neuroinflammatory conditions. Several neurologic disease-modifying drugs have shown to improve the BBB function. However, they have a broad-acting immunomodulatory function and can increase the risk of life-threatening infections. The recent development of in vitro multicomponent 3-dimensional BBB models coupled with fluidics chamber as well as a cell-type specific reporter and knockout mice gave a new boost to our understanding of the dynamics of the BBB. In the review, we discuss the current understanding of BBB composition and recent findings that illustrate the critical regulatory elements of the BBB function under physiologic and inflammatory conditions, and also suggested the strategies to control BBB structure and function. ©2018 Society for Leukocyte Biology.

Emerging pharmaceutical therapies for COPD.

PubMed

Lakshmi, Sowmya P; Reddy, Aravind T; Reddy, Raju C

2017-01-01

COPD, for which cigarette smoking is the major risk factor, remains a worldwide burden. Current therapies provide only limited short-term benefit and fail to halt progression. A variety of potential therapeutic targets are currently being investigated, including COPD-related proinflammatory mediators and signaling pathways. Other investigational compounds target specific aspects or complications of COPD such as mucus hypersecretion and pulmonary hypertension. Although many candidate therapies have shown no significant effects, other emerging therapies have improved lung function, pulmonary hypertension, glucocorticoid sensitivity, and/or the frequency of exacerbations. Among these are compounds that inhibit the CXCR2 receptor, mitogen-activated protein kinase/Src kinase, myristoylated alanine-rich C kinase substrate, selectins, and the endothelin receptor. Activation of certain transcription factors may also be relevant, as a large retrospective cohort study of COPD patients with diabetes found that the peroxisome proliferator-activated receptor γ (PPARγ) agonists rosiglitazone and pioglitazone were associated with reduced COPD exacerbation rate. Notably, several therapies have shown efficacy only in identifiable subgroups of COPD patients, suggesting that subgroup identification may become more important in future treatment strategies. This review summarizes the status of emerging therapeutic pharmaceuticals for COPD and highlights those that appear most promising.

Altruism as hedonism: a social development perspective on the relationship of negative mood state and helping.

PubMed

Cialdini, R B; Kenrick, D T

1976-11-01

A study was conducted to provide a means for reconciliation of the conflicting data on the relationship of negative mood state to altruism. Whereas some studies have shown that negative mood leads to increases in altruistic action, others have shown the reverse. It was hypothesized that the inconsistency of these results was due to differences in the ages and consequent levels of socialization of the subjects employed in the earlier studies. In order to test the hypothesis, subjects from three age groups (6-8, 10-12, and 15-18 years old) were asked to think of either depressing or neutral events and were subsequently given the opportunity to be privately generous. Consistent with predictions from the negative state relief model of altruism, the youngest, least socialized subjects were somewhat less generous in the negative mood condition, but this relationship progressively reversed itself until in the oldest, most socialized group, the negative mood subjects were significantly more generous than neutral mood controls. The data were taken as support for a hedonistic conception of altruism that views adult benevolence as self-gratification. It is suggested that the reward character of benevolence derives from the socialization experience.

Increased expression of progesterone receptor membrane component 1 is associated with aggressive phenotype and poor prognosis in ER-positive and negative breast cancer.

PubMed

Ruan, Xiangyan; Zhang, Ying; Mueck, Alfred O; Willibald, Marina; Seeger, Harald; Fehm, Tanja; Brucker, Sara; Neubauer, Hans

2017-02-01

Expression of progesterone receptor membrane component 1 (PGRMC1) has been shown to be higher in breast cancer than normal tissue. We have previously shown that certain progestogens strongly stimulate proliferation of breast cancer cells overexpressing PGRMC1, and therefore hypothesize that PGRMC1 may play a critical role in breast cancer progression. Because little information is available if expression of PGRMC1 is also associated with worse prognosis for breast cancer patients, in this study we investigated the clinicopathologic significance of PGRMC1 expression in breast cancer tissue. Expression of PGRMC1 was analyzed by immunohistochemical staining of primary tumor tissues obtained from 69 breast cancer patients. A labeling score was developed, and results were correlated with tumor size, lymph node metastasis, and clinical outcome. Overexpression of PGRMC1 is correlating with larger tumor size and lymph node metastasis. Kaplan-Meier survival curves indicate that patients with PGRMC1 tumors have poorer disease-free and overall survival independent from the estrogen receptor status than breast cancer patients with PGRMC1 tumors. Our findings suggest that the expression of PGRMC1 might be useful for predicting prognosis in patients with breast cancer.

Research Thinking Development by Teaching Archaeoastronomy

NASA Astrophysics Data System (ADS)

Muglova, P. V.; Stoev, A. D.

2006-08-01

A model of research thinking development by teaching archaeoastronomy in specialized three-year extra-curriculum Astronomy programme and creation of favourable socio-educational surroundings is suggested. It is shown as a didactic system of conditions, influences and possibilities of answering specific hierarchic complex of personal needs in the 14 - 18 year age interval. Transformation of these needs in worldly values secures an active position of the students in the educational process and determines their personality development. It is also shown that the Archaeoastronomy School, as an educational environment, executes specific work of students' teaching, upbringing and progress as well as their inclusion in the real process of scientific research. Thus, they have the possibility of generating scientific ideas and obtaining results in the science archaeoastronomy. In consequence of this, their activity acquires social significance. Usages of this model of scientific school in the extra-curriculum Astronomy education reproduces norms and traditions of the real scientific research and directly relay subject content, cultural norms and values of archaeoastronomy in the educative process. Students' participation in archaeoastronomical expeditions, their competent work during the research of concrete archaeoastronomical objects create an investigation style of thinking and steady habits of scientific activity.

Obesity and heart failure.

PubMed

De Pergola, Giovanni; Nardecchia, Adele; Giagulli, Vito Angelo; Triggiani, Vincenzo; Guastamacchia, Edoardo; Minischetti, Manuela Castiglione; Silvestris, Franco

2013-03-01

Epidemiological studies have recently shown that obesity, and abdominal obesity in particular, is an independent risk factor for the development of heart failure (HF). Higher cardiac oxidative stress is the early stage of heart dysfunction due to obesity, and it is the result of insulin resistance, altered fatty acid and glucose metabolism, and impaired mitochondrial biogenesis. Extense myocyte hypertrophy and myocardial fibrosis are early microscopic changes in patients with HF, whereas circumferential strain during the left ventricular (LV) systole, LV increase in both chamber size and wall thickness (LV hypertrophy), and LV dilatation are the early macroscopic and functional alterations in obese developing heart failure. LV hypertrophy leads to diastolic dysfunction and subendocardial ischemia in obesity, and pericardial fat has been shown to be significantly associated with LV diastolic dysfunction. Evolving abnormalities of diastolic dysfunction may include progressive hypertrophy and systolic dysfunction, and various degrees of eccentric and/or concentric LV hypertrophy may be present with time. Once HF is established, overweight and obese have a better prognosis than do their lean counterparts with the same level of cardiovascular disease, and this phenomenon is called "obesity paradox". It is mainly due to lower muscle protein degradation, brain natriuretic peptide circulating levels and cardio-respiratory fitness than normal weight patients with HF.

Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions.

PubMed

Wang, Meining; Shen, Aijun; Zhang, Chi; Song, Zilan; Ai, Jing; Liu, Hongchun; Sun, Liping; Ding, Jian; Geng, Meiyu; Zhang, Ao

2016-06-23

Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.

Emerging pharmaceutical therapies for COPD

PubMed Central

Lakshmi, Sowmya P; Reddy, Aravind T; Reddy, Raju C

2017-01-01

COPD, for which cigarette smoking is the major risk factor, remains a worldwide burden. Current therapies provide only limited short-term benefit and fail to halt progression. A variety of potential therapeutic targets are currently being investigated, including COPD-related proinflammatory mediators and signaling pathways. Other investigational compounds target specific aspects or complications of COPD such as mucus hypersecretion and pulmonary hypertension. Although many candidate therapies have shown no significant effects, other emerging therapies have improved lung function, pulmonary hypertension, glucocorticoid sensitivity, and/or the frequency of exacerbations. Among these are compounds that inhibit the CXCR2 receptor, mitogen-activated protein kinase/Src kinase, myristoylated alanine-rich C kinase substrate, selectins, and the endothelin receptor. Activation of certain transcription factors may also be relevant, as a large retrospective cohort study of COPD patients with diabetes found that the peroxisome proliferator-activated receptor γ (PPARγ) agonists rosiglitazone and pioglitazone were associated with reduced COPD exacerbation rate. Notably, several therapies have shown efficacy only in identifiable subgroups of COPD patients, suggesting that subgroup identification may become more important in future treatment strategies. This review summarizes the status of emerging therapeutic pharmaceuticals for COPD and highlights those that appear most promising. PMID:28790817

Effects of Magnesium on the Phosphate Toxicity in Chronic Kidney Disease: Time for Intervention Studies.

PubMed

Sakaguchi, Yusuke; Hamano, Takayuki; Isaka, Yoshitaka

2017-02-06

Magnesium, an essential mineral for human health, plays a pivotal role in the cardiovascular system. Epidemiological studies in the general population have found an association between lower dietary magnesium intake and an elevated risk of cardiovascular events. In addition, magnesium supplementation was shown to improve blood pressure control, insulin sensitivity, and endothelial function. The relationship between magnesium and cardiovascular prognosis among patients with chronic kidney disease (CKD) has been increasingly investigated as it is becoming evident that magnesium can inhibit vascular calcification, a prominent risk of cardiovascular events, which commonly occurs in CKD patients. Cohort studies in patients receiving dialysis have shown a lower serum magnesium level as a significant risk for cardiovascular mortality. Interestingly, the cardiovascular mortality risk associated with hyperphosphatemia is alleviated among those with high serum magnesium levels, consistent with in vitro evidence that magnesium inhibits high-phosphate induced calcification of vascular smooth muscle cells. Furthermore, a harmful effect of high phosphate on the progression of CKD is also attenuated among those with high serum magnesium levels. The potential usefulness of magnesium as a remedy for phosphate toxicity should be further explored by future intervention studies.

Effects of Magnesium on the Phosphate Toxicity in Chronic Kidney Disease: Time for Intervention Studies

PubMed Central

Sakaguchi, Yusuke; Hamano, Takayuki; Isaka, Yoshitaka

2017-01-01

Magnesium, an essential mineral for human health, plays a pivotal role in the cardiovascular system. Epidemiological studies in the general population have found an association between lower dietary magnesium intake and an elevated risk of cardiovascular events. In addition, magnesium supplementation was shown to improve blood pressure control, insulin sensitivity, and endothelial function. The relationship between magnesium and cardiovascular prognosis among patients with chronic kidney disease (CKD) has been increasingly investigated as it is becoming evident that magnesium can inhibit vascular calcification, a prominent risk of cardiovascular events, which commonly occurs in CKD patients. Cohort studies in patients receiving dialysis have shown a lower serum magnesium level as a significant risk for cardiovascular mortality. Interestingly, the cardiovascular mortality risk associated with hyperphosphatemia is alleviated among those with high serum magnesium levels, consistent with in vitro evidence that magnesium inhibits high-phosphate induced calcification of vascular smooth muscle cells. Furthermore, a harmful effect of high phosphate on the progression of CKD is also attenuated among those with high serum magnesium levels. The potential usefulness of magnesium as a remedy for phosphate toxicity should be further explored by future intervention studies. PMID:28178182

On the self-damping nature of densification in photonic sintering of nanoparticles

PubMed Central

MacNeill, William; Choi, Chang-Ho; Chang, Chih-Hung; Malhotra, Rajiv

2015-01-01

Sintering of nanoparticle inks over large area-substrates is a key enabler for scalable fabrication of patterned and continuous films, with multiple emerging applications. The high speed and ambient condition operation of photonic sintering has elicited significant interest for this purpose. In this work, we experimentally characterize the temperature evolution and densification in photonic sintering of silver nanoparticle inks, as a function of nanoparticle size. It is shown that smaller nanoparticles result in faster densification, with lower temperatures during sintering, as compared to larger nanoparticles. Further, high densification can be achieved even without nanoparticle melting. Electromagnetic Finite Element Analysis of photonic heating is coupled to an analytical sintering model, to examine the role of interparticle neck growth in photonic sintering. It is shown that photonic sintering is an inherently self-damping process, i.e., the progress of densification reduces the magnitude of subsequent photonic heating even before full density is reached. By accounting for this phenomenon, the developed coupled model better captures the experimentally observed sintering temperature and densification as compared to conventional photonic sintering models. Further, this model is used to uncover the reason behind the experimentally observed increase in densification with increasing weight ratio of smaller to larger nanoparticles. PMID:26443492

Beta-adrenergic signaling promotes tumor angiogenesis and prostate cancer progression through HDAC2-mediated suppression of thrombospondin-1.

PubMed

Hulsurkar, M; Li, Z; Zhang, Y; Li, X; Zheng, D; Li, W

2017-03-01

Chronic behavioral stress and beta-adrenergic signaling have been shown to promote cancer progression, whose underlying mechanisms are largely unclear, especially the involvement of epigenetic regulation. Histone deacetylase-2 (HDAC2), an epigenetic regulator, is critical for stress-induced cardiac hypertrophy. It is unknown whether it is necessary for beta-adrenergic signaling-promoted cancer progression. Using xenograft models, we showed that chronic behavioral stress and beta-adrenergic signaling promote angiogenesis and prostate cancer progression. HDAC2 was induced by beta-adrenergic signaling in vitro and in mouse xenografts. We next uncovered that HDAC2 is a direct target of cAMP response element-binding protein (CREB) that is activated by beta-adrenergic signaling. Notably, HDAC2 is necessary for beta-adrenergic signaling to induce angiogenesis. We further demonstrated that, upon CREB activation, HDAC2 represses thrombospondin-1 (TSP1), a potent angiogenesis inhibitor, through epigenetic regulation. Together, these data establish a novel pathway that HDAC2 and TSP1 act downstream of CREB activation in beta-adrenergic signaling to promote cancer progression.

Telomere length and telomere repeating factors: Cellular markers for post-traumatic stress disorder-like model.

PubMed

Dong, Yuanjun; Zhang, Guiqing; Yuan, Xiuyu; Zhang, Yueqi; Hu, Min

2016-05-01

The aim of the present study was to explore the telomere length of peripheral blood leukocytes from a rat model of post-traumatic stress disorder (PTSD), as well as the expression level of telomere-binding protein in the hippocampal CA1 region. The PTSD model was established with 42 adult male Wistar rats. The relative telomere length of the leukocytes was measured by real-time fluorescence quantitative polymerase chain reaction, and the expression levels of telomere repeating factor 1 (TRF1) and telomere repeating factor 2 (TRF2) in the hippocampal CA1 region of the PTSD rat model were determined by immunofluorescence technology. The covariance analysis of repeated measurements by the mixed model approach was used for the telomere length analysis. The comparison of averaged data among groups was performed using least significant difference and analysis of variance. The Student's t test or the Mann-Whitney U test was used for intragroup comparison. The association study among groups was conducted using the Spearman test. The shortening speed of telomere length significantly accelerated in rats after Single Prolonged Stress (SPS) stimulation (P<0.05). The expression levels of TRF1 and TRF2 increased with the progress of PTSD, and the expression peak was shown in day 14, which was significantly different from the control group (P<0.05). The shortening speed of the telomere length of peripheral blood leukocytes accelerated in PTSD rats, and the expression levels of TRF1 and TRF2 increased in hippocampus, both of which were closely associated with the pathological progress of the PTSD-like model and unfavorable prognosis. Copyright © 2016 Elsevier B.V. All rights reserved.

The effect of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) on semen parameters in human males: a systematic review and meta-analysis.

PubMed

Fu, Weihua; Zhou, Zhansong; Liu, Shijian; Li, Qianwei; Yao, Jiwei; Li, Weibing; Yan, Junan

2014-01-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is one of the risk factors of impaired male fertility potential. Studies have investigated the effect of CP/CPPS on several semen parameters but have shown inconsistent results. Hence, we performed a systematic literature review and meta-analysis to assess the association between CP/CPPS and basic semen parameters in adult men. Systematic literature searches were conducted with PubMed, EMBASE and the Cochrane Library up to August 2013 for case-control studies that involved the impact of CP/CPSS on semen parameters. Meta-analysis was performed with Review Manager and Stata software. Standard mean differences (SMD) of semen parameters were identified with 95% confidence intervals (95% CI) in a random effects model. Twelve studies were identified, including 999 cases of CP/CPPS and 455 controls. Our results illustrated that the sperm concentration and the percentage of progressively motile sperm and morphologically normal sperm from patients with CP/CPPS were significantly lower than controls (SMD (95% CI) -14.12 (-21.69, -6.63), -5.94 (-8.63, -3.25) and -8.26 (-11.83, -4.66), respectively). However, semen volume in the CP/CPPS group was higher than in the control group (SMD (95% CI) 0.50 (0.11, 0.89)). There was no significant effect of CP/CPPS on the total sperm count, sperm total motility, and sperm vitality. The present study illustrates that there was a significant negative effect of CP/CPPS on sperm concentration, sperm progressive motility, and normal sperm morphology. Further studies with larger sample sizes are needed to better illuminate the negative impact of CP/CPPS on semen parameters.

Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis

PubMed Central

Inomata, Minoru; Nishioka, Yasuhiko; Azuma, Arata

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. The molecular mechanisms involved in the progression of IPF are not fully understood; however, the platelet-derived growth factor (PDGF)/PDGF receptor pathway is thought to play a critical role in fibrogenesis of the lungs. Other growth factors, including fibroblast growth factor and vascular endothelial growth factor, are also thought to contribute to the pathogenesis of pulmonary fibrosis. Nintedanib is an inhibitor of multiple tyrosine kinases, including receptors for PDGF, fibroblast growth factor, and vascular endothelial growth factor. In the Phase II TOMORROW trial, treatment with 150 mg of nintedanib twice daily showed a trend to slow the decline in lung function and significantly decrease acute exacerbations in patients with IPF, while showing an acceptable safety profile. The Phase III INPULSIS trials demonstrated a significant decrease in the annual rate of decline in forced vital capacity in IPF patients treated with 150 mg nintedanib twice daily. In the INPULSIS-2 trial, the time to the first acute exacerbation significantly increased in IPF patients who were treated with 150 mg of nintedanib twice daily. Pirfenidone, another antifibrotic drug, was shown to limit the decline in pulmonary function in patients with IPF in the ASCEND trial. Combination therapy with nintedanib and pirfenidone is anticipated, although further evaluation of its long-term safety is needed. There is limited evidence for the safety of the combination therapy although a Phase II trial conducted in Japan demonstrated that combination therapy with nintedanib and pirfenidone was tolerable for 1 month. Available antifibrotic agents (ie, pirfenidone and N-acetylcysteine) have limited efficacy as single therapies for IPF; therefore, further study of combination therapy with antifibrotic agents is needed. PMID:26346347

The role of serum osteoprotegerine in metastatic prostate cancer - a case control study.

PubMed

Siampanopoulou, M; El, Mantani; Moustakas, G; Haritanti, A; Gotzamani-Psarrakou, A

2016-01-01

Prostate cancer is one of the most common malignant neoplastic diseases in men. Early control of the disease progression contributes significantly to survival rates and patients' quality of life. Osteoprotegerin is a dimeric glycoprotein, which affects bone metabolism and inhibits osteoclastogenesis. In the present study, we evaluated the expression of osteoprotegerin in the serum of prostate cancer patients with or without skeletal metastases. The expression of serum osteoprotegerin, as measured by enzyme-linked immunosorbent assay, has been studied in 82 patients with locally controlled prostate cancer, in 49 patients with metastatic bone disease and in a control group of 41 healthy males. At sampling time 65/131 of included patients were newly diagnosed, while 66/131 patients were already under hormonal therapy. All eligible prostate cancer patients had histologically confirmed malignancy. Serum total prostate-specific antigen (PSA) was determined by an immunoradiometric assay. We investigated the expression of osteoprotegerin in hormone-dependent and hormone-refractory prostate cancer and its relation to disease progression. Among the 131 patients with prostate cancer, higher osteoprotegerin and PSA concentrations have been observed in metastatic bone patients' sera (p <0.001). ROC analysis between the metastatic and locally controlled prostate cancer patients has shown a statistically significant area curve (p <0.001) and a cut-off limit of 89.6 pg/ml. Moreover, 15.3 % of patients became hormone-resistant, with osteoprotegerin values significantly increased compared with hormone-sensitive prostate cancer patients (p <0.001). It seems that elevated levels of serum osteoprotegerin in patients with prostate cancer reflect the bone metastatic extent and may potentially be used in metastatic patients' follow-ups. Hippokratia 2016, 20(2): 133-138.

Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension

PubMed Central

Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R.; Song, Shanshan; Sysol, Justin R.; Drennan, Abigail R.; Offermanns, Stefan; Ye, Richard D.; Bonini, Marcelo G.; Minshall, Richard D.; Garcia, Joe G. N.; Machado, Roberto F.; Makino, Ayako

2014-01-01

Pulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1–3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1−/− mice were protected against the development and progression of chronic HPH, whereas Akt2−/− mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1−/− mice, with no significant effect noted in the Akt2−/− mice after chronic exposure to normobaric hypoxia (10% O2). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension. PMID:25416384

Long-Term Effect of Pravastatin on Carotid Intima–Media Complex Thickness

PubMed Central

Toyoda, Kazunori; Minematsu, Kazuo; Yasaka, Masahiro; Nagai, Yoji; Aoki, Shiro; Nezu, Tomohisa; Hosomi, Naohisa; Kagimura, Tatsuo; Origasa, Hideki; Kamiyama, Kenji; Suzuki, Rieko; Ohtsuki, Toshiho; Maruyama, Hirofumi; Kitagawa, Kazuo; Uchiyama, Shinichiro; Matsumoto, Masayasu

2018-01-01

Background and Purpose— The effect of statins on progression of carotid intima–media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. This study aimed to determine the effect of low-dose pravastatin on carotid IMT in Japanese patients with noncardioembolic ischemic stroke. Methods— This is a substudy of the J-STARS trial (Japan Statin Treatment Against Recurrent Stroke), a multicenter, randomized, open-label, parallel-group trial to examine whether pravastatin reduces stroke recurrence. Patients were randomized to receive pravastatin (10 mg daily, usual dose in Japan; pravastatin group) or not to receive any statins (control group). The primary outcome was IMT change of the common carotid artery for a 5-year observation period. IMT change was compared using mixed-effects models for repeated measures. Results— Of 864 patients registered in this substudy, 71 without baseline ultrasonography were excluded, and 388 were randomly assigned to the pravastatin group and 405 to the control group. Baseline characteristics were not significantly different, except National Institutes of Health Stroke Scale scores (median, 0 [interquartile range, 0–2] versus 1 [interquartile range, 0–2]; P=0.019) between the 2 groups. Baseline IMT (mean±SD) was 0.887±0.155 mm in the pravastatin group and 0.887±0.152 mm in the control group (P=0.99). The annual change in the IMT at 5-year visit was significantly reduced in the pravastatin group as compared with that in the control group (0.021±0.116 versus 0.040±0.118 mm; P=0.010). Conclusions— The usual Japanese dose of pravastatin significantly reduced the progression of carotid IMT at 5 years in patients with noncardioembolic stroke. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00361530. PMID:29191850

Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models

PubMed Central

Bisht, Savita; Karikari, Collins; Garrido-Laguna, Ignacio; Rasheed, Zeshaan; Ottenhof, Niki A; Dadon, Tikva; Alvarez, Hector; Fendrich, Volker; Rajeshkumar, NV; Matsui, William; Brossart, Peter; Hidalgo, Manuel; Bannerji, Rajat

2011-01-01

Pancreatic cancer is one of the most lethal of human malignancies, and potent therapeutic options are lacking. Inhibition of cell cycle progression through pharmacological blockade of cyclin-dependent kinases (CDK) has been suggested as a potential treatment option for human cancers with deregulated cell cycle control. Dinaciclib (SCH727965) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. In the current study, the therapeutic efficacy of SCH727965 on human pancreatic cancer cells was tested using in vitro and in vivo model systems. Treatment with SCH727965 significantly reduced in vitro cell growth, motility and colony formation in soft agar of MIAPaCa-2 and Pa20C cells. These phenotypic changes were accompanied by marked reduction of phosphorylation of Retinoblastoma (Rb) and reduced activation of RalA. Single agent therapy with SCH727965 (40 mg/kg i.p. twice weekly) for 4 weeks significantly reduced subcutaneous tumor growth in 10/10 (100%) of tested low-passage human pancreatic cancer xenografts. Treatment of low passage pancreatic cancer xenografts with a combination of SCH727965 and gemcitabine was significantly more effective than either agent alone. Gene Set Enrichment Analysis identified overrepresentation of the Notch and Transforming Growth Factor-β (TGFβ) signaling pathways in the xenografts least responsive to SCH727965 treatment. Treatment with the cyclin-dependent kinase inhibitor SCH727965 alone or in combination is a highly promising novel experimental therapeutic strategy against pancreatic cancer. PMID:21768779

A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumor progression in mice with preinvasive breast disease.

PubMed

Disis, Mary L; Gad, Ekram; Herendeen, Daniel R; Lai, Vy Phan-; Park, Kyong Hwa; Cecil, Denise L; O'Meara, Megan M; Treuting, Piper M; Lubet, Ronald A

2013-12-01

A multiantigen multipeptide vaccine, targeting proteins expressed in preinvasive breast lesions, can stimulate type I CD4(+) T cells which have been shown to be deficient in both patients with breast cancer and mice that develop mammary tumors. Transgenic mice (TgMMTV-neu) were immunized with a multiantigen peptide vaccine specific for neu, insulin-like growth factor-binding protein 2 and insulin-like growth factor receptor-I at a time when some of the animals already had preinvasive lesions (18 weeks of age). Although immunization with each individual antigen was partially effective in inhibiting tumor growth, immunization with the multiantigen vaccine was highly effective, blocking development of palpable lesions in 65% of mice and slowing tumor growth in the infrequent palpable tumors, which did arise. Protection was mediated by CD4(+) T cells, and the few slow-growing tumors that did develop demonstrated a significant increase in intratumoral CD8(+) T cells as compared with controls (P = 0.0007). We also combined the vaccine with agents that were, by themselves, partially effective inhibitors of tumor progression in this model; lapatinib and the RXR agonist bexarotene. Although the combination of lapatinib and vaccination performed similarly to vaccination alone (P = 0.735), bexarotene and vaccination significantly enhanced disease-free survival (P < 0.0001), and approximately 90% of the mice showed no pathologic evidence of carcinomas at one year. The vaccine also demonstrated significant clinical efficacy in an additional transgenic model of breast cancer (TgC3(I)-Tag). Chemoimmunoprevention combinations may be an effective approach to breast cancer prevention even when the vaccine is administered in the presence of subclinical disease.

Increased Brahma-related Gene 1 Expression Predicts Distant Metastasis and Shorter Survival in Patients with Invasive Ductal Carcinoma of the Breast.

PubMed

Do, Sung-Im; Yoon, Gun; Kim, Hyun-Soo; Kim, Kyungeun; Lee, Hyunjoo; Do, In-Gu; Kim, Dong-Hoon; Chae, Seoung Wan; Sohn, Jin Hee

2016-09-01

Previous studies have demonstrated aberrant Brahma-related gene 1 (BRG1) expression in various tumor types. Increased BRG1 expression has recently been shown to correlate with aggressive oncogenic behavior in many different types of human cancer. However, the role of BRG1 in breast cancer development and progression is not fully understood. We evaluated BRG1 expression in 224 patients with invasive ductal carcinoma (IDC) of the breast using tissue microarray samples and immunohistochemistry. We also investigated whether BRG1 expression status is associated with clinicopathological characteristics and outcomes of patients with IDC. Among the 224 patients with IDC, 37.5% (84/224) exhibited high BRG1 expression. IDC exhibited significantly higher BRG1 expression compared to ductal carcinoma in situ (p=0.009) and normal breast tissue (p=0.005). High BRG1 expression in IDC significantly correlated with higher histological grade (p=0.035) and presence of distant metastasis (p=0.002). Furthermore, high BRG1 expression was an independent factor for predicting distant metastasis (relative risk=4.079; p=0.007). In addition, high BRG1 expression predicted shorter overall (p=0.011) and recurrence-free (p=0.003) survival in patients with IDC. In particular, BRG1 had a significant prognostic value in predicting recurrence-free survival of patients with IDC with lymph node metastasis or stage III disease. BRG1 is involved in the progression and metastasis of breast cancer and can serve as a novel biomarker predictive of distant metastasis and patient outcomes. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Expression of breast cancer metastasis suppressor-1, BRMS-1, in human breast cancer and the biological impact of BRMS-1 on the migration of breast cancer cells.

PubMed

Zhang, Yulu; Ye, Lin; Tan, Yuxia; Sun, Pinghui; Ji, Ke; Jiang, Wen G

2014-03-01

Breast cancer metastasis suppressor-1 (BRMS1) is a candidate metastasis-suppressing gene and has been shown to potentially inhibit tumor progression without blocking the growth of orthotopic tumors, in different tumor types including non-small cell lung cancer, ovarian, melanoma and breast cancers. BRMS-1 gene transcript was quantified in breast cancer sample tissues and analyzed against histological and clinical patient outcome. Human breast cancer cell lines, MDA MB-231 and MCF-7 were used to genetically-modify the expression of BRMS-1 and test for biological responses following BRMS-1 modifications. Key candidate signal pathways, influenced by BRMS-1 were also explored. BRMS1 was present in MDA MB-231 and MCF-7 cell lines. Using anti-BRMS1 transgenes, we knocked-down the transcripts of BRMS1 in both cells at the mRNA and protein levels. Knockdown of BRMS1 gave both cells a faster cell growth rate, rapid pace of cellular migration and invasion, compared to respective wild-type and control cells (p<0.05). Blocking phospholipase-Cγ (PLCγ) had a significant influence on the BRMS-1-induced cell migration. Finally, significantly low levels of BRMS1 were observed in patients with high-grade tumors (p=0.12), in patients with distant metastasis (p=0.05) and those who died of breast cancer (p=0.0037). In addition, patients with low levels of BRMS1 had a significantly shorter overall survival (p=0.035). BRMS-1 is aberrantly expressed in human breast cancer and is inversely-correlated with disease progression and patient survival. This is likely to be occurring via its influence on invasion and migration of breast cancer cells.

[Effect of Xiaozheng Rongmu powder for the treatment of liver cirrhosis in rats].

PubMed

Mu, Yong-Ping; Chen, Xiao-Rong; Lu, Yun-Fei

2010-10-01

To observe the therapeutic effect of Xiaozheng Rongmu Powder (XRP) for the treatment of progressive CCl4-induced liver cirrhosis in rats. Rat liver cirrhosis model was established by subcutaneous injection of 50% CCl4-olive oil 2 mL/kg twice a week for 12 weeks. Experimental rats were divided into the control group treated by saline and the two treatment groups, treated with XRP and Xiaochaihu Decoction, respectively, with the treatment starting from the 9th week of modeling. Rats were sacrificed at the terminal of experiment, the death rate, character of ascites, liver histological changes, liver function, mRNA expression of hepatocyte mitosis and the liver fibrosis associated markers in rats were observed. At the end of the 8th week of modeling, serum levels of ALT, AST and TBil were increased, and Alb decreased significantly in rats (P < 0.01), cirrhosis formation with ascites could be seen in all rats. Meantime, levels of vascular smooth muscle alpha-actin, transforming growth factor-beta1, collagen I A2, tumor necrosis factor-alpha, tissue inhibitor of melalloproteinase-1 mRNA increased, while matrix melalloproteinase-13 mRNA were decreased significantly (P < 0.01), with visible liver proliferation to some extents. Further changes of above-mentioned abnormalities and clear suppression of hepatocytes mitosis were found in the modeled rats at the end of the 12th week. As compared to those occurred in the control group, changes in the XRP treated group were significantly milder at the corresponding duration, and clearly active hepatocytes mitosis was shown. XRP, a Chinese drug with the effect of dissolving phlegm, removing stasis and supplementing qi, could reverse the progress of cirrhosis formation induced by CCl4, and it brings potential new hope for the treatment of advanced cirrhosis by Chinese medicine.

Epigenetic Regulation of miRNAs and Breast Cancer Stem Cells

PubMed Central

Duru, Nadire; Gernapudi, Ramkishore; Eades, Gabriel; Eckert, Richard; Zhou, Qun

2015-01-01

MicroRNAs have emerged as important targets of chemopreventive strategies in breast cancer. We have found that miRNAs are dysregulated at an early stage in breast cancer, in non-malignant Ductal Carcinoma In Situ. Many dietary chemoprevention agents can act by epigenetically activating miRNA-signaling pathways involved in tumor cell proliferation and invasive progression. In addition, many miRNAs activated via chemopreventive strategies target cancer stem cell signaling and prevent tumor progression or relapse. Specifically, we have found that miRNAs regulate DCIS stem cells, which may play important roles in breast cancer progression to invasive disease. We have shown that chemopreventive agents can directly inhibit DCIS stem cells and block tumor formation in vivo, via activation of tumor suppressor miRNAs. PMID:26052481

Assessing the Applicability of Digital Image Correlation (DIC) Technique in Tensile Testing of Fabric Composites

DTIC Science & Technology

2013-02-01

glass composites and 318.51±6.77 MPa for the basalt fibers . On average, the S2 glass composite had a higher modulus of elasticity of 12.94±0.84 GPa...5. The progression of strain on the tool side of the tensile sample. 9 The results of the tensile testing for the basalt fibers are shown in...reported modulus values shown in table 1. Figure 6. Results of the tensile testing of the basalt fiber composites. 3.1.2 Results of the Line

Endothelial microparticles-mediated transfer of microRNA-19b promotes atherosclerosis via activating perivascular adipose tissue inflammation in apoE-/- mice.

PubMed

Li, Changlong; Li, Sufang; Zhang, Feng; Wu, Manyan; Liang, Huizhu; Song, Junxian; Lee, Chongyou; Chen, Hong

2018-01-08

Microparticles(MPs) are the major carriers of circulating microRNAs. Our previous study has shown that microRNA (miR)-19b in endothelial cell-derived microparticles (EMPs) is significantly increased in patients with unstable angina. However, little is known about the relationship between miR-19b in EMPs and the progression of atherosclerosis. The aim of the present study was to define the role and potential mechanism of miR-19b incorporated in EMPs in the development of atherosclerosis. Western-diet-fed apoE -/- mice were injected with phosphate buffered solution(PBS), EMP carrying microRNA control(EMP control ) or miR-19b mimic (EMP miR19b ) intravenously. Systemic treatment with EMP miR19b significantly accelerated carotid artery atherosclerosis progression by increasing lipid, macrophages and smooth muscle cells and decreasing collagen content in atherosclerotic plaque. Fluorescence-labelled EMP miR19b injection proved that miR-19b could be transported into perivascular adipose tissue(PVAT) by EMPs. EMP miR19b treatment also promoted inflammatory cytokines secretion and macrophages infiltration in PVAT. In further experiment, apoE -/- mice were divided into 3 groups: EMP control PVAT(+), EMP miR19b PVAT(+) and EMP miR19b PVAT(-), based on removing or keeping pericarotid adipose tissue and injected with EMP control or EMP miR19b . Loss of PVAT attenuated EMP miR19b -mediated effects on increasing carotid atherosclerosis formation and inflammatory cytokines level in plaque. EMP miR19b inhibited suppressor of cytokine signaling 3 (SOCS3) expression in PVAT. Our findings demonstrate that miR-19b in EMPs exaggerates atherosclerosis progression by augmenting PVAT-specific inflammation proceeded by downregulating SOCS3 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

The Role of Mechanical Variance and Spatial Clustering on the Likelihood of Tumor Incidence and Growth

NASA Astrophysics Data System (ADS)

Mirzakhel, Zibah

When considering factors that contribute to cancer progression, modifications to both the biological and mechanical pathways play significant roles. However, less attention is placed on how the mechanical pathways can specifically contribute to cancerous behavior. Experimental studies have found that malignant cells are significantly softer than healthy, normal cells. In a tissue environment where healthy or malignant cells exist, a distribution of cell stiffness values is observed, with the mean values used to differentiate between these two populations. Rather than focus on the mean values, emphasis will be placed on the distribution, where instances of soft and stiff cells exist in the healthy tissue environment. Since cell deformability is a trait associated with cancer, the question arises as to whether the mechanical variation observed in healthy tissue cell stiffness distributions can influence any instances of tumor growth. To approach this, a 3D discrete model of cells is used, able to monitor and predict the behavior of individual cells while determining any instances of tumor growth in a healthy tissue. In addition to the mechanical variance, the spatial arrangement of cells will also be modeled, as cell interaction could further implicate any incidences of tumor-like malignant populations within the tissue. Results have shown that the likelihood of tumor incidence is driven by both by the increases in the mechanical variation in the distributions as well as larger clustering of cells that are mechanically similar, quantified primarily through higher proliferation rates of tumor-like soft cells. This can be observed though prominent negative shifts in the mean of the distribution, as it begins to transition and show instances of earlystage tumor growth. The model reveals the impact that both the mechanical variation and spatial arrangement of cells has on tumor progression, suggesting the use of these parameters as potential novel biomarkers. With a patient-specific approach in mind, the model may be applied for early-stage cancer detection, useful to establish a timeline on tumor progression.

Pretreatment oral hygiene habits and survival of head and neck squamous cell carcinoma (HNSCC) patients.

PubMed

Friemel, Juliane; Foraita, Ronja; Günther, Kathrin; Heibeck, Mathias; Günther, Frauke; Pflueger, Maren; Pohlabeln, Hermann; Behrens, Thomas; Bullerdiek, Jörn; Nimzyk, Rolf; Ahrens, Wolfgang

2016-03-11

The survival time of patients with head and neck squamous cell carcinoma (HNSCC) is related to health behavior, such as tobacco smoking and alcohol consumption. Poor oral health (OH), dental care (DC) and the frequent use of mouthwash have been shown to represent independent risk factors for head and neck cancerogenesis, but their impact on the survival of HNSCC patients has not been systematically investigated. Two hundred seventy-six incident HNSCC cases recruited for the ARCAGE study were followed through a period of 6-10 years. Interview-based information on wearing of dentures, gum bleeding, teeth brushing, use of floss and dentist visits were grouped into weighted composite scores, i.e. oral health (OH) and dental care (DH). Use of mouthwash was assessed as frequency per day. Also obtained were other types of health behavior, such as smoking, alcohol drinking and diet, appreciated as both confounding and study variables. Endpoints were progression-free survival, overall survival and tumor-specific survival. Prognostic values were estimated using Kaplan-Meier analysis and Cox proportional hazards regression models. A good dental care score, summarizing annual dental visits, daily teeth cleaning and use of floss was associated with longer overall survival time (p = .001). The results of the Cox regression models similarly suggested a higher risk of tumor progression and shortened overall survival in patients with poor dental care, but the results lost their statistical significance after other types of health behavior had been controlled for. Frequent use of mouthwash (≥ 2 times/day) significantly increased the risk of tumor-specific death (HR = 2.26; CI = 1.19-4.32). Alcohol consumption and tobacco smoking were dose-dependently associated with tumor progression and shorter overall survival. Frequent mouthwash use of ≥ 2 times/day seems to elevate the risk of tumor-specific death in HNSCC patients. Good dental care scores are associated with longer overall survival.

Low Prostate Concentration of Lycopene Is Associated with Development of Prostate Cancer in Patients with High-Grade Prostatic Intraepithelial Neoplasia

PubMed Central

Mariani, Simone; Lionetto, Luana; Cavallari, Michele; Tubaro, Andrea; Rasio, Debora; De Nunzio, Cosimo; Hong, Gena M.; Borro, Marina; Simmaco, Maurizio

2014-01-01

Prostate cancer (PC) is a frequent male malignancy and represents the second most diagnosed cancer in men. Since pre-cancerous lesions, i.e., the high-grade prostatic intraepithelial neoplasia (HGPIN), can be detected years before progression to PC, early diagnosis and chemoprevention are targeted strategies to reduce PC rates. Animal studies have shown that lycopene, a carotenoid contained in tomatoes, is a promising candidate for the chemoprevention of PC. However, its efficacy in humans remains controversial. The present study aimed to investigate the relevance of plasma and prostate concentration of lycopene after a lycopene-enriched diet in patients diagnosed with HGPIN. Thirty-two patients diagnosed with HGPIN were administered a lycopene-enriched diet (20–25 mg/day of lycopene; through 30 g/day of triple concentrated tomato paste) for 6 months. A 6-month follow-up prostate biopsy assessed progression to PC. Patients were classified into three groups according to the histopathological features of the 6-month follow-up biopsy results: prostatitis; HGPIN and PC. PSA and plasma lycopene levels were measured before and after the dietary lycopene supplementation. Prostatic lycopene concentration was only assessed after the supplementation diet. Only prostatic lycopene concentration showed significant differences between the three groups (p = 0.03). Prostatic lycopene concentration below a 1 ng/mg threshold was associated with PC at 6-month follow-up biopsy (p = 0.003). We observed no overall benefits from a 6-month lycopene supplementation, as the rate of HGPIN progression to PC in our population (9/32, 28%) was similar to rates reported in the literature. Baseline PSA levels also showed no significant changes after a lycopene-enriched diet. Our findings point to prostatic lycopene concentration as a promising biomarker of PC. Further prospective longitudinal studies are needed to assess the prognostic role of prostatic lycopene in PC. PMID:24451130

Therapists' and clients' ratings of real relationship, attachment, therapist self-disclosure, and treatment progress.

PubMed

Fuertes, Jairo N; Moore, Michael; Ganley, Jennifer

2018-01-20

While there has been much research on the role of the working alliance in psychotherapy, researchers only recently began investigating the role of the real relationship in treatment. In the current study on therapist and client dyads, we used actor-partner interdependence modeling (APIM) to examine associations between therapists' and clients' ratings of the real relationship, therapist self-disclosure, attachment, and treatment progress. APIM analyses allowed for an examination into how therapists' and clients' views of a particular phenomenon might affect their own ratings (actor), as well as the others' (partner) ratings of that same phenomenon. Significant negative associations between therapist self-reported attachment anxiety and avoidance and therapist-rated real relationship and treatment progress. Significant positive associations were found between client-rated real relationship and client-rated treatment progress. These results and others are discussed in the context of the literature along with implications for future research in this area. Clinical or methodological significance of this article: The current study has uncovered evidence that therapists' ratings of their attachment anxiety and avoidance are negatively and significantly associated with their ratings of the real relationship and of treatment progress. The results also indicate that both therapists' and clients' ratings of the real relationship were positively and significantly associated with their ratings of clients' treatment progress.

Brain Dynamics Sustaining Rapid Rule Extraction from Speech

ERIC Educational Resources Information Center

de Diego-Balaguer, Ruth; Fuentemilla, Lluis; Rodriguez-Fornells, Antoni

2011-01-01

Language acquisition is a complex process that requires the synergic involvement of different cognitive functions, which include extracting and storing the words of the language and their embedded rules for progressive acquisition of grammatical information. As has been shown in other fields that study learning processes, synchronization…

19. WESTERLY VIEW ALONG SPILLWAY BUCKET, SHOWING CONSTRUCTION OPERATIONS IN ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

19. WESTERLY VIEW ALONG SPILLWAY BUCKET, SHOWING CONSTRUCTION OPERATIONS IN PROGRESS. THE DAM EMBANKMENT IS SHOWN IN THE LEFT DISTANCE.... Volume XX, No. 6, September 5, 1940. - Prado Dam, Spillway, Santa Ana River near junction of State Highways 71 & 91, Corona, Riverside County, CA

Fire Suppression, District 5

Treesearch

Roy Headley

1916-01-01

The increasing effectiveness of suppression practice is shown by the fact that in 1915 fire suppression cost one-third as much as in 1914, and damage to Government property was kept down to one-fourth the 1914 figure. The seasons were approximately equal in danger. Is further progress to be expected?

Semiconductor Measurement Technology: Progress Report October 1 to December 31, 1974

DTIC Science & Technology

1975-11-01

the Nomarski differential interference contrast mode. The magnification as measured on the photo- microgranh was 58?X. From these photo...linear encoder or a laser Interferometrically controlled stage. A schematic diagram of this system Is shown In figure 23. The required resolution of

FINE AMBIENT AIR PARTICULAR MATTER EXPOSURE INDUCES MOLECULAR ALTERATIONS INDICATIVE OF CARDIOVASCULAR DISEASE PROGRESSION IN ATHEROSCLEROTIC SUSCEPTIBLE MICE

EPA Science Inventory

Epidemiological, clinical, and toxicological studies have demonstrated that exposure to ambient air particulate matter (PM) can alter cardiovascular function and may influence cardiovascular disease (CVD). It has been shown that exposure to concentrated ambient air particles (CA...

Mathieu Progressive Waves

NASA Astrophysics Data System (ADS)

Andrei, B. Utkin

2011-10-01

A new family of exact solutions to the wave equation representing relatively undistorted progressive waves is constructed using separation of variables in the elliptic cylindrical coordinates and one of the Bateman transforms. The general form of this Bateman transform in an orthogonal curvilinear cylindrical coordinate system is discussed and a specific problem of physical feasibility of the obtained solutions, connected with their dependence on the cyclic coordinate, is addressed. The limiting case of zero eccentricity, in which the elliptic cylindrical coordinates turn into their circular cylindrical counterparts, is shown to correspond to the focused wave modes of the Bessel-Gauss type.

Progress in vacuum susceptibilities and their applications to the chiral phase transition of QCD

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

Cui, Zhu-Fang, E-mail: phycui@nju.edu.cn; State Key Laboratory of Theoretical Physics, Institute of Theoretical Physics, CAS, Beijing, 100190; Hou, Feng-Yao

2015-07-15

The QCD vacuum condensates and various vacuum susceptibilities are all important parameters which characterize the nonperturbative properties of the QCD vacuum. In the QCD sum rules external field formula, various QCD vacuum susceptibilities play important roles in determining the properties of hadrons. In this paper, we review the recent progress in studies of vacuum susceptibilities together with their applications to the chiral phase transition of QCD. The results of the tensor, the vector, the axial–vector, the scalar, and the pseudo-scalar vacuum susceptibilities are shown in detail in the framework of Dyson–Schwinger equations.

First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study.

PubMed

Shi, Y K; Wang, L; Han, B H; Li, W; Yu, P; Liu, Y P; Ding, C M; Song, X; Ma, Z Y; Ren, X L; Feng, J F; Zhang, H L; Chen, G Y; Han, X H; Wu, N; Yao, C; Song, Y; Zhang, S C; Song, W; Liu, X Q; Zhao, S J; Lin, Y C; Ye, X Q; Li, K; Shu, Y Q; Ding, L M; Tan, F L; Sun, Y

2017-10-01

Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety. Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group. First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Micro-computed tomographic analysis of progression of artificial enamel lesions in primary and permanent teeth after resin infiltration.

PubMed

Ozgul, Betul Memis; Orhan, Kaan; Oz, Firdevs Tulga

2015-09-01

We investigated inhibition of lesion progression in artificial enamel lesions. Lesions were created on primary and permanent anterior teeth (n = 10 each) and were divided randomly into two groups with two windows: Group 1 (window A: resin infiltration; window B: negative control) and Group 2 (window A: resin infiltration + fluoride varnish; window B: fluoride varnish). After pH cycling, micro-computed tomography was used to analyze progression of lesion depth and changes in mineral density. Resin infiltration and resin infiltration + fluoride varnish significantly inhibited progression of lesion depth in primary teeth (P < 0.05). Inhibition of lesion depth progression in permanent teeth was significantly greater after treatment with resin infiltration + fluoride varnish than in the negative control (P < 0.05). Change in mineral density was smaller in the resin infiltration and resin infiltration + fluoride varnish groups; however, the difference was not significant for either group (P > 0.05). Resin infiltration is a promising method of inhibiting progression of caries lesions.

Subfractions of high-density lipoprotein (HDL) and dysfunctional HDL in chronic kidney disease patients.

PubMed

Rysz-Górzyńska, Magdalena; Banach, Maciej

2016-08-01

A number of studies have shown that chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease (CVD). Chronic kidney disease is characterized by significant disturbances in lipoprotein metabolism, including differences in quantitative and qualitative content of high-density lipoprotein (HDL) particles. Recent studies have revealed that serum HDL cholesterol levels do not predict CVD in CKD patients; thus CKD-induced modifications in high-density lipoprotein (HDL) may be responsible for the increase in CV risk in CKD patients. Various methods are available to separate several subclasses of HDL and confirm their atheroprotective properties. However, under pathological conditions associated with inflammation and oxidation, HDL can progressively lose normal biological activities and be converted into dysfunctional HDL. In this review, we highlight the current state of knowledge on subfractions of HDL and HDL dysfunction in CKD.

Secondary School Students' Epistemic Insight into the Relationships Between Science and Religion—A Preliminary Enquiry

NASA Astrophysics Data System (ADS)

Billingsley, Berry; Taber, Keith; Riga, Fran; Newdick, Helen

2013-08-01

A number of previous studies have shown that there is a widespread view among young people that science and religion are opposed. In this paper, we suggest that it requires a significant level of what can be termed "epistemic insight" to access the idea that some people see science and religion as compatible while others do not. To explore this further, we draw on previous work to devise a methodology to discover students' thinking about apparent contradictions between scientific and religious explanations of the origins of the universe. In our discussion of the findings, we highlight that students' epistemic insight in this context does seem in many cases to be limited and we outline some of the issues emerging from the study that seem to boost or limit students' progress in this area.

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

G.Y. Fu; L.P. Ku; M.H. Redi

A key issue for compact stellarators is the stability of beta-limiting MHD modes, such as external kink modes driven by bootstrap current and pressure gradient. We report here recent progress in MHD stability studies for low-aspect-ratio Quasi-Axisymmetric Stellarators (QAS) and Quasi-Omnigeneous Stellarators (QOS). We find that the N = 0 periodicity-preserving vertical mode is significantly more stable in stellarators than in tokamaks because of the externally generated rotational transform. It is shown that both low-n external kink modes and high-n ballooning modes can be stabilized at high beta by appropriate 3D shaping without a conducting wall. The stabilization mechanism formore » external kink modes in QAS appears to be an enhancement of local magnetic shear due to 3D shaping. The stabilization of ballooning mode in QOS is related to a shortening of the normal curvature connection length.« less

Parametric studies of North East Corridor rail passenger service between New York City and Washington, D. C.. [propulsive efficiency studies

NASA Technical Reports Server (NTRS)

Stallkamp, J. A.

1977-01-01

Speed profiles of rail passenger service between New York City and Washington, D.C. were developed and showed progressively fewer speed restrictions and increasing maximum speeds. The significant equipment characteristics include the portion of the total weight on driven axles, i.e., multiple unit (MU) cars versus locomotive hauled trains, and the short term tractive effort rating of the motors. The ratio of acceleration plus braking time to total time is provided for validation of the use of the short term propulsion equipment ratings. Absolute trip times are shown to be determined primarily by the allowed speed profile. Locomotive hauled train weights and lengths and the locomotive capabilities and characteristics that are required to make the performance of this type of train comparable to that of MU trains are given.

Determination of atomic vacancies in InAs/GaSb strained-layer superlattices by atomic strain

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

Kim, Honggyu; Meng, Yifei; Kwon, Ji-Hwan

Determining vacancy in complex crystals or nanostructures represents an outstanding crystallographic problem that has a large impact on technology, especially for semiconductors, where vacancies introduce defect levels and modify the electronic structure. However, vacancy is hard to locate and its structure is difficult to probe experimentally. Reported here are atomic vacancies in the InAs/GaSb strained-layer superlattice (SLS) determined by atomic-resolution strain mapping at picometre precision. It is shown that cation and anion vacancies in the InAs/GaSb SLS give rise to local lattice relaxations, especially the nearest atoms, which can be detected using a statistical method and confirmed by simulation. Themore » ability to map vacancy defect-induced strain and identify its location represents significant progress in the study of vacancy defects in compound semiconductors.« less

Coannular plug nozzle noise reduction and impact of exhaust system designs

NASA Technical Reports Server (NTRS)

Lee, R.

1976-01-01

Reducing the noise generated by high velocity jets has confronted engine designers and acoustics workers alike for the past fifteen years. Some of the jet noise suppressor configurations that are investigated are shown. With the exception of the early CJ-805 daisy suppressor nozzle which found successful application on the Convair 990 airplane, the others were developmental hardware at different stages of the effort in the past eight years - all aiming at potential supersonic cruise aircraft applications. Some significant progress was made as the result of work supported by NASA and FAA in the past two to three years. This work pertains to the concept demonstration and scale model testing of coannular plug nozzles with inverted velocity profile, and to the preliminary study of its application to advanced variable cycle engines (VCE) appropriate for supersonic cruise aircraft.

Potential for immunotherapy in soft tissue sarcoma

PubMed Central

Tseng, William W; Somaiah, Neeta; Engleman, Edgar G

2015-01-01

Soft tissue sarcomas (STS) are rare, heterogeneous tumors of mesenchymal origin. Despite optimal treatment, a large proportion of patients will develop recurrent and metastatic disease. For these patients, current treatment options are quite limited. Significant progress has been made recently in the use of immunotherapy for the treatment of other solid tumors (e.g. prostate cancer, melanoma). There is a strong rationale for immunotherapy in STS, based on an understanding of disease biology. For example, STS frequently have chromosomal translocations which result in unique fusion proteins and specific subtypes have been shown to express cancer testis antigens. In this review, we discuss the current status of immunotherapy in STS, including data from human studies with cancer vaccines, adoptive cell therapy, and immune checkpoint blockade. Further research into STS immunology is needed to help design logical, subtype-specific immunotherapeutic strategies. PMID:25625925

[Risc factors for assisted suicide for cancer patients - mental burden of bereaved].

PubMed

Gärtner, Caroline; Müller-Busch, H Christof

2015-12-01

Chronic and progressive disease represents a significant risk factor for suicidal behavior. Cancer patients have almost twice the rate of suicides compared to the general population. Based on a case report, the suicidal risk factors for cancer patients are presented. It is further investigated to what extent professional support by a mobile palliative care team can affect the wish for assisted suicide or the suicidal behavior generally among patients receiving palliative care. In addition, the mental impact on individuals, who were witnesses of assisted suicide of relatives or close friends are presented. The occurrence of posttraumatic stress disorder (PTSD), depressions, anxiety disorders and complicated grief (CG) in close family members is shown. However, further research will be necessary to develop adequate support for patients (and their relatives), who plan an assisted suicide.

Perspectives of drug-based neuroprotection targeting mitochondria.

PubMed

Procaccio, V; Bris, C; Chao de la Barca, J M; Oca, F; Chevrollier, A; Amati-Bonneau, P; Bonneau, D; Reynier, P

2014-05-01

Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

New insights into adipokines as potential biomarkers for type-2 diabetes mellitus.

PubMed

Olivera Santa-Catalina, Marta; Redondo, Pedro C; Cantonero, C; Granados, Maria P; Sanchez-Collado, Jose; Albarran, Letizia; Lopez, Jose Javier

2017-12-05

A large number of studies have been focused on investigating serum biomarkers associated with risk or diagnosis of type-2 diabetes mellitus. In the last decade, promising studies have shown that circulating levels of adipokines could be used as a relevant biomarker for diabetes mellitus progression as well as therapeutic future targets. Here we discuss the possible use of recent described adipokines, including apelin, omentin-1, resistin, FGF-21, neuregulin-4 and visfatin, as early biomarkers for diabetes. In addition, we also include recent findings of other well know adipokines such as leptin and adiponectin. In conclusion, further studies are needed to clarify the pathophysiological significance and clinical value of these biological factors as potential biomarkers in type-2 diabetes and related dysfunctions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Combining UASB technology and advanced oxidation processes (AOPs) to treat food processing wastewaters.

PubMed

Sigge, G O; Britz, J; Fourie, P C; Barnardt, C A; Strydom, R

2002-01-01

UASB treatment of fruit cannery and winery effluents was shown to be feasible. However, the treated effluents still have residual COD levels well above the legal limit of 75 mg.l(-1) for direct discharge to a water system and a form of post-treatment is necessary to reduce the COD further. Ozone and ozone/hydrogen peroxide were used in combination with a granular activated carbon contacting column to assess the effectiveness as a post-treatment option for the UASB treated fruit cannery and winery effluent. Colour reduction in the effluents ranged from 66 to 90% and COD reductions of 27-55% were achieved. The combination of ozone and hydrogen peroxide gave better results than ozonation alone. Significant progress was thus made in achieving the legal limit of 75 mg.l(-1).

Genetic diversity of the human immunoglobulin heavy chain VH region.

PubMed

Li, Honghua; Cui, Xiangfeng; Pramanik, Sreemanta; Chimge, Nyam-Osor

2002-12-01

The human immunoglobulin heavy chain VH region is one of the most complex regions in the human genome. The high level of diversity of this region has been shown by a number of studies. However, because of the limitations of the conventional experimental methods, it has been difficult to learn the extent of the diversity and the underlying mechanisms. This review describes a number of new genetic approaches developed in the authors' laboratory. By using these approaches, significant progress has been made in assigning different VH sequences to their respective loci, in learning the diversity of gene segment number and composition among the VH haplotypes, and in learning VH gene segment organization in individual haplotypes. Information obtained toward this direction could help in understanding the mechanisms underlying VH region diversity and the biological impact of the VH region diversity.

Transmission environmental scanning electron microscope with scintillation gaseous detection device.

PubMed

Danilatos, Gerasimos; Kollia, Mary; Dracopoulos, Vassileios

2015-03-01

A transmission environmental scanning electron microscope with use of a scintillation gaseous detection device has been implemented. This corresponds to a transmission scanning electron microscope but with addition of a gaseous environment acting both as environmental and detection medium. A commercial type of low vacuum machine has been employed together with appropriate modifications to the detection configuration. This involves controlled screening of various emitted signals in conjunction with a scintillation gaseous detection device already provided with the machine for regular surface imaging. Dark field and bright field imaging has been obtained along with other detection conditions. With a progressive series of modifications and tests, the theory and practice of a novel type of microscopy is briefly shown now ushering further significant improvements and developments in electron microscopy as a whole. Copyright © 2014 Elsevier B.V. All rights reserved.

Determination of atomic vacancies in InAs/GaSb strained-layer superlattices by atomic strain

DOE PAGES

Kim, Honggyu; Meng, Yifei; Kwon, Ji-Hwan; ...

2018-01-01

Determining vacancy in complex crystals or nanostructures represents an outstanding crystallographic problem that has a large impact on technology, especially for semiconductors, where vacancies introduce defect levels and modify the electronic structure. However, vacancy is hard to locate and its structure is difficult to probe experimentally. Reported here are atomic vacancies in the InAs/GaSb strained-layer superlattice (SLS) determined by atomic-resolution strain mapping at picometre precision. It is shown that cation and anion vacancies in the InAs/GaSb SLS give rise to local lattice relaxations, especially the nearest atoms, which can be detected using a statistical method and confirmed by simulation. Themore » ability to map vacancy defect-induced strain and identify its location represents significant progress in the study of vacancy defects in compound semiconductors.« less

Circular RNAs: Regulators of Cancer-Related Signaling Pathways and Potential Diagnostic Biomarkers for Human Cancers

PubMed Central

Yang, Zuozhang; Xie, Lin; Han, Lei; Qu, Xin; Yang, Yihao; Zhang, Ya; He, Zewei; Wang, Yu; Li, Jing

2017-01-01

Circular RNAs (circRNAs) are newly discovered endogenous non-coding RNAs featuring structural stability, high abundance, and tissue-specific expression. CircRNAs are prevalent and conserved in mammalian cells. They are involved in cellular processes and regulate gene expression at the transcriptional or post-transcriptional level by interacting with microRNAs (miRNAs) and other molecules. Recent studies have shown that circRNAs play an important role in the progression of various human diseases including atherosclerosis, nervous system disorders, diabetes, and cancer. In this review, we summarize the advances on endogenous circRNAs in eukaryotic cells and elucidate their diagnostic and prognostic significance in human cancers. Especially, we highlight the involvement of circRNAs in signal transduction pathways as well as their clinical potential to serve as biomarkers. PMID:28839467

Impact of Tumour Epithelial Subtype on Circulating microRNAs in Breast Cancer Patients

PubMed Central

Brougham, Cathy; Glynn, Claire L.; Wall, Deirdre; Hyland, Peter; Duignan, Maria; McLoughlin, Mark; Newell, John; Kerin, Michael J.

2014-01-01

While a range of miRNAs have been shown to be dysregulated in the circulation of patients with breast cancer, little is known about the relationship between circulating levels and tumour characteristics. The aim of this study was to analyse alterations in circulating miRNA expression during tumour progression in a murine model of breast cancer, and to detemine the clinical relevance of identified miRNAs at both tissue and circulating level in patient samples. Athymic nude mice received a subcutaneous or mammary fat pad injection of MDA-MB-231 cells. Blood sampling was performed at weeks 1, 3 and 6 following tumour induction, and microRNA extracted. MicroRNA microArray analysis was performed comparing samples harvested at week 1 to those collected at week 6 from the same animals. Significantly altered miRNAs were validated across all murine samples by RQ-PCR (n = 45). Three miRNAs of interest were then quantified in the circulation(n = 166) and tissue (n = 100) of breast cancer patients and healthy control individuals. MicroArray-based analysis of murine blood samples revealed levels of 77 circulating microRNAs to be changed during disease progression, with 44 demonstrating changes >2-fold. Validation across all samples revealed miR-138 to be significantly elevated in the circulation of animals during disease development, with miR-191 and miR-106a levels significantly decreased. Analysis of patient tissue and blood samples revealed miR-138 to be significantly up-regulated in the circulation of patients with breast cancer, with no change observed in the tissue setting. While not significantly changed overall in breast cancer patients compared to controls, circulating miR-106a and miR-191 were significantly decreased in patients with basal breast cancer. In tissue, both miRNAs were significantly elevated in breast cancer compared to normal breast tissue. The data demonstrates an impact of tumour epithelial subtype on circulating levels of miRNAs, and highlights divergent miRNA profiles between tissue and blood samples from breast cancer patients. PMID:24626163

A single cyclin–CDK complex is sufficient for both mitotic and meiotic progression in fission yeast

PubMed Central

Gutiérrez-Escribano, Pilar; Nurse, Paul

2015-01-01

The dominant model for eukaryotic cell cycle control proposes that cell cycle progression is driven by a succession of CDK complexes with different substrate specificities. However, in fission yeast it has been shown that a single CDK complex generated by the fusion of the Cdc13 cyclin with the CDK protein Cdc2 can drive the mitotic cell cycle. Meiosis is a modified cell cycle programme in which a single S-phase is followed by two consecutive rounds of chromosome segregation. Here we systematically analyse the requirements of the different fission yeast cyclins for meiotic cell cycle progression. We also show that a single Cdc13–Cdc2 complex, in the absence of the other cyclins, can drive the meiotic cell cycle. We propose that qualitatively different CDK complexes are not absolutely required for cell cycle progression either during mitosis or meiosis, and that a single CDK complex can drive both cell cycle programmes. PMID:25891897

Clinical role of non-invasive assessment of portal hypertension.

PubMed

Bolognesi, Massimo; Di Pascoli, Marco; Sacerdoti, David

2017-01-07

Measurement of portal pressure is pivotal in the evaluation of patients with liver cirrhosis. The measurement of the hepatic venous pressure gradient represents the reference method by which portal pressure is estimated. However, it is an invasive procedure that requires significant hospital resources, including experienced staff, and is associated with considerable cost. Non-invasive methods that can be reliably used to estimate the presence and the degree of portal hypertension are urgently needed in clinical practice. Biochemical and morphological parameters have been proposed for this purpose, but have shown disappointing results overall. Splanchnic Doppler ultrasonography and the analysis of microbubble contrast agent kinetics with contrast-enhanced ultrasonography have shown better accuracy for the evaluation of patients with portal hypertension. A key advancement in the non-invasive evaluation of portal hypertension has been the introduction in clinical practice of methods able to measure stiffness in the liver, as well as stiffness/congestion in the spleen. According to the data published to date, it appears to be possible to rule out clinically significant portal hypertension in patients with cirrhosis ( i.e ., hepatic venous pressure gradient ≥ 10 mmHg) with a level of clinically-acceptable accuracy by combining measurements of liver stiffness and spleen stiffness along with Doppler ultrasound evaluation. It is probable that the combination of these methods may also allow for the identification of patients with the most serious degree of portal hypertension, and ongoing research is helping to ensure progress in this field.

Clinical role of non-invasive assessment of portal hypertension

PubMed Central

Bolognesi, Massimo; Di Pascoli, Marco; Sacerdoti, David

2017-01-01

Measurement of portal pressure is pivotal in the evaluation of patients with liver cirrhosis. The measurement of the hepatic venous pressure gradient represents the reference method by which portal pressure is estimated. However, it is an invasive procedure that requires significant hospital resources, including experienced staff, and is associated with considerable cost. Non-invasive methods that can be reliably used to estimate the presence and the degree of portal hypertension are urgently needed in clinical practice. Biochemical and morphological parameters have been proposed for this purpose, but have shown disappointing results overall. Splanchnic Doppler ultrasonography and the analysis of microbubble contrast agent kinetics with contrast-enhanced ultrasonography have shown better accuracy for the evaluation of patients with portal hypertension. A key advancement in the non-invasive evaluation of portal hypertension has been the introduction in clinical practice of methods able to measure stiffness in the liver, as well as stiffness/congestion in the spleen. According to the data published to date, it appears to be possible to rule out clinically significant portal hypertension in patients with cirrhosis (i.e., hepatic venous pressure gradient ≥ 10 mmHg) with a level of clinically-acceptable accuracy by combining measurements of liver stiffness and spleen stiffness along with Doppler ultrasound evaluation. It is probable that the combination of these methods may also allow for the identification of patients with the most serious degree of portal hypertension, and ongoing research is helping to ensure progress in this field. PMID:28104976

Integrating Pet Therapy into Daily School Life

ERIC Educational Resources Information Center

Brous, Miriam T.

2010-01-01

Stories abound in literature of the ways that people and their pets have fostered and created valuable relationships. More recently, research has shown a strong impact from the pet relationship in health-related settings. Positive changes have been seen in people developing resilience, self-reliance, and in making progress in treatment. Children…

Creating Community through Mentoring

ERIC Educational Resources Information Center

Erickson, Deborah E.; Travick-Jackson, Cecelia

2006-01-01

This research studies a doctoral program that includes a cohort component. Candidates engage in active learning and in the skill of mentoring. Research on peer mentoring has shown to support graduate students as they progress in their study (Luna & Cullen, 1998). Analysis of the data found themes relating to mentoring and community: candidates…

The roles of picornavirus untranslated regions in infection and innate immunity

USDA-ARS?s Scientific Manuscript database

Viral genomes have evolved to maximize their potential of overcoming host defense mechanisms and to induce a variety of disease syndromes. Structurally, a genome of a virus consists of coding and noncoding regions, and both have been shown to contribute to initiation and progression of disease. Ac...

Spatializing Critical Education: Progress and Cautions

ERIC Educational Resources Information Center

Ferrare, Joseph J.; Apple, Michael W.

2010-01-01

Recently critical scholars have shown a renewed interest in spatial relations in educational contexts. In this essay we use selections from Gulson and Symes's edited volume "Spatial theories of education" as a point of departure to examine what spatial analysis can contribute to the critical education traditions. We argue that, when done…

Including Students with Visual Impairments: Softball

ERIC Educational Resources Information Center

Brian, Ali; Haegele, Justin A.

2014-01-01

Research has shown that while students with visual impairments are likely to be included in general physical education programs, they may not be as active as their typically developing peers. This article provides ideas for equipment modifications and game-like progressions for one popular physical education unit, softball. The purpose of these…

Sugar-sweetened beverage but not diet soda consumption is positively associated with progression of insulin resistance and prediabetes

USDA-ARS?s Scientific Manuscript database

Background: Previous studies have shown an inconsistent relationship between habitual beverage consumption and insulin resistance and prediabetes. Objective: The objective of the present study was to test the hypothesis that the consumption of sugar-sweetened beverages (SSBs), rather than diet soda,...

Financing Class Size Reduction

ERIC Educational Resources Information Center

Achilles, C. M.

2005-01-01

Class size reduction has been shown to, among other things, improve academic achievement for all students and particularly for low-income and minority students. With the No Child Left Behind Act's heavy emphasis on scientifically based research, adequate yearly progress, and disaggregated results, one wonders why all children aren't enrolled in…

Progress on genotyping and phenotyping recombinant inbred line populations of peanut

USDA-ARS?s Scientific Manuscript database

The biolistic method is reliable for delivering genes of interest into various species. Low transformation efficiency has been a limiting factor for its application. The DNA coating agent protamine was shown to improve transformation efficiency in rice, while a reduction of plasmid DNA in the bomb...

The Impact of Brain-Based Strategies: One School's Perspective

ERIC Educational Resources Information Center

Hodges, Jane Allen

2013-01-01

Research has shown student inattention, off-task behaviors, and lack of listening skills in the classroom can impact progress in reading, math, and language development. Lack of verbal interaction in home environments, variations in learning and teaching modalities, and larger class sizes contribute to the difficulties students have in developing…

Restoration of normal phenotype in cancer cells

DOEpatents

Bissell, M.J.; Weaver, V.M.

1998-12-08

A method for reversing expression of malignant phenotype in cancer cells is described. The method comprises applying {beta}{sub 1} integrin function-blocking antibody to the cells. The method can be used to assess the progress of cancer therapy. Human breast epithelial cells were shown to be particularly responsive. 14 figs.

The Federal Role in Education Reform.

ERIC Educational Resources Information Center

Allen, James E., Jr.

One principal set of obstacles preventing public education from having shown more progress in realizing the national objective of equal educational opportunity has to do with the way schools are financed. Resolving problems of school finance is, U.S. Commissioner of Education Allen says, an absolute essential in achieving equal opportunity. Some…

Motivating the Drug Addict in Treatment

ERIC Educational Resources Information Center

St. Pierre, C. Andre

1971-01-01

Experience with numbers of drug addicts has shown them to be singularly unmotivated to discontinue drug use. To develop motivation, a treatment program is described in terms of motivational progression: (1) confrontation of the problem; (2) development of an intellectual understanding of the problem and its harmful effects; and (3) development of…