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Sample records for reduce clinical target

  1. Using Histopathology Breast Cancer Data to Reduce Clinical Target Volume Margins at Radiotherapy

    SciTech Connect

    Stroom, Joep Schlief, Angelique; Alderliesten, Tanja; Peterse, Hans; Bartelink, Harry; Gilhuijs, Kenneth

    2009-07-01

    Purpose: This study aimed to quantify the incidence and extension of microscopic disease around primary breast tumors in patients undergoing breast-conserving therapy (BCT), focusing on a potential application to reduce radiotherapy boost volumes. Methods and Materials: An extensive pathology tumor-distribution study was performed using 38 wide local excision specimens of BCT patients. Specimen orientation was recorded and microscopic findings reconstructed to assess the incidence of microscopic disease around the macroscopic tumor. A model of disease spread was built, showing probability of disease extension outside a treated volume (P{sub out,vol}). The model was applied in 10 new BCT patients. Taking asymmetry of tumor excision into account, new asymmetric margins for the clinical target volume of the boost (CTV{sub boost}) were evaluated that minimize the volume without increasing P{sub out,TTV} (TTV being total treated volume: V{sub surgery} + CTV{sub boost}). Potential reductions in CTV{sub boost} and TTV were evaluated. Results: Microscopic disease beyond the tumor boundary occurred isotropically at distances > 1 cm (intended surgical margin) and > 1.5 cm (intended TTV margin) in 53% and 36% of the excision specimens, respectively. In the 10 prospective patients, the average P{sub out,TTV} was, however, only 16% due to larger surgical margins than intended in some directions. Asymmetric CTV{sub boost} margins reduced the CTV{sub boost} and TTV by 27% (20 cc) and 12% (21 cc) on average, without compromising tumor coverage. Conclusions: Microscopic disease extension may occur beyond the current CTV{sub boost} in approximately one sixth of patients. An asymmetric CTV{sub boost} that corrects for asymmetry of the surgical excision has the potential to reduce boost volumes while maintaining tumor coverage.

  2. Targeting the Use of Pooled HIV RNA Screening to Reduce Cost in Health Department STD Clinics: New York City, 2009–2011

    PubMed Central

    Pathela, Preeti; Pirillo, Robert; Blank, Susan

    2015-01-01

    Objective Staff at public New York City sexually transmitted disease (STD) clinics screen patients for acute HIV infection (AHI) using pooled nucleic acid amplification tests. AHI screening is expensive but important for populations at high risk of acquiring HIV. We analyzed if targeting AHI screening in STD clinics could reduce program costs while maintaining AHI case detection. Methods From January 2009 through May 2010, we screened all patients with negative rapid HIV tests for AHI. Using risk information on cases detected during this universal screening period, we developed criteria for targeted AHI screening and compared case yields and testing costs during 12 months of universal screening (June 2009 through May 2010) vs. 12 months of targeted screening (June 2010 through May 2011). Results During the defined period of universal screening, we identified 40 AHI cases, and during targeted screening, we identified 35 AHI cases. Because of targeting efforts, the number needed to test to find one AHI case dropped from 1,631 to 254. With targeted screening, it cost an average of $4,535 per case detected and 39.3 cases were detected per 10,000 specimens; using universal screening, $29,088 was spent per case detected and 6.1 cases were detected per 10,000 specimens processed. Conclusion Targeted screening identified similar numbers of AHI cases as when screening all clinic patients seeking HIV testing, but at one-seventh the cost. PMID:25552758

  3. Community-Based Health Education Programs Designed to Improve Clinical Measures Are Unlikely to Reduce Short-Term Costs or Utilization Without Additional Features Targeting These Outcomes.

    PubMed

    Burton, Joe; Eggleston, Barry; Brenner, Jeffrey; Truchil, Aaron; Zulkiewicz, Brittany A; Lewis, Megan A

    2016-06-07

    Stakeholders often expect programs for persons with chronic conditions to "bend the cost curve." This study assessed whether a diabetes self-management education (DSME) program offered as part of a multicomponent initiative could affect emergency department (ED) visits, hospital stays, and the associated costs for an underserved population in addition to the clinical indicators that DSME programs attempt to improve. The program was implemented in Camden, New Jersey, by the Camden Coalition of Healthcare Providers to address disparities in diabetes care. Data used are from medical records and from patient-level information about hospital services from Camden's hospitals. Using multivariate regression models to control for individual characteristics, changes in utilization over time and changes relative to 2 comparison groups were assessed. No reductions in ED visits, inpatient stays, or costs for participants were found over time or relative to the comparison groups. High utilization rates and costs for diabetes are associated with longer term disease progression and its sequelae; thus, DSME or peer support may not affect these in the near term. Some clinical indicators improved among participants, and these might lead to fewer costly adverse health events in the future. DSME deployed at the community level, without explicit segmentation and targeting of high health care utilizers or without components designed to affect costs and utilization, should not be expected to reduce short-term medical needs for participating individuals or care-seeking behaviors such that utilization is reduced. Stakeholders must include financial outcomes in a program's design if those outcomes are to improve. (Population Health Management 20XX;XX:XXX-XXX).

  4. Targets set to reduce Lake Erie algae

    USGS Publications Warehouse

    Evans, Mary

    2016-01-01

    In February 2016, the Great Lakes Executive Committee, which oversees the implementation of the Great Lakes Water Quality Agreement (GLWQA) between the U.S. and Canada, approved phosphorus loading targets for Lake Erie to reduce the size of harmful algal blooms (HABs), reduce the presence of the low oxygen zone in the central basin, and protect nearshore water quality. The targets are set with respect to the nutrient loads calculated for 2008. To reduce the impacts of HABs on Lake Erie a target was set of a 40 percent reduction in total and soluble reactive phosphorus loads in the spring from two Canadian rivers and several Michigan and Ohio rivers, especially the Maumee River (https://binational.net/2016/02/22/ finalptargets-ciblesfinalesdep/). States and the province of Ontario are already developing Domestic Action Plans to accomplish the reductions and scientists are developing research and monitoring plans to assess progress.

  5. Isochoric Heating of Reduced Mass Targets

    SciTech Connect

    Akli, Kramer

    2015-11-13

    This report summarizes the experimental results of a study aimed at achieving star-like plasmas in the laboratory by isochrically heating solid-density targets with intense lasers. Of special interest is the investigation of spatial/temporal temperature and density gradients and their dependence on the target geometry and mass. The investigation was carried out in two phases. In the first phase, solid targets with variable transverse and longitudinal dimensions were investigated. We found that electron beam recirculation is enhanced for reduced mass targets. As a result, the temperature gradients are minimized for these targets yielding more uniform temperature hot plasmas. In the second phase, reduced mass targets were irradiated with intense ultra-short laser pulses. Bright monochromatic x-rays and broadband Extreme ultraviolet radiation (EUV or XUV) emissions were achieved by optimizing the electrostatic sheath fields surrounding the target. The study also revealed that this laser-driven source of radiation has a small source size, short duration, and high photon fluxes suitable for point projection radiography and for probing matter under extreme environments.

  6. Targeting incentives to reduce habitat fragmentation

    Treesearch

    David Lewis; Andrew Plantinga; Junjie Wu

    2009-01-01

    This article develops a theoretical model to analyze the spatial targeting of incentives for the restoration of forested landscapes when wildlife habitat can be enhanced by reducing fragmentation. The key theoretical result is that the marginal net benefits of increasing forest can be convex, in which case corner solutions--converting either none or all of the...

  7. Targeting Quality Improvement in Clinical Practice Guidelines.

    PubMed

    Mims, James W

    2015-12-01

    Clinical practice guidelines provide key action statements targeted at quality improvements. Areas of potential quality improvement can be identified by exploring known contributors to cognitive errors. Three common contributors to medical error and reduced quality care are (1) the complexity of modern medicine, (2) the tendency to apply cause and effect to random associations, and (3) our bias to our first intuition. Future authors of clinical practice guidelines should consider these 3 influences when deciding how to best provide guidance to improve patient care. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

  8. The proinsulin/insulin (PI/I) ratio is reduced by postprandial targeting therapy in type 2 diabetes mellitus: a small-scale clinical study

    PubMed Central

    2013-01-01

    Background An elevated PI/I ratio is attributable to increased secretory demand on β-cells. However, the effect of postprandial targeting therapy on proinsulin level is unknown. We evaluated the metabolic effect of glinide and sulfonylurea (SU) using the meal tolerance test (MTT). Methods MTT was applied to previously untreated Type 2 Diabetes Mellitus (T2DM) subjects. Twenty-two participants were given a test meal (450 kcal). Plasma glucose and insulin were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum proinsulin and C-peptide immunoreactivity (CPR) were measured at 0 and 120 min. Postprandial profile was assessed at baseline and following 3 months treatment with either mitiglinide or glimepiride. Results Plasma glucose level at 30, 60, 120, and 180 min was significantly improved by mitiglinide. Whereas, glimepiride showed a significant improve plasma glucose at 0, 180 min. Peak IRI shifted from 120 to 30 min by mitiglinide treatment. The pattern of insulin secretion was not changed by glimepiride treatment. Whereas mitiglinide did not affect the PI/I ratio, glimepiride tended to increase the PI/I ratio. Moreover, although mitiglinide did not affect PI/I ratio as a whole, marked reduction was noted in some patients treated by mitiglinide. PI/I ratio was reduced significantly in the responder group. The responder subgroup exhibited less insulin resistance and higher insulinogenic index at baseline than non-responders. Moreover, the triglyceride level of responders was significantly lower than that of non-responders. Conclusions Mitiglinide improved postprandial insulin secretion pattern and thereby suppressed postprandial glucose spike. In T2DM patients with low insulin resistance and low triglyceride, mitiglinide recovered impaired β-cell function from the viewpoint of the PI/I ratio. Trial registration UMIN-CTR: UMIN000010467 PMID:24215809

  9. Targeting lysyl oxidase reduces peritoneal fibrosis

    PubMed Central

    Wu, Xuan; van Deemter, Marielle; Gardiner, Fiona; Poland, Craig; Green, Rebecca; Sarvi, Sana; Brown, Pamela; Kadler, Karl E.; Lu, Yinhui; Mason, J. Ian; Critchley, Hilary O. D.; Hillier, Stephen G.

    2017-01-01

    Background Abdominal surgery and disease cause persistent abdominal adhesions, pelvic pain, infertility and occasionally, bowel obstruction. Current treatments are ineffective and the aetiology is unclear, although excessive collagen deposition is a consistent feature. Lysyl oxidase (Lox) is a key enzyme required for crosslinking and deposition of insoluble collagen, so we investigated whether targeting Lox might be an approach to reduce abdominal adhesions. Methods Female C57Bl/6 mice were treated intraperitoneally with multiwalled carbon nanotubes (NT) to induce fibrosis, together with chemical (ß-aminoproprionitrile–BAPN) or miRNA Lox inhibitors, progesterone or dexamethasone. Fibrotic lesions on the diaphragm, and expression of fibrosis-related genes in abdominal wall peritoneal mesothelial cells (PMC) were measured. Effects of BAPN and dexamethasone on collagen fibre alignment were observed by TEM. Isolated PMC were cultured with interleukin-1 alpha (IL-1α) and progesterone to determine effects on Lox mRNA in vitro. Results NT-induced fibrosis and collagen deposition on the diaphragm was ameliorated by BAPN, Lox miRNA, or steroids. BAPN and dexamethasone disrupted collagen fibres. NT increased PMC Lox, Col1a1, Col3a1 and Bmp1 mRNA, which was inhibited by steroids. Progesterone significantly inhibited IL-1α induced Lox expression by PMC in vitro. Conclusion Our results provide proof-of-concept that targeting peritoneal Lox could be an effective approach in ameliorating fibrosis and adhesion development. PMID:28800626

  10. Targeting ApoC-III to Reduce Coronary Disease Risk.

    PubMed

    Khetarpal, Sumeet A; Qamar, Arman; Millar, John S; Rader, Daniel J

    2016-09-01

    Triglyceride-rich lipoproteins (TRLs) are causal contributors to the risk of developing coronary artery disease (CAD). Apolipoprotein C-III (apoC-III) is a component of TRLs that elevates plasma triglycerides (TGs) through delaying the lipolysis of TGs and the catabolism of TRL remnants. Recent human genetics approaches have shown that heterozygous loss-of-function mutations in APOC3, the gene encoding apoC-III, lower plasma TGs and protect from CAD. This observation has spawned new interest in therapeutic efforts to target apoC-III. Here, we briefly review both currently available as well as developing therapies for reducing apoC-III levels and function to lower TGs and cardiovascular risk. These therapies include existing options including statins, fibrates, thiazolidinediones, omega-3-fatty acids, and niacin, as well as an antisense oligonucleotide targeting APOC3 currently in clinical development. We review the mechanisms of action by which these drugs reduce apoC-III and the current understanding of how reduction in apoC-III may impact CAD risk.

  11. Optimizing biologically targeted clinical trials for neurofibromatosis

    PubMed Central

    Gutmann, David H; Blakeley, Jaishri O; Korf, Bruce R; Packer, Roger J

    2014-01-01

    Introduction The neurofibromatoses (neurofibromatosis type 1, NF1 and neurofibromatosis type 2, NF2) comprise the most common inherited conditions in which affected children and adults develop tumors of the central and peripheral nervous system. In this review, the authors discuss how the establishment of the Neurofibromatosis Clinical Trials Consortium (NFCTC) has positively impacted on the design and execution of treatment studies for individuals with NF1 and NF2. Areas covered Using an extensive PUBMED search in collaboration with select NFCTC members expert in distinct NF topics, the authors discuss the clinical features of NF1 and NF2, the molecular biology of the NF1 and NF2 genes, the development and application of clinically relevant Nf1 and Nf2 genetically engineered mouse models and the formation of the NFCTC to enable efficient clinical trial design and execution. Expert opinion The NFCTC has resulted in a more seamless integration of mouse preclinical and human clinical trials efforts. Leveraging emerging enabling resources, current research is focused on identifying subtypes of tumors in NF1 and NF2 to deliver the most active compounds to the patients most likely to respond to the targeted therapy. PMID:23425047

  12. Optimizing biologically targeted clinical trials for neurofibromatosis.

    PubMed

    Gutmann, David H; Blakeley, Jaishri O; Korf, Bruce R; Packer, Roger J

    2013-04-01

    The neurofibromatoses (neurofibromatosis type 1, NF1 and neurofibromatosis type 2, NF2) comprise the most common inherited conditions in which affected children and adults develop tumors of the central and peripheral nervous system. In this review, the authors discuss how the establishment of the Neurofibromatosis Clinical Trials Consortium (NFCTC) has positively impacted on the design and execution of treatment studies for individuals with NF1 and NF2. Using an extensive PUBMED search in collaboration with select NFCTC members expert in distinct NF topics, the authors discuss the clinical features of NF1 and NF2, the molecular biology of the NF1 and NF2 genes, the development and application of clinically relevant Nf1 and Nf2 genetically engineered mouse models and the formation of the NFCTC to enable efficient clinical trial design and execution. The NFCTC has resulted in a more seamless integration of mouse preclinical and human clinical trials efforts. Leveraging emerging enabling resources, current research is focused on identifying subtypes of tumors in NF1 and NF2 to deliver the most active compounds to the patients most likely to respond to the targeted therapy.

  13. Quality of clinical trials: A moving target

    PubMed Central

    Bhatt, Arun

    2011-01-01

    Quality of clinical trials depends on data integrity and subject protection. Globalization, outsourcing and increasing complexicity of clinical trials have made the target of achieving global quality challenging. The quality, as judged by regulatory inspections of the investigator sites, sponsors/contract research organizations and Institutional Review Board, has been of concern to the US Food and Drug Administration, as there has been hardly any change in frequency and nature of common deficiencies. To meet the regulatory expectations, the sponsors need to improve quality by developing systems with specific standards for each clinical trial process. The quality systems include: personnel roles and responsibilities, training, policies and procedures, quality assurance and auditing, document management, record retention, and reporting and corrective and preventive action. With an objective to improve quality, the FDA has planned new inspection approaches such as risk-based inspections, surveillance inspections, real-time oversight, and audit of sponsor quality systems. The FDA has partnered with Duke University for Clinical Trials Transformation Initiative, which will conduct research projects on design principles, data quality and quantity including monitoring, study start-up, and adverse event reporting. These recent initiatives will go a long way in improving quality of clinical trials. PMID:22145122

  14. Targeting inflammation: multiple innovative ways to reduce prostaglandin E₂.

    PubMed

    Norberg, Jessica K; Sells, Earlphia; Chang, Hui-Hua; Alla, Srinivas R; Zhang, Shuxing; Meuillet, Emmanuelle J

    2013-03-01

    The PGE2 pathway is important in inflammation-driven diseases and specific targeting of the inducible mPGES-1 is warranted due to the cardiovascular problems associated with the long-term use of COX-2 inhibitors. This review focuses on patents issued on methods of measuring mPGES-1 activity, on drugs targeting mPGES-1 and on other modulators of free extracellular PGE2 concentration. Perspectives and conclusions regarding the status of these drugs are also presented. Importantly, no selective inhibitors targeting mPGES-1 have been identified and, despite the high number of published patents, none of these drugs have yet made it to clinical trials.

  15. Targeting inflammation: multiple innovative ways to reduce prostaglandin E2

    PubMed Central

    Norberg, Jessica K; Sells, Earlphia; Chang, Hui-Hua; Alla, Srinivas R; Zhang, Shuxing; Meuillet, Emmanuelle J

    2014-01-01

    The PGE2 pathway is important in inflammation-driven diseases and specific targeting of the inducible mPGES-1 is warranted due to the cardiovascular problems associated with the long-term use of COX-2 inhibitors. This review focuses on patents issued on methods of measuring mPGES-1 activity, on drugs targeting mPGES-1 and on other modulators of free extracellular PGE2 concentration. Perspectives and conclusions regarding the status of these drugs are also presented. Importantly, no selective inhibitors targeting mPGES-1 have been identified and, despite the high number of published patents, none of these drugs have yet made it to clinical trials. PMID:24237030

  16. Targeted proteomic strategy for clinical biomarker discovery.

    PubMed

    Schiess, Ralph; Wollscheid, Bernd; Aebersold, Ruedi

    2009-02-01

    The high complexity and large dynamic range of blood plasma proteins currently prohibit the sensitive and high-throughput profiling of disease and control plasma proteome sample sets large enough to reliably detect disease indicating differences. To circumvent these technological limitations we describe here a new two-stage strategy for the mass spectrometry (MS) assisted discovery, verification and validation of disease biomarkers. In an initial discovery phase N-linked glycoproteins with distinguishable expression patterns in primary normal and diseased tissue are detected and identified. In the second step the proteins identified in the initial phase are subjected to targeted MS analysis in plasma samples, using the highly sensitive and specific selected reaction monitoring (SRM) technology. Since glycosylated proteins, such as those secreted or shed from the cell surface are likely to reside and persist in blood, the two-stage strategy is focused on the quantification of tissue derived glycoproteins in plasma. The focus on the N-glycoproteome not only reduces the complexity of the analytes, but also targets an information-rich subproteome which is relevant for remote sensing of diseases in the plasma. The N-glycoprotein based biomarker discovery and validation workflow reviewed here allows for the robust identification of protein candidate panels that can finally be selectively monitored in the blood plasma at high sensitivity in a reliable, non-invasive and quantitative fashion.

  17. Reduced Brillouin backscatter in CO2 laser-target interaction

    NASA Astrophysics Data System (ADS)

    Ng, A.; Offenberger, A. A.; Karttunen, S. J.

    1981-02-01

    A substantially reduced Brillouin reflection has been found for CO2 laser-irradiated high-density gas targets. In contrast to the high reflectivity (60%) previously observed for underdense hydrogen plasma, total backscatter (stimulated plus specular) is found to peak at 30% for incident intensity 5 times 10 to the twelfth W per square centimeter and decrease thereafter to 18% at 10 to the thirteenth W per square centimeter. The ponderomotive effects are postulated to account for these observations.

  18. Clinical targeting of the TNF and TNFR superfamilies

    PubMed Central

    Croft, Michael; Benedict, Chris A.; Ware, Carl F.

    2013-01-01

    Inhibitors of tumour necrosis factor (TNF) are among the most successful protein-based drugs (biologics) and have proven to be clinically efficacious at reducing inflammation associated with several autoimmune diseases. As a result, attention is focusing on the therapeutic potential of additional members of the TNF superfamily of structurally related cytokines. Many of these TNF-related cytokines or their cognate receptors are now in preclinical or clinical development as possible targets for modulating inflammatory diseases and cancer as well as other indications. This Review focuses on the biologics that are currently in clinical trials for immune-related diseases and other syndromes, discusses the successes and failures to date as well as the expanding therapeutic potential of modulating the activity of this superfamily of molecules. PMID:23334208

  19. Clinical applications of targeted temperature management.

    PubMed

    Perman, Sarah M; Goyal, Munish; Neumar, Robert W; Topjian, Alexis A; Gaieski, David F

    2014-02-01

    Targeted temperature management (TTM) has been investigated experimentally and used clinically for over 100 years. The initial rationale for the clinical application of TTM, historically referred to as therapeutic hypothermia, was to decrease the metabolic rate, allowing the injured brain time to heal. Subsequent research demonstrated the temperature dependence of diverse cellular mechanisms including endothelial dysfunction, production of reactive oxygen species, and apoptosis. Consequently, modern use of TTM centers on neuroprotection following focal or global neurologic injury. Despite a solid basic science rationale for applying TTM in a variety of disease processes, including cardiac arrest, traumatic brain injury, ischemic stroke, neonatal ischemic encephalopathy, sepsis-induced encephalopathy, and hepatic encephalopathy, human efficacy data are limited and vary greatly from disease to disease. Ten years ago, two landmark investigations yielded high-quality data supporting the application of TTM in comatose survivors of out-of-hospital cardiac arrest. Additionally, TTM has been demonstrated to improve outcomes for neonatal patients with anoxic brain injury secondary to hypoxic ischemic encephalopathy. Trials are currently under way, or have yielded conflicting results in, examining the utility of TTM for the treatment of ischemic stroke, traumatic brain injury, and acute myocardial infarction. In this review, we place TTM in historic context, discuss the pathophysiologic rationale for its use, review the general concept of a TTM protocol for the management of brain injury, address some of the common side effects encountered when lowering human body temperature, and examine the data for its use in diverse disease conditions with in-depth examination of TTM for postarrest care and pediatric applications.

  20. Reaching the global target to reduce stunting: an investment framework.

    PubMed

    Shekar, Meera; Kakietek, Jakub; D'Alimonte, Mary R; Rogers, Hilary E; Eberwein, Julia Dayton; Akuoku, Jon Kweku; Pereira, Audrey; Soe-Lin, Shan; Hecht, Robert

    2017-06-01

    Childhood stunting, being short for one's age, has life-long consequences for health, human capital and economic growth. Being stunted in early childhood is associated with slower cognitive development, reduced schooling attainment and adult incomes decreased by 5-53%. The World Health Assembly has endorsed global nutrition targets including one to reduce the number of stunted children under five by 40% by 2025. The target has been included in the Sustainable Development Goals (SDG target 2.2). This paper estimates the cost of achieving this target and develops scenarios for generating the necessary financing. We focus on a key intervention package for stunting (KIPS) with strong evidence of effectiveness. Annual scale-up costs for the period of 2016-25 were estimated for a sample of 37 high burden countries and extrapolated to all low and middle income countries. The Lives Saved Tool was used to model the impact of the scale-up on stunting prevalence. We analysed data on KIPS budget allocations and expenditure by governments, donors and households to derive a global baseline financing estimate. We modelled two financing scenarios, a 'business as usual', which extends the current trends in domestic and international financing for nutrition through 2025, and another that proposes increases in financing from all sources under a set of burden-sharing rules. The 10-year financial need to scale up KIPS is US$49.5 billion. Under 'business as usual', this financial need is not met and the global stunting target is not reached. To reach the target, current financing will have to increase from US$2.6 billion to US$7.4 billion a year on average. Reaching the stunting target is feasible but will require large coordinated investments in KIPS and a supportive enabling environment. The example of HIV scale-up over 2001-11 is instructive in identifying the factors that could drive such a global response to childhood stunting. © The Author 2017. Published by Oxford University

  1. Reaching the global target to reduce stunting: an investment framework

    PubMed Central

    Shekar, Meera; D’Alimonte, Mary R; Rogers, Hilary E; Eberwein, Julia Dayton; Akuoku, Jon Kweku; Pereira, Audrey; Soe-Lin, Shan; Hecht, Robert

    2017-01-01

    Abstract Childhood stunting, being short for one’s age, has life-long consequences for health, human capital and economic growth. Being stunted in early childhood is associated with slower cognitive development, reduced schooling attainment and adult incomes decreased by 5–53%. The World Health Assembly has endorsed global nutrition targets including one to reduce the number of stunted children under five by 40% by 2025. The target has been included in the Sustainable Development Goals (SDG target 2.2). This paper estimates the cost of achieving this target and develops scenarios for generating the necessary financing. We focus on a key intervention package for stunting (KIPS) with strong evidence of effectiveness. Annual scale-up costs for the period of 2016–25 were estimated for a sample of 37 high burden countries and extrapolated to all low and middle income countries. The Lives Saved Tool was used to model the impact of the scale-up on stunting prevalence. We analysed data on KIPS budget allocations and expenditure by governments, donors and households to derive a global baseline financing estimate. We modelled two financing scenarios, a ‘business as usual’, which extends the current trends in domestic and international financing for nutrition through 2025, and another that proposes increases in financing from all sources under a set of burden-sharing rules. The 10-year financial need to scale up KIPS is US$49.5 billion. Under ‘business as usual’, this financial need is not met and the global stunting target is not reached. To reach the target, current financing will have to increase from US$2.6 billion to US$7.4 billion a year on average. Reaching the stunting target is feasible but will require large coordinated investments in KIPS and a supportive enabling environment. The example of HIV scale-up over 2001–11 is instructive in identifying the factors that could drive such a global response to childhood stunting. PMID:28453717

  2. Distributed Particle Filter for Target Tracking: With Reduced Sensor Communications.

    PubMed

    Ghirmai, Tadesse

    2016-09-09

    For efficient and accurate estimation of the location of objects, a network of sensors can be used to detect and track targets in a distributed manner. In nonlinear and/or non-Gaussian dynamic models, distributed particle filtering methods are commonly applied to develop target tracking algorithms. An important consideration in developing a distributed particle filtering algorithm in wireless sensor networks is reducing the size of data exchanged among the sensors because of power and bandwidth constraints. In this paper, we propose a distributed particle filtering algorithm with the objective of reducing the overhead data that is communicated among the sensors. In our algorithm, the sensors exchange information to collaboratively compute the global likelihood function that encompasses the contribution of the measurements towards building the global posterior density of the unknown location parameters. Each sensor, using its own measurement, computes its local likelihood function and approximates it using a Gaussian function. The sensors then propagate only the mean and the covariance of their approximated likelihood functions to other sensors, reducing the communication overhead. The global likelihood function is computed collaboratively from the parameters of the local likelihood functions using an average consensus filter or a forward-backward propagation information exchange strategy.

  3. Distributed Particle Filter for Target Tracking: With Reduced Sensor Communications

    PubMed Central

    Ghirmai, Tadesse

    2016-01-01

    For efficient and accurate estimation of the location of objects, a network of sensors can be used to detect and track targets in a distributed manner. In nonlinear and/or non-Gaussian dynamic models, distributed particle filtering methods are commonly applied to develop target tracking algorithms. An important consideration in developing a distributed particle filtering algorithm in wireless sensor networks is reducing the size of data exchanged among the sensors because of power and bandwidth constraints. In this paper, we propose a distributed particle filtering algorithm with the objective of reducing the overhead data that is communicated among the sensors. In our algorithm, the sensors exchange information to collaboratively compute the global likelihood function that encompasses the contribution of the measurements towards building the global posterior density of the unknown location parameters. Each sensor, using its own measurement, computes its local likelihood function and approximates it using a Gaussian function. The sensors then propagate only the mean and the covariance of their approximated likelihood functions to other sensors, reducing the communication overhead. The global likelihood function is computed collaboratively from the parameters of the local likelihood functions using an average consensus filter or a forward-backward propagation information exchange strategy. PMID:27618057

  4. Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis

    PubMed Central

    Mortensen, Martin B.; Kjolby, Mads; Gunnersen, Stine; Larsen, Jakob V.; Palmfeldt, Johan; Falk, Erling; Nykjaer, Anders; Bentzon, Jacob F.

    2014-01-01

    Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding sortilin (SORT1) has been implicated as the causative gene within the locus, as sortilin regulates hepatic lipoprotein metabolism. Here we demonstrated that sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In a mouse model of atherosclerosis, deletion of Sort1 did not alter plasma cholesterol levels, but reduced the development of both early and late atherosclerotic lesions. We determined that sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-γ. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-γ, but not of other measured cytokines. Transfer of sortilin-deficient BM into irradiated atherosclerotic mice reduced atherosclerosis and systemic markers of inflammation. Together, these data demonstrate that sortilin influences cytokine secretion and that targeting sortilin in immune cells attenuates inflammation and reduces atherosclerosis. PMID:25401472

  5. Enhanced clinical pharmacy service targeting tools: risk-predictive algorithms.

    PubMed

    El Hajji, Feras W D; Scullin, Claire; Scott, Michael G; McElnay, James C

    2015-04-01

    This study aimed to determine the value of using a mix of clinical pharmacy data and routine hospital admission spell data in the development of predictive algorithms. Exploration of risk factors in hospitalized patients, together with the targeting strategies devised, will enable the prioritization of clinical pharmacy services to optimize patient outcomes. Predictive algorithms were developed using a number of detailed steps using a 75% sample of integrated medicines management (IMM) patients, and validated using the remaining 25%. IMM patients receive targeted clinical pharmacy input throughout their hospital stay. The algorithms were applied to the validation sample, and predicted risk probability was generated for each patient from the coefficients. Risk threshold for the algorithms were determined by identifying the cut-off points of risk scores at which the algorithm would have the highest discriminative performance. Clinical pharmacy staffing levels were obtained from the pharmacy department staffing database. Numbers of previous emergency admissions and admission medicines together with age-adjusted co-morbidity and diuretic receipt formed a 12-month post-discharge and/or readmission risk algorithm. Age-adjusted co-morbidity proved to be the best index to predict mortality. Increased numbers of clinical pharmacy staff at ward level was correlated with a reduction in risk-adjusted mortality index (RAMI). Algorithms created were valid in predicting risk of in-hospital and post-discharge mortality and risk of hospital readmission 3, 6 and 12 months post-discharge. The provision of ward-based clinical pharmacy services is a key component to reducing RAMI and enabling the full benefits of pharmacy input to patient care to be realized. © 2014 John Wiley & Sons, Ltd.

  6. Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status.

    PubMed

    van der Meel, Roy; Vehmeijer, Laurens J C; Kok, Robbert J; Storm, Gert; van Gaal, Ethlinn V B

    2013-10-01

    Since the introduction of Doxil® on the market nearly 20years ago, a number of nanomedicines have become part of treatment regimens in the clinic. With the exception of antibody-drug conjugates, these nanomedicines are all devoid of targeting ligands and rely solely on their physicochemical properties and the (patho)physiological processes in the body for their biodistribution and targeting capability. At the same time, many preclinical studies have reported on nanomedicines exposing targeting ligands, or ligand-targeted nanomedicines, yet none of these have been approved at this moment. In the present review, we provide a concise overview of 13 ligand-targeted particulate nanomedicines (ligand-targeted PNMs) that have progressed into clinical trials. The progress of each ligand-targeted PNM is discussed based on available (pre)clinical data. Main conclusions of these analyses are that (a) ligand-targeted PNMs have proven to be safe and efficacious in preclinical models; (b) the vast majority of ligand-targeted PNMs is generated for the treatment of cancer; (c) contribution of targeting ligands to the PNM efficacy is not unambiguously proven; and (d) targeting ligands do not cause localization of the PNM within the target tissue, but rather provide benefits in terms of target cell internalization and target tissue retention once the PNM has arrived at the target site. Increased understanding of the in vivo fate and interactions of the ligand-targeted PNMs with proteins and cells in the human body is mandatory to rationally advance the clinical translation of ligand-targeted PNMs. Future perspectives for ligand-targeted PNM approaches include the delivery of drugs that are unable or inefficient in passing cellular membranes, treatment of drug resistant tumors, targeting of the tumor blood supply, the generation of targeted vaccines and nanomedicines that are able to cross the blood-brain barrier.

  7. Mining internal data to reduce clinical costs.

    PubMed

    Teffeteller, Scott L; Kish, Thomas M

    2012-12-01

    Hospitals and health systems should undertake the following steps in pinpointing areas for clinical cost reduction: Identify potential areas of opportunity through an analysis of top discharges. Use severity-adjusted data to review variability by case. Review length of stay and resource consumption at a high level. Examine granular charge data and practice patterns. Determine action steps for improvement.

  8. Reducing Risk with Clinical Decision Support

    PubMed Central

    Maloney, F.L.; Feblowitz, J.; Samal, L.; Sato, L.; Wright, A.

    2014-01-01

    Summary Objective Identify clinical opportunities to intervene to prevent a malpractice event and determine the proportion of malpractice claims potentially preventable by clinical decision support (CDS). Materials and Methods Cross-sectional review of closed malpractice claims over seven years from one malpractice insurance company and seven hospitals in the Boston area. For each event, clinical opportunities to intervene to avert the malpractice event and the presence or absence of CDS that might have a role in preventing the event, were assigned by a panel of expert raters. Compensation paid out to resolve a claim (indemnity), was associated with each CDS type. Results Of the 477 closed malpractice cases, 359 (75.3%) were categorized as substantiated and 195 (54%) had at least one opportunity to intervene. Common opportunities to intervene related to performance of procedure, diagnosis, and fall prevention. We identified at least one CDS type for 63% of substantiated claims. The 41 CDS types identified included clinically significant test result alerting, diagnostic decision support and electronic tracking of instruments. Cases with at least one associated intervention accounted for $40.3 million (58.9%) of indemnity. Discussion CDS systems and other forms of health information technology (HIT) are expected to improve quality of care, but their potential to mitigate risk had not previously been quantified. Our results suggest that, in addition to their known benefits for quality and safety, CDS systems within HIT have a potential role in decreasing malpractice payments. Conclusion More than half of malpractice events and over $40 million of indemnity were potentially preventable with CDS. PMID:25298814

  9. Prostate Cancer Clinical Consortium Clinical Research Site:Targeted Therapies

    DTIC Science & Technology

    2015-10-01

    Cornell Medical College Prostate Cancer Research Program (WCMC-PCRP) is a Clinical Research Site of the Prostate Cancer Clinical Trials Consortium...effectively bring novel agents and new biomarker driven trials directly to patients 17 Table of Contents Page 1. Introduction...purpose and scope of the research. The Weill Cornell Medical College Prostate Cancer Research Program (WCMC-PCRP) is a Clinical Research Site of the

  10. Targeting the erythropoietin receptor on glioma cells reduces tumour growth

    SciTech Connect

    Peres, Elodie A.; Valable, Samuel; Guillamo, Jean-Sebastien; Marteau, Lena; Bernaudin, Jean-Francois; Roussel, Simon; Lechapt-Zalcman, Emmanuele; Bernaudin, Myriam; Petit, Edwige

    2011-10-01

    Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

  11. Evolution of targeted therapies in cancer: opportunities and challenges in the clinic.

    PubMed

    Santhosh, Sam; Kumar, Prasanna; Ramprasad, Vedam; Chaudhuri, Amitabha

    2015-01-01

    Targeted therapies have changed the course of cancer treatment in recent years. By reducing toxicity and improving outcome, these new generations of precision medicines have extended patient lives beyond what could be achieved by the use of nontargeted therapies. In the last 2 years, several new molecular entities targeting signaling proteins and immune pathways have gone through successful clinical development resulting in their approval. These new targeted therapies require patient selection and the discovery of biomarkers of response. This review discusses the evolution of targeted therapies in cancer and challenges in translating the concepts into clinical practice.

  12. PIK3R1 targeting by miR-21 suppresses tumor cell migration and invasion by reducing PI3K/AKT signaling and reversing EMT, and predicts clinical outcome of breast cancer.

    PubMed

    Yan, Li-Xu; Liu, Yan-Hui; Xiang, Jian-Wen; Wu, Qi-Nian; Xu, Lei-Bo; Luo, Xin-Lan; Zhu, Xiao-Lan; Liu, Chao; Xu, Fang-Ping; Luo, Dong-Lan; Mei, Ping; Xu, Jie; Zhang, Ke-Ping; Chen, Jie

    2016-02-01

    We have previously shown that dysregulation of miR-21 functioned as an oncomiR in breast cancer. The aim of the present study was to elucidate the mechanisms by which miR-21 regulate breast tumor migration and invasion. We applied pathway analysis on genome microarray data and target-predicting algorithms for miR-21 target screening, and used luciferase reporting assay to confirm the direct target. Thereafter, we investigated the function of the target gene phosphoinositide-3-kinase, regulatory subunit 1 (α) (PIK3R1), and detected PIK3R1 coding protein (p85α) by immunohistochemistry and miR-21 by RT-qPCR on 320 archival paraffin-embedded tissues of breast cancer to evaluate the correlation of their expression with prognosis. First, we found that PIK3R1 suppressed growth, invasiveness, and metastatic properties of breast cancer cells. Next, we identified the PIK3R1 as a direct target of miR-21 and showed that it was negatively regulated by miR-21. Furthermore, we demonstrated that p85α overexpression phenocopied the suppression effects of antimiR-21 on breast cancer cell growth, migration and invasion, indicating its tumor suppressor role in breast cancer. On the contrary, PIK3R1 knockdown abrogated antimiR‑21-induced effect on breast cancer cells. Notably, antimiR-21 induction increased p85α, accompanied by decreased p-AKT level. Besides, antimiR-21/PIK3R1-induced suppression of invasiveness in breast cancer cells was mediated by reversing epithelial-mesenchymal transition (EMT). p85α downregulation was found in 25 (7.8%) of the 320 breast cancer patients, and was associated with inferior 5-year disease-free survival (DFS) and overall survival (OS). Taken together, we provide novel evidence that miR-21 knockdown suppresses cell growth, migration and invasion partly by inhibiting PI3K/AKT activation via direct targeting PIK3R1 and reversing EMT in breast cancer. p85α downregulation defined a specific subgroup of breast cancer with shorter 5-year DFS and OS

  13. Targeting multiple opioid receptors - improved analgesics with reduced side effects?

    PubMed

    Günther, Thomas; Dasgupta, Pooja; Mann, Anika; Miess, Elke; Kliewer, Andrea; Fritzwanker, Sebastian; Steinborn, Ralph; Schulz, Stefan

    2017-04-05

    Classical opioid analgesics, including morphine, mediate all of their desired and undesired effects by specific activation of the μ-opioid receptor (μ receptor). The use of morphine for treating chronic pain, however, is limited by the development of constipation, respiratory depression, tolerance and dependence. Analgesic effects can also be mediated through other members of the opioid receptor family such as the κ-opioid receptor (κ receptor), δ-opioid receptor (δ receptor) and the nociceptin/orphanin FQ peptide receptor (NOP receptor). Currently, a new generation of opioid analgesics is being developed that can simultaneously bind with high affinity to multiple opioid receptors. With this new action profile, it is hoped that additional analgesic effects and fewer side effects can be achieved. Recent research is mainly focused on the development of bifunctional μ/NOP receptor agonists, which has already led to novel lead structures such as the spiroindole-based cebranopadol and a compound class with a piperidin-4-yl-1,3-dihydroindol-2-one backbone (SR16835/AT-202 and SR14150/AT-200). In addition, the ornivol BU08028 is an analogue of the clinically well-established buprenorphine. Moreover, the morphinan-based nalfurafine exerts its effect with a dominant κ receptor-component and is therefore utilized in the treatment of pruritus. The very potent dihydroetorphine is a true multi-receptor opioid ligand in that it binds to μ, κ and δ receptor. The main focus of this review is to assess the paradigm of opioid ligands targeting multiple receptors with a single chemical entity. We reflect on this rationale by discussing the biological actions of selected multi-opioid receptor ligands, but not on their medicinal chemistry and design.

  14. Clinical science workshop: targeting the gut-liver-brain axis.

    PubMed

    Patel, Vishal C; White, Helen; Støy, Sidsel; Bajaj, Jasmohan S; Shawcross, Debbie L

    2016-12-01

    A clinical science workshop was held at the ISHEN meeting in London on Friday 11th September 2014 with the aim of thrashing out how we might translate what we know about the central role of the gut-liver-brain axis into targets which we can use in the treatment of hepatic encephalopathy (HE). This review summarises the integral role that inter-organ ammonia metabolism plays in the pathogenesis of HE with specific discussion of the roles that the small and large intestine, liver, brain, kidney and muscle assume in ammonia and glutamine metabolism. Most recently, the salivary and gut microbiome have been shown to underpin the pathophysiological changes which culminate in HE and patients with advanced cirrhosis present with enteric dysbiosis with small bowel bacterial overgrowth and translocation of bacteria and their products across a leaky gut epithelial barrier. Resident macrophages within the liver are able to sense bacterial degradation products initiating a pro-inflammatory response within the hepatic parenchyma and release of cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-8 into the systemic circulation. The endotoxemia and systemic inflammatory response that are generated predispose both to the development of infection as well as the manifestation of covert and overt HE. Co-morbidities such as diabetes and insulin resistance, which commonly accompany cirrhosis, may promote slow gut transit, promote bacterial overgrowth and increase glutaminase activity and may need to be acknowledged in HE risk stratification assessments and therapeutic regimens. Therapies are discussed which target ammonia production, utilisation or excretion at an individual organ level, or which reduce systemic inflammation and endotoxemia which are known to exacerbate the cerebral effects of ammonia in HE. The ideal therapeutic strategy would be to use an agent that can reduce hyperammonemia and reduce systemic inflammation or perhaps to adopt a combination of

  15. Target Context Specification Can Reduce Costs in Nonfocal Prospective Memory

    ERIC Educational Resources Information Center

    Lourenço, Joana S.; White, Katherine; Maylor, Elizabeth A.

    2013-01-01

    Performing a nonfocal prospective memory (PM) task results in a cost to ongoing task processing, but the precise nature of the monitoring processes involved remains unclear. We investigated whether target context specification (i.e., explicitly associating the PM target with a subset of ongoing stimuli) can trigger trial-by-trial changes in task…

  16. Target Context Specification Can Reduce Costs in Nonfocal Prospective Memory

    ERIC Educational Resources Information Center

    Lourenço, Joana S.; White, Katherine; Maylor, Elizabeth A.

    2013-01-01

    Performing a nonfocal prospective memory (PM) task results in a cost to ongoing task processing, but the precise nature of the monitoring processes involved remains unclear. We investigated whether target context specification (i.e., explicitly associating the PM target with a subset of ongoing stimuli) can trigger trial-by-trial changes in task…

  17. Co-targeting cancer drug escape pathways confers clinical advantage for multi-target anticancer drugs.

    PubMed

    Tao, Lin; Zhu, Feng; Xu, Feng; Chen, Zhe; Jiang, Yu Yang; Chen, Yu Zong

    2015-12-01

    Recent investigations have suggested that anticancer therapeutics may be enhanced by co-targeting the primary anticancer target and the corresponding drug escape pathways. Whether this strategy confers statistically significant clinical advantage has not been systematically investigated. This question was probed by the evaluation of the clinical status and the multiple targets of 23 approved and 136 clinical trial multi-target anticancer drugs with particular focus on those co-targeting EGFR, HER2, Abl, VEGFR2, mTOR, PI3K, Alk, MEK, KIT, and DNA topoisomerase, and some of the 14, 7, 13, 20, 6, 5, 7, 2, 4 and 10 cancer drug escape pathways respectively. Most of the approved (73.9%) and phase III (75.0%), the majority of the Phase II (62.8%) and I (53.6%), and the minority of the discontinued (35.3%) multi-target drugs were found to co-target cancer drug escape pathways. This suggests that co-targeting anticancer targets and drug escape pathways confer significant clinical advantage and such strategy can be more extensively explored. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Saccadic foraging: reduced reaction time to informative targets.

    PubMed

    Bray, T J P; Carpenter, R H S

    2015-04-01

    The study of saccadic reaction times has revealed a great deal about the neural mechanisms underlying neural decision, in terms of Bayesian factors such as prior probability and information supply. In addition, recent work has shown that saccades are faster to visual targets associated with conventional monetary or food rewards. However, because the purpose of saccades is to acquire information, it could be argued that this is an unnatural situation: the most natural and fundamental reward is the amount of information supplied by a target. Here, we report the results of a study investigating the hypothesis that a saccade to a target whose colour provides information about the location of a subsequent target is faster than to one that does not. We show that the latencies of saccades to a location that provides reliable information about the location of a future target are indeed shorter, their distributions being shifted in a way that implies that the rate of rise of the underlying decision signal is increased. In a race between alternative targets, this means that expected information will be an important factor in deciding where to look, so that 'foraging' saccades are more likely to be made to useful targets. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  19. Strategies and Challenges in Clinical Trials Targeting Human Aging

    PubMed Central

    Newman, John C.; Milman, Sofiya; Hashmi, Shahrukh K.; Austad, Steve N.; Kirkland, James L.; Halter, Jeffrey B.

    2016-01-01

    Interventions that target fundamental aging processes have the potential to transform human health and health care. A variety of candidate drugs have emerged from basic and translational research that may target aging processes. Some of these drugs are already in clinical use for other purposes, such as metformin and rapamycin. However, designing clinical trials to test interventions that target the aging process poses a unique set of challenges. This paper summarizes the outcomes of an international meeting co-ordinated by the NIH-funded Geroscience Network to further the goal of developing a translational pipeline to move candidate compounds through clinical trials and ultimately into use. We review the evidence that some drugs already in clinical use may target fundamental aging processes. We discuss the design principles of clinical trials to test such interventions in humans, including study populations, interventions, and outcomes. As examples, we offer several scenarios for potential clinical trials centered on the concepts of health span (delayed multimorbidity and functional decline) and resilience (response to or recovery from an acute health stress). Finally, we describe how this discussion helped inform the design of the proposed Targeting Aging with Metformin study. PMID:27535968

  20. Molecular targets and cancer therapeutics: discovery, development and clinical validation.

    PubMed

    Teicher, Beverly A.

    2000-04-01

    The AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics held in Washington, DC on 16-19 November 1999 provided a forum for cancer research clearly showing evolution of a target and mechanism-driven science. The notion of the tumor as a tissue composed of heterogeneous populations of normal and abnormal cells as viable targets is coming to the fore with the advent of agents directed toward non-malignant cell targets. Growth control rather than eradication as a treatment strategy for malignant disease is being tested preclinically and clinically. Among targets, kinases are in the lead with nuclear, cytoplasmic and membrane kinases being selectively inhibited by small molecules and macromolecules. First generation tumor vasculature-directed agents are progressing through early clinical studies. The interest in tumor vasculature as a target has renewed interest in imaging technology to discern biological effect and in tumor hypoxia. This has resulted in elucidation of molecular responses triggered by a low oxygen environment. Challenges remain in the areas of cellular and immune therapies. Dendritic cell-based vaccines are being tested preclinically in many systems. Interleukin-12 is proceeding through clinical trials. Apoptosis-protective molecules such as bcl-2, and apoptosis-stimulating molecules such as bax, are being pursued as targets for inhibition and activation, respectively. Finally, methods and technology to aid in the identification of new targets were highlighted. This perspective, while it is by no means an exhaustive review of the presentations, brings forward some of the main topics and interests that are current in cancer research. Targets were the topic but methods of target identification and the need for increased chemical diversity to selectively focus agents to targets with small differences were also major topics of discussion. Copyright 2000 Harcourt Publishers Ltd.

  1. Targeted therapies for lung cancer: clinical experience and novel agents.

    PubMed

    Larsen, Jill E; Cascone, Tina; Gerber, David E; Heymach, John V; Minna, John D

    2011-01-01

    Although lung cancer remains the leading cancer killer in the United States, recently a number of developments indicate future clinical benefit. These include evidence that computed tomography-based screening decreases lung cancer mortality, the use of stereotactic radiation for early-stage tumors, the development of molecular methods to predict chemotherapy sensitivity, and genome-wide expression and mutation analysis data that have uncovered oncogene "addictions" as important therapeutic targets. Perhaps the most significant advance in the treatment of this challenging disease is the introduction of molecularly targeted therapies, a term that currently includes monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The development of effective targeted therapeutics requires knowledge of the genes and pathways involved and how they relate to the biologic behavior of lung cancer. Drugs targeting the epidermal growth factor receptor, anaplastic lymphoma kinase, and vascular endothelial growth factor are now U.S. Food and Drug Administration approved for the treatment of advanced non-small cell lung cancer. These agents are generally better tolerated than conventional chemotherapy and show dramatic efficacy when their use is coupled with a clear understanding of clinical data, mechanism, patient selection, drug interactions, and toxicities. Integrating genome-wide tumor analysis with drug- and targeted agent-responsive phenotypes will provide a wealth of new possibilities for lung cancer-targeted therapeutics. Ongoing research efforts in these areas as well as a discussion of emerging targeted agents being evaluated in clinical trials are the subjects of this review.

  2. Targeting the Mevalonate Pathway to Reduce Mortality from Ovarian Cancer

    DTIC Science & Technology

    2015-10-01

    protect these women from developing ovarian cancer. In addition, oral contraceptives , which reduce the frequency of ovulation, have been shown to be...effective in reducing the incidence and mortality of ovarian cancer (1). However, neither of these approaches is without concern. Oral contraceptive use...Hermon C, Peto R, Reeves G. Ovarian cancer and oral contraceptives : collaborative reanalysis of data from 45 epidemiological studies including 23,257

  3. Reduced OSM for Long Duration Targets: Individuation or Items Loaded into VSTM?

    ERIC Educational Resources Information Center

    Guest, Duncan; Gellatly, Angus; Pilling, Michael

    2012-01-01

    Typical studies of object substitution masking (OSM) employ a briefly presented search array. The target item is indicated by a cue/mask that surrounds but does not overlap the target and, compared to a common offset control condition, report of the target is reduced when the mask remains present after target offset. Given how little observers are…

  4. B-cell targeted therapeutics in clinical development

    PubMed Central

    2013-01-01

    B lymphocytes are the source of humoral immunity and are thus a critical component of the adaptive immune system. However, B cells can also be pathogenic and the origin of disease. Deregulated B-cell function has been implicated in several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B cells contribute to pathological immune responses through the secretion of cytokines, costimulation of T cells, antigen presentation, and the production of autoantibodies. DNA-and RNA-containing immune complexes can also induce the production of type I interferons, which further promotes the inflammatory response. B-cell depletion with the CD20 antibody rituximab has provided clinical proof of concept that targeting B cells and the humoral response can result in significant benefit to patients. Consequently, the interest in B-cell targeted therapies has greatly increased in recent years and a number of new biologics exploiting various mechanisms are now in clinical development. This review provides an overview on current developments in the area of B-cell targeted therapies by describing molecules and subpopulations that currently offer themselves as therapeutic targets, the different strategies to target B cells currently under investigation as well as an update on the status of novel therapeutics in clinical development. Emerging data from clinical trials are providing critical insight regarding the role of B cells and autoantibodies in various autoimmune conditions and will guide the development of more efficacious therapeutics and better patient selection. PMID:23566679

  5. Targeting dormant micrometastases: rationale, evidence to date and clinical implications.

    PubMed

    Hurst, Robert E; Bastian, Anja; Bailey-Downs, Lora; Ihnat, Michael A

    2016-03-01

    In spite of decades of research, cancer survival has increased only modestly. This is because most research is based on models of primary tumors. Slow recognition has begun that disseminated, dormant cancer cells (micrometastatic cells) that are generally resistant to chemotherapy are the culprits in recurrence, and until these are targeted effectively we can expect only slow progress in increasing overall survival from cancer. This paper reviews efforts to understand the mechanisms by which cancer cells can become dormant, and thereby identify potential targets and drugs either on the market or in clinical trials that purport to prevent metastasis. This review targets the most recent literature because several excellent reviews have covered the literature from more than two years ago. The paper also describes recent work in the authors' laboratories to develop a screening-based approach that does not require understanding of mechanisms of action or the molecular target. Success of this approach shows that targeting micrometastatic cells is definitely feasible.

  6. Lung cancer biomarkers, targeted therapies and clinical assays

    PubMed Central

    Ersek, Jennifer L.; Kim, Edward S.

    2015-01-01

    Until recently, the majority of genomic cancer research has been in discovery and validation; however, as our knowledge of tumor molecular profiling improves, the idea of genomic application in the clinic becomes increasingly tangible, paralleled with the drug development of newer targeted therapies. A number of profiling methodologies exist to identify biomarkers found within the patient (germ-line DNA) and tumor (somatic DNA). Subsequently, commercially available clinical assays to test for both germ-line and somatic alterations that are prognostic and/or predictive of disease outcome, toxicity or treatment response have significantly increased. This review aims to summarize clinically relevant cancer biomarkers that serve as targets for therapy and their potential relationship to lung cancer. In order to realize the full potential of genomic cancer medicine, it is imperative that clinicians understand these intricate molecular pathways, the therapeutic implication of mutations within these pathways, and the availability of clinical assays to identify such biomarkers. PMID:26629419

  7. Imbalanced target prediction with pattern discovery on clinical data repositories.

    PubMed

    Chan, Tak-Ming; Li, Yuxi; Chiau, Choo-Chiap; Zhu, Jane; Jiang, Jie; Huo, Yong

    2017-04-20

    Clinical data repositories (CDR) have great potential to improve outcome prediction and risk modeling. However, most clinical studies require careful study design, dedicated data collection efforts, and sophisticated modeling techniques before a hypothesis can be tested. We aim to bridge this gap, so that clinical domain users can perform first-hand prediction on existing repository data without complicated handling, and obtain insightful patterns of imbalanced targets for a formal study before it is conducted. We specifically target for interpretability for domain users where the model can be conveniently explained and applied in clinical practice. We propose an interpretable pattern model which is noise (missing) tolerant for practice data. To address the challenge of imbalanced targets of interest in clinical research, e.g., deaths less than a few percent, the geometric mean of sensitivity and specificity (G-mean) optimization criterion is employed, with which a simple but effective heuristic algorithm is developed. We compared pattern discovery to clinically interpretable methods on two retrospective clinical datasets. They contain 14.9% deaths in 1 year in the thoracic dataset and 9.1% deaths in the cardiac dataset, respectively. In spite of the imbalance challenge shown on other methods, pattern discovery consistently shows competitive cross-validated prediction performance. Compared to logistic regression, Naïve Bayes, and decision tree, pattern discovery achieves statistically significant (p-values < 0.01, Wilcoxon signed rank test) favorable averaged testing G-means and F1-scores (harmonic mean of precision and sensitivity). Without requiring sophisticated technical processing of data and tweaking, the prediction performance of pattern discovery is consistently comparable to the best achievable performance. Pattern discovery has demonstrated to be robust and valuable for target prediction on existing clinical data repositories with imbalance and

  8. Identification of clinical target areas in the brainstem of prion‐infected mice

    PubMed Central

    Mirabile, Ilaria; Jat, Parmjit S.; Brandner, Sebastian

    2015-01-01

    Aims While prion infection ultimately involves the entire brain, it has long been thought that the abrupt clinical onset and rapid neurological decline in laboratory rodents relates to involvement of specific critical neuroanatomical target areas. The severity and type of clinical signs, together with the rapid progression, suggest the brainstem as a candidate location for such critical areas. In this study we aimed to correlate prion pathology with clinical phenotype in order to identify clinical target areas. Method We conducted a comprehensive survey of brainstem pathology in mice infected with two distinct prion strains, which produce different patterns of pathology, in mice overexpressing prion protein (with accelerated clinical onset) and in mice in which neuronal expression was reduced by gene targeting (which greatly delays clinical onset). Results We identified specific brainstem areas that are affected by prion pathology during the progression of the disease. In the early phase of disease the locus coeruleus, the nucleus of the solitary tract, and the pre‐Bötzinger complex were affected by prion protein deposition. This was followed by involvement of the motor and autonomic centres of the brainstem. Conclusions Neurodegeneration in the locus coeruleus, the nucleus of the solitary tract and the pre‐Bötzinger complex predominated and corresponded to the manifestation of the clinical phenotype. Because of their fundamental role in controlling autonomic function and the overlap with clinical signs in sporadic Creutzfeldt–Jakob disease, we suggest that these nuclei represent key clinical target areas in prion diseases. PMID:25311251

  9. Precision Targeting: Reduced Pesticide Use Strategy for Pharaoh’s Ant (Hymenoptera: Formicidae) Control

    DTIC Science & Technology

    1999-07-19

    AND SUBTITLE Precision Targeting: Reduced Pesticide Use Strategy for Pharaoh’s Ant (Hymenoptera: Formicidae ) Control 6. AUTHOR(S) David F. Williams...TARGETING: REDUCED PESTICIDE USE STRATEGY FOR PHARAOH’S ANT (HYMENOPTERA: FORMICIDAE ) CONTROL DAVID F. WILLIAMS, RICHARD J. BRENNER AND DAVID MILNE...space may benefit from this method of control. This Precision targeting - reduced pesticide use strategy for Pharaoh’s ant (Hymenoptera: Formicidae

  10. Reducing methylglyoxal as a therapeutic target for diabetic heart disease.

    PubMed

    Vulesevic, Branka; Milne, Ross W; Suuronen, Erik J

    2014-04-01

    Diabetes is a well-known risk factor for the development of cardiovascular diseases. Diabetes affects cardiac tissue through several different, yet interconnected, pathways. Damage to endothelial cells from direct exposure to high blood glucose is a primary cause of deregulated heart function. Toxic by-products of non-enzymatic glycolysis, mainly methylglyoxal, have been shown to contribute to the endothelial cell damage. Methylglyoxal is a precursor for advanced glycation end-products, and, although it is detoxified by the glyoxalase system, this protection mechanism fails in diabetes. Recent work has identified methylglyoxal as a therapeutic target for the prevention of cardiovascular complications in diabetes. A better understanding of the glyoxalase system and the effects of methylglyoxal may lead to more advanced strategies for treating cardiovascular complications associated with diabetes.

  11. Enhancing outpatient clinics management software by reducing patients' waiting time.

    PubMed

    Almomani, Iman; AlSarheed, Ahlam

    The Kingdom of Saudi Arabia (KSA) gives great attention to improving the quality of services provided by health care sectors including outpatient clinics. One of the main drawbacks in outpatient clinics is long waiting time for patients-which affects the level of patient satisfaction and the quality of services. This article addresses this problem by studying the Outpatient Management Software (OMS) and proposing solutions to reduce waiting times. Many hospitals around the world apply solutions to overcome the problem of long waiting times in outpatient clinics such as hospitals in the USA, China, Sri Lanka, and Taiwan. These clinics have succeeded in reducing wait times by 15%, 78%, 60% and 50%, respectively. Such solutions depend mainly on adding more human resources or changing some business or management policies. The solutions presented in this article reduce waiting times by enhancing the software used to manage outpatient clinics services. Both quantitative and qualitative methods have been used to understand current OMS and examine level of patient's satisfaction. Five main problems that may cause high or unmeasured waiting time have been identified: appointment type, ticket numbering, doctor late arrival, early arriving patient and patients' distribution list. These problems have been mapped to the corresponding OMS components. Solutions to the above problems have been introduced and evaluated analytically or by simulation experiments. Evaluation of the results shows a reduction in patient waiting time. When late doctor arrival issues are solved, this can reduce the clinic service time by up to 20%. However, solutions for early arriving patients reduces 53.3% of vital time, 20% of the clinic time and overall 30.3% of the total waiting time. Finally, well patient-distribution lists make improvements by 54.2%. Improvements introduced to the patients' waiting time will consequently affect patients' satisfaction and improve the quality of health care services.

  12. [Clinical to planning target volume margins in prostate cancer radiotherapy].

    PubMed

    Ramiandrisoa, F; Duvergé, L; Castelli, J; Nguyen, T D; Servagi-Vernat, S; de Crevoisier, R

    2016-10-01

    The knowledge of inter- and intrafraction motion and deformations of the intrapelvic target volumes (prostate, seminal vesicles, prostatectomy bed and lymph nodes) as well as the main organs at risk (bladder and rectum) allow to define rational clinical to planning target volume margins, depending on the different radiotherapy techniques and their uncertainties. In case of image-guided radiotherapy, prostate margins and seminal vesicles margins can be between 5 and 10mm. The margins around the prostatectomy bed vary from 10 to 15mm and those around the lymph node clinical target volume between 7 and 10mm. Stereotactic body radiotherapy allows lower margins, which are 3 to 5mm around the prostate. Image-guided and stereotactic body radiotherapy with adequate margins allow finally moderate or extreme hypofractionation.

  13. Reducing and eliminating health disparities: a targeted approach.

    PubMed Central

    Green, B. Lee; Lewis, Rhonda K.; Bediako, Shawn M.

    2005-01-01

    Health disparities have dominated recent discourse among public health and medical researchers. Ever since the United States began to compile health statistics, differences in health status have been noted between majority and non-majority populations. Myriad approaches have been undertaken in an attempt to reduce or eliminate racial and ethnic disparities in health. However, the disparities continue to persist. We are at a point in our history where innovative strategies must be explored that will be more effective in addressing racial and ethnic disparities in health. In large part, health disparities exist as a result of inequitable distribution of goods, resources, services and power in America. We have learned that improvements in health cannot come about solely through primary and secondary interventions but rather through an examination of the availability of resources that would allow individuals to improve their health. The goal of this paper is to provide an overview of the contextual factors that affect health disparities, to integrate theory to address disparities and to provide recommendations to encourage systematic changes to eliminate health disparities. It is hoped that this paper will bring about a national discussion relating to addressing the real issues we face in reducing and ultimately eliminating health disparities. PMID:15719868

  14. Targeting cancer epigenetics: Linking basic biology to clinical medicine.

    PubMed

    Shinjo, Keiko; Kondo, Yutaka

    2015-12-01

    Recent studies provide compelling evidence that epigenetic dysregulation is involved in almost every step of tumor development and progression. Differences in tumor behavior, which ultimately reflects clinical outcome, can be explained by variations in gene expression patterns generated by epigenetic mechanisms, such as DNA methylation. Therefore, epigenetic abnormalities are considered potential biomarkers and therapeutic targets. DNA methylation is stable at certain specific loci in cancer cells and predominantly reflects the characteristic clinicopathological features. Thus, it is an ideal biomarker for cancer screening, classification and prognostic purposes. Epigenetic treatment for cancers is based on the pharmacologic targeting of various core transcriptional programs that sustains cancer cell identity. Therefore, targeting aberrant epigenetic modifiers may be effective for multiple processes compared with using a selective inhibitor of aberrant single signaling pathway. This review provides an overview of the epigenetic alterations in human cancers and discusses about novel therapeutic strategies targeting epigenetic alterations.

  15. Reducing youth exposure to alcohol ads: targeting public transit.

    PubMed

    Simon, Michele

    2008-07-01

    Underage drinking is a major public health problem. Youth drink more heavily than adults and are more vulnerable to the adverse effects of alcohol. Previous research has demonstrated the connection between alcohol advertising and underage drinking. Restricting outdoor advertising in general and transit ads in particular, represents an important opportunity to reduce youth exposure. To address this problem, the Marin Institute, an alcohol industry watchdog group in Northern California, conducted a survey of alcohol ads on San Francisco bus shelters. The survey received sufficient media attention to lead the billboard company, CBS Outdoor, into taking down the ads. Marin Institute also surveyed the 25 largest transit agencies; results showed that 75 percent of responding agencies currently have policies that ban alcohol advertising. However, as the experience in San Francisco demonstrated, having a policy on paper does not necessarily mean it is being followed. Communities must be diligent in holding accountable government officials, the alcohol industry, and the media companies through which advertising occurs.

  16. Clinical Advancements in the Targeted Therapies against Liver Fibrosis

    PubMed Central

    Nagórniewicz, Beata; Prakash, Jai

    2016-01-01

    Hepatic fibrosis, characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to liver dysfunction, is a growing cause of mortality worldwide. Hepatocellular damage owing to liver injury leads to the release of profibrotic factors from infiltrating inflammatory cells that results in the activation of hepatic stellate cells (HSCs). Upon activation, HSCs undergo characteristic morphological and functional changes and are transformed into proliferative and contractile ECM-producing myofibroblasts. Over recent years, a number of therapeutic strategies have been developed to inhibit hepatocyte apoptosis, inflammatory responses, and HSCs proliferation and activation. Preclinical studies have yielded numerous targets for the development of antifibrotic therapies, some of which have entered clinical trials and showed improved therapeutic efficacy and desirable safety profiles. Furthermore, advancements have been made in the development of noninvasive markers and techniques for the accurate disease assessment and therapy responses. Here, we focus on the clinical developments attained in the field of targeted antifibrotics for the treatment of liver fibrosis, for example, small molecule drugs, antibodies, and targeted drug conjugate. We further briefly highlight different noninvasive diagnostic technologies and will provide an overview about different therapeutic targets, clinical trials, endpoints, and translational efforts that have been made to halt or reverse the progression of liver fibrosis. PMID:27999454

  17. Reducing Youth Exposure to Alcohol Ads: Targeting Public Transit

    PubMed Central

    2008-01-01

    Underage drinking is a major public health problem. Youth drink more heavily than adults and are more vulnerable to the adverse effects of alcohol. Previous research has demonstrated the connection between alcohol advertising and underage drinking. Restricting outdoor advertising in general and transit ads in particular, represents an important opportunity to reduce youth exposure. To address this problem, the Marin Institute, an alcohol industry watchdog group in Northern California, conducted a survey of alcohol ads on San Francisco bus shelters. The survey received sufficient media attention to lead the billboard company, CBS Outdoor, into taking down the ads. Marin Institute also surveyed the 25 largest transit agencies; results showed that 75 percent of responding agencies currently have policies that ban alcohol advertising. However, as the experience in San Francisco demonstrated, having a policy on paper does not necessarily mean it is being followed. Communities must be diligent in holding accountable government officials, the alcohol industry, and the media companies through which advertising occurs. PMID:18389374

  18. Caring in nursing education: reducing anxiety in the clinical setting.

    PubMed

    Audet, M C

    1995-01-01

    It has been well-documented that the clinical experience is one of the most anxiety-producing aspects of nursing education. When feelings of anxiety become severe, they present a clear threat to the student's success in the program. This article explores the role of "caring" in nursing education as a means of reducing student anxiety. Caring, described at length by Jean Watson, has become one of the most popular trends in the education of young nurses. When caring behaviors are demonstrated in a meaningful way by clinical instructors, the student may experience a sense of comfort and belonging, which may in turn be effective in reducing anxiety and enabling the student to successfully complete a clinical rotation. The aim of this article is to inspire nurses, not only those in the educational setting but in all settings and at all levels of their careers, to reconsider the effects and benefits of displaying a caring attitude.

  19. Clinical Trials Methods for Evaluation of Potential Reduced Exposure Products

    PubMed Central

    Hatsukami, Dorothy K.; Hanson, Karen; Briggs, Anna; Parascandola, Mark; Genkinger, Jeanine M.; O'Connor, Richard; Shields, Peter

    2009-01-01

    Potential reduced exposure tobacco products (PREPs) may have promise in reducing tobacco-related morbidity or mortality or may promote greater harm to individuals or the population. Critical to determining the risks or benefits from these products are valid human clinical trial PREP assessment methods. Assessment involves determining the effects of these products on biomarkers of exposure and of effect, which serve as proxies for harm, and assessing the potential for consumer uptake and abuse of the product. This article raises the critical methodological issues associated with PREP assessment, reviews the methods that have been used to assess PREPs, and describes the strengths and limitations of these methods. Additionally, recommendations for clinical trials PREP assessment methods and future research directions in this area based on this review and on the deliberations from a National Cancer Institute sponsored Clinical Trials PREP Methods Workshop are provided. PMID:19959672

  20. Recent advances in targeted proteomics for clinical applications.

    PubMed

    Domon, Bruno; Gallien, Sebastien

    2015-04-01

    MS-based approaches using targeted methods have been widely adopted by the proteomics community to study clinical questions such as the evaluation of biomarkers. At present, the most widely used targeted MS method is the SRM technique typically performed on a triple quadrupole instrument. However, the high analytical demands for performing clinical studies in combination with the extreme complexity of the samples involved are a serious challenge. The segmentation of the biomarker evaluation workflow has only partially alleviated these issues by differently balancing the analytical requirements and throughput at different stages of the process. The recent introduction of targeted high-resolution and accurate-mass analyses on fast sequencing mass spectrometers operated in parallel reaction monitoring (PRM) mode offers new avenues to conduct clinical studies and thus overcome some of the limitations of the triple quadrupole instrument. This article discusses the attributes and specificities of the PRM technique, in terms of experimental design, execution, and data analysis, and the implications for biomarker evaluation. The benefits of PRM on data quality and the impact on the consistency of results are highlighted and the definitive progress on the overall output of clinical studies, including high throughput, is discussed.

  1. [Radiotherapy for cervix carcinomas: clinical target volume delineation].

    PubMed

    Gnep, K; Mazeron, R

    2013-10-01

    Concurrent chemoradiation followed by brachytherapy is currently the standard treatment for locally advanced cervix carcinomas. Modern radiation techniques require planning based on 3D images, and therefore an accurate delineation of target volumes. The clinical target volume (CTV) used for the different phases of treatment are now well defined, but are not always easy to delineate on a CT scan which is currently the standard examination for simulation in radiotherapy. MRI and PET-CT are routinely performed at diagnosis, and can be used to improve the accuracy of the delineation. The objective of this review is to describe the definitions and recommendations of CTV in the treatment of cervical cancer.

  2. Molecular Pathways: New Signaling Considerations When Targeting Cytoskeletal Balance to Reduce Tumor Growth.

    PubMed

    Chakrabarti, Kristi R; Hessler, Lindsay; Bhandary, Lekhana; Martin, Stuart S

    2015-12-01

    The dynamic balance between microtubule extension and actin contraction regulates mammalian cell shape, division, and motility, which has made the cytoskeleton an attractive and very successful target for cancer drugs. Numerous compounds in clinical use to reduce tumor growth cause microtubule breakdown (vinca alkaloids, colchicine-site, and halichondrins) or hyperstabilization of microtubules (taxanes and epothilones). However, both of these strategies indiscriminately alter the assembly and dynamics of all microtubules, which causes significant dose-limiting toxicities on normal tissues. Emerging data are revealing that posttranslational modifications of tubulin (detyrosination, acetylation) or microtubule-associated proteins (Tau, Aurora kinase) may allow for more specific targeting of microtubule subsets, thereby avoiding the broad disruption of all microtubule polymerization. Developing approaches to reduce tumor cell migration and invasion focus on disrupting actin regulation by the kinases SRC and ROCK. Because the dynamic balance between microtubule extension and actin contraction also regulates cell fate decisions and stem cell characteristics, disrupting this cytoskeletal balance could yield unexpected effects beyond tumor growth. This review will examine recent data demonstrating that cytoskeletal cancer drugs affect wound-healing responses, microtentacle-dependent reattachment efficiency, and stem cell characteristics in ways that could affect the metastatic potential of tumor cells, both beneficially and detrimentally. ©2015 American Association for Cancer Research.

  3. Finasteride Reduces the Risk of Incident Clinical Benign Prostatic Hyperplasia

    PubMed Central

    Parsons, J. Kellogg; Schenk, Jeannette M.; Arnold, Kathryn B.; Messer, Karen; Till, Cathee; Thompson, Ian M.; Kristal, Alan R.

    2014-01-01

    Background Despite the high prevalence of clinical benign prostatic hyperplasia (BPH) among older men, there remains a notable absence of studies focused on BPH prevention. Objective To determine if finasteride prevents incident clinical BPH in healthy older men. Design, setting, and participants Data for this study are from the Prostate Cancer Prevention Trial. After excluding those with a history of BPH diagnosis or treatment, or an International Prostate Symptom Score (IPSS) ≥8 at study entry, 9253 men were available for analysis. Outcome measurements and statistical analysis The primary outcome was incident clinical BPH, defined as the initiation of medical treatment, surgery, or sustained, clinically significant urinary symptoms (IPSS >14). Finasteride efficacy was estimated using Cox proportional regression models to generate hazards ratios (HRs). Results and limitations Mean length of follow-up was 5.3 yr. The rate of clinical BPH was 19 per 1000 person-years in the placebo arm and 11 per 1000 person-years in the finasteride arm (p < 0.001). In a covariate-adjusted model, finasteride reduced the risk of incident clinical BPH by 40% (HR: 0.60; 95% confidence interval, 0.51–0.69; p < 0.001). The effect of finasteride on incident clinical BPH was attenuated in men with a body mass index ≥30 kg/m2 (pinteraction = 0.04) but otherwise did not differ significantly by physical activity, age, race, current diabetes, or current smoking. The post hoc nature of the analysis is a potential study limitation. Conclusions Finasteride substantially reduces the risk of incident clinical BPH in healthy older men. These results should be considered in formulating recommendations for the use of finasteride to prevent prostate diseases in asymptomatic older men. PMID:22459892

  4. Clinical Application of Targeted Next Generation Sequencing for Colorectal Cancers

    PubMed Central

    Fontanges, Quitterie; De Mendonca, Ricardo; Salmon, Isabelle; Le Mercier, Marie; D’Haene, Nicky

    2016-01-01

    Promising targeted therapy and personalized medicine are making molecular profiling of tumours a priority. For colorectal cancer (CRC) patients, international guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-epidermal growth factor receptor agents (anti-EGFR). Daily, new data emerge on the theranostic and prognostic role of molecular biomarkers, which is a strong incentive for a validated, sensitive and broadly available molecular screening test in order to implement and improve multi-modal therapy strategy and clinical trials. Next generation sequencing (NGS) has begun to supplant other technologies for genomic profiling. Targeted NGS is a method that allows parallel sequencing of thousands of short DNA sequences in a single test offering a cost-effective approach for detecting multiple genetic alterations with a minimum amount of DNA. In the present review, we collected data concerning the clinical application of NGS technology in the setting of colorectal cancer. PMID:27999270

  5. Frameless stereotactic targeting devices: technical features, targeting errors and clinical results.

    PubMed

    Widmann, Gerlig; Schullian, Peter; Ortler, Martin; Bale, Reto

    2012-03-01

    Brain biopsies (BB) and depth electrode placements (DEP) are increasingly performed using frameless stereotactic targeting devices. This paper is intended to provide a comprehensive review of the technical features, targeting errors and clinical results. A PubMed literature search from 1995-2010 was performed. (A) Modified stereotactic arcs, (B) arm-based devices with and without aiming facilities, and (C) skull affixed devices were found. Guidance technologies were navigation systems (all groups), prospective stereotaxy and custom designed platforms (group C). Mean total errors ranged between 4.4 and 5.4 mm for BB and 2.0 and 3.2 mm for DEP. Diagnostic yield of BB was 89-100%. The clinical success rate for DEP was 96-100%. Frameless stereotactic targeting devices may reach targeting errors and clinical results comparable with standard frame-based stereotaxy. Advantages and disadvantages of different devices should be acknowledged to ensure optimal technical performance. Copyright © 2011 John Wiley & Sons, Ltd.

  6. Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy.

    PubMed

    Choi, Joung-Woo; Kim, Hyun Ah; Nam, Kihoon; Na, Youjin; Yun, Chae-Ok; Kim, SungWan

    2015-12-28

    Despite adenovirus (Ad) vector's numerous advantages for cancer gene therapy, such as high ability of endosomal escape, efficient nuclear entry mechanism, and high transduction, and therapeutic efficacy, tumor specific targeting and antiviral immune response still remain as a critical challenge in clinical setting. To overcome these obstacles and achieve cancer-specific targeting, we constructed tumor targeting bioreducible polymer, an arginine grafted bio-reducible polymer (ABP)-PEG-HCBP1, by conjugating PEGylated ABP with HCBP1 peptides which has high affinity and selectivity towards hepatoma. The ABP-PEG-HCBP1-conjugated replication incompetent GFP-expressing ad, (Ad/GFP)-ABP-PEG-HCBP1, showed a hepatoma cancer specific uptake and transduction compared to either naked Ad/GFP or Ad/GFP-ABP. Competition assays demonstrated that Ad/GFP-ABP-PEG-HCBP1-mediated transduction was specifically inhibited by HCBP1 peptide rather than coxsackie and adenovirus receptor specific antibody. In addition, ABP-PEG-HCBP1 can protect biological activity of Ad against serum, and considerably reduced both innate and adaptive immune response against Ad. shMet-expressing oncolytic Ad (oAd; RdB/shMet) complexed with ABP-PEG-HCBP1 delivered oAd efficiently into hepatoma cancer cells. The oAd/ABP-PEG-HCBP1 demonstrated enhanced cancer cell killing efficacy in comparison to oAd/ABP complex. Furthermore, Huh7 and HT1080 cancer cells treated with oAd/shMet-ABP-PEG-HCBP1 complex had significantly decreased Met and VEGF expression in hepatoma cancer, but not in non-hepatoma cancer. In sum, these results suggest that HCBP1-conjugated bioreducible polymer could be used to deliver oncolytic Ad safely and efficiently to treat hepatoma.

  7. Target biomarker profile for the clinical management of paracetamol overdose

    PubMed Central

    Vliegenthart, A D Bastiaan; Antoine, Daniel J; Dear, James W

    2015-01-01

    Paracetamol (acetaminophen) overdose is one of the most common causes of acute liver injury in the Western world. To improve patient care and reduce pressure on already stretched health care providers new biomarkers are needed that identify or exclude liver injury soon after an overdose of paracetamol is ingested. This review highlights the current state of paracetamol poisoning management and how novel biomarkers could improve patient care and save healthcare providers money. Based on the widely used concept of defining a target product profile, a target biomarker profile is proposed that identifies desirable and acceptable key properties for a biomarker in development to enable the improved treatment of this patient population. The current biomarker candidates, with improved hepatic specificity and based on the fundamental mechanistic basis of paracetamol-induced liver injury, are reviewed and their performance compared with our target profile. PMID:26076366

  8. Target biomarker profile for the clinical management of paracetamol overdose.

    PubMed

    Vliegenthart, A D Bastiaan; Antoine, Daniel J; Dear, James W

    2015-09-01

    Paracetamol (acetaminophen) overdose is one of the most common causes of acute liver injury in the Western world. To improve patient care and reduce pressure on already stretched health care providers new biomarkers are needed that identify or exclude liver injury soon after an overdose of paracetamol is ingested. This review highlights the current state of paracetamol poisoning management and how novel biomarkers could improve patient care and save healthcare providers money. Based on the widely used concept of defining a target product profile, a target biomarker profile is proposed that identifies desirable and acceptable key properties for a biomarker in development to enable the improved treatment of this patient population. The current biomarker candidates, with improved hepatic specificity and based on the fundamental mechanistic basis of paracetamol-induced liver injury, are reviewed and their performance compared with our target profile. © 2015 The British Pharmacological Society.

  9. Targeting Neuroendocrine Prostate Cancer: Molecular and Clinical Perspectives

    PubMed Central

    Vlachostergios, Panagiotis J.; Papandreou, Christos N.

    2015-01-01

    Neuroendocrine prostate carcinoma, either co-present with the local adenocarcinoma disease or as a result of transdifferentiation later in time, was described as one major process of emerging resistance to androgen deprivation therapies, and at the clinical level it is consistent with the development of rapidly progressive visceral disease, often in the absence of elevated serum prostate-specific antigen level. Until present, platinum-based chemotherapy has been the only treatment modality, able to produce a fair amount of responses but of short duration. Recently, several efforts for molecular characterization of this lethal phenotype have resulted in identification of novel signaling factors involved in microenvironment interactions, mitosis, and neural reprograming as potential therapeutic targets. Ongoing clinical testing of specific inhibitors of these targets, for example, Aurora kinase A inhibitors, in carefully selected patients and exploitation of expression changes of the target before and after manipulation is anticipated to increase the existing data and facilitate therapeutic decision making at this late stage of the disease when hormonal manipulations, even with the newest androgen-directed therapies are no longer feasible. PMID:25699233

  10. Targeted Intraceptor Nanoparticle Therapy Reduces Angiogenesis and Fibrosis in Primate & Murine Macular Degeneration

    PubMed Central

    Luo, Ling; Zhang, Xiaohui; Hirano, Yoshio; Tyagi, Puneet; Barabás, Péter; Uehara, Hironori; Miya, Tadashi R.; Singh, Nirbhai; Archer, Bonnie; Qazi, Yureeda; Jackman, Kyle; Das, Subrata K.; Olsen, Thomas; Chennamaneni, Srinivas R.; Stagg, Brian C.; Ahmed, Faisal; Emerson, Lyska; Zygmunt, Kristen; Whitaker, Ross; Mamalis, Christina; Huang, Wei; Gao, Guangping; Srinivas, Sangly P.; Krizaj, David; Baffi, Judit; Ambati, Jayakrishna; Kompella, Uday B.; Ambati, Balamurali K.

    2013-01-01

    Monthly intraocular injections are widely used to deliver protein-based drugs that cannot cross the blood-retina barrier for the treatment of leading blinding diseases such as age-related macular degeneration (AMD). This invasive treatment carries significant risks, including bleeding, pain, infection, and retinal detachment. Further, current therapies are associated with a rate of retinal fibrosis and geographic atrophy significantly higher than that which occurs in the described natural history of AMD. A novel therapeutic strategy which improves outcomes in a less invasive manner, reduces risk, and provides long-term inhibition of angiogenesis and fibrosis is a felt medical need. Here we show that a single intravenous injection of targeted, biodegradable nanoparticles delivering a recombinant Flt23k intraceptor plasmid homes to neovascular lesions in the retina and regresses CNV in primate and murine AMD models. Moreover, this treatment suppressed subretinal fibrosis, which is currently not addressed by clinical therapies. Murine vision, as tested by OptoMotry©, significantly improved with nearly 40% restoration of visual loss induced by CNV. We found no evidence of ocular or systemic toxicity from nanoparticle treatment. These findings offer a nanoparticle-based platform for targeted, vitreous-sparing, extended-release, nonviral gene therapy. PMID:23464925

  11. Targeted intraceptor nanoparticle therapy reduces angiogenesis and fibrosis in primate and murine macular degeneration.

    PubMed

    Luo, Ling; Zhang, Xiaohui; Hirano, Yoshio; Tyagi, Puneet; Barabás, Péter; Uehara, Hironori; Miya, Tadashi R; Singh, Nirbhai; Archer, Bonnie; Qazi, Yureeda; Jackman, Kyle; Das, Subrata K; Olsen, Thomas; Chennamaneni, Srinivas R; Stagg, Brian C; Ahmed, Faisal; Emerson, Lyska; Zygmunt, Kristen; Whitaker, Ross; Mamalis, Christina; Huang, Wei; Gao, Guangping; Srinivas, Sangly P; Krizaj, David; Baffi, Judit; Ambati, Jayakrishna; Kompella, Uday B; Ambati, Balamurali K

    2013-04-23

    Monthly intraocular injections are widely used to deliver protein-based drugs that cannot cross the blood-retina barrier for the treatment of leading blinding diseases such as age-related macular degeneration (AMD). This invasive treatment carries significant risks, including bleeding, pain, infection, and retinal detachment. Further, current therapies are associated with a rate of retinal fibrosis and geographic atrophy significantly higher than that which occurs in the described natural history of AMD. A novel therapeutic strategy which improves outcomes in a less invasive manner, reduces risk, and provides long-term inhibition of angiogenesis and fibrosis is a felt medical need. Here we show that a single intravenous injection of targeted, biodegradable nanoparticles delivering a recombinant Flt23k intraceptor plasmid homes to neovascular lesions in the retina and regresses CNV in primate and murine AMD models. Moreover, this treatment suppressed subretinal fibrosis, which is currently not addressed by clinical therapies. Murine vision, as tested by OptoMotry, significantly improved with nearly 40% restoration of visual loss induced by CNV. We found no evidence of ocular or systemic toxicity from nanoparticle treatment. These findings offer a nanoparticle-based platform for targeted, vitreous-sparing, extended-release, nonviral gene therapy.

  12. [Regional clinical audit, guideline targets, and local and regional benchmarks].

    PubMed

    Casino, F G; Lopez, T

    2005-01-01

    Regional clinical Audit, guideline Targets and local and regional Benchmarks In order to improve the quality of dialysis treatment, we have devised some routines, particularly suitable for electronic data management systems. First, we suggest a systematic monthly analysis of 10 common clinical performance measures (CPM), with the following guideline based targets: predialysis systolic blood pressure (SBP) < 140 mmHg; session length >/= 240 min; dialysis dose (spKt/V) >/=1.3; normalized protein catabolic rate (NPCR) >/=1.2 g/kg/d; hemoglobin (Hb) >/=11 g/dL; serum calcium (Ca) 8.4-9.5 mg/dL; serum phosphorus (P) 3.5-5.5 mg/dL; Ca x P /=20 mmol/L; serum potassium (K) 3.5-6.0 mmol/L. The Hb target should be reached in at least 85% of all maintenance hemodialysis (HD) patients in the unit; for all other targets, an arbitrary >/=80% is proposed. Since the above percentages are quite difficult to reach on a short-term basis, an intermediate local or regional standard (benchmark) could be devised as an average of the percentage of patients who actually reach the targets for each CPM at any dialysis unit in a given regional area; and therefore, from truly comparable patients. As an example, we simulated a regional audit by using the above targets with available data from 398 patients from southern Italy. A further step in this process was to find the cause(s) of failure in each patient who did not reach the targets. To this end, we suggest a systematic search of the well-known factors that could affect each CPM, for each failed patient. As an example, we screened all patients with Hb < 11 g/dL at a single unit, to establish the presence/absence of any common cause associated with inadequate response to epoetin treatment. Moreover, by using criteria for prescribing iron therapy or increasing epoetin dose, we found that some patients did not receive the appropriate therapy after blood sampling results. To avoid this possible

  13. Interobserver Variation of Clinical Target Volume Delineation in Gastric Cancer

    SciTech Connect

    Jansen, Edwin; Verheij, Marcel

    2010-07-15

    Purpose: To evaluate interobserver variability in clinical target volume (CTV) delineation in gastric cancer performed with the help of a delineation guide. Patients and Methods: Ten radiotherapy centers that participate in the CRITICS Phase III trial were provided with a delineation atlas, preoperative CT scans, a postoperative planning CT scan, and clinical information for a gastric cancer case and were asked to construct a CTV and create a dosimetric plan according to departmental policy. Results: The volumes of the CTVs and planning target volumes (PTVs) differed greatly, with a mean (SD) CTV volume of 392 (176) cm{sup 3} (range, 240-821cm{sup 3}) and PTV volume of 915 (312) cm{sup 3} (range, 634-1677cm{sup 3}). The overlapping volume was 376cm{sup 3} for the CTV and 890cm{sup 3} for the PTV. The greatest differences in the CTV were seen at the cranial and caudal parts. After planning, dose coverage of the overlapping PTV volume showed less variability than the CTV. Conclusion: In this series of 10 plans, variability of the CTV in postoperative chemoradiotherapy for gastric cancer is large. Strict and clear delineation guidelines should be provided, especially in Phase III multicenter studies. Adaptations of these guidelines should be evaluated in clinical studies.

  14. [Clinical research of targeting therapy for cancer stem cells].

    PubMed

    Shitara, Kohei; Doi, Toshihiko

    2015-05-01

    To achieve cure is difficult and progression after response to treatment is common for patients with several type of malignancies. One possible reason is existence of cancer stem cells, which have self-renewal activity and resistance to chemotherapy and radiotherapy. Several cellular markers and signal pathways are investigated to identify cancer stem cell. Targeting cancer stem cell is considered as promising to achieve cure in combination with other treatment. Although no cancer stem cell specific treatment is established at the present moment, several targeting agents are under development. We conducted a phase I study of specific inhibitor of xCT, a glutamate-cystine transporter, of CD44 splice variant (CD44v) expressed cancer stem like cell to confirm the mode of action. Clinical study of combination therapy with cisplatin is ongoing.

  15. Clinical Implementation of Novel Targeted Therapeutics in Advanced Breast Cancer.

    PubMed

    Chamberlin, Mary D; Bernhardt, Erica B; Miller, Todd W

    2016-11-01

    The majority of advanced breast cancers have genetic alterations that are potentially targetable with drugs. Through initiatives such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), data can be mined to provide context for next-generation sequencing (NGS) results in the landscape of advanced breast cancer. Therapies for targets other than estrogen receptor alpha (ER) and HER2, such as cyclin-dependent kinases CDK4 and CDK6, were recently approved based on efficacy in patient subpopulations, but no predictive biomarkers have been found, leaving clinicians to continue a trial-and-error approach with each patient. Next-generation sequencing identifies potentially actionable alterations in genes thought to be drivers in the cancerous process including phosphatidylinositol 3-kinase (PI3K), AKT, fibroblast growth factor receptors (FGFRs), and mutant HER2. Epigenetically directed and immunologic therapies have also shown promise for the treatment of breast cancer via histone deacetylases (HDAC) 1 and 3, programmed T cell death 1 (PD-1), and programmed T cell death ligand 1 (PD-L1). Identifying biomarkers to predict primary resistance in breast cancer will ultimately affect clinical decisions regarding adjuvant therapy in the first-line setting. However, the bulk of medical decision-making is currently made in the secondary resistance setting. Herein, we review the clinical potential of PI3K, AKT, FGFRs, mutant HER2, HDAC1/3, PD-1, and PD-L1 as therapeutic targets in breast cancer, focusing on the rationale for therapeutic development and the status of clinical testing. J. Cell. Biochem. 117: 2454-2463, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. Targeting annexin A2 reduces tumorigenesis and therapeutic resistance of nasopharyngeal carcinoma

    PubMed Central

    Chao, Pin-Zhir; Chiou, Jeng-Fong; Kuo, Chia-Chun; Lee, Fei-Peng; Lin, Yung-Feng; Sung, Yu-Hsuan; Lin, Yun-Tien; Li, Chang-Fan

    2015-01-01

    The expression of annexin A2 (ANXA2) in nasopharyngeal carcinoma (NPC) cells induces the immunosuppressive response in dendritic cells; however, the oncogenic effect and clinical significance of ANXA2 have not been fully investigated in NPC cells. Immunohistochemical staining for ANXA2 was performed in 61 patients and the association with clinicopathological status was determined. Short hairpin (sh)RNA knockdown of ANXA2 was used to examine cellular effects of ANXA2, by investigating alterations in cell proliferation, migration, invasion, adhesion, tube-formation assay, and chemo- and radiosensitivity assays were performed. RT-qPCR, Western blotting, and immunofluorescence were applied to determine molecular expression levels. Clinical association studies showed that the expression of ANXA2 was significantly correlated with metastasis (p = 0.0326) and poor survival (p = 0.0256). Silencing of ANXA2 suppressed the abilities of cell proliferation, adhesion, migration, invasion, and vascular formation in NPC cell. ANXA2 up-regulated epithelial-mesenchymal transition associated signal proteins. Moreover, ANXA2 reduced sensitivities to irradiation and chemotherapeutic drugs. These results define ANXA2 as a novel prognostic factor for malignant processes, and it can serve as a molecular target of therapeutic interventions for NPC. PMID:26196246

  17. Reduced Treatment-Emergent Sexual Dysfunction as a Potential Target in the Development of New Antidepressants

    PubMed Central

    Baldwin, David S.; Palazzo, M. Carlotta; Masdrakis, Vasilios G.

    2013-01-01

    Pleasurable sexual activity is an essential component of many human relationships, providing a sense of physical, psychological, and social well-being. Epidemiological and clinical studies show that depressive symptoms and depressive illness are associated with impairments in sexual function and satisfaction, both in untreated and treated patients. The findings of randomized placebo-controlled trials demonstrate that most of the currently available antidepressant drugs are associated with the development or worsening of sexual dysfunction, in a substantial proportion of patients. Sexual difficulties during antidepressant treatment often resolve as depression lifts but can endure over long periods and may reduce self-esteem and affect mood and relationships adversely. Sexual dysfunction during antidepressant treatment is typically associated with many possible causes, but the risk and type of dysfunction vary with differing compounds and should be considered when making decisions about the relative merits and drawbacks of differing antidepressants. A range of interventions can be considered when managing patients with sexual dysfunction associated with antidepressants, including the prescription of phosphodiesterase-5 inhibitors, but none of these approaches can be considered “ideal.” As treatment-emergent sexual dysfunction is less frequent with certain drugs, presumably related to differences in their pharmacological properties, and because current management approaches are less than ideal, a reduced burden of treatment-emergent sexual dysfunction represents a tolerability target in the development of novel antidepressants. PMID:23431429

  18. Biological targets for therapeutic interventions in COPD: clinical potential

    PubMed Central

    Pelaia, Girolamo; Vatrella, Alessandro; Gallelli, Luca; Renda, Teresa; Caputi, Mario; Maselli, Rosario; Marsico, Serafino A

    2006-01-01

    COPD is a widespread inflammatory respiratory disorder characterized by a progressive, poorly reversible airflow limitation. Currently available therapies are mostly based on those used to treat asthma. However, such compounds are not able to effectively reduce the gradual functional deterioration, as well as the ongoing airway and lung inflammation occurring in COPD patients. Therefore, there is an urgent need to improve the efficacy of the existing drug classes and to develop new treatments, targeting the main cellular and molecular mechanisms underlying disease pathogenesis. These therapeutic strategies will be highlighted in the present review. PMID:18046869

  19. Multimodality molecular imaging--from target description to clinical studies.

    PubMed

    Schober, O; Rahbar, K; Riemann, B

    2009-02-01

    This highlight lecture was presented at the closing session of the Annual Congress of the European Association of Nuclear Medicine (EANM) in Munich on 15 October 2008. The Congress was a great success: there were more than 4,000 participants, and 1,597 abstracts were submitted. Of these, 1,387 were accepted for oral or poster presentation, with a rejection rate of 14%. In this article a choice was made from 100 of the 500 lectures which received the highest scores by the scientific review panel. This article outlines the major findings and trends at the EANM 2008, and is only a brief summary of the large number of outstanding abstracts presented. Among the great number of oral and poster presentations covering nearly all fields of nuclear medicine some headlines have to be defined highlighting the development of nuclear medicine in the 21st century. This review focuses on the increasing impact of molecular and multimodality imaging in the field of nuclear medicine. In addition, the question may be asked as to whether the whole spectrum of nuclear medicine is nothing other than molecular imaging and therapy. Furthermore, molecular imaging will and has to go ahead to multimodality imaging. In view of this background the review was structured according to the single steps of molecular imaging, i.e. from target description to clinical studies. The following topics are addressed: targets, radiochemistry and radiopharmacy, devices and computer science, animals and preclinical evaluations, and patients and clinical evaluations.

  20. Targeting cancer stem cells by curcumin and clinical applications.

    PubMed

    Li, Yanyan; Zhang, Tao

    2014-05-01

    Curcumin is a well-known dietary polyphenol derived from the rhizomes of turmeric, an Indian spice. The anticancer effect of curcumin has been demonstrated in many cell and animal studies, and recent research has shown that curcumin can target cancer stem cells (CSCs). CSCs are proposed to be responsible for initiating and maintaining cancer, and contribute to recurrence and drug resistance. A number of studies have suggested that curcumin has the potential to target CSCs through regulation of CSC self-renewal pathways (Wnt/β-catenin, Notch, sonic hedgehog) and specific microRNAs involved in acquisition of epithelial-mesenchymal transition (EMT). The potential impact of curcumin, alone or in combination with other anticancer agents, on CSCs was evaluated as well. Furthermore, the safety and tolerability of curcumin have been well-established by numerous clinical studies. Importantly, the low bioavailability of curcumin has been dramatically improved through the use of structural analogues or special formulations. More clinical trials are underway to investigate the efficacy of this promising agent in cancer chemoprevention and therapy. In this article, we review the effects of curcumin on CSC self-renewal pathways and specific microRNAs, as well as its safety and efficacy in recent human studies. In conclusion, curcumin could be a very promising adjunct to traditional cancer treatments. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

    PubMed Central

    Rider, Peleg; Carmi, Yaron

    2016-01-01

    Proinflammatory cytokines are potent mediators of numerous biological processes and are tightly regulated in the body. Chronic uncontrolled levels of such cytokines can initiate and derive many pathologies, including incidences of autoimmunity and cancer. Therefore, therapies that regulate the activity of inflammatory cytokines, either by supplementation of anti-inflammatory recombinant cytokines or by neutralizing them by using blocking antibodies, have been extensively used over the past decades. Over the past few years, new innovative biological agents for blocking and regulating cytokine activities have emerged. Here, we review some of the most recent approaches of cytokine targeting, focusing on anti-TNF antibodies or recombinant TNF decoy receptor, recombinant IL-1 receptor antagonist (IL-1Ra) and anti-IL-1 antibodies, anti-IL-6 receptor antibodies, and TH17 targeting antibodies. We discuss their effects as biologic drugs, as evaluated in numerous clinical trials, and highlight their therapeutic potential as well as emphasize their inherent limitations and clinical risks. We suggest that while systemic blocking of proinflammatory cytokines using biological agents can ameliorate disease pathogenesis and progression, it may also abrogate the hosts defense against infections. Moreover, we outline the rational need to develop new therapies, which block inflammatory cytokines only at sites of inflammation, while enabling their function systemically. PMID:28083070

  2. Clinical actionability enhanced through deep targeted sequencing of solid tumors

    PubMed Central

    Chen, Ken; Meric-Bernstam, Funda; Zhao, Hao; Zhang, Qingxiu; Ezzeddine, Nader; Tang, Lin-ya; Qi, Yuan; Mao, Yong; Chen, Tenghui; Chong, Zechen; Zhou, Wanding; Zheng, Xiaofeng; Johnson, Amber; Aldape, Kenneth D.; Routbort, Mark J.; Luthra, Rajyalakshmi; Kopetz, Scott; Davies, Michael A.; de Groot, John; Moulder, Stacy; Vinod, Ravi; Farhangfar, Carol J.; Shaw, Kenna Mills; Mendelsohn, John; Mills, Gordon B.; Eterovic, Agda Karina

    2015-01-01

    Background Further advances of targeted cancer therapy require comprehensive in-depth profiling of somatic mutations that are present in subpopulations of tumor cells in a clinical tumor sample. However, it is unclear to what extent such intra-tumor heterogeneity is present and whether it may affect clinical decision making. To unravel this challenge, we established a deep targeted sequencing platform to identify potentially actionable DNA alterations in tumor samples. Methods We assayed 515 FFPE tumor samples and matched germline (475 patients) from 11 disease sites by capturing and sequencing all the exons in 201 cancer related genes. Mutations, indels and copy number data were reported. Results We obtained a 1000-fold average sequencing depth and identified 4794 non-synonymous mutations in the samples analyzed, which 15.2% were present at less than 10% allele frequency. Most of these low level mutations occurred at known oncogenic hotspots and are likely functional. Identifying low level mutations improved identification of mutations in actionable genes in 118 (24.84%) patients, among which 47 (9.8%) would otherwise be unactionable. In addition, acquiring ultra-high depth also ensured a low false discovery rate (less than 2.2%) from FFPE samples. Conclusion Our results were as accurate as a commercially available CLIA-compliant hotspot panel, but allowed the detection of a higher number of mutations in actionable genes. Our study revealed the critical importance of acquiring and utilizing high depth in profiling clinical tumor samples and presented a very useful platform for implementing routine sequencing in a cancer care institution. PMID:25626406

  3. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation†

    PubMed Central

    Kamaly, Nazila; Xiao, Zeyu; Valencia, Pedro M.; Radovic-Moreno, Aleksandar F.; Farokhzad, Omid C.

    2013-01-01

    Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development

  4. The coronary sinus reducer: clinical evidence and technical aspects.

    PubMed

    Giannini, Francesco; Aurelio, Andrea; Jabbour, Richard J; Ferri, Luca; Colombo, Antonio; Latib, Azeem

    2017-01-01

    Chronic refractory angina is often a disabling condition, predominantly due to severe obstructive coronary artery disease, that is inadequately controlled by optimal medical therapy and not amenable to further percutaneous or surgical revascularization. mortality rates associated with this condition are relatively low in clinically stable patients. however, it is associated with a high hospitalization rate and a reduction in both exercise capacity and quality of life. due to the paucity of available treatment options, there is an unmet need for new therapies for these patients and for a reduction in the associated economic healthcare burden. Areas covered: This review is focusing on the clinical evidence and technical aspects of this new therapeutic modality in refractory angina patients unsuitable for revascularization. Expert commentary: The Coronary Sinus Reducer (Neovasc Inc. Richmond B.C., Canada) is a new percutaneous device designed to achieve a controlled narrowing of the coronary sinus that may alleviate myocardial ischemia, possibly by redistributing blood from the less ischemic sub-epicardium to the more ischemic sub-endocardium, or by neoangiogenesis. Recently, a randomized, double-blind, multi-center clinical trial demonstrated a benefit in improving symptoms in 104 refractory angina patients, when compared to placebo.

  5. Clinical audit: a useful tool for reducing severe postpartum haemorrhages?

    PubMed

    Dupont, Corinne; Deneux-Tharaux, Catherine; Touzet, Sandrine; Colin, Cyrille; Bouvier-Colle, Marie-Hélène; Lansac, Jacques; Thevenet, Simone; Boberie-Moyrand, Claire; Piccin, Gaëlle; Fernandez, Marie-Pierre; Rudigoz, René-Charles

    2011-10-01

    Reducing the rate of severe postpartum haemorrhage (PPH) is a major challenge in obstetrics today. One potentially effective tool for improving the quality of care is the clinical audit, that is, peer evaluation and comparison of actual practices against explicit criteria. Our objective was to assess the impact of regular criteria-based audits on the prevalence of severe PPH. Quasi-experimental before-and-after survey. Two French maternity units in the Rhône-Alpes region, with different organization of care. All staff of both units. Quarterly clinical audit meetings at which a team of reviewers analysed all cases of severe PPH and provided feedback on quality of care and where all staff actively participated. The primary outcome was the prevalence of severe PPH. Secondary outcomes included the global quality of care for women with severe PPH, including the performance rate for each recommended procedure. Differences in these variables between 2005 and 2008 were tested. The prevalence of severe PPH declined significantly in both units, from 1.52 to 0.96% of deliveries in the level III hospital (P = 0.048) and from 2.08 to 0.57% in the level II hospital (P < 0.001). From 2005 to 2008, the proportion of deliveries with severe PPH that was managed consistently with the guidelines increased for all of its main components, in both units. Regular clinical audits of cases severe PPH were associated with a persistent reduction in the prevalence of severe PPH.

  6. Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations.

    PubMed

    Arout, Caroline A; Edens, Ellen; Petrakis, Ismene L; Sofuoglu, Mehmet

    2015-06-01

    Opioid analgesics have become a cornerstone in the treatment of moderate to severe pain, resulting in a steady rise of opioid prescriptions. Subsequently, there has been a striking increase in the number of opioid-dependent individuals, opioid-related overdoses, and fatalities. Clinical use of opioids is further complicated by an increasingly deleterious profile of side effects beyond addiction, including tolerance and opioid-induced hyperalgesia (OIH), where OIH is defined as an increased sensitivity to already painful stimuli. This paradoxical state of increased nociception results from acute and long-term exposure to opioids, and appears to develop in a substantial subset of patients using opioids. Recently, there has been considerable interest in developing an efficacious treatment regimen for acute and chronic pain. However, there are currently no well-established treatments for OIH. Several substrates have emerged as potential modulators of OIH, including the N-methyl-D-aspartate and γ-aminobutyric acid receptors, and most notably, the innate neuroimmune system. This review summarizes the neurobiology of OIH in the context of clinical treatment; specifically, we review evidence for several pathways that show promise for the treatment of pain going forward, as prospective adjuvants to opioid analgesics. Overall, we suggest that this paradoxical state be considered an additional target of clinical treatment for chronic pain.

  7. Microcirculation: target therapy in cardiovascular diseases - a clinical perspective.

    PubMed

    Abarquez, Ramon F; Cinco, Jude Erric L

    2003-01-01

    Microcirculation conduit, distribution, exchange and reception vessels usually retain a demand-dependent vascular-tissue match as well as a nutrient friendly capillary-matrix tissue match. Various stimuli can initiate a vascular-capillary matrix-tissue mismatch. Counter-regulatory mechanisms result in hyperplasia or apoptosis. Microvascular disease (MVD) as a consequence or outcome of supply-demand mismatch has clinical therapeutic and prognostic implications in the hypertensive syndrome and coronary artery disease (CAD) cases. Recognition of the role of apoptosis and MVD may initiate a paradigm shift in clinical practice. Digitalis and other anti-hypertensive agents have anti-apoptotic action and MVD blunting effects that can control LVH development to reduce congestive heart failure (CHF) progression.

  8. Cardiorenal syndrome: pathophysiology and potential targets for clinical management.

    PubMed

    Hatamizadeh, Parta; Fonarow, Gregg C; Budoff, Matthew J; Darabian, Sirous; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar

    2013-02-01

    Combined dysfunction of the heart and the kidneys, which can be associated with haemodynamic impairment, is classically referred to as cardiorenal syndrome (CRS). Cardiac pump failure with resulting volume retention by the kidneys, once thought to be the major pathophysiologic mechanism of CRS, is now considered to be only a part of a much more complicated phenomenon. Multiple body systems may contribute to the development of this pathologic constellation in an interconnected network of events. These events include heart failure (systolic or diastolic), atherosclerosis and endothelial cell dysfunction, uraemia and kidney failure, neurohormonal dysregulation, anaemia and iron disorders, mineral metabolic derangements including fibroblast growth factor 23, phosphorus and vitamin D disorders, and inflammatory pathways that may lead to malnutrition-inflammation-cachexia complex and protein-energy wasting. Hence, a pathophysiologically and clinically relevant classification of CRS based on the above components would be prudent. With the existing medical knowledge, it is almost impossible to identify where the process has started in any given patient. Rather, the events involved are closely interrelated, so that once the process starts at a particular point, other pathways of the network are potentially activated. Current therapies for CRS as well as ongoing studies are mostly focused on haemodynamic adjustments. The timely targeting of different components of this complex network, which may eventually lead to haemodynamic and vascular compromise and cause refractoriness to conventional treatments, seems necessary. Future studies should focus on interventions targeting these components.

  9. β-escin selectively targets the glioblastoma-initiating cell population and reduces cell viability

    PubMed Central

    Harford-Wright, Elizabeth; Bidère, Nicolas; Gavard, Julie

    2016-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive tumour of the central nervous system and is associated with an extremely poor prognosis. Within GBM exists a subpopulation of cells, glioblastoma-initiating cells (GIC), which possess the characteristics of progenitor cells, have the ability to initiate tumour growth and resist to current treatment strategies. We aimed at identifying novel specific inhibitors of GIC expansion through use of a large-scale chemical screen of approved small molecules. Here, we report the identification of the natural compound β-escin as a selective inhibitor of GIC viability. Indeed, β-escin was significantly cytotoxic in nine patient-derived GIC, whilst exhibiting no substantial effect on the other human cancer or control cell lines tested. In addition, β-escin was more effective at reducing GIC growth than current clinically used cytotoxic agents. We further show that β-escin triggers caspase-dependent cell death combined with a loss of stemness properties. However, blocking apoptosis could not rescue the β-escin-induced reduction in sphere formation or stemness marker activity, indicating that β-escin directly modifies the stem identity of GIC, independent of the induction of cell death. Thus, this study has repositioned β-escin as a promising potential candidate to selectively target the aggressive population of initiating cells within GBM. PMID:27589691

  10. β-escin selectively targets the glioblastoma-initiating cell population and reduces cell viability.

    PubMed

    Harford-Wright, Elizabeth; Bidère, Nicolas; Gavard, Julie

    2016-10-11

    Glioblastoma multiforme (GBM) is a highly aggressive tumour of the central nervous system and is associated with an extremely poor prognosis. Within GBM exists a subpopulation of cells, glioblastoma-initiating cells (GIC), which possess the characteristics of progenitor cells, have the ability to initiate tumour growth and resist to current treatment strategies. We aimed at identifying novel specific inhibitors of GIC expansion through use of a large-scale chemical screen of approved small molecules. Here, we report the identification of the natural compound β-escin as a selective inhibitor of GIC viability. Indeed, β-escin was significantly cytotoxic in nine patient-derived GIC, whilst exhibiting no substantial effect on the other human cancer or control cell lines tested. In addition, β-escin was more effective at reducing GIC growth than current clinically used cytotoxic agents. We further show that β-escin triggers caspase-dependent cell death combined with a loss of stemness properties. However, blocking apoptosis could not rescue the β-escin-induced reduction in sphere formation or stemness marker activity, indicating that β-escin directly modifies the stem identity of GIC, independent of the induction of cell death. Thus, this study has repositioned β-escin as a promising potential candidate to selectively target the aggressive population of initiating cells within GBM.

  11. Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes.

    PubMed

    Justice, Jamie; Miller, Jordan D; Newman, John C; Hashmi, Shahrukh K; Halter, Jeffrey; Austad, Steve N; Barzilai, Nir; Kirkland, James L

    2016-11-01

    Therapies targeted at fundamental processes of aging may hold great promise for enhancing the health of a wide population by delaying or preventing a range of age-related diseases and conditions-a concept dubbed the "geroscience hypothesis." Early, proof-of-concept clinical trials will be a key step in the translation of therapies emerging from model organism and preclinical studies into clinical practice. This article summarizes the outcomes of an international meeting partly funded through the NIH R24 Geroscience Network, whose purpose was to generate concepts and frameworks for early, proof-of-concept clinical trials for therapeutic interventions that target fundamental processes of aging. The goals of proof-of-concept trials include generating preliminary signals of efficacy in an aging-related disease or outcome that will reduce the risk of conducting larger trials, contributing data and biological samples to support larger-scale research by strategic networks, and furthering a dialogue with regulatory agencies on appropriate registration indications. We describe three frameworks for proof-of-concept trials that target age-related chronic diseases, geriatric syndromes, or resilience to stressors. We propose strategic infrastructure and shared resources that could accelerate development of therapies that target fundamental aging processes.

  12. Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes

    PubMed Central

    Justice, Jamie; Miller, Jordan D.; Newman, John C.; Hashmi, Shahrukh K.; Halter, Jeffrey; Austad, Steve N.; Barzilai, Nir

    2016-01-01

    Therapies targeted at fundamental processes of aging may hold great promise for enhancing the health of a wide population by delaying or preventing a range of age-related diseases and conditions—a concept dubbed the “geroscience hypothesis.” Early, proof-of-concept clinical trials will be a key step in the translation of therapies emerging from model organism and preclinical studies into clinical practice. This article summarizes the outcomes of an international meeting partly funded through the NIH R24 Geroscience Network, whose purpose was to generate concepts and frameworks for early, proof-of-concept clinical trials for therapeutic interventions that target fundamental processes of aging. The goals of proof-of-concept trials include generating preliminary signals of efficacy in an aging-related disease or outcome that will reduce the risk of conducting larger trials, contributing data and biological samples to support larger-scale research by strategic networks, and furthering a dialogue with regulatory agencies on appropriate registration indications. We describe three frameworks for proof-of-concept trials that target age-related chronic diseases, geriatric syndromes, or resilience to stressors. We propose strategic infrastructure and shared resources that could accelerate development of therapies that target fundamental aging processes. PMID:27535966

  13. An intensive family intervention clinic for reducing childhood obesity.

    PubMed

    Endevelt, Ronit; Elkayam, Orit; Cohen, Rinat; Peled, Ronit; Tal-Pony, Limor; Michaelis Grunwald, Ruth; Valinsky, Liora; Porath, Avi; Heymann, Anthony David

    2014-01-01

    Childhood and adolescent obesity constitute a significant public health concern. Family health care settings with multidisciplinary teams provide an opportunity for weight loss treatment. The objective of this study was to examine the effect of intensive treatment designed to reduce weight using a parent-child lifestyle modification intervention in a family health care clinic for obese and overweight children who had failed previous treatment attempts. This was a practice-based 6-month intervention at Maccabi Health Care Services, an Israeli health maintenance organization, consisting of parental education, individual child consultation, and physical activity classes. We included in the intervention 100 obese or overweight children aged 5 to 14 years and their parents and 943 comparison children and their parents. Changes in body mass index z-scores, adjusted for socioeconomic status, were analyzed, with a follow-up at 14 months and a delayed follow-up at an average of 46.7 months. The mean z-score after the intervention was lower in the intervention group compared to the comparison group (1.74 and 1.95, respectively; P = .019). The intervention group sustained the reduction in z-score after an average of 46.7 months (P < .001). Of the overweight or obese children, 13% became normal weight after the intervention, compared with 4% of the comparison children. This multidisciplinary team treatment of children and their parents in family health care clinics positively affected measures of childhood obesity. Additional randomized trials are required to verify these findings.

  14. Combination of chemotherapy and cancer stem cell targeting agents: Preclinical and clinical studies.

    PubMed

    Li, Yanyan; Atkinson, Katharine; Zhang, Tao

    2017-03-12

    The cancer stem cell model claims that the initiation, maintenance, and growth of a tumor are driven by a small population of cancer cells termed cancer stem cells. Cancer stem cells possess a variety of phenotypes associated with therapeutic resistance and often cause recurrence of the diseases. Several strategies have been investigated to target cancer stem cells in a variety of cancers, such as blocking one or more self-renewal signaling pathways, reducing the expression of drug efflux and ATP-binding cassette efflux transporters, modulating epigenetic aberrations, and promoting cancer stem cell differentiation. A number of cell and animal studies strongly support the potential benefits of combining chemotherapeutic drugs with cancer stem cell targeting agents. Clinical trials are still underway to address the pharmacokinetics, safety, and efficacy of combination treatment. This mini-review provides an updated discussion of these preclinical and clinical studies.

  15. An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria.

    PubMed

    Liebow, Abigail; Li, Xingsheng; Racie, Timothy; Hettinger, Julia; Bettencourt, Brian R; Najafian, Nader; Haslett, Patrick; Fitzgerald, Kevin; Holmes, Ross P; Erbe, David; Querbes, William; Knight, John

    2017-02-01

    Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylate metabolism, arises from mutations in the enzyme alanine-glyoxylate aminotransferase. The resulting deficiency in this enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other tissues, with systemic oxalosis and ESRD being a common outcome. Although a small subset of patients manages the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant, which requires life-long immune suppression and carries significant mortality risk. In this report, we discuss the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis. Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and nonhuman primates. ALN-GO1 also increased urinary glycolate concentrations in normal nonhuman primates and in a genetic mouse model of PH1. Notably, ALN-GO1 reduced urinary oxalate concentration up to 50% after a single dose in the genetic mouse model of PH1, and up to 98% after multiple doses in a rat model of hyperoxaluria. These data demonstrate the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and provide a clear rationale for clinical trials with this compound.

  16. Measuring and Reducing Off-Target Activities of Programmable Nucleases Including CRISPR-Cas9.

    PubMed

    Koo, Taeyoung; Lee, Jungjoon; Kim, Jin-Soo

    2015-06-01

    Programmable nucleases, which include zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and RNA-guided engineered nucleases (RGENs) repurposed from the type II clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system are now widely used for genome editing in higher eukaryotic cells and whole organisms, revolutionising almost every discipline in biological research, medicine, and biotechnology. All of these nucleases, however, induce off-target mutations at sites homologous in sequence with on-target sites, limiting their utility in many applications including gene or cell therapy. In this review, we compare methods for detecting nuclease off-target mutations. We also review methods for profiling genome-wide off-target effects and discuss how to reduce or avoid off-target mutations.

  17. Robust energy enhancement of ultrashort pulse laser accelerated protons from reduced mass targets

    NASA Astrophysics Data System (ADS)

    Zeil, K.; Metzkes, J.; Kluge, T.; Bussmann, M.; Cowan, T. E.; Kraft, S. D.; Sauerbrey, R.; Schmidt, B.; Zier, M.; Schramm, U.

    2014-08-01

    This paper reports on a systematic investigation of the ultrashort pulse laser driven acceleration of protons from thin targets of finite size, so-called reduced mass targets (RMTs). Reproducible series of targets, manufactured with lithographic techniques, and varying in size, thickness, and mounting geometry, were irradiated with ultrashort (30 fs) laser pulses of intensities of about 8 × 1020 W cm-2. A robust maximum energy enhancement of almost a factor of two was found when comparing gold RMTs to reference irradiations of plain gold foils of the same thickness. Furthermore, a change of the thickness of these targets has less influence on the measured maximum proton energy when compared to standard foils, which, based on detailed particle-in-cell simulations, can be explained by the influence of the RMT geometry on the electron sheath. The performance gain was, however, restricted to lateral target sizes of greater than 50 µm, which can be attributed to edge and mounting structure influences.

  18. Measuring and Reducing Off-Target Activities of Programmable Nucleases Including CRISPR-Cas9

    PubMed Central

    Koo, Taeyoung; Lee, Jungjoon; Kim, Jin-Soo

    2015-01-01

    Programmable nucleases, which include zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and RNA-guided engineered nucleases (RGENs) repurposed from the type II clustered, regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system are now widely used for genome editing in higher eukaryotic cells and whole organisms, revolutionising almost every discipline in biological research, medicine, and biotechnology. All of these nucleases, however, induce off-target mutations at sites homologous in sequence with on-target sites, limiting their utility in many applications including gene or cell therapy. In this review, we compare methods for detecting nuclease off-target mutations. We also review methods for profiling genome-wide off-target effects and discuss how to reduce or avoid off-target mutations. PMID:25985872

  19. Curcumin and insulin resistance-Molecular targets and clinical evidences.

    PubMed

    Jiménez-Osorio, Angélica Saraí; Monroy, Adriana; Alavez, Silvestre

    2016-11-12

    Curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), the main component of the Indian spice turmeric, has been used in traditional medicine to improve diabetes and its comorbidities. Since the last two decades, scientific research has shown that in addition to its antioxidant properties, curcumin could also work as protein homeostasis regulator and it is able to modulate other intracellular pathways. Curcumin supplementation has been proposed to improve insulin resistance (IR) through the activation of the insulin receptor and its downstream pathways in several experimental models, pointing out that its clinical use may be a good and innocuous strategy to improve IR-related diseases. IR is associated with many diseases and syndromes like carbohydrate intolerance, diabetes, metabolic syndrome, and cardiovascular disease. Therefore, it is imperative to identify safe therapeutic interventions aimed to reduce side effects that could lead the patient to leave the treatment. To date, many clinical trials have been carried out using turmeric and curcumin to improve metabolic syndrome, carbohydrate intolerance, diabetes, and obesity in individuals with IR. Results so far are inconclusive because dose, time of treatment, and type of curcumin can change the study outcome significantly. However, there is some clinical evidence suggesting a beneficial effect of curcumin on IR. In this review, we discuss the factors that could influence curcumin effects in clinical trials aimed to improve IR and related diseases, and the conclusions that can be drawn from results obtained so far. © 2016 BioFactors, 42(6):561-580, 2016.

  20. Active learning reduces annotation time for clinical concept extraction.

    PubMed

    Kholghi, Mahnoosh; Sitbon, Laurianne; Zuccon, Guido; Nguyen, Anthony

    2017-10-01

    To investigate: (1) the annotation time savings by various active learning query strategies compared to supervised learning and a random sampling baseline, and (2) the benefits of active learning-assisted pre-annotations in accelerating the manual annotation process compared to de novo annotation. There are 73 and 120 discharge summary reports provided by Beth Israel institute in the train and test sets of the concept extraction task in the i2b2/VA 2010 challenge, respectively. The 73 reports were used in user study experiments for manual annotation. First, all sequences within the 73 reports were manually annotated from scratch. Next, active learning models were built to generate pre-annotations for the sequences selected by a query strategy. The annotation/reviewing time per sequence was recorded. The 120 test reports were used to measure the effectiveness of the active learning models. When annotating from scratch, active learning reduced the annotation time up to 35% and 28% compared to a fully supervised approach and a random sampling baseline, respectively. Reviewing active learning-assisted pre-annotations resulted in 20% further reduction of the annotation time when compared to de novo annotation. The number of concepts that require manual annotation is a good indicator of the annotation time for various active learning approaches as demonstrated by high correlation between time rate and concept annotation rate. Active learning has a key role in reducing the time required to manually annotate domain concepts from clinical free text, either when annotating from scratch or reviewing active learning-assisted pre-annotations. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Attuning one's steps to visual targets reduces comfortable walking speed in both young and older adults.

    PubMed

    Peper, C Lieke E; de Dreu, Miek J; Roerdink, Melvyn

    2015-03-01

    Comfortable walking speed (CWS) is indicative of clinically relevant factors in the elderly, such as fall risk and mortality. Standard CWS tests involve walking on a straight, unobstructed surface, while in reality surfaces are uneven and cluttered and so walkers rely on visually guided adaptations to avoid trips or slips. Hence, the predictive value of CWS may be expected to increase when assessed for walking in more realistic (visually guided) conditions. We examined CWS in young (n=18) and older (n=18) adults for both overground and treadmill walking. Overground CWS was assessed using the 10-meter walk test with and without visual stepping targets. For treadmill walking, four conditions were examined: (i) uncued walking, and (ii-iv) cued walking with visual stepping targets where the inter-stepping target distance varied by 0%, 20%, or 40%. Pre-experimental measures were taken so that the average inter-stepping target distance could be adjusted for each belt speed based on each participant's self-selected gait characteristics. Results showed that CWS was significantly slower when stepping targets were present in both overground (p<.001) and treadmill walking (p<.001). Thus, attuning steps to visual targets significantly affected CWS, even when the patterning of these targets matched the participant's own gait pattern (viz. 0%-treadmill-walking condition). Results from the treadmill-walking task showed that the amount of variation in inter-stepping target distance did not differentially affect CWS. Our results suggest that it may be worthwhile in clinical assessments to not only determine walking speed using standard conditions but also in situations that require visually guided stepping.

  2. Simulations of High-Intensity Short-Pulse Lasers Incident on Reduced Mass Targets

    NASA Astrophysics Data System (ADS)

    King, Frank W.

    This thesis presents the results of a series of fully kinetic particle-in-cell (PIC) simulations of reduced mass targets with pre-plasma subjected to high-intensity short-pulse lasers. The simulations are performed in one, two, and three dimensions. The results of these simulations show that the creation of an electrostatic collisionless ion shock in the preplasma controls the creation of an above solid density ion perturbation in the target bulk, and this determines the reduced mass target heating and deformation. The ion perturbation is initiated by a population of high-energy electrons that rapidly spread throughout the target and reflux. The perturbation spreads longitudinally and transversely through the target and results in compression followed by the destruction of the target. This deformation requires a kinetic treatment due to the generation of non-equilibrium particle distributions and the role of ballistic electrons and ions. Kinetic and fluid simulations are compared and both exhibit the basic features of the above solid density ion perturbation, but the magnitude of the effect and the speed of propagation vary significantly between the two methods. Kinetic simulations do not naturally include equation-of-state physics and other aspects of the problem. Both approaches are complementary. The requirements on spatial resolution, particle count, and other numerical parameters are addressed in this work. From these simulations, the behavior of the reduced mass targets is found to vary significantly depending on the laser focal spot size or the intensity of the laser pulse. This occurs even if the energy and power of the laser pulses are held constant. The number of dimensions used in the particle-in-cell simulations has been observed to have a significant effect on late-time heating of the target, but not during or shortly after laser excitation. This is due to the representation of the equilibration process as the initial population of laser heated

  3. A Behavioral Intervention to Reduce Child Exposure to Indoor Air Pollution: Identifying Possible Target Behaviors

    ERIC Educational Resources Information Center

    Barnes, Brendon R.; Mathee, Angela; Shafritz, Lonna B.; Krieger, Laurie; Zimicki, Susan

    2004-01-01

    Indoor air pollution has been causally linked to acute lower respiratory infections in children younger than 5. The aim of this study was to identify target behaviors for a behavioral intervention to reduce child exposure to indoor air pollution by attempting to answer two research questions: Which behaviors are protective of child respiratory…

  4. A Behavioral Intervention to Reduce Child Exposure to Indoor Air Pollution: Identifying Possible Target Behaviors

    ERIC Educational Resources Information Center

    Barnes, Brendon R.; Mathee, Angela; Shafritz, Lonna B.; Krieger, Laurie; Zimicki, Susan

    2004-01-01

    Indoor air pollution has been causally linked to acute lower respiratory infections in children younger than 5. The aim of this study was to identify target behaviors for a behavioral intervention to reduce child exposure to indoor air pollution by attempting to answer two research questions: Which behaviors are protective of child respiratory…

  5. Ultrasound Characteristics of Clinically Dislocated But Reducible Hips With DDH.

    PubMed

    Striano, Brendan; Schaeffer, Emily K; Matheney, Travis H; Upasani, Vidayadhar V; Price, Charles T; Mulpuri, Kishore; Sankar, Wudbhav N

    2017-07-21

    Although ultrasound (US) is frequently used in diagnosis and management of infantile developmental dysplasia of the hip, precise ultrasonographic parameters of what constitutes a dislocation, subluxation etc remain poorly defined. The purpose of this study was (1) to describe the ultrasonographic characteristics of a large cohort of clinically dislocated but reducible hips and (2) to begin to develop ultrasonographic definitions for what constitutes a hip dislocation. A retrospective review of prospectively collected data from an international multicenter study group on developmental dysplasia of the hip was conducted on all patients under 6 months of age with hip(s) that were dislocated at rest but reducible based on initial physical examination (ie, Ortolani positive). Femoral head coverage (FHC), alpha angle (α), and beta angle (β) were measured on pretreatment US by the individual treating surgeon, and were recorded directly into the database. Based on 325 Ortolani positive hips, the median FHC on presentation was 10% with an interquartile range of 0% to 23%. A total of 126 of the 327 hips (39%) demonstrated 0% FHC. The 90th percentile was found to be at 33% FHC. Of 264 hips with sufficient α data, the median α was 43 degrees with an interquartile range from 37 to 49 degrees. The 90th percentile for α was at 54 degrees. A total of 164 hips had documented β with a median of 66 degrees and an interquartile range of 57 to 79 degrees; the 90th percentile was at 94 degrees. Analysis of a large cohort of patients with dislocated but reducible hips reveals a median percent FHC of 10%, a median α of 43 degrees, and a median β of 66 degrees on initial US. Using a threshold at the 90th percentile, a sensible ultrasonographic definition of a dislocated hip seems to be FHC≤33%, implying that FHC between 34% and 50% may be reasonably termed a subluxation. Although these findings are consistent with previous, smaller reports, further prospective research is

  6. Targets and timelines for reducing salt in processed food in the Americas.

    PubMed

    Campbell, Norm; Legowski, Barbara; Legetic, Branka; Ferrante, Daniel; Nilson, Eduardo; Campbell, Christine; L'Abbé, Mary

    2014-09-01

    Reducing dietary salt is one of the most effective interventions to lessen the burden of premature death and disability. In high-income countries and those in nutrition transition, processed foods are a significant if not the main source of dietary salt. Reformulating these products to reduce their salt content is recommended as a best buy to prevent chronic diseases across populations. In the Americas, there are targets and timelines for reduced salt content of processed foods in 8 countries--Argentina, Brazil, Canada, Chile, Ecuador, Mexico, and the National Salt Reduction Initiative in the United States and Paraguay. While there are common elements across the countries, there are notable differences in their approaches: 4 countries have exclusively voluntary targets, 2 countries have combined voluntary and regulated components, and 1 country has only regulations. The countries have set different types of targets and in some cases combined them: averages, sales-weighted averages, upper limits, and percentage reductions. The foods to which the targets apply vary from single categories to comprehensive categories accounting for all processed products. The most accessible and transparent targets are upper limits per food category. Most likely to have a substantive and sustained impact on salt intake across whole populations is the combination of sales-weighted averages and upper limits. To assist all countries with policies to improve the overall nutritional value of processed foods, the authors call for food companies to supply food composition data and product sales volume data to transparent and open-access platforms and for global companies to supply the products that meet the strictest targets to all markets. Countries participating in common markets at the subregional level can consider harmonizing targets, nutrition labels, and warning labels. ©2014 Wiley Periodicals, Inc.

  7. Isochoric heating of reduced mass targets by ultra-intense laser produced relativistic electrons

    SciTech Connect

    Neumayer, P; Lee, H J; Offerman, D; Shipton, E; Kemp, A; Kritcher, A L; Doppner, T; Back, C A; Glenzer, S H

    2009-02-04

    We present measurements of the chlorine K-alpha emission from reduced mass targets, irradiated with ultra-high intensity laser pulses. Chlorinated plastic targets with diameters down to 50 micrometers and mass of a few 10{sup -8} g were irradiated with up to 7 J of laser energy focused to intensities of several 10{sup 19} W/cm{sup 2}. The conversion of laser energy to K-alpha radiation is measured, as well as high resolution spectra that allow observation of line shifts, indicating isochoric heating of the target up to 18 eV. A zero-dimensional 2-temperature equilibration model, combined with electron impact K-shell ionization and post processed spectra from collisional radiative calculations reproduces the observed K-alpha yields and line shifts, and shows the importance of target expansion due to the hot electron pressure.

  8. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab

    PubMed Central

    Smolej, Lukáš

    2015-01-01

    Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL. PMID:25691812

  9. Targeting zero non-attendance in healthcare clinics.

    PubMed

    Chan, Ka C; Chan, David B

    2012-01-01

    Non-attendance represents a significant cost to many health systems, resulting in inefficiency, wasted resources, poorer service delivery and lengthened waiting queues. Past studies have considered extensively the reasons for non-attendance and have generally concluded that the use of reminder systems is effective. Despite this, there will always be a certain level of non-attendance arising from unforeseeable and unpreventable circumstances, such as illness or accidents, leading to unfilled appointments. This paper reviews current approaches to the non-attendance problem, and presents a high-level approach to fill last minute appointments arising out of unforeseeable non-attendance. However, no single approach will work for all clinics and implementation of these ideas must occur at a local level. These approaches include use of social networks, such as Twitter and Facebook, as a communication tool in order to notify prospective patients when last-minute appointments become available. In addition, teleconsultation using video-conferencing technologies would be suitable for certain last-minute appointments where travel time would otherwise be inhibiting. Developments of new and innovative technologies and the increasing power of social media, means that zero non-attendance is now an achievable target. We hope that this will lead to more evidence-based evaluations from the implementation of these strategies in various settings at a local level.

  10. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab.

    PubMed

    Smolej, Lukáš

    2015-01-01

    Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL.

  11. Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis.

    PubMed

    Sa, Zhining; Zhou, Jingqi; Zou, Yangyun; Su, Zhixi; Gu, Xun

    2017-08-01

    Side effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs, we analyzed two types (type-I and type-II) of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors (GPCRs) at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-II amino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR, which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-1R. The divergent features between GCGR and GLP-1R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  12. Targeted Toxins for Glioblastoma Multiforme: pre-clinical studies and clinical implementation

    PubMed Central

    Candolfi, Marianela; Kroeger, Kurt M.; Xiong, Weidong; Liu, Chunyan; Puntel, Mariana; Yagiz, Kader; Ghulam Muhammad, AKM; Mineharu, Yohei; Foulad, David; Wibowo, Mia; Assi, Hikmat; Baker, Gregory J.; Lowenstein, Pedro R.; Castro, Maria G.

    2011-01-01

    Glioblastoma multiforme (GBM) is most common primary brain tumor in adults. GBM is very aggressive due to its poor cellular differentiation and invasiveness, which makes complete surgical resection virtually impossible. Therefore, GBM’s invasive nature as well as its intrinsic resistance to current treatment modalities makes it a unique therapeutic challenge. Extensive examination of human GBM specimens has uncovered that these tumors overexpress a variety of receptors that are virtually absent in the surrounding non-neoplastic brain. Human GBMs overexpress receptors for cytokines, growth factors, ephrins, urokinase-type plasminogen activator (uPA), and transferrin, which can be targeted with high specificity by linking their ligands with highly cytotoxic molecules, such as Diptheria toxin and Pseudomonas exotoxin A. We review the preclinical development and clinical translation of targeted toxins for GBM. In view of the clinical experience, we conclude that although these are very promising therapeutic modalities for GBM patients, efforts should be focused on improving the delivery systems utilized in order to achieve better distribution of the immuno-toxins in the tumor/resection cavity. Delivery of targeted toxins using viral vectors would also benefit enormously from improved strategies for local delivery. PMID:21707497

  13. Targeting geranylgeranylation reduces adrenal gland tumor burden in a murine model of prostate cancer metastasis

    PubMed Central

    Reilly, Jacqueline E; Neighbors, Jeffrey D; Tong, Huaxiang; Henry, Michael D; Hohl, Raymond J

    2016-01-01

    The isoprenoid biosynthetic pathway (IBP) is critical for providing substrates for the post-translational modification of proteins key in regulating malignant cell properties, including proliferation, invasion, and migration. Inhibitors of the IBP, including statins and nitrogenous bisphosphonates, are used clinically for the treatment of hypercholesterolemia and bone disease respectively. The statins work predominantly in the liver, while the nitrogenous bisphosphonates are highly sequestered to bone. Inhibition of the entire IBP is limited by organ specificity and side effects resulting from depletion of all isoprenoids. We have developed a novel compound, disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which selectively targets geranylgeranyl diphosphate synthase (GGDPS), reducing post-translational protein geranylgeranylation. Intracardiac injection of luciferase-expressing human-derived 22Rv1 PCa cells into SCID mice resulted in tumor development in bone (100%), adrenal glands (72%), mesentery (22%), liver (17%), and the thoracic cavity (6%). Three weeks after tumor inoculation, daily subcutaneous (SQ) injections of 1.5 mg/kg GGOHBP or the vehicle were given for one month. Dissected tumors revealed areduction in adrenal gland tumors corresponding to a 54% (P < 0.005) reduction in total adrenal gland tumor weight of the treated mice as compared to vehicle-treated controls. Western blot analysis of the harvested tissues showed a reduction in Rap1A geranylgeranylation in adrenal glands and mesenteric tumors of the treated mice while non-tumorous tissues and control mice showed no Rap1A alteration. Our findings detail a novel bisphosphonate compound capable of preferentially altering the IBP in tumor-burdened adrenal glands of a murine model of PCa metastasis. PMID:26070429

  14. Targeting geranylgeranylation reduces adrenal gland tumor burden in a murine model of prostate cancer metastasis.

    PubMed

    Reilly, Jacqueline E; Neighbors, Jeffrey D; Tong, Huaxiang; Henry, Michael D; Hohl, Raymond J

    2015-08-01

    The isoprenoid biosynthetic pathway (IBP) is critical for providing substrates for the post-translational modification of proteins key in regulating malignant cell properties, including proliferation, invasion, and migration. Inhibitors of the IBP, including statins and nitrogenous bisphosphonates, are used clinically for the treatment of hypercholesterolemia and bone disease respectively. The statins work predominantly in the liver, while the nitrogenous bisphosphonates are highly sequestered to bone. Inhibition of the entire IBP is limited by organ specificity and side effects resulting from depletion of all isoprenoids. We have developed a novel compound, disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which selectively targets geranylgeranyl diphosphate synthase, reducing post-translational protein geranylgeranylation. Intracardiac injection of luciferase-expressing human-derived 22Rv1 PCa cells into SCID mice resulted in tumor development in bone (100 %), adrenal glands (72 %), mesentery (22 %), liver (17 %), and the thoracic cavity (6 %). Three weeks after tumor inoculation, daily subcutaneous (SQ) injections of 1.5 mg/kg GGOHBP or the vehicle were given for one month. Dissected tumors revealed a reduction in adrenal gland tumors corresponding to a 54 % (P < 0.005) reduction in total adrenal gland tumor weight of the treated mice as compared to vehicle-treated controls. Western blot analysis of the harvested tissues showed a reduction in Rap1A geranylgeranylation in adrenal glands and mesenteric tumors of the treated mice while non-tumorous tissues and control mice showed no Rap1A alteration. Our findings detail a novel bisphosphonate compound capable of preferentially altering the IBP in tumor-burdened adrenal glands of a murine model of PCa metastasis.

  15. The World Health Organization's global target for reducing childhood stunting by 2025: rationale and proposed actions.

    PubMed

    de Onis, Mercedes; Dewey, Kathryn G; Borghi, Elaine; Onyango, Adelheid W; Blössner, Monika; Daelmans, Bernadette; Piwoz, Ellen; Branca, Francesco

    2013-09-01

    In 2012, the World Health Organization adopted a resolution on maternal, infant and young child nutrition that included a global target to reduce by 40% the number of stunted under-five children by 2025. The target was based on analyses of time series data from 148 countries and national success stories in tackling undernutrition. The global target translates to a 3.9% reduction per year and implies decreasing the number of stunted children from 171 million in 2010 to about 100 million in 2025. However, at current rates of progress, there will be 127 million stunted children by 2025, that is, 27 million more than the target or a reduction of only 26%. The translation of the global target into national targets needs to consider nutrition profiles, risk factor trends, demographic changes, experience with developing and implementing nutrition policies, and health system development. This paper presents a methodology to set individual country targets, without precluding the use of others. Any method applied will be influenced by country-specific population growth rates. A key question is what countries should do to meet the target. Nutrition interventions alone are almost certainly insufficient, hence the importance of ongoing efforts to foster nutrition-sensitive development and encourage development of evidence-based, multisectoral plans to address stunting at national scale, combining direct nutrition interventions with strategies concerning health, family planning, water and sanitation, and other factors that affect the risk of stunting. In addition, an accountability framework needs to be developed and surveillance systems strengthened to monitor the achievement of commitments and targets. © 2013 John Wiley & Sons Ltd.

  16. Reducing emissions from agriculture to meet the 2 °C target.

    PubMed

    Wollenberg, Eva; Richards, Meryl; Smith, Pete; Havlík, Petr; Obersteiner, Michael; Tubiello, Francesco N; Herold, Martin; Gerber, Pierre; Carter, Sarah; Reisinger, Andrew; van Vuuren, Detlef P; Dickie, Amy; Neufeldt, Henry; Sander, Björn O; Wassmann, Reiner; Sommer, Rolf; Amonette, James E; Falcucci, Alessandra; Herrero, Mario; Opio, Carolyn; Roman-Cuesta, Rosa Maria; Stehfest, Elke; Westhoek, Henk; Ortiz-Monasterio, Ivan; Sapkota, Tek; Rufino, Mariana C; Thornton, Philip K; Verchot, Louis; West, Paul C; Soussana, Jean-François; Baedeker, Tobias; Sadler, Marc; Vermeulen, Sonja; Campbell, Bruce M

    2016-12-01

    More than 100 countries pledged to reduce agricultural greenhouse gas (GHG) emissions in the 2015 Paris Agreement of the United Nations Framework Convention on Climate Change. Yet technical information about how much mitigation is needed in the sector vs. how much is feasible remains poor. We identify a preliminary global target for reducing emissions from agriculture of ~1 GtCO2 e yr(-1) by 2030 to limit warming in 2100 to 2 °C above pre-industrial levels. Yet plausible agricultural development pathways with mitigation cobenefits deliver only 21-40% of needed mitigation. The target indicates that more transformative technical and policy options will be needed, such as methane inhibitors and finance for new practices. A more comprehensive target for the 2 °C limit should be developed to include soil carbon and agriculture-related mitigation options. Excluding agricultural emissions from mitigation targets and plans will increase the cost of mitigation in other sectors or reduce the feasibility of meeting the 2 °C limit.

  17. Impact of Multiple Daily Clinical Pharmacist-Enforced Assessments on Time in Target Sedation Range.

    PubMed

    Lizza, Bryan D; Jagow, Benjamin; Hensler, David; Cooper, Craig J; Short, Elizabeth J; Maas, Matthew B; Naidech, Andrew M; Wunderink, Richard G

    2017-01-01

    Incorporation of a single daily assessment by a clinical pharmacist to improve adherence with a sedation protocol is associated with reduced duration of mechanical ventilation and intensive care unit (ICU) length of stay (LOS). We test the feasibility of incorporating a clinical pharmacist into more frequent sedation assessments and observed whether there are any potential differences in the sedatives administered. Prospective, quasi-experimental, pilot study of patients admitted to the medical ICU. Patients were included in the analysis if ≥18 years of age within the first 24 hours of initiation of mechanical ventilation. Our primary intent was to test the clinical feasibility surrounding more frequent sedation assessments by a clinical pharmacist by evaluating potential differences in time in target sedation range and sedative administration. Exploratory efficacy end points included time in target sedation range (0 to -2) using the Richmond Agitation Sedation Scale (RASS) and sedative exposure. Patients were assigned to receive either 3 assessments with a clinical pharmacist per day (intervention) or a single assessment by a clinical pharmacist per day (standard of care). During the assessments, clinical pharmacists participated in the RASS administration and made dosing adjustments according to an established sedation protocol. Seventeen patients were enrolled (n = 6 intervention group, n = 11 standard of care). Duration of mechanical ventilation was similar in the 2 groups (intervention 100.0 hours [52.5-197.5] vs control 76.0 hours [46.0-201.0], P = .95), but patients in the intervention group exhibited a greater percentage time in the target RASS range (intervention 76.0% [53.7-81.5%] vs control 45.2% [35.3-67.0], P = .11) that was not statistically significant. Patients in the intervention group received less fentanyl per day (820.9 µg [227.3-1579.4] vs 1997 µg [1648.2-2477.2], P = .02) than in the control group. Incorporating a clinical pharmacist into

  18. Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease

    PubMed Central

    Solfrizzi, Vincenzo; Imbimbo, Bruno P.; Lozupone, Madia; Santamato, Andrea; Zecca, Chiara; Barulli, Maria Rosaria; Bellomo, Antonello; Pilotto, Alberto; Daniele, Antonio; Greco, Antonio

    2016-01-01

    The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid. PMID:27429978

  19. Tumor targeting RGD conjugated bio-reducible polymer for VEGF siRNA expressing plasmid delivery.

    PubMed

    Kim, Hyun Ah; Nam, Kihoon; Kim, Sung Wan

    2014-08-01

    Targeted delivery of therapeutic genes to the tumor site is critical for successful and safe cancer gene therapy. The arginine grafted bio-reducible poly (cystamine bisacrylamide-diaminohexane, CBA-DAH) polymer (ABP) conjugated poly (amido amine) (PAMAM), PAM-ABP (PA) was designed previously as an efficient gene delivery carrier. To achieve high efficacy in cancer selective delivery, we developed the tumor targeting bio-reducible polymer, PA-PEG1k-RGD, by conjugating cyclic RGDfC (RGD) peptides, which bind αvβ3/5 integrins, to the PAM-ABP using polyethylene glycol (PEG, 1 kDa) as a spacer. Physical characterization showed nanocomplex formation with bio-reducible properties between PA-PEG1k-RGD and plasmid DNA (pDNA). In transfection assays, PA-PEG1k-RGD showed significantly higher transfection efficiency in comparison with PAM-ABP or PA-PEG1k-RAD in αvβ3/5 positive MCF7 breast cancer and PANC-1 pancreatic cancer cells. The targeting ability of PA-PEG1k-RGD was further established using a competition assay. To confirm the therapeutic effect, the VEGF siRNA expressing plasmid was constructed and then delivered into cancer cells using PA-PEG1k-RGD. PA-PEG1k-RGD showed 20-59% higher cellular uptake rate into MCF7 and PANC-1 than that of non-targeted polymers. In addition, MCF7 and PANC-1 cancer cells transfected with PA-PEG1k-RGD/pshVEGF complexes had significantly decreased VEGF gene expression (51-71%) and cancer cell viability (35-43%) compared with control. These results demonstrate that a tumor targeting bio-reducible polymer with an anti-angiogenic therapeutic gene could be used for efficient and safe cancer gene therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Tumor targeting RGD conjugated bio-reducible polymer for VEGF siRNA expressing plasmid delivery

    PubMed Central

    Kim, Hyun Ah; Nam, Kihoon; Kim, Sung Wan

    2014-01-01

    Targeted delivery of therapeutic genes to the tumor site is critical for successful and safe cancer gene therapy. The arginine grafted bio-reducible poly (cystamine bisacrylamide-diaminohexane, CBA-DAH) polymer (ABP) conjugated poly (amido amine) (PAMAM), PAM-ABP (PA) was designed previously as an efficient gene delivery carrier. To achieve high efficacy in cancer selective delivery, we developed the tumor targeting bio-reducible polymer, PA-PEG1k-RGD, by conjugating cyclic RGDfC (RGD) peptides, which bind αvβ3/5 integrins, to the PAM-ABP using polyethylene glycol (PEG,1kDa) as a spacer. Physical characterization showed nanocomplex formation with bio-reducible properties between PA-PEG1k-RGD and plasmid DNA (pDNA). In transfection assays, PA-PEG1k-RGD showed significantly higher transfection efficiency in comparison with PAM-ABP or PA-PEG1k-RGD in αvβ3/5 positive MCF7 breast cancer and PANC-1 pancreatic cancer cells. The targeting ability of PA-PEG1k-RGD was further established using a competition assay. To confirm the therapeutic effect, the VEGF siRNA expressing plasmid was constructed and then delivered into cancer cells using PA-PEG1k-RGD. PA-PEG1k-RGD showed 20-59% higher cellular uptake rate into MCF7 and PANC-1 than that of non-targeted polymers. In addition, MCF7 and PANC-1 cancer cells transfected with PA-PEG1k-RGD/pshVEGF complexes had significantly decreased VEGF gene expression (51-71%) and cancer cell viability (35-43%) compared with control. These results demonstrate that a tumor targeting bio-reducible polymer with an anti-angiogenic therapeutic gene could be used for efficient and safe cancer gene therapy. PMID:24894645

  1. Identification of therapeutic targets applicable to clinical strategies in ovarian cancer.

    PubMed

    Kim, Marianne K; Caplen, Natasha; Chakka, Sirisha; Hernandez, Lidia; House, Carrie; Pongas, Georgios; Jordan, Elizabeth; Annunziata, Christina M

    2016-08-24

    shRNA-mediated lethality screening is a useful tool to identify essential targets in cancer biology. Ovarian cancer (OC) is extremely heterogeneous and most cases are advanced stages at diagnosis. OC has a high response rate initially, but becomes resistant to standard chemotherapy. We previously employed high throughput global shRNA sensitization screens to identify NF-kB related pathways. Here, we re-analyzed our previous shRNA screens in an unbiased manner to identify clinically applicable molecular targets. We proceeded with siRNA lethality screening using the top 55 genes in an expanded set of 6 OC cell lines. We investigated clinical relevance of candidate targets in The Cancer Genome Atlas OC dataset. To move these findings towards the clinic, we chose four pharmacological inhibitors to recapitulate the top siRNA effects: Oxozeaenol (for MAP3K7/TAK1), BI6727 (PLK1), MK1775 (WEE1), and Lapatinib (ERBB2). Cytotoxic effects were measured by cellular viability assay, as single agents and in 2-way combinations. Co-treatments were evaluated in either sequential or simultaneous exposure to drug for short term and extended periods to simulate different treatment strategies. Loss-of-function shRNA screens followed by short-term siRNA validation screens identified therapeutic targets in OC cells. Candidate genes were dysregulated in a subset of TCGA OCs although the alterations of these genes showed no statistical significance to overall survival. Pharmacological inhibitors such as Oxozeaenol, BI6727, and MK1775 showed cytotoxic effects in OC cells regardless of cisplatin responsiveness, while all OC cells tested were cytostatic to Lapatinib. Co-treatment with BI6727 and MK1775 at sub-lethal concentrations was equally potent to BI6727 alone at lethal concentrations without cellular re-growth after the drugs were washed off, suggesting the co-inhibition at reduced dosages may be more efficacious than maximal single-agent cytotoxic concentrations. Loss

  2. Accessory stimuli speed reaction times and reduce distraction in a target-distractor task.

    PubMed

    Tudge, Luke; Schubert, Torsten

    2016-05-01

    Eye movements in a visual search task are drawn towards items irrelevant to the search (distractors). Advance information about the position or features of distractors can reduce this effect, by speeding the resolution of conflict between search target and distractor. The present study investigated whether this can also be achieved by a prime that merely warns of an impending task without providing any other information (an accessory stimulus). We found that accessory stimuli speed the initiation of a saccade to the target, but also speed the resolution of target-distractor conflict. This finding suggests that the oculomotor system can be prepared to counteract distraction in advance of task onset, without requiring information about a specific spatial location or feature.

  3. Laser coupling to reduced-scale targets at NIF Early Light

    SciTech Connect

    Hinkel, D E; Schneider, M B; Young, B K; Holder, J P; Langdon, A B; Baldis, H A; Bonanno, G; Bower, D E; Bruns, H C; Campbell, K M; Celeste, J R; Compton, S; Costa, R L; Dewald, E L; Dixit, S N; Eckart, M J; Eder, D C; Edwards, M J; Ellis, A D; Emig, J A; Froula, D H; Glenzer, S H; Hargrove, D; Haynam, C A; Heeter, R F; Henesian, M A; Holtmeier, G; James, D L; Jancaitis, K S; Kalantar, D H; Kamperschroer, J H; Kauffman, R L; Kimbrough, J; Kirkwood, R K; Koniges, A E; Landen, O L; Landon, M; Lee, F D; MacGowan, B J; Mackinnon, A J; Manes, K R; Marshall, C; May, M J; McDonald, J W; Menapace, J; Moses, S I; Munro, D H; Murray, J R; Niemann, C; Pellinen, D; Power, G D; Rekow, V; Ruppe, J A; Schein, J; Shepherd, R; Singh, M S; Springer, P; Still, C H; Suter, L J; Tietbohl, G L; Turner, R E; VanWonterghem, B M; Wallace, R J; Warrick, A; Watts, P; Weber, F; Wegner, P J; Williams, E A; Young, P E

    2005-08-31

    Deposition of maximum laser energy into a small, high-Z enclosure in a short laser pulse creates a hot environment. Such targets were recently included in an experimental campaign using the first four of the 192 beams of the National Ignition Facility [J. A. Paisner, E. M. Campbell, and W. J. Hogan, Fusion Technology 26, 755 (1994)], under construction at the University of California Lawrence Livermore National Laboratory. These targets demonstrate good laser coupling, reaching a radiation temperature of 340 eV. In addition, the Raman backscatter spectrum contains features consistent with Brillouin backscatter of Raman forward scatter [A. B. Langdon and D. E. Hinkel, Physical Review Letters 89, 015003 (2002)]. Also, NIF Early Light diagnostics indicate that 20% of the direct backscatter from these reduced-scale targets is in the polarization orthogonal to that of the incident light.

  4. Reducing Diagnostic Error with Computer-Based Clinical Decision Support

    ERIC Educational Resources Information Center

    Greenes, Robert A.

    2009-01-01

    Information technology approaches to delivering diagnostic clinical decision support (CDS) are the subject of the papers to follow in the proceedings. These will address the history of CDS and present day approaches (Miller), evaluation of diagnostic CDS methods (Friedman), and the role of clinical documentation in supporting diagnostic decision…

  5. Reducing Diagnostic Error with Computer-Based Clinical Decision Support

    ERIC Educational Resources Information Center

    Greenes, Robert A.

    2009-01-01

    Information technology approaches to delivering diagnostic clinical decision support (CDS) are the subject of the papers to follow in the proceedings. These will address the history of CDS and present day approaches (Miller), evaluation of diagnostic CDS methods (Friedman), and the role of clinical documentation in supporting diagnostic decision…

  6. HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples.

    PubMed

    Moens, Lotte N J; Falk-Sörqvist, Elin; Ljungström, Viktor; Mattsson, Johanna; Sundström, Magnus; La Fleur, Linnéa; Mathot, Lucy; Micke, Patrick; Nilsson, Mats; Botling, Johan

    2015-11-01

    In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomolecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings.

  7. Bill restricts abortion blockades. Clinic violence is target of action.

    PubMed

    1993-11-17

    On November 16, 1993, the US Senate voted approval, by 69 to 30 members, to impose stiff penalties on those obstructing access to abortion clinics. The penalties include up to 1 year in jail and a $100,000 fine for first violent offenses. Obstruction without violence would lead to a fine of $10,000 and 6 months in jail. The legislation was deemed necessary after the murder of a doctor in Florida and the wounding of another doctor in Kansas. Democratic Senator Edward Kennedy said that those who do not obstruct access have nothing to fear. Support came not only from abortion rights advocates, but from those against lawlessness in the pro-life movement. Maryland's Democratic Senators Mikulski and Sarbanes and California's Democratic Senator Barbara Boxes supported the bill, as well as Attorney General Janet Reno and President Clinton. House Speaker Thomas S. Foley announced that the House would consider its version of the bill on November 18, 1993. The original version was changed to reduce fines for nonviolent offenders from $100,000 to $10,000. Opponents argued that the legislation treated peaceful protesters as felons, and was directed in a singular=sided way with no regard to civil disobedience by animal rights activists, antinuclear protesters, and AIDS activists. North Carolina Republican Senator Jesse Helms thought that the Supreme Court would find the bill unconstitutional. Other arguments were that civil disobedience should be allowed for anti-abortion protesters, as it was allowed for civil rights protesters such as Dr. Martin Luther King, Jr. Senator Kennedy pointed out the Dr. King was trying to secure a constitutional right, unlike anti-abortion protesters who were trying to deny a constitutional right.

  8. CIP2A is a candidate therapeutic target in clinically challenging prostate cancer cell populations

    PubMed Central

    Khanna, Anchit; Rane, Jayant K.; Kivinummi, Kati K.; Urbanucci, Alfonso; Helenius, Merja A.; Tolonen, Teemu T.; Saramäki, Outi R.; Latonen, Leena; Manni, Visa; Pimanda, John E.; Maitland, Norman J.; Westermarck, Jukka; Visakorpi, Tapio

    2015-01-01

    Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach. Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target. CIP2A is significantly overexpressed in both hormone-naïve prostate cancer (HN-PC) and CRPC patients. CIP2A is also overexpressed, by 3- and 30-fold, in HN-PC and CRPC SCs respectively. In vivo binding of the AR to the intronic region of CIP2A and its functionality in the AR-moderate and AR-high expressing LNCaP cell-model systems is also demonstrated. Further, we show that AR positively regulates CIP2A expression, both at the mRNA and protein level. Finally, CIP2A depletion reduced cell viability and colony forming efficiency of AR-independent PPECs as well as AR-responsive LNCaP cells, in which anchorage-independent growth is also impaired. These findings identify CIP2A as a common denominator for AR-signaling and cancer SC functionality, highlighting its potential therapeutic significance in the most clinically challenging prostate pathology: castration-resistant prostate cancer. PMID:25965834

  9. CIGB-300, a synthetic peptide-based drug that targets the CK2 phosphoaceptor domain. Translational and clinical research.

    PubMed

    Perea, Silvio E; Baladron, Idania; Garcia, Yanelda; Perera, Yasser; Lopez, Adlin; Soriano, Jorge L; Batista, Noyde; Palau, Aley; Hernández, Ignacio; Farina, Hernán; Garcia, Idrian; Gonzalez, Lidia; Gil, Jeovanis; Rodriguez, Arielis; Solares, Margarita; Santana, Agueda; Cruz, Marisol; Lopez, Matilde; Valenzuela, Carmen; Reyes, Osvaldo; López-Saura, Pedro A; González, Carlos A; Diaz, Alina; Castellanos, Lila; Sanchez, Aniel; Betancourt, Lazaro; Besada, Vladimir; González, Luis J; Garay, Hilda; Gómez, Roberto; Gómez, Daniel E; Alonso, Daniel F; Perrin, Phillipe; Renualt, Jean-Yves; Sigman, Hugo; Herrera, Luis; Acevedo, Boris

    2011-10-01

    CK2 represents an oncology target scientifically validated. However, clinical research with inhibitors of the CK2-mediated phosphorylation event is still insufficient to recognize it as a clinically validated target. CIGB-300, an investigational peptide-based drug that targets the phosphoaceptor site, binds to a CK2 substrate array in vitro but mainly to B23/nucleophosmin in vivo. The CIGB-300 proapoptotic effect is preceded by its nucleolar localization, inhibition of the CK2-mediated phosphorylation on B23/nucleophosmin and nucleolar disassembly. Importantly, CIGB-300 shifted a protein array linked to apoptosis, ribosome biogenesis, cell proliferation, glycolisis, and cell motility in proteomic studies which helped to understand its mechanism of action. In the clinical ground, CIGB-300 has proved to be safe and well tolerated in a First-in-Human trial in women with cervical malignancies who also experienced signs of clinical benefit. In a second Phase 1 clinical trial in women with cervical cancer stage IB2/II, the MTD and DLT have been also identified in the clinical setting. Interestingly, in cervical tumors the B23/nucleophosmin protein levels were significantly reduced after CIGB-300 treatment at the nucleus compartment. In addition, expanded use of CIGB-300 in case studies has evidenced antitumor activity when administered as compassional option. Collectively, our data outline important clues on translational and clinical research from this novel peptide-based drug reinforcing its perspectives to treat cancer and paving the way to validate CK2 as a promising target in oncology.

  10. The clinical potential of targeted nanomedicine: delivering to cancer stem-like cells.

    PubMed

    Kim, Sang-Soo; Rait, Antonina; Rubab, Farwah; Rao, Abhi K; Kiritsy, Michael C; Pirollo, Kathleen F; Wang, Shangzi; Weiner, Louis M; Chang, Esther H

    2014-02-01

    Cancer stem-like cells (CSCs) have been implicated in recurrence and treatment resistance in many human cancers. Thus, a CSC-targeted drug delivery strategy to eliminate CSCs is a desirable approach for developing a more effective anticancer therapy. We have developed a tumor-targeting nanodelivery platform (scL) for systemic administration of molecular medicines. Following treatment with the scL nanocomplex carrying various payloads, we have observed exquisite tumor-targeting specificity and significant antitumor response with long-term survival benefit in numerous animal models. We hypothesized that this observed efficacy might be attributed, at least in part, to elimination of CSCs. Here, we demonstrate the ability of scL to target both CSCs and differentiated nonstem cancer cells (non-CSCs) in various mouse models including subcutaneous and intracranial xenografts, syngeneic, and chemically induced tumors. We also show that systemic administration of scL carrying the wtp53 gene was able to induce tumor growth inhibition and the death of both CSCs and non-CSCs in subcutaneous colorectal cancer xenografts suggesting that this could be an effective method to reduce cancer recurrence and treatment resistance. This scL nanocomplex is being evaluated in a number of clinical trials where it has been shown to be well tolerated with indications of anticancer activity.

  11. Reducing missing fracture clinic radiographs by entrusting them to patients.

    PubMed Central

    Calder, Peter R.; Hynes, Matthew C.; Goodier, W. David

    2004-01-01

    BACKGROUND: Missing radiographs in fracture clinics may compromise fracture management and lead to inappropriate use of clerical resources. METHODS: We prospectively compared the number of missing radiographs in two hospitals over a period of two months. In hospital A the radiographs were retained and in hospital B they were entrusted to the patients. RESULTS: At the completion of the study, entrusting patients with their radiographs resulted in statistically less radiographs missing from the clinic. PMID:15333169

  12. Reducing hypoxia and inflammation during invasive pulmonary aspergillosis by targeting the Interleukin-1 receptor

    PubMed Central

    Gresnigt, Mark S.; Rekiki, Abdessalem; Rasid, Orhan; Savers, Amélie; Jouvion, Grégory; Dannaoui, Eric; Parlato, Marianna; Fitting, Catherine; Brock, Matthias; Cavaillon, Jean-Marc; van de Veerdonk, Frank L.; Ibrahim-Granet, Oumaïma

    2016-01-01

    Hypoxia as a result of pulmonary tissue damage due to unresolved inflammation during invasive pulmonary aspergillosis (IPA) is associated with a poor outcome. Aspergillus fumigatus can exploit the hypoxic microenvironment in the lung, but the inflammatory response required for fungal clearance can become severely disregulated as a result of hypoxia. Since severe inflammation can be detrimental to the host, we investigated whether targeting the interleukin IL-1 pathway could reduce inflammation and tissue hypoxia, improving the outcome of IPA. The interplay between hypoxia and inflammation was investigated by in vivo imaging of hypoxia and measurement of cytokines in the lungs in a model of corticosteroid immunocompromised and in Cxcr2 deficient mice. Severe hypoxia was observed following Aspergillus infection in both models and correlated with development of pulmonary inflammation and expression of hypoxia specific transcripts. Treatment with IL-1 receptor antagonist reduced hypoxia and slightly, but significantly reduced mortality in immunosuppressed mice, but was unable to reduce hypoxia in Cxcr2−/− mice. Our data provides evidence that the inflammatory response during invasive pulmonary aspergillosis, and in particular the IL-1 axis, drives the development of hypoxia. Targeting the inflammatory IL-1 response could be used as a potential immunomodulatory therapy to improve the outcome of aspergillosis. PMID:27215684

  13. Trends in pharmaceutical targeting of clinical indications: 1930-2013.

    PubMed

    Kinch, Michael S; Merkel, Janie; Umlauf, Sheila

    2014-11-01

    An analysis of FDA-approved new molecular entities (NMEs) reveals trends in therapeutic applications. Four groupings (infectious diseases, cardiovascular diseases, autoimmune/inflammatory diseases and cancer) capture more than 60% of NMEs. Infectious diseases are the most targeted indications. Near the turn of the new millennium, the rate of new approvals for infectious diseases decreased. The absolute and relative number of NMEs targeting psychiatric, neurological and pain/itch indications also declined. By contrast, NMEs targeting cancer have risen in the past two decades as have NMEs targeting orphan indications. These results suggest the drug development community has largely been responsive to public health and market needs. However, finite resources might indicate emphasis on some unmet needs could come at the cost of others.

  14. Targeted epigenetic editing of SPDEF reduces mucus production in lung epithelial cells.

    PubMed

    Song, Juan; Cano-Rodriquez, David; Winkle, Melanie; Gjaltema, Rutger A F; Goubert, Désirée; Jurkowski, Tomasz P; Heijink, Irene H; Rots, Marianne G; Hylkema, Machteld N

    2017-03-01

    Airway mucus hypersecretion contributes to the morbidity and mortality in patients with chronic inflammatory lung diseases. Reducing mucus production is crucial for improving patients' quality of life. The transcription factor SAM-pointed domain-containing Ets-like factor (SPDEF) plays a critical role in the regulation of mucus production and, therefore, represents a potential therapeutic target. This study aims to reduce lung epithelial mucus production by targeted silencing SPDEF using the novel strategy, epigenetic editing. Zinc fingers and CRISPR/dCas platforms were engineered to target repressors (KRAB, DNA methyltransferases, histone methyltransferases) to the SPDEF promoter. All constructs were able to effectively suppress both SPDEF mRNA and protein expression, which was accompanied by inhibition of downstream mucus-related genes [anterior gradient 2 (AGR2), mucin 5AC (MUC5AC)]. For the histone methyltransferase G9A, and not its mutant or other effectors, the obtained silencing was mitotically stable. These results indicate efficient SPDEF silencing and downregulation of mucus-related gene expression by epigenetic editing, in human lung epithelial cells. This opens avenues for epigenetic editing as a novel therapeutic strategy to induce long-lasting mucus inhibition.

  15. Reducing US cardiovascular disease burden and disparities through national and targeted dietary policies: A modelling study.

    PubMed

    Pearson-Stuttard, Jonathan; Bandosz, Piotr; Rehm, Colin D; Penalvo, Jose; Whitsel, Laurie; Gaziano, Tom; Conrad, Zach; Wilde, Parke; Micha, Renata; Lloyd-Williams, Ffion; Capewell, Simon; Mozaffarian, Dariush; O'Flaherty, Martin

    2017-06-01

    Large socio-economic disparities exist in US dietary habits and cardiovascular disease (CVD) mortality. While economic incentives have demonstrated success in improving dietary choices, the quantitative impact of different dietary policies on CVD disparities is not well established. We aimed to quantify and compare the potential effects on total CVD mortality and disparities of specific dietary policies to increase fruit and vegetable (F&V) consumption and reduce sugar-sweetened beverage (SSB) consumption in the US. Using the US IMPACT Food Policy Model and probabilistic sensitivity analyses, we estimated and compared the reductions in CVD mortality and socio-economic disparities in the US population potentially achievable from 2015 to 2030 with specific dietary policy scenarios: (a) a national mass media campaign (MMC) aimed to increase consumption of F&Vs and reduce consumption of SSBs, (b) a national fiscal policy to tax SSBs to increase prices by 10%, (c) a national fiscal policy to subsidise F&Vs to reduce prices by 10%, and (d) a targeted policy to subsidise F&Vs to reduce prices by 30% among Supplemental Nutrition Assistance Program (SNAP) participants only. We also evaluated a combined policy approach, combining all of the above policies. Data sources included the Surveillance, Epidemiology, and End Results Program, National Vital Statistics System, National Health and Nutrition Examination Survey, and published meta-analyses. Among the individual policy scenarios, a national 10% F&V subsidy was projected to be most beneficial, potentially resulting in approximately 150,500 (95% uncertainty interval [UI] 141,400-158,500) CVD deaths prevented or postponed (DPPs) by 2030 in the US. This far exceeds the approximately 35,100 (95% UI 31,700-37,500) DPPs potentially attributable to a 30% F&V subsidy targeting SNAP participants, the approximately 25,800 (95% UI 24,300-28,500) DPPs for a 1-y MMC, or the approximately 31,000 (95% UI 26,800-35,300) DPPs for a 10% SSB

  16. Reducing US cardiovascular disease burden and disparities through national and targeted dietary policies: A modelling study

    PubMed Central

    Rehm, Colin D.; Gaziano, Tom; Wilde, Parke; Micha, Renata; Lloyd-Williams, Ffion; Capewell, Simon

    2017-01-01

    Background Large socio-economic disparities exist in US dietary habits and cardiovascular disease (CVD) mortality. While economic incentives have demonstrated success in improving dietary choices, the quantitative impact of different dietary policies on CVD disparities is not well established. We aimed to quantify and compare the potential effects on total CVD mortality and disparities of specific dietary policies to increase fruit and vegetable (F&V) consumption and reduce sugar-sweetened beverage (SSB) consumption in the US. Methods and findings Using the US IMPACT Food Policy Model and probabilistic sensitivity analyses, we estimated and compared the reductions in CVD mortality and socio-economic disparities in the US population potentially achievable from 2015 to 2030 with specific dietary policy scenarios: (a) a national mass media campaign (MMC) aimed to increase consumption of F&Vs and reduce consumption of SSBs, (b) a national fiscal policy to tax SSBs to increase prices by 10%, (c) a national fiscal policy to subsidise F&Vs to reduce prices by 10%, and (d) a targeted policy to subsidise F&Vs to reduce prices by 30% among Supplemental Nutrition Assistance Program (SNAP) participants only. We also evaluated a combined policy approach, combining all of the above policies. Data sources included the Surveillance, Epidemiology, and End Results Program, National Vital Statistics System, National Health and Nutrition Examination Survey, and published meta-analyses. Among the individual policy scenarios, a national 10% F&V subsidy was projected to be most beneficial, potentially resulting in approximately 150,500 (95% uncertainty interval [UI] 141,400–158,500) CVD deaths prevented or postponed (DPPs) by 2030 in the US. This far exceeds the approximately 35,100 (95% UI 31,700–37,500) DPPs potentially attributable to a 30% F&V subsidy targeting SNAP participants, the approximately 25,800 (95% UI 24,300–28,500) DPPs for a 1-y MMC, or the approximately 31,000 (95

  17. Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials.

    PubMed

    Gao, Xiao-Fei; Zhang, Jun-Jie; Jiang, Xiao-Min; Ge, Zhen; Wang, Zhi-Mei; Li, Bing; Mao, Wen-Xing; Chen, Shao-Liang

    2017-01-01

    Pulmonary arterial hypertension (PAH) is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs), phosphodiesterase 5 inhibitors (PDE-5Is), and soluble guanylate cyclase stimulator (sGCS), have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH. Medline, the Cochrane Library, and other Internet sources were searched for randomized clinical trials exploring the efficacy of targeted drugs for patients with PAH. The primary effective end point of this network meta-analysis was a 6-minute walk distance (6MWD). Thirty-two eligible trials including 6,758 patients were identified. There was a statistically significant improvement in 6MWD, mean pulmonary arterial pressure, pulmonary vascular resistance, and clinical worsening events associated with each of the four targeted drugs compared with placebo. Combination therapy improved 6MWD by 20.94 m (95% confidence interval [CI]: 6.94, 34.94; P=0.003) vs prostanoids, and 16.94 m (95% CI: 4.41, 29.47; P=0.008) vs ERAs. PDE-5Is improved 6MWD by 17.28 m (95% CI: 1.91, 32.65; P=0.028) vs prostanoids, with a similar result with combination therapy. In addition, combination therapy reduced mean pulmonary artery pressure by 3.97 mmHg (95% CI: -6.06, -1.88; P<0.001) vs prostanoids, 8.24 mmHg (95% CI: -10.71, -5.76; P<0.001) vs ERAs, 3.38 mmHg (95% CI: -6.30, -0.47; P=0.023) vs PDE-5Is, and 3.94 mmHg (95% CI: -6.99, -0.88; P=0.012) vs sGCS. There were no significant differences in all-cause mortality and severe adverse events between prostanoids, ERAs, PDE-5Is, sGCS, combination therapy, and placebo. All targeted drugs for PAH are associated with improved clinical outcomes, especially combination therapy

  18. Combined Recipe for Clinical Target Volume and Planning Target Volume Margins

    SciTech Connect

    Stroom, Joep; Gilhuijs, Kenneth; Vieira, Sandra; Chen, Wei; Salguero, Javier; Moser, Elizabeth; Sonke, Jan-Jakob

    2014-03-01

    Purpose: To develop a combined recipe for clinical target volume (CTV) and planning target volume (PTV) margins. Methods and Materials: A widely accepted PTV margin recipe is M{sub geo} = aΣ{sub geo} + bσ{sub geo}, with Σ{sub geo} and σ{sub geo} standard deviations (SDs) representing systematic and random geometric uncertainties, respectively. On the basis of histopathology data of breast and lung tumors, we suggest describing the distribution of microscopic islets around the gross tumor volume (GTV) by a half-Gaussian with SD Σ{sub micro}, yielding as possible CTV margin recipe: M{sub micro} = ƒ(N{sub i}) × Σ{sub micro}, with N{sub i} the average number of microscopic islets per patient. To determine ƒ(N{sub i}), a computer model was developed that simulated radiation therapy of a spherical GTV with isotropic distribution of microscopic disease in a large group of virtual patients. The minimal margin that yielded D{sub min} <95% in maximally 10% of patients was calculated for various Σ{sub micro} and N{sub i}. Because Σ{sub micro} is independent of Σ{sub geo}, we propose they should be added quadratically, yielding for a combined GTV-to-PTV margin recipe: M{sub GTV-PTV} = √([aΣ{sub geo}]{sup 2} + [ƒ(N{sub i})Σ{sub micro}]{sup 2}) + bσ{sub geo}. This was validated by the computer model through numerous simultaneous simulations of microscopic and geometric uncertainties. Results: The margin factor ƒ(N{sub i}) in a relevant range of Σ{sub micro} and N{sub i} can be given by: ƒ(N{sub i}) = 1.4 + 0.8log(N{sub i}). Filling in the other factors found in our simulations (a = 2.1 and b = 0.8) yields for the combined recipe: M{sub GTV-PTV} = √((2.1Σ{sub geo}){sup 2} + ([1.4 + 0.8log(N{sub i})] × Σ{sub micro}){sup 2}) + 0.8σ{sub geo}. The average margin difference between the simultaneous simulations and the above recipe was 0.2 ± 0.8 mm (1 SD). Calculating M{sub geo} and M{sub micro} separately and adding them linearly overestimated PTVs by on

  19. A New Strategy to Reduce Influenza Escape: Detecting Therapeutic Targets Constituted of Invariance Groups

    PubMed Central

    Lao, Julie; Vanet, Anne

    2017-01-01

    The pathogenicity of the different flu species is a real public health problem worldwide. To combat this scourge, we established a method to detect drug targets, reducing the possibility of escape. Besides being able to attach a drug candidate, these targets should have the main characteristic of being part of an essential viral function. The invariance groups that are sets of residues bearing an essential function can be detected genetically. They consist of invariant and synthetic lethal residues (interdependent residues not varying or slightly varying when together). We analyzed an alignment of more than 10,000 hemagglutinin sequences of influenza to detect six invariance groups, close in space, and on the protein surface. In parallel we identified five potential pockets on the surface of hemagglutinin. By combining these results, three potential binding sites were determined that are composed of invariance groups located respectively in the vestigial esterase domain, in the bottom of the stem and in the fusion area. The latter target is constituted of residues involved in the spring-loaded mechanism, an essential step in the fusion process. We propose a model describing how this potential target could block the reorganization of the hemagglutinin HA2 secondary structure and prevent viral entry into the host cell. PMID:28257108

  20. A New Strategy to Reduce Influenza Escape: Detecting Therapeutic Targets Constituted of Invariance Groups.

    PubMed

    Lao, Julie; Vanet, Anne

    2017-03-02

    The pathogenicity of the different flu species is a real public health problem worldwide. To combat this scourge, we established a method to detect drug targets, reducing the possibility of escape. Besides being able to attach a drug candidate, these targets should have the main characteristic of being part of an essential viral function. The invariance groups that are sets of residues bearing an essential function can be detected genetically. They consist of invariant and synthetic lethal residues (interdependent residues not varying or slightly varying when together). We analyzed an alignment of more than 10,000 hemagglutinin sequences of influenza to detect six invariance groups, close in space, and on the protein surface. In parallel we identified five potential pockets on the surface of hemagglutinin. By combining these results, three potential binding sites were determined that are composed of invariance groups located respectively in the vestigial esterase domain, in the bottom of the stem and in the fusion area. The latter target is constituted of residues involved in the spring-loaded mechanism, an essential step in the fusion process. We propose a model describing how this potential target could block the reorganization of the hemagglutinin HA2 secondary structure and prevent viral entry into the host cell.

  1. Non-achievement of clinical targets in patients with type 2 diabetes mellitus.

    PubMed

    Eid, M; Mafauzy, M; Faridah, A R

    2004-06-01

    The study was conducted to determine whether the clinical targets for the control of diabetes recommended by American Diabetes Association can be met in the context of routine diabetes practice. This cross-sectional study was undertaken on 211 type 2 diabetic patients at the Outpatients Diabetes Clinic, Hospital Universisti Sains Malaysia (HUSM) Kubang Kerian, Kelantan between the year 2001-2002. Patients' physical examination and their medical history as well as their family history were obtained by administering a structured questionnaire. Samples of patients' venous blood during fasting were taken and analysed for plasma glucose, glycated haemoglobin and lipid profile. Analysis showed that many patients had comorbidities or complications. A large number of them had poor glycaemic control (73%). Systolic and diastolic blood pressures of 75% and 85% subjects were > or = 130 and > or = 80 mmHg, respectively. Body Mass Index (BMI) values of 66% of the patients were outside the clinical target (BMI > or = 25 in male and > or = 24 kg/m2 in female). The lipid profile showed that 96% of the patients had at least one lipid value outside the clinical target level. In this study, 70% of the patients had total cholesterol > or = 5.2 mmol/L, 87% had LDL cholesterol > or = 2.6 mmol/L, 57% had HDL cholesterol less than the normal range, < or = 1.15 mmol/L in men and < or = 1.4 mmol/L in women, while 46% had triglycerides > or = 1.71 mmol/L. Complications of diabetes were observed in 48% of the total number of patients. As for the patients' systolic blood pressure, age and duration of diabetes were found to have significant effects. Older subjects with a longer duration of diabetes were more hypertensive. Variables that had significant effects on BMI were age, duration of diabetes, glycaemic control and gender. Younger females and newly diagnosed subjects with better glycaemic control (A1C < 7%) were found to have higher BMI values. The overall clinical targets were suboptimal

  2. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction

    PubMed Central

    Hulsmans, Maarten; Courties, Gabriel; Sun, Yuan; Heidt, Timo; Vinegoni, Claudio; Borodovsky, Anna; Fitzgerald, Kevin; Wojtkiewicz, Gregory R.; Iwamoto, Yoshiko; Tricot, Benoit; Khan, Omar F.; Kauffman, Kevin J.; Xing, Yiping; Shaw, Taylor E.; Libby, Peter; Langer, Robert; Weissleder, Ralph; Swirski, Filip K.

    2016-01-01

    Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE−/− mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively silences five key adhesion molecules. Simultaneously encapsulating small interfering RNA (siRNA)–targeting intercellular cell adhesion molecules 1 and 2 (Icam1 and Icam2), vascular cell adhesion molecule 1 (Vcam1), and E- and P-selectins (Sele and Selp) into polymeric endothelial-avid nanoparticles reduced post-MI neutrophil and monocyte recruitment into atherosclerotic lesions and decreased matrix-degrading plaque protease activity. Five-gene combination RNAi also curtailed leukocyte recruitment to ischemic myocardium. Therefore, targeted multigene silencing may prevent complications after acute MI. PMID:27280687

  3. Intranasal sirna targeting c-kit reduces airway inflammation in experimental allergic asthma.

    PubMed

    Wu, Wei; Chen, Hui; Li, Ya-Ming; Wang, Sheng-Yu; Diao, Xin; Liu, Kai-Ge

    2014-01-01

    Allergic asthma is characterized by airway inflammation caused by infiltration and activation of inflammatory cells that produce cytokines. Many studies have revealed that c-kit, a proto-oncogene, and its ligand, stem cell factor (SCF), play an important role in the development of asthmatic inflammation. Intranasal small interference RNA (siRNA) nanoparticles targeting specific viral gene could inhibit airway inflammation. In this study, we assessed whether silencing of c-kit with intranasal small interference RNA could reduce inflammation in allergic asthma. A mouse model of experimental asthma was treated with intranasal administration of anti-c-kit siRNA to inhibit the expression of the c-kit gene. We assessed the inflammatory response in both anti-c-kit siRNA-treated and control mice. Local administration of siRNA effectively inhibited the expression of the c-kit gene and reduced airway mucus secretion and the infiltration of eosinophils in bronchoalveolar lavage fluid. Moreover, c-kit siRNA reduced the production of SCF, interleukin-4 (IL-4), and IL-5, but had no effect on interferon-γ (IFN-γ) generation. These results show that intranasal siRNA nanoparticles targeting c-kit can decrease the inflammatory response in experimental allergic asthma.

  4. Clinical Challenges to Current Molecularly Targeted Therapies in Lung Cancer.

    PubMed

    Chhabra, Gagan; Eggert, Ashley; Puri, Neelu

    Lung cancer is difficult to treat with a poor prognosis and a five year survival of 15%. Current molecularly targeted therapies are initially effective in non-small cell lung cancer (NSCLC) patients; however, they are plagued with difficulties including induced resistance and small therapeutically responsive populations. This mini review describes the mechanism of resistance to several molecularly targeted therapies which are currently being used to treat NSCLC. The major targets discussed are c-Met, EGFR, HER2, ALK, VEGFR, and BRAF. The first generation tyrosine kinase inhibitors (TKIs) resulted in resistance; however, second and third generation TKIs are being developed, which are generally more efficacious and have potential to treat NSCLC patients with resistance to first generation TKIs. Combination therapies could also be effective in preventing TKI resistance in NSCLC patients.

  5. Reducing inadvertent clinical errors: Guidelines from functional analytic psychotherapy.

    PubMed

    Tsai, Mavis; Mandell, Tien; Maitland, Daniel; Kanter, Jonathan; Kohlenberg, Robert J

    2016-09-01

    Two common types of clinical errors, inadvertently reinforcing client problem behaviors or inadvertently punishing client improvements, are conceptualized from the viewpoint of Functional Analytic Psychotherapy (FAP), a treatment that harnesses the power of the therapeutic relationship. Understanding the functions of client behaviors such as incessant talking and over compliance can lead to more compassionate and effective intervention, and a functional analysis of seemingly problematic behaviors such as silence and lack of cooperation indicate how they may be client improvements. Suggestions are provided for how to more accurately conceptualize whether client behaviors are problems or improvements, and to increase awareness of therapist vulnerabilities that can lead to errors. While FAP is rooted in a functional contextual philosophy, the goal of this article is to offer a framework that crosses theoretical boundaries to decrease the likelihood of clinical errors and to facilitate client growth. (PsycINFO Database Record

  6. Molecular characterization of clinical Streptococcus pneumoniae isolates with reduced susceptibility to fluoroquinolones emerging in Italy.

    PubMed

    Montanari, Maria Pia; Tili, Emily; Cochetti, Ileana; Mingoia, Marina; Manzin, Aldo; Varaldo, Pietro Emanuele

    2004-01-01

    Fifteen Streptococcus pneumoniae clinical isolates with reduced fluoroquinolone susceptibility (defined as a ciprofloxacin MIC of > or = 4 microg/ml), all collected in Italy in 2000-2003, were typed and subjected to extensive molecular characterization to define the contribution of drug target alterations and efflux mechanisms to their resistance. Serotyping and pulsed-field gel electrophoresis analysis indicated substantial genetic unrelatedness among the 15 isolates, suggesting that the new resistance traits arise in multiple indigenous strains rather than through clonal dissemination. Sequencing of the quinolone resistance-determining regions of gyrA, gyrB, parC, and parE demonstrated that point mutations producing single amino acid changes were more frequent in topoisomerase IV (parC mutations in 14 isolates and parE mutations in 13) than in DNA gyrase subunits (gyrA mutations in 7 isolates and no gyrB mutations observed). No isolate displayed a quinolone efflux system susceptible to carbonyl cyanide m-chlorophenylhydrazone; conversely, four-fold or greater MIC reductions in the presence of reserpine were observed in all 15 isolates with ethidium bromide, in 13 with ulifloxacin, in 9 with ciprofloxacin, in 5 with norfloxacin, and in none with five other fluoroquinolones. The effect of efflux pump activity on the level and profile of fluoroquinolone resistance in our strains was minor compared with that of target site modifications. DNA mutations and/or efflux systems other than those established so far might contribute to the fluoroquinolone resistance expressed by our strains. Susceptibility profiles to nonquinolone class antibiotics and resistance-associated phenotypic and genotypic characteristics were also determined and correlated with fluoroquinolone resistance. A unique penicillin-binding protein profile was observed in all five penicillin-resistant isolates, whereas the same PBP profile as S. pneumoniae R6 was exhibited by all six penicillin

  7. Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target?

    PubMed Central

    Lin, Li-Chun; Sibille, Etienne

    2013-01-01

    Our knowledge of the pathophysiology of affect dysregulation has progressively increased, but the pharmacological treatments remain inadequate. Here, we summarize the current literature on deficits in somatostatin, an inhibitory modulatory neuropeptide, in major depression and other neurological disorders that also include mood disturbances. We focus on direct evidence in the human postmortem brain, and review rodent genetic and pharmacological studies probing the role of the somatostatin system in relation to mood. We also briefly go over pharmacological developments targeting the somatostatin system in peripheral organs and discuss the challenges of targeting the brain somatostatin system. Finally, the fact that somatostatin deficits are frequently observed across neurological disorders suggests a selective cellular vulnerability of somatostatin-expressing neurons. Potential cell intrinsic factors mediating those changes are discussed, including nitric oxide induced oxidative stress, mitochondrial dysfunction, high inflammatory response, high demand for neurotrophic environment, and overall aging processes. Together, based on the co-localization of somatostatin with gamma-aminobutyric acid (GABA), its presence in dendritic-targeting GABA neuron subtypes, and its temporal-specific function, we discuss the possibility that deficits in somatostatin play a central role in cortical local inhibitory circuit deficits leading to abnormal corticolimbic network activity and clinical mood symptoms across neurological disorders. PMID:24058344

  8. Prolonged target deprivation reduces the capacity of injured motoneurons to regenerate.

    PubMed

    Furey, Matthew J; Midha, Rajiv; Xu, Qing-Gui; Belkas, Jason; Gordon, Tessa

    2007-04-01

    To investigate whether or not it is the frustrated growth state (no axon growth) that reduces regenerative capacity or the inability of axotomized motoneurons to remake muscle connections (axon growth-no muscle contact) that accounts for poor regenerative capacity of chronically axotomized motoneurons. We chronically axotomized rat femoral motoneurons for 2 months by cutting the nerve and either capping the proximal nerve to prevent axon regeneration (Group 1, no axon growth for 2 mo) or encouraging axon regeneration but not target reinnervation by suture to the distal stump of cut saphenous nerve (Group 2, axon growth with no muscle contact). In the control fresh axotomy group (axon growth with muscle contact), femoral nerve stumps were resutured immediately. Two months later, the femoral nerve was recut and sutured immediately to encourage regeneration in a freshly cut saphenous nerve stump for 6 weeks. Regenerating axons in the saphenous nerve were back-labeled with fluorogold for enumeration of the femoral motoneurons that regenerated their axons into the distal nerve stump. We found that significantly fewer chronically axotomized motoneurons regenerated their axons than freshly axotomized motoneurons that regenerated their axons to reform nerve-muscle connections in the same length of time. The number of motoneurons that regenerated their axons was reduced in both the conditions of no axon growth and axon growth with no muscle contact; thus chronic axotomy for a 2-month period reduced regenerative success irrespective of whether the motoneurons were prevented from regenerating or encouraged to regenerate their axons in that same period of time. Axonal regeneration does not protect motoneurons from the negative effects of prolonged axotomy on regenerative capacity. It is the period of chronic axotomy, in which motoneurons remain without target nerve-muscle connection, and not simply a state of frustrated growth that accounts for the reduced regenerative

  9. Targeted intervention reduces refracture rates in patients with incident non-vertebral osteoporotic fractures: a 4-year prospective controlled study.

    PubMed

    Lih, A; Nandapalan, H; Kim, M; Yap, C; Lee, P; Ganda, K; Seibel, M J

    2011-03-01

    In the present prospective controlled observational study, we investigated the effect of a coordinated intervention program on 4-year refracture rates in patients with recent osteoporotic fractures. Compared to standard care, targeted identification, and management significantly reduced the risk of refracture by more than 80%. The risk of refracture following an incident osteoporotic fracture is high. Despite the availability of treatments that reduce refracture and mortality rates, most patients with minimal trauma fracture (MTF) are not managed appropriately. The present prospective controlled observational study investigated the effect of a coordinated intervention program on 4-year refracture rates and time to refracture in patients with recent osteoporotic fractures. Patients presenting with a non-vertebral MTF were actively identified and offered referral to a dedicated intervention program. Patients attending the clinic underwent a standardized set of investigations, were treated as indicated and reviewed at 12-monthly intervals ('MTF group'). Patients who elected to follow-up with their primary care physician were assigned to the concurrent control group. Groups were balanced for baseline anthropometric, socio-economic, and clinical risk factors. Over 4 years, 10 out of 246 patients (4.1%) in the MTF group and 31 of 157 patients (19.7%) in the control group suffered a new fracture, with a median time to refracture of 26 and 16 months, respectively (p < 0.01). Compared to the intervention group, the risk of refracture was increased by 5.3-fold in the control group (95% CI: 2.8-12.2, p < 0.01), and remained elevated (HR 5.63, 95%CI 2.73-11.6, p < 0.01) after adjustment for other significant predictors of refracture such as age and body weight. In patients presenting with a minimal trauma non-vertebral fracture, active identification and management significantly reduces the risk of refracture (Australian New Zealand Clinical Trials Registry ACTRN

  10. Interpretation modification training reduces social anxiety in clinically anxious children.

    PubMed

    Klein, Anke M; Rapee, Ronald M; Hudson, Jennifer L; Schniering, Carolyn A; Wuthrich, Viviana M; Kangas, Maria; Lyneham, Heidi J; Souren, Pierre M; Rinck, Mike

    2015-12-01

    The present study was designed to examine the effects of training in positive interpretations in clinically anxious children. A total of 87 children between 7 and 12 years of age were randomly assigned to either a positive cognitive bias modification training for interpretation (CMB-I) or a neutral training. Training included 15 sessions in a two-week period. Children with an interpretation bias prior to training in the positive training group showed a significant reduction in interpretation bias on the social threat scenarios after training, but not children in the neutral training group. No effects on interpretation biases were found for the general threat scenarios or the non-threat scenarios. Furthermore, children in the positive training did not self-report lower anxiety than children in the neutral training group. However, mothers and fathers reported a significant reduction in social anxiety in their children after positive training, but not after neutral training. This study demonstrated that clinically anxious children with a prior interpretation bias can be trained away from negative social interpretation biases and there is some evidence that this corresponds to reductions in social anxiety. This study also highlights the importance of using specific training stimuli.

  11. Mesoporous Silica Coated Polydopamine Functionalized Reduced Graphene Oxide for Synergistic Targeted Chemo-Photothermal Therapy.

    PubMed

    Shao, Leihou; Zhang, Ruirui; Lu, Jianqing; Zhao, Caiyan; Deng, Xiongwei; Wu, Yan

    2017-01-18

    The integration of different therapies into a single nanoplatform has shown great promise for synergistic tumor treatment. Herein, mesoporous silica (MS) coated polydopamine functionalized reduced graphene oxide (pRGO) further modified with hyaluronic acid (HA) (pRGO@MS-HA) has been utilized as a versatile nanoplatform for synergistic targeted chemo-photothermal therapy against cancer. A facile and green chemical method is adopted for the simultaneous reduction and noncovalent functionalization of graphene oxide (GO) by using mussel inspired dopamine (DA) to enhance biocompatibility and the photothermal effect. Then, it was coated with mesoporous silica (MS) (pRGO@MS) to enhance doxorubicin (DOX) loading and be further modified with the targeting moieties hyaluronic acid (HA). The pH-dependent and near-infrared (NIR) laser irradiation-triggered DOX release from pRGO@MS(DOX)-HA is observed, which could enhance the chemo-photothermal therapy effect. In vitro experimental results confirm that pRGO@MS(DOX)-HA exhibits good dispersibility, excellent photothermal property, remarkable tumor cell killing efficiency, and specificity to target tumor cells. In vivo antitumor experiments further demonstrated that pRGO@MS(DOX)-HA could exhibit an excellent synergistic antitumor efficacy, which is much more distinct than any monotherapy. This work presents a novel nanoplatform which could load chemotherapy drugs with high efficiency and be used as light-mediated photothermal cancer therapy agent.

  12. A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria.

    PubMed

    Trnka, Jan; Blaikie, Frances H; Smith, Robin A J; Murphy, Michael P

    2008-04-01

    Piperidine nitroxides such as TEMPOL act as antioxidants in vivo due to their interconversion among nitroxide, hydroxylamine, and oxoammonium derivatives, but the mechanistic details of these reactions are unclear. As mitochondria are a significant site of piperidine nitroxide metabolism and action, we synthesized a mitochondria-targeted nitroxide, MitoTEMPOL, by conjugating TEMPOL to the lipophilic triphenylphosphonium cation. MitoTEMPOL was accumulated several hundred-fold into energized mitochondria where it was reduced to the hydroxylamine by direct reaction with ubiquinol. This reaction occurred by transfer of H() from ubiquinol to the nitroxide, with the ubisemiquinone radical product predominantly dismutating to ubiquinone and ubiquinol, together with a small amount reacting with oxygen to form superoxide. The piperidine nitroxides TEMPOL, TEMPO, and butylTEMPOL reacted similarly with ubiquinol in organic solvents but in mitochondrial membranes the rates varied in the order: MitoTEMPOL > butylTEMPOL > TEMPO > TEMPOL, which correlated with the extent of access of the nitroxide moiety to ubiquinol within the membrane. These findings suggest ways of using mitochondria-targeted compounds to modulate the coenzyme Q pool within mitochondria in vivo, and indicate that the antioxidant effects of mitochondria-targeted piperidine nitroxides can be ascribed to their corresponding hydroxylamines.

  13. Targeting of Alpha-V Integrins Reduces Malignancy of Bladder Carcinoma

    PubMed Central

    van der Horst, Geertje; Bos, Lieke; van der Mark, Maaike; Cheung, Henry; Heckmann, Bertrand; Clément-Lacroix, Philippe; Lorenzon, Giocondo; Pelger, Rob C. M.; Bevers, Rob F. M.; van der Pluijm, Gabri

    2014-01-01

    Low survival rates of metastatic cancers emphasize the need for a drug that can prevent and/or treat metastatic cancer. αv integrins are involved in essential processes for tumor growth and metastasis and targeting of αv integrins has been shown to decrease angiogenesis, tumor growth and metastasis. In this study, the role of αv integrin and its potential as a drug target in bladder cancer was investigated. Treatment with an αv integrin antagonist as well as knockdown of αv integrin in the bladder carcinoma cell lines, resulted in reduced malignancy invitro, as illustrated by decreased proliferative, migratory and clonogenic capacity. The CDH1/CDH2 ratio increased, indicating a shift towards a more epithelial phenotype. This shift appeared to be associated with downregulation of EMT-inducing transcription factors including SNAI2. The expression levels of the self-renewal genes NANOG and BMI1 decreased as well as the number of cells with high Aldehyde Dehydrogenase activity. In addition, self-renewal ability decreased as measured with the urosphere assay. In line with these observations, knockdown or treatment of αv integrins resulted in decreased metastatic growth in preclinical invivo models as assessed by bioluminescence imaging. In conclusion, we show that αv integrins are involved in migration, EMT and maintenance of Aldehyde Dehydrogenase activity in bladder cancer cells. Targeting of αv integrins might be a promising approach for treatment and/or prevention of metastatic bladder cancer. PMID:25247809

  14. Carbapenem susceptibility breakpoints, clinical implications with the moving target.

    PubMed

    O'Donnell, J Nicholas; Miglis, Cristina M; Lee, Jane Y; Tuvell, Merika; Lertharakul, Tina; Scheetz, Marc H

    2016-01-01

    Carbapenems are primary agents used to treat a variety of Gram-negative multi-drug resistant infections. In parallel with increasing use, increasing resistance to carbapenem agents has manifested as increased minimum inhibitory concentrations (MICs). To attempt to improve clinical outcomes with carbapenems, the Clinical Laboratory Standards Institute and the Food Drug Administration decreased susceptibility breakpoints. The European equivalent expert committee, the European Committee on Antimicrobial Susceptibility Testing, also utilizes lower MIC susceptibility breakpoints. This review focuses on the rationale for recent breakpoint changes and the associated clinical outcomes for patients treated with carbapenems for infections with varying MICs proximal to the breakpoint. Supporting pharmacokinetics and pharmacodynamics that underpin the breakpoints are also reviewed.

  15. P-Selectin Targeted Dexamethasone-Loaded Lipid Nanoemulsions: A Novel Therapy to Reduce Vascular Inflammation

    PubMed Central

    Simion, Viorel; Constantinescu, Cristina Ana; Stan, Daniela; Deleanu, Mariana; Tucureanu, Monica Madalina; Butoi, Elena; Manduteanu, Ileana; Simionescu, Maya

    2016-01-01

    Inflammation is a common process associated with numerous vascular pathologies. We hypothesized that targeting the inflamed endothelium by coupling a peptide with high affinity for P-selectin to the surface of dexamethasone-loaded lipid nanoemulsions will highly increase their specific binding to activated endothelial cells (EC) and reduce the cell activation. We developed and characterized dexamethasone-loaded lipid nanoemulsions directed towards P-selectin (PLN-Dex) and monitored their anti-inflammatory effects in vitro using cultured EC (EA.hy926 cells) and in vivo using a mouse model of acute inflammation [lipopolysaccharides (LPS) intravenously administered in C57BL/6 mice]. We found that PLN-Dex bound specifically to the surface of activated EC are efficiently internalized by EC and reduced the expression of proinflammatory genes, thus preventing the monocyte adhesion and transmigration to/through activated EC. Given intravenously in mice with acute inflammation, PLN-Dex accumulated at a significant high level in the lungs (compared to nontargeted nanoemulsions) and significantly reduced mRNA expression level of key proinflammatory cytokines such as IL-1β, IL-6, and MCP-1. In conclusion, the newly developed nanoformulation, PLN-Dex, is functional in vitro and in vivo, reducing selectively the endothelium activation and the consequent monocyte infiltration and diminishing significantly the lungs' inflammation, in a mouse model of acute inflammation. PMID:27703301

  16. Reducible hyaluronic acid-siRNA conjugate for target specific gene silencing.

    PubMed

    Park, Kitae; Yang, Jeong-A; Lee, Min-Young; Lee, Hwiwon; Hahn, Sei Kwang

    2013-07-17

    Despite wide applications of polymer-drug conjugates, there are only a few polymer-siRNA conjugates like poly(ethylene glycol) conjugated siRNA. In this work, reducible hyaluronic acid (HA)-siRNA conjugate was successfully developed for target specific systemic delivery of siRNA to the liver. The conjugation of siRNA to HA made it possible to form a compact nanocomplex of siRNA with relatively nontoxic linear polyethyleneimine (LPEI). After characterization of HA-siRNA conjugate by size exclusion chromatography (SEC) and gel electrophoresis, its complex formation with LPEI was investigated with a particle analyzer. The HA-siRNA/LPEI complex had a mean particle size of ca. 250 nm and a negative or neutral surface charge at physiological condition. The reducible HA-siRNA/LPEI complex showed a higher in vitro gene silencing efficiency than noncleavable HA-siRNA/LPEI complex. Furthermore, after systemic delivery, apolipoprotein B (ApoB) specific HA-siApoB/LPEI complex was target specifically delivered to the liver, which resulted in statistically significant reduction of ApoB mRNA expression in a dose dependent manner. The HA-siRNA conjugate can be effectively applied as a model system to the treatment of liver diseases using various siRNAs and relatively nontoxic polycations.

  17. The Economic Gains of Achieving Reduced Alcohol Consumption Targets for Australia

    PubMed Central

    Magnus, Anne; Cadilhac, Dominique; Sheppard, Lauren; Cumming, Toby; Pearce, Dora; Carter, Rob

    2012-01-01

    Objectives. To inform prevention policy, we estimated the economic benefits to health, production, and leisure in the 2008 Australian population of a realistic target reduction in per capita annual adult alcohol consumption. Methods. We chose a target of 6.4 liters annually per capita on average. We modeled lifetime health benefits as fewer incident cases of alcohol-related disease, deaths, and disability adjusted life years. We estimated production gains with surveyed participation and absenteeism rates. We valued gains with friction cost and human capital methods. We estimated and valued household production and leisure gains from time-use surveys. Results. A reduction of 3.4 liters of alcohol consumed annually per capita would result in one third fewer incident cases of disease (98 000), deaths (380), working days lost (5 million), days of home-based production lost (54 000), and a A$ 789-million health sector cost reduction. Workforce production had a A$ 427 million gain when we used the friction cost method. By contrast, we estimated a loss of 28 000 leisure days and 1000 additional early retirements. Conclusions. Economic savings and health benefits from reduced alcohol consumption may be substantial—particularly in the health sector with reduced alcohol-related disease and injury. PMID:22594720

  18. Cost-effective targeting of conservation investments to reduce the northern Gulf of Mexico hypoxic zone

    PubMed Central

    Rabotyagov, Sergey S.; Campbell, Todd D.; White, Michael; Arnold, Jeffrey G.; Atwood, Jay; Norfleet, M. Lee; Kling, Catherine L.; Gassman, Philip W.; Valcu, Adriana; Richardson, Jeffrey; Turner, R. Eugene; Rabalais, Nancy N.

    2014-01-01

    A seasonally occurring summer hypoxic (low oxygen) zone in the northern Gulf of Mexico is the second largest in the world. Reductions in nutrients from agricultural cropland in its watershed are needed to reduce the hypoxic zone size to the national policy goal of 5,000 km2 (as a 5-y running average) set by the national Gulf of Mexico Task Force’s Action Plan. We develop an integrated assessment model linking the water quality effects of cropland conservation investment decisions on the more than 550 agricultural subwatersheds that deliver nutrients into the Gulf with a hypoxic zone model. We use this integrated assessment model to identify the most cost-effective subwatersheds to target for cropland conservation investments. We consider targeting of the location (which subwatersheds to treat) and the extent of conservation investment to undertake (how much cropland within a subwatershed to treat). We use process models to simulate the dynamics of the effects of cropland conservation investments on nutrient delivery to the Gulf and use an evolutionary algorithm to solve the optimization problem. Model results suggest that by targeting cropland conservation investments to the most cost-effective location and extent of coverage, the Action Plan goal of 5,000 km2 can be achieved at a cost of $2.7 billion annually. A large set of cost-hypoxia tradeoffs is developed, ranging from the baseline to the nontargeted adoption of the most aggressive cropland conservation investments in all subwatersheds (estimated to reduce the hypoxic zone to less than 3,000 km2 at a cost of $5.6 billion annually). PMID:25512489

  19. Cost-effective targeting of conservation investments to reduce the northern Gulf of Mexico hypoxic zone.

    PubMed

    Rabotyagov, Sergey S; Campbell, Todd D; White, Michael; Arnold, Jeffrey G; Atwood, Jay; Norfleet, M Lee; Kling, Catherine L; Gassman, Philip W; Valcu, Adriana; Richardson, Jeffrey; Turner, R Eugene; Rabalais, Nancy N

    2014-12-30

    A seasonally occurring summer hypoxic (low oxygen) zone in the northern Gulf of Mexico is the second largest in the world. Reductions in nutrients from agricultural cropland in its watershed are needed to reduce the hypoxic zone size to the national policy goal of 5,000 km(2) (as a 5-y running average) set by the national Gulf of Mexico Task Force's Action Plan. We develop an integrated assessment model linking the water quality effects of cropland conservation investment decisions on the more than 550 agricultural subwatersheds that deliver nutrients into the Gulf with a hypoxic zone model. We use this integrated assessment model to identify the most cost-effective subwatersheds to target for cropland conservation investments. We consider targeting of the location (which subwatersheds to treat) and the extent of conservation investment to undertake (how much cropland within a subwatershed to treat). We use process models to simulate the dynamics of the effects of cropland conservation investments on nutrient delivery to the Gulf and use an evolutionary algorithm to solve the optimization problem. Model results suggest that by targeting cropland conservation investments to the most cost-effective location and extent of coverage, the Action Plan goal of 5,000 km(2) can be achieved at a cost of $2.7 billion annually. A large set of cost-hypoxia tradeoffs is developed, ranging from the baseline to the nontargeted adoption of the most aggressive cropland conservation investments in all subwatersheds (estimated to reduce the hypoxic zone to less than 3,000 km(2) at a cost of $5.6 billion annually).

  20. Preparation of Clinically Useful Sennoside-reduced Rhubarb.

    PubMed

    Arai, Makoto; Nakada, Yoshinobu; Kajiwara, Kagemasa; Kimura, Minoru; Ishii, Naoaki

    2016-03-20

    The aim of this study was to develop a method of removing sennoside to reduce the cathartic effect of rhubarb while conserving its other pharmacological activities. Rhubarb powder was steam autoclaved at 121°C and 0.14 MPa for 20, 60, or 120 minutes, and HPLC analysis was conducted to determine levels of rhubarb components. Mice were fed non-autoclaved or 20-minute-autoclaved rhubarb extracts. Feces were collected and weighed over a 24-hour period. India ink was orally administered to determine the distance of fecal migration through the intestinal tract. Autoclaving 20, 60, and 120 minutes decreased sennoside A and B to trace levels but only autoclaving 20 minutes conserved most of the (+)-catechin, (-)-epicatechin, and (-)-epicatechin gallate contents (i.e., 69%, 90%, 88%, respectively). Therefore only rhubarb autoclaved for 20 minutes was used in subsequent experiments. Fecal output (in g) in mice treated with water (control), autoclaved rhubarb, and non-autoclaved rhubarb was 2.78 ± 0.07, 3.30 ± 0.13 (p = 0.348), and 3.81 ± 0.07 (p = 0.005). India ink migration was far less in mice treated with autoclaved rhubarb vs non-autoclaved rhubarb. Steam autoclaving the rhubarb for 20 minutes reduces sennoside levels and its cathartic activity while conserving its other pharmacological activities.

  1. Reducing falls among geriatric rehabilitation patients: a controlled clinical trial.

    PubMed

    Vieira, Edgar Ramos; Berean, Colleen; Paches, Debra; Caveny, Penny; Yuen, Doris; Ballash, Lauralee; Freund-Heritage, Rosalie

    2013-04-01

    To evaluate the effectiveness of an intervention programme to reduce falls among geriatric rehabilitation patients. Pre/post-test design with independent pre-test and matched post-test samples. Inpatient geriatric wards in a rehabilitation hospital. Seventy-six matched pairs (n = 152) of geriatric rehabilitation patients from one control and one intervention ward participated in the study, and 36 nursing staff surveys were completed. The intervention programme was developed based on interviews and systematic reviews. Educational materials were distributed to patients and families, and preventive measures were implemented. The rates of falls before and after the intervention both within and between the wards were compared, and surveys were completed. The matched patients presented no significant differences on age, gender or medical conditions. The falls rates, proportion of fallers and length of stay was higher among those in the control ward (P< 0.043). The percentage of fallers and the rate of falls/1000 patient days were lower on the intervention ward after implementation: odds ratio (95% confidence interval) = -2.9 (-6.6, -1.2) and -1.8 (-6.0, 0.5). Thirty of 36 respondents considered the tool to be helpful and beneficial for use on other wards. The intervention programme was effective in reducing falls among geriatric rehabilitation patients.

  2. Targeting care: tailoring nonsurgical management according to clinical presentation.

    PubMed

    Eyles, Jillian; Lucas, Barbara R; Hunter, David J

    2013-02-01

    International evidence-based guidelines recommend a multitude of nonsurgical treatment options for the management of osteoarthritis. This article summarizes the evidence available for patient characteristics that have been analyzed as potential predictors of response to nonsurgical interventions for patients with hip and knee osteoarthritis. The specific variables targeted for this review include body mass index, psychological factors, muscle strength, tibiofemoral alignment, radiographic changes, and signs of inflammation. Several studies provide moderate to good evidence of potential predictors of response to nonsurgical treatments, and areas for future research are illuminated. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial.

    PubMed

    Coric, Vladimir; Salloway, Stephen; van Dyck, Christopher H; Dubois, Bruno; Andreasen, Niels; Brody, Mark; Curtis, Craig; Soininen, Hilkka; Thein, Stephen; Shiovitz, Thomas; Pilcher, Gary; Ferris, Steven; Colby, Susan; Kerselaers, Wendy; Dockens, Randy; Soares, Holly; Kaplita, Stephen; Luo, Feng; Pachai, Chahin; Bracoud, Luc; Mintun, Mark; Grill, Joshua D; Marek, Ken; Seibyl, John; Cedarbaum, Jesse M; Albright, Charles; Feldman, Howard H; Berman, Robert M

    2015-11-01

    Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms. To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia. A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity. Oral avagacestat or placebo daily. Safety and tolerability of avagacestat. Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD

  4. Targeting breast cancer through its microenvironment: current status of preclinical and clinical research in finding relevant targets.

    PubMed

    Nienhuis, H H; Gaykema, S B M; Timmer-Bosscha, H; Jalving, M; Brouwers, A H; Lub-de Hooge, M N; van der Vegt, B; Overmoyer, B; de Vries, E G E; Schröder, C P

    2015-03-01

    It is increasingly evident that not only breast cancer cells, but also the tissue embedding these cells: the tumor microenvironment, plays an important role in tumor progression, metastasis formation and treatment sensitivity. This review focuses on the current knowledge of processes by which the microenvironment affects breast cancer, including formation of the metastatic niche, metabolic stimulation, stimulation of tumor cell migration, immune modulation, angiogenesis and matrix remodeling. The number of drugs targeting key factors in these processes is expanding, and the available clinical data is increasing. Therefore current strategies for intervention and prediction of treatment response are outlined. At present, targeting the formation of the metastatic niche and metabolic stimulation by the breast cancer microenvironment, are already showing clinical efficacy. Intervening in the stimulation of tumor cell migration and immune modulation by the microenvironment upcoming fields of great research interest. In contrast, targeting microenvironmental angiogenesis or matrix remodeling appears to be of limited clinical relevance in breast cancer treatment so far. Further research is warranted to optimize intervention strategies and develop predictive tests for the relevance of targeting involved factors within the microenvironment in order to optimally personalize breast cancer treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Care transitions programs: a review of hospital-based programs targeted to reduce readmissions.

    PubMed

    Delisle, Dennis R

    2013-01-01

    An emphasis on a value-based payment model is expected to provide motivation for developing effective care transitions programs. For such programs to succeed, organizations must adopt an evidence-based, financially feasible model that enables improved coordination with providers, alignment of incentives, and measurement of key performance metrics, both clinical and operational. Evidence of cost-effective care transitions programs is important for deploying successful models broadly. Hospital-based programs. Current literature on care transitions programs highlights different strategies, patient populations, settings, and outcomes; however, it lacks sufficient supporting financial evidence that these programs are operationally sustainable and cost-effective within current and projected reimbursement schemes. Care transitions interventions need to be further studied in different settings with different patient populations to identify the optimal approach(es). An additional opportunity for future investigation lies in translation of interventional programs targeted at readmission diseases in line for penalty by Medicare.

  6. Suppressing unwanted memories reduces their unconscious influence via targeted cortical inhibition.

    PubMed

    Gagnepain, Pierre; Henson, Richard N; Anderson, Michael C

    2014-04-01

    Suppressing retrieval of unwanted memories reduces their later conscious recall. It is widely believed, however, that suppressed memories can continue to exert strong unconscious effects that may compromise mental health. Here we show that excluding memories from awareness not only modulates medial temporal lobe regions involved in explicit retention, but also neocortical areas underlying unconscious expressions of memory. Using repetition priming in visual perception as a model task, we found that excluding memories of visual objects from consciousness reduced their later indirect influence on perception, literally making the content of suppressed memories harder for participants to see. Critically, effective connectivity and pattern similarity analysis revealed that suppression mechanisms mediated by the right middle frontal gyrus reduced activity in neocortical areas involved in perceiving objects and targeted the neural populations most activated by reminders. The degree of inhibitory modulation of the visual cortex while people were suppressing visual memories predicted, in a later perception test, the disruption in the neural markers of sensory memory. These findings suggest a neurobiological model of how motivated forgetting affects the unconscious expression of memory that may be generalized to other types of memory content. More generally, they suggest that the century-old assumption that suppression leaves unconscious memories intact should be reconsidered.

  7. Targeting acid sphingomyelinase reduces cardiac ceramide accumulation in the post-ischemic heart

    PubMed Central

    Klevstig, M; Ståhlman, M; Lundqvist, A; Scharin Täng, M; Fogelstrand, P; Adiels, M; Andersson, L; Kolesnick, R; Jeppsson, A; Borén, J; Levin, MC

    2016-01-01

    Ceramide accumulation is known to accompany acute myocardial ischemia, but its role in the pathogenesis of ischemic heart disease is unclear. In this study, we aimed to determine how ceramides accumulate in the ischemic heart and to determine if cardiac function following ischemia can be improved by reducing ceramide accumulation. To investigate the association between ceramide accumulation and heart function, we analyzed myocardial left ventricle biopsies from subjects with chronic ischemia and found that ceramide levels were higher in biopsies from subjects with reduced heart function. Ceramides are produced by either de novo synthesis or hydrolysis of sphingomyelin catalyzed by acid and/or neutral sphingomyelinase. We used cultured HL-1 cardiomyocytes to investigate these pathways and showed that acid sphingomyelinase activity rather than neutral sphingomyelinase activity or de novo sphingolipid synthesis was important for hypoxia-induced ceramide accumulation. We also used mice with a partial deficiency in acid sphingomyelinase (Smpd1+/- mice) to investigate if limiting ceramide accumulation under ischemic conditions would have a beneficial effect on heart function and survival. Although we showed that cardiac ceramide accumulation was reduced in Smpd1+/- mice 24 h after an induced myocardial infarction, this reduction was not accompanied by an improvement in heart function or survival. Our findings show that accumulation of cardiac ceramides in the post-ischemic heart is mediated by acid sphingomyelinase. However, targeting ceramide accumulation in the ischemic heart may not be a beneficial treatment strategy. PMID:26930027

  8. Reducing acquisition time in clinical MRI by data undersampling and compressed sensing reconstruction.

    PubMed

    Hollingsworth, Kieren Grant

    2015-11-07

    MRI is often the most sensitive or appropriate technique for important measurements in clinical diagnosis and research, but lengthy acquisition times limit its use due to cost and considerations of patient comfort and compliance. Once an image field of view and resolution is chosen, the minimum scan acquisition time is normally fixed by the amount of raw data that must be acquired to meet the Nyquist criteria. Recently, there has been research interest in using the theory of compressed sensing (CS) in MR imaging to reduce scan acquisition times. The theory argues that if our target MR image is sparse, having signal information in only a small proportion of pixels (like an angiogram), or if the image can be mathematically transformed to be sparse then it is possible to use that sparsity to recover a high definition image from substantially less acquired data. This review starts by considering methods of k-space undersampling which have already been incorporated into routine clinical imaging (partial Fourier imaging and parallel imaging), and then explains the basis of using compressed sensing in MRI. The practical considerations of applying CS to MRI acquisitions are discussed, such as designing k-space undersampling schemes, optimizing adjustable parameters in reconstructions and exploiting the power of combined compressed sensing and parallel imaging (CS-PI). A selection of clinical applications that have used CS and CS-PI prospectively are considered. The review concludes by signposting other imaging acceleration techniques under present development before concluding with a consideration of the potential impact and obstacles to bringing compressed sensing into routine use in clinical MRI.

  9. Connexins and pannexins: from biology towards clinical targets.

    PubMed

    Meda, Paolo; Haefliger, Jacques-Antoine

    2016-01-01

    Efficient cell communication is a prerequisite for the coordinated function of tissues and organs. In vertebrates, this communication is mediated by a variety of mechanisms, including the exchange of molecules between cells, and between cells and the extracellular medium, via membrane channels made of connexin and pannexin proteins. These channels are a necessary component of all human tissues. Here, we review the biological essentials of the connexin and pannexin families, and the roles of these proteins in the function of cells which are central to major human diseases. We then discuss how connexins and pannexins participate in human pathology, and the clinical perspectives that this knowledge opens.

  10. Hallmarks of hyperthermia in driving the future of clinical hyperthermia as targeted therapy: translation into clinical application.

    PubMed

    Issels, Rolf; Kampmann, Eric; Kanaar, Roland; Lindner, Lars H

    2016-01-01

    Regional hyperthermia is described as a targeted therapy and the definitions of six hallmarks of hyperthermia are proposed, representing the pleiotropic effect of this therapeutic modality to counteract tumour growth and progression. We recommend the considerations of these hallmarks in the design of clinical trials involving regional hyperthermia as targeted therapy. Randomised clinical studies using loco-regional hyperthermia as an adjuvant to radiotherapy or to chemotherapy for locally advanced tumours demonstrate the benefit of the combination compared to either of the standard treatments alone for tumour response, disease control, and patient survival outcome. These impressive results were obtained from proof-of-concept trials for superficial or deep-seated malignancies in unselected patients. None of these trials was designed as tailored approaches for the treatment of specified targets or to select potentially more sensitive subpopulations of patients using eligibility criteria. Based upon clinical examples of targeted chemotherapy, some guidelines are described for the successful development of targeted therapeutic combinations. We also retrospectively analyse the stepwise process of generating an ongoing new clinical trial using hyperthermia as targeted therapy to evade DNA repair in combination with a DNA damaging anticancer agent to implement this new vision.

  11. Targeted filtering reduces the complexity of UHPLC-Orbitrap-HRMS data to decipher polyphenol polymerization.

    PubMed

    Vallverdú-Queralt, Anna; Meudec, Emmanuelle; Eder, Matthias; Lamuela-Raventos, Rosa M; Sommerer, Nicolas; Cheynier, Véronique

    2017-07-15

    UHPLC-LTQ-Orbitrap-high resolution mass spectrometry (HRMS) was applied to investigate complex polymeric polyphenols, before and after acid-catalysed depolymerisation in the presence of a nucleophile (phloroglucinol). Reaction products of (-)-epicatechin with acetaldehyde formed in model solution were selected for a proof-of concept experiment. The complexity of the UHPLC-HRMS dataset obtained after 4h incubation was reduced with petroleomics-inspired strategies using Van Krevelen diagrams and modified Kendrick mass defect filtering targeting ethyl-epicatechin (C17H16O6) units. Combining these approaches with mass fragmentation and phloroglucinolysis allowed us to describe reaction of epicatechin and acetaldehyde. More than 65 compounds were found, including the homogeneous bridged derivatives (up to the undecamer), vinyl and ethanol adducts, and xanthene and xanthylium salt derivatives which were identified for the first time.

  12. Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts.

    PubMed

    Griffin, Carly; Karnik, Aditya; McNulty, James; Pandey, Siyaram

    2011-01-01

    The naturally occurring Amaryllidaceae alkaloid pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53-mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, pancratistatin was found to be ineffective against mtDNA-depleted (ρ(0)) cancer cells. Moreover, pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter β-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice (n = 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth.

  13. Optimal antisense target reducing INS intron 1 retention is adjacent to a parallel G quadruplex

    PubMed Central

    Kralovicova, Jana; Lages, Ana; Patel, Alpa; Dhir, Ashish; Buratti, Emanuele; Searle, Mark; Vorechovsky, Igor

    2014-01-01

    Splice-switching oligonucleotides (SSOs) have been widely used to inhibit exon usage but antisense strategies that promote removal of entire introns to increase splicing-mediated gene expression have not been developed. Here we show reduction of INS intron 1 retention by SSOs that bind transcripts derived from a human haplotype expressing low levels of proinsulin. This haplotype is tagged by a polypyrimidine tract variant rs689 that decreases the efficiency of intron 1 splicing and increases the relative abundance of mRNAs with extended 5' untranslated region (5' UTR), which curtails translation. Co-expression of haplotype-specific reporter constructs with SSOs bound to splicing regulatory motifs and decoy splice sites in primary transcripts revealed a motif that significantly reduced intron 1-containing mRNAs. Using an antisense microwalk at a single nucleotide resolution, the optimal target was mapped to a splicing silencer containing two pseudoacceptor sites sandwiched between predicted RNA guanine (G) quadruplex structures. Circular dichroism spectroscopy and nuclear magnetic resonance of synthetic G-rich oligoribonucleotide tracts derived from this region showed formation of a stable parallel 2-quartet G-quadruplex on the 3' side of the antisense retention target and an equilibrium between quadruplexes and stable hairpin-loop structures bound by optimal SSOs. This region interacts with heterogeneous nuclear ribonucleoproteins F and H that may interfere with conformational transitions involving the antisense target. The SSO-assisted promotion of weak intron removal from the 5' UTR through competing noncanonical and canonical RNA structures may facilitate development of novel strategies to enhance gene expression. PMID:24944197

  14. Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion

    PubMed Central

    Alonso, Florian; Domingos-Pereira, Sonia; Le Gal, Loïc; Derré, Laurent; Meda, Paolo; Jichlinski, Patrice; Nardelli-Haefliger, Denise; Haefliger, Jacques-Antoine

    2016-01-01

    Endothelial connexin40 (Cx40) contributes to regulate the structure and function of vessels. We have examined whether the protein also modulates the altered growth of vessels in tumor models established in control mice (WT), mice lacking Cx40 (Cx40−/−), and mice expressing the protein solely in endothelial cells (Tie2-Cx40). Tumoral angiogenesis and growth were reduced, whereas vessel perfusion, smooth muscle cell (SMC) coverage and animal survival were increased in Cx40−/− but not Tie2-Cx40 mice, revealing a critical involvement of endothelial Cx40 in transformed tissues independently of the hypertensive status of Cx40−/− mice. As a result, Cx40−/− mice bearing tumors survived significantly longer than corresponding controls, including after a cytotoxic administration. Comparable observations were made in WT mice injected with a peptide targeting Cx40, supporting the Cx40 involvement. This involvement was further confirmed in the absence of Cx40 or by peptide-inhibition of this connexin in aorta-sprouting, matrigel plug and SMC migration assays, and associated with a decreased expression of the phosphorylated form of endothelial nitric oxide synthase. The data identify Cx40 as a potential novel target in cancer treatment. PMID:26883111

  15. Combining contact tracing with targeted indoor residual spraying significantly reduces dengue transmission

    PubMed Central

    Vazquez-Prokopec, Gonzalo M.; Montgomery, Brian L.; Horne, Peter; Clennon, Julie A.; Ritchie, Scott A.

    2017-01-01

    The widespread transmission of dengue viruses (DENV), coupled with the alarming increase of birth defects and neurological disorders associated with Zika virus, has put the world in dire need of more efficacious tools for Aedes aegypti–borne disease mitigation. We quantitatively investigated the epidemiological value of location-based contact tracing (identifying potential out-of-home exposure locations by phone interviews) to infer transmission foci where high-quality insecticide applications can be targeted. Space-time statistical modeling of data from a large epidemic affecting Cairns, Australia, in 2008–2009 revealed a complex pattern of transmission driven primarily by human mobility (Cairns accounted for ~60% of virus transmission to and from residents of satellite towns, and 57% of all potential exposure locations were nonresidential). Targeted indoor residual spraying with insecticides in potential exposure locations reduced the probability of future DENV transmission by 86 to 96%, compared to unsprayed premises. Our findings provide strong evidence for the effectiveness of combining contact tracing with residual spraying within a developed urban center, and should be directly applicable to areas with similar characteristics (for example, southern USA, Europe, or Caribbean countries) that need to control localized Aedes-borne virus transmission or to protect pregnant women’s homes in areas with active Zika transmission. Future theoretical and empirical research should focus on evaluation of the applicability and scalability of this approach to endemic areas with variable population size and force of DENV infection. PMID:28232955

  16. Combining contact tracing with targeted indoor residual spraying significantly reduces dengue transmission.

    PubMed

    Vazquez-Prokopec, Gonzalo M; Montgomery, Brian L; Horne, Peter; Clennon, Julie A; Ritchie, Scott A

    2017-02-01

    The widespread transmission of dengue viruses (DENV), coupled with the alarming increase of birth defects and neurological disorders associated with Zika virus, has put the world in dire need of more efficacious tools for Aedes aegypti-borne disease mitigation. We quantitatively investigated the epidemiological value of location-based contact tracing (identifying potential out-of-home exposure locations by phone interviews) to infer transmission foci where high-quality insecticide applications can be targeted. Space-time statistical modeling of data from a large epidemic affecting Cairns, Australia, in 2008-2009 revealed a complex pattern of transmission driven primarily by human mobility (Cairns accounted for ~60% of virus transmission to and from residents of satellite towns, and 57% of all potential exposure locations were nonresidential). Targeted indoor residual spraying with insecticides in potential exposure locations reduced the probability of future DENV transmission by 86 to 96%, compared to unsprayed premises. Our findings provide strong evidence for the effectiveness of combining contact tracing with residual spraying within a developed urban center, and should be directly applicable to areas with similar characteristics (for example, southern USA, Europe, or Caribbean countries) that need to control localized Aedes-borne virus transmission or to protect pregnant women's homes in areas with active Zika transmission. Future theoretical and empirical research should focus on evaluation of the applicability and scalability of this approach to endemic areas with variable population size and force of DENV infection.

  17. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction.

    PubMed

    Sager, Hendrik B; Dutta, Partha; Dahlman, James E; Hulsmans, Maarten; Courties, Gabriel; Sun, Yuan; Heidt, Timo; Vinegoni, Claudio; Borodovsky, Anna; Fitzgerald, Kevin; Wojtkiewicz, Gregory R; Iwamoto, Yoshiko; Tricot, Benoit; Khan, Omar F; Kauffman, Kevin J; Xing, Yiping; Shaw, Taylor E; Libby, Peter; Langer, Robert; Weissleder, Ralph; Swirski, Filip K; Anderson, Daniel G; Nahrendorf, Matthias

    2016-06-08

    Myocardial infarction (MI) leads to a systemic surge of vascular inflammation in mice and humans, resulting in secondary ischemic complications and high mortality. We show that, in ApoE(-/-) mice with coronary ligation, increased sympathetic tone up-regulates not only hematopoietic leukocyte production but also plaque endothelial expression of adhesion molecules. To counteract the resulting arterial leukocyte recruitment, we developed nanoparticle-based RNA interference (RNAi) that effectively silences five key adhesion molecules. Simultaneously encapsulating small interfering RNA (siRNA)-targeting intercellular cell adhesion molecules 1 and 2 (Icam1 and Icam2), vascular cell adhesion molecule 1 (Vcam1), and E- and P-selectins (Sele and Selp) into polymeric endothelial-avid nanoparticles reduced post-MI neutrophil and monocyte recruitment into atherosclerotic lesions and decreased matrix-degrading plaque protease activity. Five-gene combination RNAi also curtailed leukocyte recruitment to ischemic myocardium. Therefore, targeted multigene silencing may prevent complications after acute MI. Copyright © 2016, American Association for the Advancement of Science.

  18. Targeted rehabilitation reduces visual dependency and improves balance in severe traumatic brain injury: a case study.

    PubMed

    Kaski, Diego; Buttell, Joseph; Greenwood, Richard

    2017-01-23

    To further understand the mechanisms underlying gait impairment following traumatic brain injury. A 58-year-old man presented with marked unsteadiness and motion sensitivity following a severe traumatic brain injury. He underwent a 6-week inpatient rehabilitation program focused on re-weighting and subsequently re-integrating ascending interoceptive information, by gradual reduction of maladaptive visual fixation techniques. We report clinical neurological outcomes and measures of functional outcome, as well as an objective assessment of visual dependency (the rod and disk test) at baseline and after the rehabilitation. Clinically, the patient had gait unsteadiness exacerbated by visual motion. A significant reduction in visual dependency occurred with tailored multi-disciplinary rehabilitation via gradual removal of visual fixation strategies that the patient had developed to maintain balance (t-test; p < 0.01), as well as clinical improvements in gait, balance, and functional outcome. We highlight the importance of visual dependency in the generation of maladaptive gait strategies following brain injury. Our data suggest assessing and treating visual dependency to be an important component of gait rehabilitation after traumatic brain injury. Implications for rehabilitation Whilst gait disturbance in TBI is multifactorial, abnormal visual dependency may be important but under-recognised component of the disorder. Visual dependency can be easily and objectively assessed by the bedside in patients using a dynamic rod and disc test. Tailored rehabilitation with gradual reduction of maladaptive visual fixation can reduce visual dependency and contribute to improved gait and balance following TBI.

  19. Clinical trial will investigate targeted radionuclide therapy for inoperable rare tumors | Center for Cancer Research

    Cancer.gov

    In an upcoming phase II clinical trial, Center for Cancer Research investigators will explore the ability of a targeted radioactive drug to treat inoperable pheochromocytoma and paraganglioma, both rare tumors.  Learn more...

  20. Texas hospitals share creative uses of non-clinical staff to reduce ER costs.

    PubMed

    2006-01-01

    Texas hospitals share creative uses of non-clinical staff to reduce ER costs. In central Texas, Christus Spohn Hospital and Seton Health Care are independently exploring the use of non-clinical staff to improve utilization of clinical and emergency services, but their existing programs employ different structures and outcomes measurements.

  1. Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases.

    PubMed

    Brennan, Frank R; Cauvin, Annick; Tibbitts, Jay; Wolfreys, Alison

    2014-05-01

    An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex-mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and

  2. Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aβ Generation and Amyloid Plaque Pathogenesis.

    PubMed

    Xiao, Qingli; Yan, Ping; Ma, Xiucui; Liu, Haiyan; Perez, Ronaldo; Zhu, Alec; Gonzales, Ernesto; Tripoli, Danielle L; Czerniewski, Leah; Ballabio, Andrea; Cirrito, John R; Diwan, Abhinav; Lee, Jin-Moo

    2015-09-02

    In AD, an imbalance between Aβ production and removal drives elevated brain Aβ levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via α-cleavage at the plasma membrane, amyloidogenic β- and γ-cleavage within endosomes to generate Aβ, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased amyloidogenic processing of APP, we explored the efficacy of targeting transcription factor EB (TFEB), a master regulator of lysosomal pathways, to reduce Aβ levels. CMV promoter-driven TFEB, transduced via stereotactic hippocampal injections of adeno-associated virus particles in APP/PS1 mice, localized primarily to neuronal nuclei and upregulated lysosome biogenesis. This resulted in reduction of APP protein, the α and β C-terminal APP fragments (CTFs), and in the steady-state Aβ levels in the brain interstitial fluid. In aged mice, total Aβ levels and amyloid plaque load were selectively reduced in the TFEB-transduced hippocampi. TFEB transfection in N2a cells stably expressing APP695, stimulated lysosome biogenesis, reduced steady-state levels of APP and α- and β-CTFs, and attenuated Aβ generation by accelerating flux through the endosome-lysosome pathway. Cycloheximide chase assays revealed a shortening of APP half-life with exogenous TFEB expression, which was prevented by concomitant inhibition of lysosomal acidification. These data indicate that TFEB enhances flux through lysosomal degradative pathways to induce APP degradation and reduce Aβ generation. Activation of TFEB in neurons is an effective strategy to attenuate Aβ generation and attenuate amyloid plaque deposition in AD. A key driver for AD pathogenesis is the net balance between production and clearance of Aβ, the major component of amyloid plaques. Here we demonstrate that lysosomal degradation of holo-APP influences Aβ production by limiting the availability of APP for amyloidogenic

  3. Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aβ Generation and Amyloid Plaque Pathogenesis

    PubMed Central

    Xiao, Qingli; Yan, Ping; Ma, Xiucui; Liu, Haiyan; Perez, Ronaldo; Zhu, Alec; Gonzales, Ernesto; Tripoli, Danielle L.; Czerniewski, Leah; Ballabio, Andrea; Cirrito, John R.

    2015-01-01

    In AD, an imbalance between Aβ production and removal drives elevated brain Aβ levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via α-cleavage at the plasma membrane, amyloidogenic β- and γ-cleavage within endosomes to generate Aβ, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased amyloidogenic processing of APP, we explored the efficacy of targeting transcription factor EB (TFEB), a master regulator of lysosomal pathways, to reduce Aβ levels. CMV promoter-driven TFEB, transduced via stereotactic hippocampal injections of adeno-associated virus particles in APP/PS1 mice, localized primarily to neuronal nuclei and upregulated lysosome biogenesis. This resulted in reduction of APP protein, the α and β C-terminal APP fragments (CTFs), and in the steady-state Aβ levels in the brain interstitial fluid. In aged mice, total Aβ levels and amyloid plaque load were selectively reduced in the TFEB-transduced hippocampi. TFEB transfection in N2a cells stably expressing APP695, stimulated lysosome biogenesis, reduced steady-state levels of APP and α- and β-CTFs, and attenuated Aβ generation by accelerating flux through the endosome-lysosome pathway. Cycloheximide chase assays revealed a shortening of APP half-life with exogenous TFEB expression, which was prevented by concomitant inhibition of lysosomal acidification. These data indicate that TFEB enhances flux through lysosomal degradative pathways to induce APP degradation and reduce Aβ generation. Activation of TFEB in neurons is an effective strategy to attenuate Aβ generation and attenuate amyloid plaque deposition in AD. SIGNIFICANCE STATEMENT A key driver for AD pathogenesis is the net balance between production and clearance of Aβ, the major component of amyloid plaques. Here we demonstrate that lysosomal degradation of holo-APP influences Aβ production by limiting the availability of

  4. A kallikrein-targeting RNA aptamer inhibits the intrinsic pathway of coagulation and reduces bradykinin release.

    PubMed

    Steen Burrell, K-A; Layzer, J; Sullenger, B A

    2017-09-01

    Essentials Kallikrein amplifies contact activation and is a potential target for preventing thrombosis. We developed and characterized a kallikrein aptamer using convergent evolution and kinetic assays. Kall1-T4 prolongs intrinsic clotting time by inhibiting factor XIIa-mediated prekallikrein activation. Kall1-T4 decreases high-molecular-weight kininogen cleavage and bradykinin release. Background Plasma kallikrein is a serine protease that plays an integral role in many biological processes, including coagulation, inflammation, and fibrinolysis. The main function of kallikrein in coagulation is the amplification of activated factor XII (FXIIa) production, which ultimately leads to thrombin generation and fibrin clot formation. Kallikrein is generated by FXIIa-mediated cleavage of the zymogen prekallikrein, which is usually complexed with the non-enzymatic cofactor high molecular weight kininogen (HK). HK also serves as a substrate for kallikrein to generate the proinflammatory peptide bradykinin (BK). Interestingly, prekallikrein-deficient mice are protected from thrombotic events while retaining normal hemostatic capacity. Therefore, therapeutic targeting of kallikrein may provide a safer alternative to traditional anticoagulants with anti-inflammatory benefits. Objectives To isolate and characterize an RNA aptamer that binds to and inhibits plasma kallikrein, and to elucidate its mechanism of action. Methods and Results Using convergent Systematic Evolution of Ligands by Exponential Enrichment (SELEX), we isolated an RNA aptamer that targets kallikrein. This aptamer, Kall1-T4, specifically binds to both prekallikrein and kallikrein with similar subnanomolar binding affinities, and dose-dependently prolongs fibrin clot formation in an activated partial thromboplastin time (APTT) coagulation assay. In a purified in vitro system, Kall1-T4 inhibits the reciprocal activation of prekallikrein and FXII primarily by reducing the rate of FXIIa-mediated prekallikrein

  5. Reduce in Variation and Improve Efficiency of Target Volume Delineation by a Computer-Assisted System Using a Deformable Image Registration Approach

    SciTech Connect

    Chao, K.S. Clifford . E-mail: cchao@mdanderson.org; Bhide, Shreerang FRCR; Chen, Hansen; Asper, Joshua PAC; Bush, Steven; Franklin, Gregg; Kavadi, Vivek; Liengswangwong, Vichaivood; Gordon, William; Raben, Adam; Strasser, Jon; Koprowski, Christopher; Frank, Steven; Chronowski, Gregory; Ahamad, Anesa; Malyapa, Robert; Zhang Lifei; Dong Lei

    2007-08-01

    Purpose: To determine whether a computer-assisted target volume delineation (CAT) system using a deformable image registration approach can reduce the variation of target delineation among physicians with different head and neck (HN) IMRT experiences and reduce the time spent on the contouring process. Materials and Methods: We developed a deformable image registration method for mapping contours from a template case to a patient case with a similar tumor manifestation but different body configuration. Eight radiation oncologists with varying levels of clinical experience in HN IMRT performed target delineation on two HN cases, one with base-of-tongue (BOT) cancer and another with nasopharyngeal cancer (NPC), by first contouring from scratch and then by modifying the contours deformed by the CAT system. The gross target volumes were provided. Regions of interest for comparison included the clinical target volumes (CTVs) and normal organs. The volumetric and geometric variation of these regions of interest and the time spent on contouring were analyzed. Results: We found that the variation in delineating CTVs from scratch among the physicians was significant, and that using the CAT system reduced volumetric variation and improved geometric consistency in both BOT and NPC cases. The average timesaving when using the CAT system was 26% to 29% for more experienced physicians and 38% to 47% for the less experienced ones. Conclusions: A computer-assisted target volume delineation approach, using a deformable image-registration method with template contours, was able to reduce the variation among physicians with different experiences in HN IMRT while saving contouring time.

  6. Review: Targeting trachoma: Strategies to reduce the leading infectious cause of blindness.

    PubMed

    Baneke, Alex

    2012-03-01

    The World Health Organisation (WHO) estimated that in 2002, 1.3 million people were blind due to trachoma, an eye infection caused by Chlamydia trachomatis. This review examines the evidence behind current strategies to reduce the global burden of trachoma. Trachoma disappeared from most western nations before the advent of antibiotics, probably due to improvements in water, sanitation and hygiene. The current effort to target trachoma, headed by the WHO and the Alliance for the Global Elimination of Trachoma by 2020, is called the SAFE (Surgery, Antibiotics, Facial cleanliness and Environmental improvement) strategy. Surgery for trachoma is more cost effective than extra-capsular cataract surgery and can reverse trichiasis (in-growing eyelashes), but needs to be repeated every few years. A single oral dose of azithromycin can eliminate trachoma infection, but cannot be used in infants under 6 months old, and needs to be given every few years in communities with a high prevalence of disease. Improved health education and facial hygiene has been linked to a lower incidence of trachoma, but the evidence is less clear than for surgery and antibiotics. Pit latrines and spraying with permethrin insecticide may reduce the spread of trachoma via eye-seeking flies.

  7. Clinical proteomics-driven precision medicine for targeted cancer therapy: current overview and future perspectives.

    PubMed

    Zhou, Li; Wang, Kui; Li, Qifu; Nice, Edouard C; Zhang, Haiyuan; Huang, Canhua

    2016-01-01

    Cancer is a common disease that is a leading cause of death worldwide. Currently, early detection and novel therapeutic strategies are urgently needed for more effective management of cancer. Importantly, protein profiling using clinical proteomic strategies, with spectacular sensitivity and precision, offer excellent promise for the identification of potential biomarkers that would direct the development of targeted therapeutic anticancer drugs for precision medicine. In particular, clinical sample sources, including tumor tissues and body fluids (blood, feces, urine and saliva), have been widely investigated using modern high-throughput mass spectrometry-based proteomic approaches combined with bioinformatic analysis, to pursue the possibilities of precision medicine for targeted cancer therapy. Discussed in this review are the current advantages and limitations of clinical proteomics, the available strategies of clinical proteomics for the management of precision medicine, as well as the challenges and future perspectives of clinical proteomics-driven precision medicine for targeted cancer therapy.

  8. [Clinical to target volume margins determination in radiotherapy for anal cancers].

    PubMed

    Libois, V; Mahé, M-A; Rio, E; Maingon, P

    2016-10-01

    There are very few data on the expansion from the clinical target volume (CTV) to the planning target volume (PTV) in the anal cancer treatment. This article aims to collect the different elements needed for the construction of a PTV from scientific data based on a literature analysis. We reviewed the articles published in the medical literature from the last 20years. They concerned setup errors and internal organ mobility of the different volumes of patients treated by conformational radiotherapy and intensity-modulated radiotherapy (anal canal, meso-rectum, common, intern and extern, inguinal and pre-sacral lymph nodes). CTV to PTV margins admitted in the guidelines and atlas of consensus groups (SFRO, RTOG, AGITG) are from 0.7 to 1cm in all directions, based on expert's opinions but not on scientific data. There are no specific studies on the canal anal mobility. Most of the data are from other pelvis cancers (gynecologic, rectum and prostate). Setup errors can be reduced by daily imaging. Patient repositioning and immobilization modalities are mostly local habits rather than scientific consensus. A three-dimensional 1cm margin is generally admitted. Margins reduction must be careful and has to be assessed.

  9. Small interfering RNA therapy in cancer: mechanism, potential targets, and clinical applications.

    PubMed

    Huang, Chuan; Li, Min; Chen, Changyi; Yao, Qizhi

    2008-05-01

    Small interfering RNA (siRNA) has become a powerful tool in knocking down or silencing gene expression in most cells. siRNA-based therapy has shown great promise for many diseases such as cancer. Major targets for siRNA therapy include oncogenes and genes that are involved in angiogenesis, metastasis, survival, antiapoptosis and resistance to chemotherapy. This review briefly summarizes current advances in siRNA therapy and clinical applications in cancers, especially in pancreatic cancer. This review article covers several aspects of siRNA therapy in cancer, which include the types of siRNA, the delivery systems for siRNA, and the major targets for siRNA therapy. Specific attention is given to siRNA in pancreatic cancer, which is our main research focus. siRNA can be introduced into the cells by using either chemically synthesized siRNA oligonucleotides (oligos), or vector-based siRNA (shRNA), which allows long lasting and more stable gene silencing. Nanoparticles and liposomes are commonly used carriers, delivering the siRNA with better transfection efficiency and protecting it from degradation. In combination with standard chemotherapy, siRNA therapy can also reduce the chemoresistance of certain cancers, demonstrating the potential of siRNA therapy for treating many malignant diseases. This review will provide valuable information for clinicians and researchers who want to recognize the newest endeavors within this field and identify possible lines of investigation in cancer.

  10. Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice.

    PubMed

    Obara, Ilona; Medrano, Maria C; Signoret-Genest, Jérémy; Jiménez-Díaz, Lydia; Géranton, Sandrine M; Hunt, Stephen P

    2015-08-01

    Activated mammalian target of rapamycin (P-mTOR) has been shown to maintain the sensitivity of subsets of small-diameter primary afferent A-nociceptors. Local or systemic inhibition of the mTOR complex 1 (mTORC1) pathway reduced punctate mechanical and cold sensitivity in neuropathic pain and therefore offered a new approach to chronic pain control. In this study, we have investigated the effects of the rapamycin analog temsirolimus (CCI-779) on itch. Bouts of scratching induced by the histamine-dependent pruritogenic compound 48/80 and histamine-independent pruritogens, chloroquine and SLIGRL-NH2, injected intradermally were significantly reduced by local (intradermal) or systemic (intraperitoneal, i.p.) pretreatment with CCI-779. We also investigated the action of metformin, a drug taken to control type 2 diabetes and recently shown to inhibit mTORC1 in vivo. Although the response to nonhistaminergic stimuli was reduced at all of the time points tested, scratching to compound 48/80 was modified by metformin only when the drug was injected 24 hours before this pruritogen. We also examined the colocalization of P-mTOR with gastrin-releasing peptide, a putative marker for some itch-sensitive primary afferents, and found that P-mTOR was coexpressed in less than 5% of gastrin-releasing peptide-positive fibers in the mouse skin. Taken together, the data highlight the role that P-mTOR-positive A-fibers play in itch signaling and underline the importance of the mTORC1 pathway in the regulation of homeostatic primary afferent functions such as pain and itch. The actions of the antidiabetic drug metformin in ameliorating nonhistamine-mediated itch also suggest a new therapeutic route for the control of this category of pruritus.

  11. Interventions targeting absences increase adherence and reduce abandonment of childhood cancer treatment in El Salvador.

    PubMed

    Salaverria, Carmen; Rossell, Nuria; Hernandez, Angelica; Fuentes Alabi, Soad; Vasquez, Roberto; Bonilla, Miguel; Lam, Catherine G; Ribeiro, Raul C

    2015-09-01

    In El Salvador, about 200 new cases of pediatric cancer are diagnosed each year, and survival rates approach 70%. Although treatment is available at no cost, abandonment of therapy has remained at a steady yearly rate of 13% during the past decade. A time sensitive adherence tracking procedure (TS-ATP) was recently implemented to detect missed appointments, identify their causes, and intervene promptly. Procedure The study team was informed daily of patient/family failure to attend medical appointments in the pediatric oncology unit; the families were contacted and interviewed to ascertain and address the reasons. Patients who did not return after this initial contact were contacted again through local health clinics and municipalities. Law enforcement was a last resort for patients undergoing frontline treatment with a good prognosis., The system was adapted to clinical urgency: families of patients undergoing induction therapy were contacted within 24 hr, those in other therapy phases, within 48 hr, and those who had completed treatment, within one week. Reasons for absence were obtained by telephone or in person. The annual rate of abandonment was reduced from 13-3% during the 2 years period. There were 1,111 absences reported and 1,472 contacts with caregivers and institutions. The three main reasons for absences were financial needs (165, 23%), unforeseen barriers (116, 16%), and domestic needs (86, 12%). Use of the treatment adherence tracking system to locate and communicate with patients/families after missed appointments and the allocated aid stemming from these interviews substantially reduced abandonment and non-adherence. © 2015 Wiley Periodicals, Inc.

  12. INTERVENTIONS TARGETING ABSENCES INCREASE ADHERENCE AND REDUCE ABANDONMENT OF CHILDHOOD CANCER TREATMENT IN EL SALVADOR

    PubMed Central

    Salaverria, Carmen; Rossell, Nuria; Hernandez, Angelica; Alabi, Soad Fuentes; Vasquez, Roberto; Bonilla, Miguel; Lam, Catherine G.; Ribeiro, Raul C.

    2015-01-01

    Background In El Salvador, about 200 new cases of pediatric cancer are diagnosed each year, and survival rates approach 70%. Although treatment is available at no cost, abandonment of therapy has remained at a steady yearly rate of 13% during the past decade. A time sensitive adherence tracking procedure (TS-ATP) was recently implemented to detect missed appointments, identify their causes, and intervene promptly. Procedure The study team was informed daily of patient/family failure to attend medical appointments in the pediatric oncology unit; the families were contacted and interviewed to ascertain and address the reasons. Patients who did not return after this initial contact were contacted again through local health clinics and municipalities. Law enforcement was a last resort for patients undergoing frontline treatment with a good prognosis., The system was adapted to clinical urgency: families of patients undergoing induction therapy were contacted within 24 hours, those in other therapy phases, within 48 hours, and those who had completed treatment, within one week. Reasons for absence were obtained by telephone or in person. Results The annual rate of abandonment was reduced from 13% to 3% during the 2-year period. There were 1111 absences reported and 1472 contacts with caregivers and institutions. The three main reasons for absences were financial needs (165, 23%), unforeseen barriers (116, 16%), and domestic needs (86, 12%). Conclusions Use of the treatment adherence tracking system to locate and communicate with patients/families after missed appointments and the allocated aid stemming from these interviews substantially reduced abandonment and non-adherence. PMID:25925227

  13. Targeting formyl peptide receptor 2 reduces leukocyte-endothelial interactions in a murine model of stroke.

    PubMed

    Smith, Helen K; Gil, Cristiane Damas; Oliani, Sonia M; Gavins, Felicity N E

    2015-05-01

    Ischemia/reperfusion (I/R) injury following stroke can worsen patient outcome through excess inflammation. This study investigated the pharmacologic potential of targeting an endogenous anti-inflammatory circuit via formyl peptide receptor (FPR) 2/lipoxin receptor (ALX) (Fpr2/3 in mouse) in global cerebral I/R. Mice (C57BL/6 and Fpr2/3(-/-)) were subjected to bilateral common carotid artery occlusion, followed by reperfusion and treatment with FPR agonists: AnxA1Ac2-26 [Annexin A1 mimetic peptide (Ac-AMVSEFLKQAWFIENEEQEYVQTVK), 2.5 μg/kg] and 15-epimer-lipoxin A4 (15-epi-LXA4; FPR2/ALX specific, 12.5 and 100 ng/kg). Leukocyte-endothelial (L-E) interactions in the cerebral microvasculature were then quantified in vivo using intravital fluorescence microscopy. 15-epi-LXA4 administration at the start of reperfusion reduced L-E interactions after 40 min (which was sustained at 2 h with high-dose 15-epi-LXA4) to levels seen in sham-operated animals. AnxA1Ac2-26 treatment decreased leukocyte adhesion at 40 min and all L-E interactions at 2 h (up to 95%). Combined treatment with AnxA1Ac2-26 plus FPR antagonists t-Boc-FLFLF (250 ng/kg) or WRW4 (FPR2/ALX selective, 1.4 μg/kg) abrogated the effects of AnxA1Ac2-26 fully at 40 min. Antagonists were less effective at 2 h, which we demonstrate is likely because of their impact on early L-E interactions. Our findings indicate that FPR2/ALX activity elicits considerable control over vascular inflammatory responses during cerebral I/R and, therefore, provide evidence that targeting FPR2/ALX may be beneficial for patients who suffered from stroke. © FASEB.

  14. A target-controlled infusion regimen for reducing remifentanil-induced coughs

    PubMed Central

    Kim, Jong-Yeop; Chae, Yun Jeong; Kim, Jin-Soo; Park, Yoon-Jeong

    2012-01-01

    Background This study evaluates the effectiveness of the target-controlled infusion (TCI) of remifentanil through stepwise increases in the effect-site concentration (Ceff) in preventing coughs. Methods In a preliminary study, we randomly selected 140 patients to receive remifentanil through two-step increases in Ceff (1.0 ng/ml to 4.0 ng/ml: Group R1-4; 2.0 ng/ml to 4.0 ng/ml: Group R2-4). Based on the results of the preliminary study, we employed another sample of 140 patients and implemented a three-step increase in TCI (1.0 ng/ml to 2.0 ng/ml to 4.0 ng/ml: Group R1-2-4). We then compared this treatment with direct targeting based on 4.0 ng/ml TCI (Group R4). We recorded the episodes of coughs, rating them as mild (1-2), moderate (3-4), or severe (5 or more). Results In Group R1-4, one patient (1.5%) coughed during the first step, and five (7.3%) coughed during the second step. In Group R2-4, nine (13.2%) coughed during the first step, but none coughed during the next step. Only one patient had a mild cough during the three-step increase in TCI, that is, patients in Group R1-2-4 were significantly less likely to cough than those in Group R4 (P < 0.001). Conclusions Stepwise increases in the TCI of remifentanil reduced the incidence of remifentanil-induced coughing, and the three-step increase in TCI nearly eliminated remifentanil-induced coughing. PMID:22870362

  15. Stromal cell derived factor-1 (SDF-1) targeting reperfusion reduces myocardial infarction in isolated rat hearts.

    PubMed

    Jang, Young-Ho; Kim, June-Hong; Ban, Changill; Ahn, Kyohan; Cheong, Jae-Hun; Kim, Hyung-Hoi; Kim, Jung-Soo; Park, Yong-Hyun; Kim, Jun; Chun, Kook-Jin; Lee, Gyeong-Ho; Kim, Miju; Kim, Cheolmin; Xu, Zhelong

    2012-10-01

    Recent studies have shown that stromal cell derived factor-1 (SDF-1), first known as a cytokine involved in recruiting stem cells into injured organs, confers myocardial protection in myocardial infarction, which is not dependent on stem cell recruitment but related with modulation of ischemia-reperfusion (I/R) injury. However, the effect of SDF has been studied only in a preischemic exposure model, which is not clinically relevant if SDF is to be used as a therapeutic agent. Our study was aimed at evaluating whether or not SDF-1 confers cardioprotection during the reperfusion period. Hearts from SD rats were isolated and perfused with the Langendorff system. Proximal left coronary artery ligation, reperfusion, and SDF perfusion in KH buffer was done according to study protocol. Area of necrosis (AN) relative to area at risk (AR) was the primary endpoint of the study. Significant reduction of AN/AR by SDF in an almost dose-dependent manner was noted during both the preischemic exposure and reperfusion periods. In particular, infusion of a high concentration of SDF (25 nM/L) resulted in a dramatic reduction of infarct size, which was greater than that achieved with ischemic pre- or postconditioning. SDF perfusion during reperfusion was associated with a similar significant reduction of infarct size as preischemic SDF exposure. Further studies are warranted to assess the potential of SDF as a therapeutic agent for reducing I/R injury in clinical practice.

  16. Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes

    PubMed Central

    Rezvani, Andrew R.; McCune, Jeannine S.; Storer, Barry E.; Batchelder, Ami; Kida, Aiko; Deeg, H. Joachim; McDonald, George B.

    2013-01-01

    Targeted busulfan/cyclophosphamide (TBU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from TBU/CY to CY/TBU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/TBU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800–900 ng/mL. CY/TBU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to TBU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with TBU/CY for the same indications. In patients with myelofibrosis, CY/TBU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after TBU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/TBU cohort (2% vs. 13%, p=0.01). CY/TBU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/TBU is superior to TBU/CY as conditioning for patients with myelofibrosis. PMID:23583825

  17. Lipid targets in clinical practice: successes, failures and lessons to be learned.

    PubMed

    Dunne, M; Mac Ananey, O; Markham, C; Maher, V

    2013-12-01

    Optimal risk factor control is integral to managing patients with proven coronary heart disease (CHD+) and for those at risk of coronary heart disease (CHD-). The primary aim of the study was to assess the success rate of reaching lipid risk factor targets in a multiple risk factor clinic. A retrospective audit was conducted in 488 patients (CHD+, n = 112; CHD-, n = 376) who attended the Cardiovascular Risk Factor Clinic at Tallaght Hospital, Dublin in 2009 and 2010. Risk factor targets achieved in CHD+ and CHD- patients were LDLc (54/62 %), HDLc (67/67 %), systolic blood pressure (35/38 %), diastolic blood pressure (82/75 %), smoking cessation (27/26 %), BMI ≤ 30 (39/50 %) and normal waist circumference (27/39 %). Patients not reaching LDLc targets were found to be receiving fewer lipid-lowering drugs and having higher LDL levels at the initial clinic visit than those reaching targets. This retrospective audit highlights gaps in achieving target lipid levels at a multiple risk factor clinic level. High initial LDLc levels and lack of drug titration are evident. Guideline changes, staff rotation, clinic visit frequency and multiplicity of targets may be contributory. More emphasis needs to be placed on education and algorithm-based strategies to achieve better risk factor control.

  18. Clinically targeted screening for congenital CMV - potential for integration into the National Hearing Screening Programme.

    PubMed

    Kadambari, S; Luck, S; Davis, A; Williams, Ej; Berrington, J; Griffiths, Pd; Sharland, M

    2013-10-01

    Screening for a condition should only be undertaken if certain strict criteria are met. Congenital CMV (cCMV) is a leading cause of sensorineuronal hearing loss (SNHL) and meets many of these criteria, but is not currently screened for in the UK. Ganciclovir reduces CMV-induced progressive SNHL if treatment is begun in the first month of life. The Newborn Hearing Screening Programme (NHSP) has been shown to identify SNHL at the earliest possible age. The potential of integrating screening for cCMV into the NHSP is discussed to consolidate the link between screening, early diagnosis and management. The early diagnosis and treatment of cCMV may prevent a small proportion of late SNHL. In the absence of any screening programme, we provide evidence that clinically targeted screening through the NHSP is a potential option in the UK, enhancing the diagnostic pathway and enabling appropriate early treatment to reduce long-term morbidity. ©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  19. Science to Practice: Molecularly Targeted US of Inflammation-Important Steps toward Clinical Translation.

    PubMed

    Kiessling, Fabian

    2015-09-01

    Dual P- and E-selectin-targeted microbubbles (MBs) have previously been used for ultrasonography (US) of acute inflammatory bowel disease in mice. In the study by Wang and colleagues, such dual-targeted MBs were evaluated in pigs. After induction of ileitis by means of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)/ethanol installation, early inflammation, as well as mild and severe disease stages, could be distinguished. The molecularly targeted US method was characterized by high reproducibility and matched with histologic findings. This work is considered an important intermediate step in translating molecularly targeted US of inflammation from preclinical toward clinical application.

  20. AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability

    PubMed Central

    Lykens, Nicole M.; Reddi, Jyoti M.

    2017-01-01

    Glutamate-activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) mediate the majority of excitatory neurotransmission in brain and thus are major drug targets for diseases associated with hyperexcitability or neurotoxicity. Due to the critical nature of AMPA-Rs in normal brain function, typical AMPA-R antagonists have deleterious effects on cognition and motor function, highlighting the need for more precise modulators. A dramatic increase in the flip isoform of alternatively spliced AMPA-R GluA1 subunits occurs post-seizure in humans and animal models. GluA1-flip produces higher gain AMPA channels than GluA1-flop, increasing network excitability and seizure susceptibility. Splice modulating oligonucleotides (SMOs) bind to pre-mRNA to influence alternative splicing, a strategy that can be exploited to develop more selective drugs across therapeutic areas. We developed a novel SMO, GR1, which potently and specifically decreased GluA1-flip expression throughout the brain of neonatal mice lasting at least 60 days after single intracerebroventricular injection. GR1 treatment reduced AMPA-R mediated excitatory postsynaptic currents at hippocampal CA1 synapses, without affecting long-term potentiation or long-term depression, cellular models of memory, or impairing GluA1-dependent cognition or motor function in mice. Importantly, GR1 demonstrated anti-seizure properties and reduced post-seizure hyperexcitability in neonatal mice, highlighting its drug candidate potential for treating epilepsies and other neurological diseases involving network hyperexcitability. PMID:28178321

  1. AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability.

    PubMed

    Lykens, Nicole M; Coughlin, David J; Reddi, Jyoti M; Lutz, Gordon J; Tallent, Melanie K

    2017-01-01

    Glutamate-activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) mediate the majority of excitatory neurotransmission in brain and thus are major drug targets for diseases associated with hyperexcitability or neurotoxicity. Due to the critical nature of AMPA-Rs in normal brain function, typical AMPA-R antagonists have deleterious effects on cognition and motor function, highlighting the need for more precise modulators. A dramatic increase in the flip isoform of alternatively spliced AMPA-R GluA1 subunits occurs post-seizure in humans and animal models. GluA1-flip produces higher gain AMPA channels than GluA1-flop, increasing network excitability and seizure susceptibility. Splice modulating oligonucleotides (SMOs) bind to pre-mRNA to influence alternative splicing, a strategy that can be exploited to develop more selective drugs across therapeutic areas. We developed a novel SMO, GR1, which potently and specifically decreased GluA1-flip expression throughout the brain of neonatal mice lasting at least 60 days after single intracerebroventricular injection. GR1 treatment reduced AMPA-R mediated excitatory postsynaptic currents at hippocampal CA1 synapses, without affecting long-term potentiation or long-term depression, cellular models of memory, or impairing GluA1-dependent cognition or motor function in mice. Importantly, GR1 demonstrated anti-seizure properties and reduced post-seizure hyperexcitability in neonatal mice, highlighting its drug candidate potential for treating epilepsies and other neurological diseases involving network hyperexcitability.

  2. Reducing the use of the target animal batch safety test for veterinary vaccines.

    PubMed

    Roberts, B; Lucken, R N

    1996-01-01

    The need to submit each batch of every veterinary vaccine to a target animal safety test is questioned. It is proposed that a risk/benefit analysis should be conducted, on a product by product basis, to determine whether the continued application of this test to each batch of a product is beneficial and justified. For an established product, the analysis should consider: the number of batches manufactured; the length of time for which the product has been manufactured; the testing experience and the incidence of reported adverse reactions; the level of GMP compliance and the standard of QA practised by the manufacturer; the method and conditions of manufacture; the use of animals for other batch tests; the recommendations for the use of the product. For a newly developed product the analysis should take into account: the safety data generated during development; the inherent risks in the product and its manufacture; the use of the other animal tests. It is suggested that the continued use of the test could be reduced on a phased basis e.g. after 10 consecutive satisfactory tests the frequency could be reduced by limiting it to the first batch of each production campaign or to every n th batch. Furthermore, the possibility of discontinuing the test altogether, for the product in question, could be considered. A return to full testing frequency would be required in the event of: a test failure; a batch related adverse reaction; introduction of a new seed; a change of manufacturer; a process of modification; a specification amendment; or an interruption of batch continuity. When a manufacturer has established consistency of production and testing, an alternative approach to the need for batch testing, with a view to avoiding or minimising the use of animals, is both desirable and possible.

  3. Pharmacogenomic biomarkers as inclusion criteria in clinical trials of oncology-targeted drugs: a mapping of ClinicalTrials.gov.

    PubMed

    Vivot, Alexandre; Li, Jacques; Zeitoun, Jean-David; Mourah, Samia; Crequit, Perrine; Ravaud, Philippe; Porcher, Raphaël

    2016-08-01

    The aim of this study was to describe pharmacogenomics-based inclusion criteria (enrichment) and the main characteristics of clinical trials involving oncology-targeted therapies. Clinical trials of oncology-targeted therapies approved after 2005 with pharmacogenomic testing required or recommended in their label were retrieved from a mapping of the ClinicalTrials.gov database. We examined information for 12 drugs and 858 trials. Overall, 434 trials (51%) were enriched on the biomarker first mentioned in the label and 145 (17%) were enriched on another biomarker, whereas 270 trials (31%) included all patients. The median proportion of trials corresponding to both the drug's indication and drug's target was 35%. Of the 361 trials that tested drugs in another disease than the first one in the label, 219 (61%) were without enrichment and 87 (24%) were actually enriched but on another biomarker than the first one in the label. Several drugs have been tested in trials enriched on many different biomarkers. Nonetheless, most targeted therapies have been developed only using biomarker-positive patients; therefore, exclusion of biomarker-negative patients from treatment relies on only preclinical data and on biological understanding of the disease and target.Genet Med 18 8, 796-805.

  4. Microinterventions Targeting Regulatory Focus and Regulatory Fit Selectively Reduce Dysphoric and Anxious Mood

    PubMed Central

    Strauman, Timothy J.; Socolar, Yvonne; Kwapil, Lori; Cornwell, James F. M.; Franks, Becca; Sehnert, Steen; Higgins, E. Tory

    2015-01-01

    Depression and generalized anxiety, separately and as comorbid states, continue to represent a significant public health challenge. Current cognitive-behavioral treatments are clearly beneficial but there remains a need for continued development of complementary interventions. This manuscript presents two proof-of-concept studies, in analog samples, of “microinterventions” derived from regulatory focus and regulatory fit theories and targeting dysphoric and anxious symptoms. In Study 1, participants with varying levels of dysphoric and/or anxious mood were exposed to a brief intervention either to increase or to reduce engagement in personal goal pursuit, under the hypothesis that dysphoria indicates under-engagement of the promotion system whereas anxiety indicates over-engagement of the prevention system. In Study 2, participants with varying levels of dysphoric and/or anxious mood received brief training in counterfactual thinking, under the hypothesis that inducing individuals in a state of promotion failure to generate subtractive counterfactuals for past failures (a non-fit) will lessen their dejection/depression-related symptoms, whereas inducing individuals in a state of prevention failure to generate additive counterfactuals for past failures (a non-fit) will lessen their agitation/anxiety-related symptoms. In both studies, we observed discriminant patterns of reduction in distress consistent with the hypothesized links between dysfunctional states of the two motivational systems and dysphoric versus anxious symptoms. PMID:26163353

  5. Distorted Coarse Axon Targeting and Reduced Dendrite Connectivity Underlie Dysosmia after Olfactory Axon Injury

    PubMed Central

    Iwata, Ryo; Fujimoto, Satoshi; Aihara, Shuhei

    2016-01-01

    The glomerular map in the olfactory bulb (OB) is the basis for odor recognition. Once established during development, the glomerular map is stably maintained throughout the life of an animal despite the continuous turnover of olfactory sensory neurons (OSNs). However, traumatic damage to OSN axons in the adult often leads to dysosmia, a qualitative and quantitative change in olfaction in humans. A mouse model of dysosmia has previously indicated that there is an altered glomerular map in the OB after the OSN axon injury; however, the underlying mechanisms that cause the map distortion remain unknown. In this study, we examined how the glomerular map is disturbed and how the odor information processing in the OB is affected in the dysosmia model mice. We found that the anterior–posterior coarse targeting of OSN axons is disrupted after OSN axon injury, while the local axon sorting mechanisms remained. We also found that the connectivity of mitral/tufted cell dendrites is reduced after injury, leading to attenuated odor responses in mitral/tufted cells. These results suggest that existing OSN axons are an essential scaffold for maintaining the integrity of the olfactory circuit, both OSN axons and mitral/tufted cell dendrites, in the adult. PMID:27785463

  6. Extraction of aqueous minerals on Mars using CRISM based Targeted Reduced Data Records

    NASA Astrophysics Data System (ADS)

    Gurunadham, R.; Kumar, S.

    2014-11-01

    Many scientific studies have been carried out to extract the aqueous mineral signatures on the surface of Mars, which has a record of all minerals such as silicates form by magmatic processes and aqueous minerals in the presence of watery environment. To observe these watery conditions, a visible/shortwave infrared mineral mapping camera on Mars Reconnaissance Orbiter (MRO) called Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) is used. The aim of this research is to extract the aqueous minerals on Mars using CRISM sensor. Gale Crater is selected for this study because of its past liquid water history.Gale is ~154 km in diameter and centered near 5.3° S, 138° E. Gale Crater has an interior mound named as "Aeolis Mons", which is nearly 100 km wide and 5 km high, consisting of layered sulfates and phyllosilicates. The CRISM reflectance (I/F) targeted reduced data records data of Gale crater, FRT000233AC, centred at 4°25' S and 137°20' E with high spatial (18 m, 35 m / pixel) and spectral resolution (362-1020 nm (VNIR), 1002-3920 nm (IR), 655 nm / channel) with 545 bands is acquired for this study. The detection and quantification of minerals has been carried out by using a model called modified Gaussian model (MGM). MGM is an approach that uses modified Gaussians in wave number space to model absorption shapes and fits them to a reflectance spectrum.

  7. Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain

    PubMed Central

    Angioni, Carlo; Park, Chul-Kyu; Meyer Dos Santos, Sascha; Jordan, Holger; Kuzikov, Maria; Liu, Di; Zinn, Sebastian; Hohman, Stephan W.; Schreiber, Yannick; Zimmer, Béla; Schmidt, Mike; Lu, Ruirui; Suo, Jing; Zhang, Dong-Dong; Schäfer, Stephan M. G.; Hofmann, Martine; Yekkirala, Ajay S.; de Bruin, Natasja; Parnham, Michael J.; Woolf, Clifford J.; Ji, Ru-Rong; Scholich, Klaus; Geisslinger, Gerd

    2016-01-01

    Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain. PMID:27791151

  8. Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction

    PubMed Central

    Sager, Hendrik B.; Heidt, Timo; Hulsmans, Maarten; Dutta, Partha; Courties, Gabriel; Sebas, Matthew; Wojtkiewicz, Gregory R.; Tricot, Benoit; Iwamoto, Yoshiko; Sun, Yuan; Weissleder, Ralph; Libby, Peter; Swirski, Filip K.; Nahrendorf, Matthias

    2015-01-01

    Background Myocardial infarction (MI) is an ischemic wound that recruits millions of leukocytes. MI-associated blood leukocytosis correlates inversely with patient survival, yet the signals driving heightened leukocyte production after MI remain incompletely understood. Methods and Results Using parabiosis surgery, this study shows that soluble danger signals, among them interleukin-1 beta (IL-1β), increase bone marrow hematopoietic stem cell (HSC) proliferation after MI. Data obtained in bone marrow reconstitution experiments reveal that IL-1β enhances HSC proliferation by both direct actions on hematopoietic cells and through modulating the bone marrow’s hematopoietic microenvironment. An antibody that neutralizes IL-1β suppresses these effects. Anti-IL-1β treatment dampens the post-MI increase in HSC proliferation. Consequently decreased leukocyte numbers in the blood and infarct reduce inflammation and diminish post-MI heart failure in ApoE−/− mice with atherosclerosis. Conclusions The presented insight into post-MI bone marrow activation identifies a mechanistic target for muting inflammation in the ischemically damaged heart. PMID:26358260

  9. Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction.

    PubMed

    Sager, Hendrik B; Heidt, Timo; Hulsmans, Maarten; Dutta, Partha; Courties, Gabriel; Sebas, Matthew; Wojtkiewicz, Gregory R; Tricot, Benoit; Iwamoto, Yoshiko; Sun, Yuan; Weissleder, Ralph; Libby, Peter; Swirski, Filip K; Nahrendorf, Matthias

    2015-11-17

    Myocardial infarction (MI) is an ischemic wound that recruits millions of leukocytes. MI-associated blood leukocytosis correlates inversely with patient survival, yet the signals driving heightened leukocyte production after MI remain incompletely understood. With the use of parabiosis surgery, this study shows that soluble danger signals, among them interleukin-1β, increase bone marrow hematopoietic stem cell proliferation after MI. Data obtained in bone marrow reconstitution experiments reveal that interleukin-1β enhances hematopoietic stem cell proliferation by both direct actions on hematopoietic cells and through modulation of the bone marrow's hematopoietic microenvironment. An antibody that neutralizes interleukin-1β suppresses these effects. Anti-interleukin-1β treatment dampens the post-MI increase in hematopoietic stem cell proliferation. Consequently, decreased leukocyte numbers in the blood and infarct reduce inflammation and diminish post-MI heart failure in ApoE(-/-) mice with atherosclerosis. The presented insight into post-MI bone marrow activation identifies a mechanistic target for muting inflammation in the ischemically damaged heart. © 2015 American Heart Association, Inc.

  10. Methane - quick fix or tough target? New methods to reduce emissions.

    NASA Astrophysics Data System (ADS)

    Nisbet, E. G.; Lowry, D.; Fisher, R. E.; Brownlow, R.

    2016-12-01

    Methane is a cost-effective target for greenhouse gas reduction efforts. The UK's MOYA project is designed to improve understanding of the global methane budget and to point to new methods to reduce future emissions. Since 2007, methane has been increasing rapidly: in 2014 and 2015 growth was at rates last seen in the 1980s. Unlike 20thcentury growth, primarily driven by fossil fuel emissions in northern industrial nations, isotopic evidence implies present growth is driven by tropical biogenic sources such as wetlands and agriculture. Discovering why methane is rising is important. Schaefer et al. (Science, 2016) pointed out the potential clash between methane reduction efforts and food needs of a rising, better-fed (physically larger) human population. Our own work suggests tropical wetlands are major drivers of growth, responding to weather changes since 2007, but there is no acceptable way to reduce wetland emission. Just as sea ice decline indicates Arctic warming, methane may be the most obvious tracker of climate change in the wet tropics. Technical advances in instrumentation can do much in helping cut urban and industrial methane emissions. Mobile systems can be mounted on vehicles, while drone sampling can provide a 3D view to locate sources. Urban land planning often means large but different point sources are typically clustered (e.g. landfill or sewage plant near incinerator; gas wells next to cattle). High-precision grab-sample isotopic characterisation, using Keeling plots, can separate source signals, to identify specific emitters, even where they are closely juxtaposed. Our mobile campaigns in the UK, Kuwait, Hong Kong and E. Australia show the importance of major single sources, such as abandoned old wells, pipe leaks, or unregulated landfills. If such point sources can be individually identified, even when clustered, they will allow effective reduction efforts to occur: these can be profitable and/or improve industrial safety, for example in the

  11. A targeted infection prevention intervention in nursing home residents with indwelling devices: a randomized clinical trial.

    PubMed

    Mody, Lona; Krein, Sarah L; Saint, Sanjay; Min, Lillian C; Montoya, Ana; Lansing, Bonnie; McNamara, Sara E; Symons, Kathleen; Fisch, Jay; Koo, Evonne; Rye, Ruth Anne; Galecki, Andrzej; Kabeto, Mohammed U; Fitzgerald, James T; Olmsted, Russell N; Kauffman, Carol A; Bradley, Suzanne F

    2015-05-01

    Indwelling devices (eg, urinary catheters and feeding tubes) are often used in nursing homes (NHs). Inadequate care of residents with these devices contributes to high rates of multidrug-resistant organisms (MDROs) and device-related infections in NHs. To test whether a multimodal targeted infection program (TIP) reduces the prevalence of MDROs and incident device-related infections. Randomized clinical trial at 12 community-based NHs from May 2010 to April 2013. Participants were high-risk NH residents with urinary catheters, feeding tubes, or both. Multimodal, including preemptive barrier precautions, active surveillance for MDROs and infections, and NH staff education. The primary outcome was the prevalence density rate of MDROs, defined as the total number of MDROs isolated per visit averaged over the duration of a resident's participation. Secondary outcomes included new MDRO acquisitions and new clinically defined device-associated infections. Data were analyzed using a mixed-effects multilevel Poisson regression model (primary outcome) and a Cox proportional hazards model (secondary outcome), adjusting for facility-level clustering and resident-level variables. In total, 418 NH residents with indwelling devices were enrolled, with 34,174 device-days and 6557 anatomic sites sampled. Intervention NHs had a decrease in the overall MDRO prevalence density (rate ratio, 0.77; 95% CI, 0.62-0.94). The rate of new methicillin-resistant Staphylococcus aureus acquisitions was lower in the intervention group than in the control group (rate ratio, 0.78; 95% CI, 0.64-0.96). Hazard ratios for the first and all (including recurrent) clinically defined catheter-associated urinary tract infections were 0.54 (95% CI, 0.30-0.97) and 0.69 (95% CI, 0.49-0.99), respectively, in the intervention group and the control group. There were no reductions in new vancomycin-resistant enterococci or resistant gram-negative bacilli acquisitions or in new feeding tube-associated pneumonias or

  12. Targeted ultrasound imaging of cancer: an emerging technology on its way to clinics.

    PubMed

    Kiessling, Fabian; Bzyl, Jessica; Fokong, Stanley; Siepmann, Monica; Schmitz, Georg; Palmowski, Moritz

    2012-01-01

    Ultrasound is one of the workhorses in clinical cancer diagnosis. In particular, it is routinely used to characterize lesions in liver, urogenital tract, head and neck and soft tissues. During the last years image quality steadily improved, which, among others, can be attributed to the development of harmonic image analysis. Microbubbles were introduced as intravascular contrast agents and can be detected with superb sensitivity and specificity using contrast specific imaging modes. By aid of these unspecific contrast agents tissues can be characterised regarding their vascularity. Antibodies, peptides and other targeting moieties were bound to microbubbles to target sites of angiogenesis and inflammation intending to get more disease-specific information. Indeed, many preclinical studies proved the high potential of targeted ultrasound imaging to better characterize tumors and to more sensitively monitor therapy response. Recently, first targeted microbubbles had been developed that meet the pharmacological demands of a clinical contrast agent. This review articles gives an overview on the history and current status of targeted ultrasound imaging of cancer. Different imaging concepts and contrast agent designs are introduced ranging from the use of experimental nanodroplets to agents undergoing clinical evaluation. Although it is clear that targeted ultrasound imaging works reliably, its broad acceptance is hindered by the user dependency of ultrasound imaging in general. Automated 3D-scanning techniques-like being used for breast diagnosis - and novel 3D transducers will help to make this fascinating method clinical reality.

  13. Empirical analysis shows reduced cost data collection may be an efficient method in economic clinical trials.

    PubMed

    Seidl, Hildegard; Meisinger, Christa; Wende, Rupert; Holle, Rolf

    2012-09-15

    Data collection for economic evaluation alongside clinical trials is burdensome and cost-intensive. Limiting both the frequency of data collection and recall periods can solve the problem. As a consequence, gaps in survey periods arise and must be filled appropriately. The aims of our study are to assess the validity of incomplete cost data collection and define suitable resource categories. In the randomised KORINNA study, cost data from 234 elderly patients were collected quarterly over a 1-year period. Different strategies for incomplete data collection were compared with complete data collection. The sample size calculation was modified in response to elasticity of variance. Resource categories suitable for incomplete data collection were physiotherapy, ambulatory clinic in hospital, medication, consultations, outpatient nursing service and paid household help. Cost estimation from complete and incomplete data collection showed no difference when omitting information from one quarter. When omitting information from two quarters, costs were underestimated by 3.9% to 4.6%.With respect to the observed increased standard deviation, a larger sample size would be required, increased by 3%. Nevertheless, more time was saved than extra time would be required for additional patients. Cost data can be collected efficiently by reducing the frequency of data collection. This can be achieved by incomplete data collection for shortened periods or complete data collection by extending recall windows. In our analysis, cost estimates per year for ambulatory healthcare and non-healthcare services in terms of three data collections was as valid and accurate as a four complete data collections. In contrast, data on hospitalisation, rehabilitation stays and care insurance benefits should be collected for the entire target period, using extended recall windows. When applying the method of incomplete data collection, sample size calculation has to be modified because of the increased

  14. Empirical analysis shows reduced cost data collection may be an efficient method in economic clinical trials

    PubMed Central

    2012-01-01

    Background Data collection for economic evaluation alongside clinical trials is burdensome and cost-intensive. Limiting both the frequency of data collection and recall periods can solve the problem. As a consequence, gaps in survey periods arise and must be filled appropriately. The aims of our study are to assess the validity of incomplete cost data collection and define suitable resource categories. Methods In the randomised KORINNA study, cost data from 234 elderly patients were collected quarterly over a 1-year period. Different strategies for incomplete data collection were compared with complete data collection. The sample size calculation was modified in response to elasticity of variance. Results Resource categories suitable for incomplete data collection were physiotherapy, ambulatory clinic in hospital, medication, consultations, outpatient nursing service and paid household help. Cost estimation from complete and incomplete data collection showed no difference when omitting information from one quarter. When omitting information from two quarters, costs were underestimated by 3.9% to 4.6%. With respect to the observed increased standard deviation, a larger sample size would be required, increased by 3%. Nevertheless, more time was saved than extra time would be required for additional patients. Conclusion Cost data can be collected efficiently by reducing the frequency of data collection. This can be achieved by incomplete data collection for shortened periods or complete data collection by extending recall windows. In our analysis, cost estimates per year for ambulatory healthcare and non-healthcare services in terms of three data collections was as valid and accurate as a four complete data collections. In contrast, data on hospitalisation, rehabilitation stays and care insurance benefits should be collected for the entire target period, using extended recall windows. When applying the method of incomplete data collection, sample size calculation has

  15. SU-E-J-34: Clinical Evaluation of Targeting Accuracy and Tractogrphy Delineation of Radiosurgery

    SciTech Connect

    Juh, R; Suh, T; Kim, Y; Han, J; Kim, C; Oh, C; Kim, D

    2014-06-01

    Purpose: Focal radiosurgery is a common treatment modality for trigeminal neuralgia (TN), a neuropathic facial pain condition. Assessment of treatment effectiveness is primarily clinical, given the paucity of investigational tools to assess trigeminal nerve changes. The efficiency of radiosurgery is related to its highly precise targeting. We assessed clinically the targeting accuracy of radiosurgery with Gamma knife. We hypothesized that trigeminal tractography provides more information than 2D-MR imaging, allowing detection of unique, focal changes in the target area after radiosurgery. Methods: Sixteen TN patients (2 females, 4 male, average age 65.3 years) treated with Gamma Knife radiosurgery, 40 Gy/50% isodose line underwent 1.5Tesla MR trigeminal nerve . Target accuracy was assessed from deviation of the coordinates of the target compared with the center of enhancement on post MRI. Radiation dose delivered at the borders of contrast enhancement was evaluated Results: The median deviation of the coordinates between the intended target and the center of contrast enhancement was within 1mm. The radiation doses fitting within the borders of the contrast enhancement the target ranged from 37.5 to 40 Gy. Trigeminal tractography accurately detected the radiosurgical target. Radiosurgery resulted in 47% drop in FA values at the target with no significant change in FA outside the target, suggesting that radiosurgery primarily affects myelin. Tractography was more sensitive, since FA changes were detected regardless of trigeminal nerve enhancement Conclusion: The median deviation found in clinical assessment of gamma knife treatment for TN Is low and compatible with its high rate of efficiency. DTI parameters accurately detect the effects of focal radiosurgery on the trigeminal nerve, serving as an in vivo imaging tool to study TN. This study is a proof of principle for further assessment of DTI parameters to understand the pathophysiology of TN and treatment effects.

  16. Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 1: Non-clinical and clinical insights.

    PubMed

    Schorp, Matthias K; Tricker, Anthony R; Dempsey, Ruth

    2012-11-01

    The following series of papers presents an extensive assessment of the Electrically Heated Cigarette Smoking System EHCSS series-K cigarette vs. conventional lit-end cigarettes (CC) as an example for an extended testing strategy for evaluation of reduced exposure. The EHCSS produces smoke through electrical heating of tobacco. The EHCSS series-K heater was designed for exclusive use with EHCSS cigarettes, and cannot be used to smoke (CC). Compared to the University of Kentucky Reference Research cigarette 2R4F and a series of commercial CC, mainstream cigarette smoke of both the non-menthol and menthol-flavored EHCSS cigarettes showed a reduced delivery of a series of selected harmful and potentially harmful constituents (HPHC), mutagenic activity determined using the Salmonella typhimurium Reverse Mutation (Ames) assay, and cytotoxicity in the Neutral Red Uptake Assay. Clinical evaluations confirmed reduced exposure to HPHC and excretion of mutagenic material under controlled clinical conditions. Reductions in HPHC exposure were confirmed in a real-world ambulatory clinical study. Potential biomarkers of cardiovascular risk were also reduced under real-world ambulatory conditions. A modeling approach, 'nicotine bridging', was developed based on the determination of nicotine exposure in clinical evaluations which indicated that exposure to HPHC for which biomarkers of exposure do not exist would also be reduced. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. F8-SIP mediated targeted photodynamic therapy leads to microvascular dysfunction and reduced glioma growth.

    PubMed

    Acker, G; Palumbo, A; Neri, D; Vajkoczy, P; Czabanka, M

    2016-08-01

    The extra domain A (ED A) of fibronectin has been identified as a tumor vessel specific neovascular marker in glioma. Antibody based vascular targeting against ED A of fibronectin allows precise accumulation of photosensitizer in glioma microvasculature and thereby promises to overcome drawbacks of current photodynamic therapy (PDT) for glioma treatment. Our aim was to characterize microcirculatory consequences of F8-small immunoprotein (SIP) mediated PDT by intravital microscopy (IVM) and to analyze the effects on glioma growth. For IVM SF126 glioma cells were implanted into dorsal skinfold-chamber of nude mice. PDT was performed after intravenous injection of photosensitizer (PS)-coupled F8-SIP or PBS (n = 4). IVM was performed before and after PDT for 4 days. Analysis included total and functional (TVD, FVD) vessel densities, perfusion index (PI), microvascular permeability and blood flow rate (Q). To assess tumor growth SF126 glioma cells were implanted subcutaneously. PDT was performed as a single and repetitive treatment after PS-F8-SIP injection (n = 5). Subcutaneous tumors were treated after uncoupled F8-SIP injection as control group (n = 5). PDT induced microvascular stasis and thrombosis with reduced FVD (24 h: 115.98 ± 0.7 vs. 200.8 ± 61.9 cm/cm(2)) and PI (39 ± 11 vs. 70 ± 10 %), whereas TVD was not altered (298 ± 39.2 vs. 278.2 ± 51 cm/cm(2)). Microvascular dysfunction recovered 4 days after treatment. Microvascular dysfunction led to a temporary reduction of glioma growth in the first 48 h after treatment with complete recovery 5 days after treatment. Repetitive PDT resulted in sustained reduction of tumor growth. F8-SIP mediated PDT leads to microvascular dysfunction and reduced glioma growth in a preclinical glioma model with recovery of microcirculation 4 days after treatment. Repetitive application of PDT overcomes microvascular recovery and leads to prolonged antiglioma effects.

  18. Reducing HIV infection in people who inject drugs is impossible without targeting recently-infected subjects

    PubMed Central

    Vasylyeva, Tetyana I.; Friedman, Samuel R.; Lourenco, Jose; Gupta, Sunetra; Hatzakis, Angelos; Pybus, Oliver G.; Katzourakis, Aris; Smyrnov, Pavlo; Karamitros, Timokratis; Paraskevis, Dimitrios; Magiorkinis, Gkikas

    2016-01-01

    Objective: Although our understanding of viral transmission among people who inject drugs (PWID) has improved, we still know little about when and how many times each injector transmits HIV throughout the duration of infection. We describe HIV dynamics in PWID to evaluate which preventive strategies can be efficient. Design: Due to the notably scarce interventions, HIV-1 spread explosively in Russia and Ukraine in 1990s. By studying this epidemic between 1995 and 2005, we characterized naturally occurring transmission dynamics of HIV among PWID. Method: We combined publicly available HIV pol and env sequences with prevalence estimates from Russia and Ukraine under an evolutionary epidemiology framework to characterize HIV transmissibility between PWID. We then constructed compartmental models to simulate HIV spread among PWID. Results: In the absence of interventions, each injector transmits on average to 10 others. Half of the transmissions take place within 1 month after primary infection, suggesting that the epidemic will expand even after blocking all the post–first month transmissions. Primary prevention can realistically target the first month of infection, and we show that it is very efficient to control the spread of HIV-1 in PWID. Treating acutely infected on top of primary prevention is notably effective. Conclusion: As a large proportion of transmissions among PWID occur within 1 month after infection, reducing and delaying transmissions through scale-up of harm reduction programmes should always form the backbone of HIV control strategies in PWID. Growing PWID populations in the developing world, where primary prevention is scarce, constitutes a public health time bomb. PMID:27824626

  19. Simulation of targeted pollutant-mitigation-strategies to reduce nitrate and sediment hotspots in agricultural watershed.

    PubMed

    Teshager, Awoke Dagnew; Gassman, Philip W; Secchi, Silvia; Schoof, Justin T

    2017-12-31

    About 50% of U.S. water pollution problems are caused by non-point source (NPS) pollution, primarily sediment and nutrients from agricultural areas, despite the widespread implementation of agricultural Best Management Practices (BMPs). However, the effectiveness of implementation strategies and type of BMPs at watershed scale are still not well understood. In this study, the Soil and Water Assessment Tool (SWAT) ecohydrological model was used to assess the effectiveness of pollutant mitigation strategies in the Raccoon River watershed (RRW) in west-central Iowa, USA. We analyzed fourteen management scenarios based on systematic combinations of five strategies: fertilizer/manure management, changing row-crop land to perennial grass, vegetative filter strips, cover crops and shallower tile drainage systems, specifically aimed at reducing nitrate and total suspended sediment yields from hotspot areas in the RRW. Moreover, we assessed implications of climate change on management practices, and the impacts of management practices on water availability, row crop yield, and total agricultural production. Our results indicate that sufficient reduction of nitrate load may require either implementation of multiple management practices (38.5% with current setup) or conversion of extensive areas into perennial grass (up to 49.7%) to meet and maintain the drinking water standard. However, climate change may undermine the effectiveness of management practices, especially late in the 21st century, cutting the reduction by up to 65% for nitrate and more for sediment loads. Further, though our approach is targeted, it resulted in a slight decrease (~5%) in watershed average crop yield and hence an overall reduction in total crop production, mainly due to the conversion of row-crop lands to perennial grass. Such yield reductions could be quite spatially heterogeneously distributed (0 to 40%). Copyright © 2017 Elsevier B.V. All rights reserved.

  20. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date

    PubMed Central

    Park, Jae H.; Geyer, Mark B.

    2016-01-01

    Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 has produced impressive results in treating patients with B-cell malignancies. Although these CAR-modified T cells target the same antigen, the designs of CARs vary as well as several key aspects of the clinical trials in which these CARs have been studied. It is unclear whether these differences have any impact on clinical outcome and treatment-related toxicities. Herein, we review clinical results reflecting the investigational use of CD19-targeted CAR T-cell therapeutics in patients with B-cell hematologic malignancies, in light of differences in CAR design and production, and outline the limitations inherent in comparing outcomes between studies. PMID:27207800

  1. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date.

    PubMed

    Park, Jae H; Geyer, Mark B; Brentjens, Renier J

    2016-06-30

    Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 has produced impressive results in treating patients with B-cell malignancies. Although these CAR-modified T cells target the same antigen, the designs of CARs vary as well as several key aspects of the clinical trials in which these CARs have been studied. It is unclear whether these differences have any impact on clinical outcome and treatment-related toxicities. Herein, we review clinical results reflecting the investigational use of CD19-targeted CAR T-cell therapeutics in patients with B-cell hematologic malignancies, in light of differences in CAR design and production, and outline the limitations inherent in comparing outcomes between studies. © 2016 by The American Society of Hematology.

  2. CRISPRdirect: software for designing CRISPR/Cas guide RNA with reduced off-target sites

    PubMed Central

    Naito, Yuki; Hino, Kimihiro; Bono, Hidemasa; Ui-Tei, Kumiko

    2015-01-01

    Summary: CRISPRdirect is a simple and functional web server for selecting rational CRISPR/Cas targets from an input sequence. The CRISPR/Cas system is a promising technique for genome engineering which allows target-specific cleavage of genomic DNA guided by Cas9 nuclease in complex with a guide RNA (gRNA), that complementarily binds to a ∼20 nt targeted sequence. The target sequence requirements are twofold. First, the 5′-NGG protospacer adjacent motif (PAM) sequence must be located adjacent to the target sequence. Second, the target sequence should be specific within the entire genome in order to avoid off-target editing. CRISPRdirect enables users to easily select rational target sequences with minimized off-target sites by performing exhaustive searches against genomic sequences. The server currently incorporates the genomic sequences of human, mouse, rat, marmoset, pig, chicken, frog, zebrafish, Ciona, fruit fly, silkworm, Caenorhabditis elegans, Arabidopsis, rice, Sorghum and budding yeast. Availability: Freely available at http://crispr.dbcls.jp/. Contact: y-naito@dbcls.rois.ac.jp Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25414360

  3. Interventions for reducing wrong-site surgery and invasive clinical procedures.

    PubMed

    Algie, Catherine M; Mahar, Robert K; Wasiak, Jason; Batty, Lachlan; Gruen, Russell L; Mahar, Patrick D

    2015-03-30

    patients; studies where patients were involved to avoid the incorrect procedures or studies with interventions addressed to healthcare managers, administrators, stakeholders or health insurers. Two review authors independently assesses the quality and abstracted data of all eligible studies using a standardised data extraction form, modified from the Cochrane EPOC checklists. We contacted study authors for additional information. In the initial review, we included one ITS study that evaluated a targeted educational intervention aimed at reducing the incidence of wrong-site tooth extractions. The intervention included examination of previous cases of wrong-site tooth extractions, educational intervention including a presentation of cases of erroneous extractions, explanation of relevant clinical guidelines and feedback by an instructor. Data were reported from all patients on the surveillance system of a University Medical centre in Taiwan with a total of 24,406 tooth extractions before the intervention and 28,084 tooth extractions after the intervention. We re-analysed the data using the Prais-Winsten time series and the change in level for annual number of mishaps was statistically significant at -4.52 (95% confidence interval (CI) -6.83 to -2.217) (standard error (SE) 0.5380). The change in slope was statistically significant at -1.16 (95% CI -2.22 to -0.10) (SE 0.2472; P < 0.05).This update includes an additional study reporting on the incidence of neurological WSS at a university hospital both before and after the Universal Protocol's implementation. A total of 22,743 patients undergoing neurosurgical procedures at the University of Illionois College of Medicine at Peoria, Illinois, United States of America were reported. Of these, 7286 patients were reported before the intervention and 15,456 patients were reported after the intervention. The authors found a significant difference (P < 0.001) in the incidence of WSS between the before period, 1999 to 2004, and the

  4. Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma.

    PubMed

    van de Donk, Niels W C J; Moreau, Philippe; Plesner, Torben; Palumbo, Antonio; Gay, Francesca; Laubach, Jacob P; Malavasi, Fabio; Avet-Loiseau, Hervé; Mateos, Maria-Victoria; Sonneveld, Pieter; Lokhorst, Henk M; Richardson, Paul G

    2016-02-11

    Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding

  5. Whole-Genome Thermodynamic Analysis Reduces siRNA Off-Target Effects

    PubMed Central

    Chen, Xi; Liu, Peng; Chou, Hui-Hsien

    2013-01-01

    Small interfering RNAs (siRNAs) are important tools for knocking down targeted genes, and have been widely applied to biological and biomedical research. To design siRNAs, two important aspects must be considered: the potency in knocking down target genes and the off-target effect on any nontarget genes. Although many studies have produced useful tools to design potent siRNAs, off-target prevention has mostly been delegated to sequence-level alignment tools such as BLAST. We hypothesize that whole-genome thermodynamic analysis can identify potential off-targets with higher precision and help us avoid siRNAs that may have strong off-target effects. To validate this hypothesis, two siRNA sets were designed to target three human genes IDH1, ITPR2 and TRIM28. They were selected from the output of two popular siRNA design tools, siDirect and siDesign. Both siRNA design tools have incorporated sequence-level screening to avoid off-targets, thus their output is believed to be optimal. However, one of the sets we tested has off-target genes predicted by Picky, a whole-genome thermodynamic analysis tool. Picky can identify off-target genes that may hybridize to a siRNA within a user-specified melting temperature range. Our experiments validated that some off-target genes predicted by Picky can indeed be inhibited by siRNAs. Similar experiments were performed using commercially available siRNAs and a few off-target genes were also found to be inhibited as predicted by Picky. In summary, we demonstrate that whole-genome thermodynamic analysis can identify off-target genes that are missed in sequence-level screening. Because Picky prediction is deterministic according to thermodynamics, if a siRNA candidate has no Picky predicted off-targets, it is unlikely to cause off-target effects. Therefore, we recommend including Picky as an additional screening step in siRNA design. PMID:23484018

  6. Clinical Evaluation of Stereotactic Target Localization Using 3-Tesla MRI for Radiosurgery Planning

    SciTech Connect

    MacFadden, Derek; Zhang Beibei; Brock, Kristy K.; Hodaie, Mojgan; Laperriere, Normand; Schwartz, Michael; Tsao, May; Stainsby, Jeffrey; Lockwood, Gina; Mikulis, David; Menard, Cynthia

    2010-04-15

    Purpose: Increasing the magnetic resonance imaging (MRI) field strength can improve image resolution and quality, but concerns remain regarding the influence on geometric fidelity. The objectives of the present study were to spatially investigate the effect of 3-Tesla (3T) MRI on clinical target localization for stereotactic radiosurgery. Methods and Materials: A total of 39 patients were enrolled in a research ethics board-approved prospective clinical trial. Imaging (1.5T and 3T MRI and computed tomography) was performed after stereotactic frame placement. Stereotactic target localization at 1.5T vs. 3T was retrospectively analyzed in a representative cohort of patients with tumor (n = 4) and functional (n = 5) radiosurgical targets. The spatial congruency of the tumor gross target volumes was determined by the mean discrepancy between the average gross target volume surfaces at 1.5T and 3T. Reproducibility was assessed by the displacement from an averaged surface and volume congruency. Spatial congruency and the reproducibility of functional radiosurgical targets was determined by comparing the mean and standard deviation of the isocenter coordinates. Results: Overall, the mean absolute discrepancy across all patients was 0.67 mm (95% confidence interval, 0.51-0.83), significantly <1 mm (p < .010). No differences were found in the overall interuser target volume congruence (mean, 84% for 1.5T vs. 84% for 3T, p > .4), and the gross target volume surface mean displacements were similar within and between users. The overall average isocenter coordinate discrepancy for the functional targets at 1.5T and 3T was 0.33 mm (95% confidence interval, 0.20-0.48), with no patient-specific differences between the mean values (p >.2) or standard deviations (p >.1). Conclusion: Our results have provided clinically relevant evidence supporting the spatial validity of 3T MRI for use in stereotactic radiosurgery under the imaging conditions used.

  7. Molecular targeted therapy for pancreatic adenocarcinoma: A review of completed and ongoing late phase clinical trials.

    PubMed

    Mosquera, Catalina; Maglic, Dino; Zervos, Emmanuel E

    2016-12-01

    Molecular targeted therapy is widely utilized and effective in a number of solid tumors. In pancreatic adenocarcinoma, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. The purpose of this study is to review therapeutic molecular targets in completed and ongoing later phase (II and III) clinical trials to have a better understanding of the rationale and progress towards targeted molecular therapies for pancreatic cancer. The PubMed database and the NCDI clinical trial website (www.clinicaltrials.gov) were queried to identify phase II and III completed and published (PubMed) and ongoing (clinicaltrials.gov) trials using the keywords: pancreatic cancer and molecular targeted therapy. The search engines were further limited by adding Phase II or III, active enrollment and North American. A total of 14 completed and published phase II/III clinical trials and 17 ongoing trials were identified. Evaluated strategies included inhibition of growth factor receptors (EGFR, PDGFR, VGFR, IGF-1R), tyrosine kinase inhibitors, MEK1/2, mTOR blockade and PI3K and HER2-neu pathway inhibitors. Only one trial conducted by the National Cancer Institute of Canada and the PANTAR trial have demonstrated a survival improvement from EGFR inhibition using erlotinib. These trials ultimately led to FDA approval of erlotinib/Tarceva in advanced stage disease. It remains unclear whether new combinations of cytotoxic chemotherapy or immunotherapy plus molecular targeted therapy will be beneficial in management of pancreatic adenocarcinoma. Despite a number of phase II and III trials, to date, only erlotinib has emerged as an approved targeted therapy in pancreatic adenocarcinoma. There are several ongoing late phase trials evaluating a number of targets, the results of which will become available over the next 1 to 2 years. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Statistical inference on censored data for targeted clinical trials under enrichment design.

    PubMed

    Chen, Chen-Fang; Lin, Jr-Rung; Liu, Jen-Pei

    2013-01-01

    For the traditional clinical trials, inclusion and exclusion criteria are usually based on some clinical endpoints; the genetic or genomic variability of the trial participants are not totally utilized in the criteria. After completion of the human genome project, the disease targets at the molecular level can be identified and can be utilized for the treatment of diseases. However, the accuracy of diagnostic devices for identification of such molecular targets is usually not perfect. Some of the patients enrolled in targeted clinical trials with a positive result for the molecular target might not have the specific molecular targets. As a result, the treatment effect may be underestimated in the patient population truly with the molecular target. To resolve this issue, under the exponential distribution, we develop inferential procedures for the treatment effects of the targeted drug based on the censored endpoints in the patients truly with the molecular targets. Under an enrichment design, we propose using the expectation-maximization algorithm in conjunction with the bootstrap technique to incorporate the inaccuracy of the diagnostic device for detection of the molecular targets on the inference of the treatment effects. A simulation study was conducted to empirically investigate the performance of the proposed methods. Simulation results demonstrate that under the exponential distribution, the proposed estimator is nearly unbiased with adequate precision, and the confidence interval can provide adequate coverage probability. In addition, the proposed testing procedure can adequately control the size with sufficient power. On the other hand, when the proportional hazard assumption is violated, additional simulation studies show that the type I error rate is not controlled at the nominal level and is an increasing function of the positive predictive value. A numerical example illustrates the proposed procedures.

  9. Molecular targets for the treatment of pancreatic cancer: Clinical and experimental studies

    PubMed Central

    Matsuoka, Tasuku; Yashiro, Masakazu

    2016-01-01

    Pancreatic cancer is the fourth most common cause of cancer deaths worldwide. Although recent therapeutic developments for patients with pancreatic cancer have provided survival benefits, the outcomes for patients with pancreatic cancer remain unsatisfactory. Molecularly targeted cancer therapy has advanced in the past decade with the use of a number of pathways as candidates of therapeutic targets. This review summarizes the molecular features of this refractory disease while focusing on the recent clinical and experimental findings on pancreatic cancer. It also discusses the data supporting current standard clinical outcomes, and offers conclusions that may improve the management of pancreatic cancer in the future. PMID:26811624

  10. SMC-PHD-based multi-target tracking with reduced peak extraction

    NASA Astrophysics Data System (ADS)

    Dunne, Darcy; Tharmarasa, Ratnasingham; Lang, Thomas; Kirubarajan, T.

    2009-08-01

    The Probability Hypothesis Density (PHD) filter is a powerful new tool in the field of multitarget tracking. Unlike classical multi-target tracking approaches, such as Multiple Hypothesis Tracking (MHT), in each scan it provides a complete solution to multi-target state estimation without the necessity for explicit measurement-to-track data association. The PHD filter recursively propagates the first order moment of the multi-target posterior. This allows us to determine the expected number of targets as well as their state estimates at each scan. However, there is no implicit connection between the target state estimates in consecutive scans. In this paper, a new cluster-based approach is proposed for track labeling in the Sequential Monte Carlo (SMC i.e. particle filter based) PHD filter. The method associates a likelihood vector to each particle in the SMC estimate. This vector indicates the likelihood that the particle estimate belongs to each of the established target tracks. This likelihood vector is propagated along with the PHD moment and updated with the PHD function. By maintaining a set of associations from scan to scan, the new method provides a complete PHD solution for a multi-target tracking application over time. The method is tested on both clean and noisy multi-target tracking scenarios and the results are compared to some previously published methods.

  11. The effect of image-guided radiation therapy on the margin between the clinical target volume and planning target volume in lung cancer

    SciTech Connect

    Liang, Jun; Li, Minghui; Zhang, Tao; Han, Wei; Chen, Dongfu; Hui, Zhouguang; Lv, Jima; Zhang, Zhong; Zhang, Yin; Zhang, Liansheng; Zheng, Rong; Dai, Jianrong; Wang, Luhua

    2014-02-15

    Introduction: This study aimed to evaluate the effect of image-guided radiation therapy (IGRT) on the margin between the clinical target volume (CTV) and planning target volume (PTV) in lung cancer. Methods: The CTV and PTV margin were determined in three dimensions by four radiation oncologists using a standard method in 10 lung cancer patients, and compared to consensus values. Transfer error was measured using a rigid phantom containing gold markers. Systematic error and random error set up errors were calculated in three dimensions from pre-treatment and post-treatment cone beam CT scans. Finally, the margin between the CTV and PTV was corrected for set up error and calculated. Results: The margins between the CTV and PTV with IGRT (and without IGRT) were 0.88 cm (0.96 cm), 0.99 cm (1.08 cm) and 1.28 cm (1.82 cm) in the anterior and posterior (AP), left and right (LR) and superior and inferior (SI) directions, respectively. Images from two other patients verified the validity of the corrected margin. The target delineation errors of the radiation oncologists are considered to be the largest compared with the set up errors. The application of IGRT reduced the set up errors and the margins between CTV and PTV. Conclusions: The delineation errors of radiation oncologists are the most important factor to consider for the margin between CTV and PTV for lung cancer. IGRT can reduce the margins by reducing the set up errors, especially in the SI direction. Further research is required to assess whether the reduction in the margin is solely based on set up errors.

  12. Clinical Efficacy of a Specifically Targeted Antimicrobial Peptide Mouth Rinse: Targeted Elimination of Streptococcus mutans and Prevention of Demineralization

    PubMed Central

    Sullivan, R.; Santarpia, P.; Lavender, S.; Gittins, E.; Liu, Z.; Anderson, M.H.; He, J.; Shi, W.; Eckert, R.

    2011-01-01

    Background/Aims Streptococcus mutans, the major etiological agent of dental caries, has a measurable impact on domestic and global health care costs. Though persistent in the oral cavity despite conventional oral hygiene, S. mutans can be excluded from intact oral biofilms through competitive exclusion by other microorganisms. This suggests that therapies capable of selectively eliminating S. mutans while limiting the damage to the normal oral flora might be effective long-term interventions to fight cariogenesis. To meet this challenge, we designed C16G2, a novel synthetic specifically targeted antimicrobial peptide with specificity for S. mutans. C16G2 consists of a S. mutans-selective ‘targeting region’ comprised of a fragment from S. mutans competence stimulation peptide (CSP) conjoined to a ‘killing region’ consisting of a broad-spectrum antimicrobial peptide (G2). In vitro studies have indicated that C16G2 has robust efficacy and selectivity for S. mutans, and not other oral bacteria, and affects targeted bacteria within seconds of contact. Methods In the present study, we evaluated C16G2 for clinical utility in vitro, followed by a pilot efficacy study to examine the impact of a 0.04% (w/v) C16G2 rinse in an intra-oral remineralization/demineralization model. Results and Conclusions C16G2 rinse usage was associated with reductions in plaque and salivary S. mutans, lactic acid production, and enamel demineralization. The impact on total plaque bacteria was minimal. These results suggest that C16G2 is effective against S. mutans in vivo and should be evaluated further in the clinic. PMID:21860239

  13. Clinical efficacy of a specifically targeted antimicrobial peptide mouth rinse: targeted elimination of Streptococcus mutans and prevention of demineralization.

    PubMed

    Sullivan, R; Santarpia, P; Lavender, S; Gittins, E; Liu, Z; Anderson, M H; He, J; Shi, W; Eckert, R

    2011-01-01

    Streptococcus mutans, the major etiological agent of dental caries, has a measurable impact on domestic and global health care costs. Though persistent in the oral cavity despite conventional oral hygiene, S. mutans can be excluded from intact oral biofilms through competitive exclusion by other microorganisms. This suggests that therapies capable of selectively eliminating S. mutans while limiting the damage to the normal oral flora might be effective long-term interventions to fight cariogenesis. To meet this challenge, we designed C16G2, a novel synthetic specifically targeted antimicrobial peptide with specificity for S. mutans. C16G2 consists of a S. mutans-selective 'targeting region' comprised of a fragment from S. mutans competence stimulation peptide (CSP) conjoined to a 'killing region' consisting of a broad-spectrum antimicrobial peptide (G2). In vitro studies have indicated that C16G2 has robust efficacy and selectivity for S. mutans, and not other oral bacteria, and affects targeted bacteria within seconds of contact. In the present study, we evaluated C16G2 for clinical utility in vitro, followed by a pilot efficacy study to examine the impact of a 0.04% (w/v) C16G2 rinse in an intra-oral remineralization/demineralization model. C16G2 rinse usage was associated with reductions in plaque and salivary S. mutans, lactic acid production, and enamel demineralization. The impact on total plaque bacteria was minimal. These results suggest that C16G2 is effective against S. mutans in vivo and should be evaluated further in the clinic. Copyright © 2011 S. Karger AG, Basel.

  14. Review of novel therapeutic targets for improving heart failure treatment based on experimental and clinical studies

    PubMed Central

    Bonsu, Kwadwo Osei; Owusu, Isaac Kofi; Buabeng, Kwame Ohene; Reidpath, Daniel Diamond; Kadirvelu, Amudha

    2016-01-01

    Heart failure (HF) is a major public health priority due to its epidemiological transition and the world’s aging population. HF is typified by continuous loss of contractile function with reduced, normal, or preserved ejection fraction, elevated vascular resistance, fluid and autonomic imbalance, and ventricular dilatation. Despite considerable advances in the treatment of HF over the past few decades, mortality remains substantial. Pharmacological treatments including β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists have been proven to prolong the survival of patients with HF. However, there are still instances where patients remain symptomatic, despite optimal use of existing therapeutic agents. This understanding that patients with chronic HF progress into advanced stages despite receiving optimal treatment has increased the quest for alternatives, exploring the roles of additional pathways that contribute to the development and progression of HF. Several pharmacological targets associated with pathogenesis of HF have been identified and novel therapies have emerged. In this work, we review recent evidence from proposed mechanisms to the outcomes of experimental and clinical studies of the novel pharmacological agents that have emerged for the treatment of HF. PMID:27350750

  15. Postoperative Radiotherapy for Glioma: Improved Delineation of the Clinical Target Volume Using the Geodesic Distance Calculation

    PubMed Central

    Yan, DanFang; Yan, SenXiang; Lu, ZhongJie; Xie, Cong; Chen, Wei; Xu, Xing; Li, Xinke; Yu, Haogang; Zhu, Xinli; Zheng, LingYan

    2014-01-01

    Objects To introduce a new method for generating the clinical target volume (CTV) from gross tumor volume (GTV) using the geodesic distance calculation for glioma. Methods One glioblastoma patient was enrolled. The GTV and natural barriers were contoured on each slice of the computer tomography (CT) simulation images. Then, a graphic processing unit based on a parallel Euclidean distance transform was used to generate the CTV considering natural barriers. Three-dimensional (3D) visualization technique was applied to show the delineation results. Speed of operation and precision were compared between this new delineation method and the traditional method. Results In considering spatial barriers, the shortest distance from the point sheltered from these barriers equals the sum of the distance along the shortest path between the two points; this consists of several segments and evades the spatial barriers, rather than being the direct Euclidean distance between two points. The CTV was generated irregularly rather than as a spherical shape. The time required to generate the CTV was greatly reduced. Moreover, this new method improved inter- and intra-observer variability in defining the CTV. Conclusions Compared with the traditional CTV delineation, this new method using geodesic distance calculation not only greatly shortens the time to modify the CTV, but also has better reproducibility. PMID:24896082

  16. Comparison of FDA Approved Kinase Targets to Clinical Trial Ones: Insights from Their System Profiles and Drug-Target Interaction Networks

    PubMed Central

    Xu, Jingyu; Wang, Panpan; Yang, Hong; Li, Yinghong; Yu, Chunyan; Tian, Yubin

    2016-01-01

    Kinase is one of the most productive classes of established targets, but the majority of approved drugs against kinase were developed only for cancer. Intensive efforts were therefore exerted for releasing its therapeutic potential by discovering new therapeutic area. Kinases in clinical trial could provide great opportunities for treating various diseases. However, no systematic comparison between system profiles of established targets and those of clinical trial ones was conducted. The reveal of probable difference or shift of trend would help to identify key factors defining druggability of established targets. In this study, a comparative analysis of system profiles of both types of targets was conducted. Consequently, the systems profiles of the majority of clinical trial kinases were identified to be very similar to those of established ones, but percentages of established targets obeying the system profiles appeared to be slightly but consistently higher than those of clinical trial targets. Moreover, a shift of trend in the system profiles from the clinical trial to the established targets was identified, and popular kinase targets were discovered. In sum, this comparative study may help to facilitate the identification of the druggability of established drug targets by their system profiles and drug-target interaction networks. PMID:27547755

  17. Clinical and psychosocial predictors of exceeding target length of stay during inpatient stroke rehabilitation.

    PubMed

    Lai, Wesley; Buttineau, Mackenzie; Harvey, Jennifer K; Pucci, Rebecca A; Wong, Anna P M; Dell'Erario, Linda; Bosnyak, Stephanie; Reid, Shannon; Salbach, Nancy M

    2017-05-09

    In Ontario, Canada, patients admitted to inpatient rehabilitation hospitals post-stroke are classified into rehabilitation patient groups based on age and functional level. Clinical practice guidelines, called quality-based procedures, recommend a target length of stay (LOS) for each group. The study objective was to evaluate the extent to which patients post-stroke at an inpatient rehabilitation hospital are meeting LOS targets and to identify patient characteristics that predict exceeding target LOS. A quantitative, longitudinal study from an inpatient rehabilitation hospital was conducted. Participants included adult patients (≥18 years) with stroke, admitted to an inpatient rehabilitation hospital between 2014 and 2015. The percentage of patients exceeding the recommended target LOS was determined. Logistic regression was performed to identify clinical and psychosocial patient characteristics associated with exceeding target LOS after adjusting for stroke severity. Of 165 patients, 38.8% exceeded their target LOS. Presence of ataxia, recurrent stroke, living alone, absence of a caregiver at admission, and acquiring a caregiver during hospital LOS was each associated with significantly higher odds of exceeding target LOS in comparison to patients without these characteristics after adjusting for stroke severity (p < 0.05). Findings suggest that social and stroke-specific factors may be helpful to adjust LOS expectations and promote efficient resource allocation. This exploratory study was limited to findings from one inpatient rehabilitation hospital. Cross-validation of results using data-sets from multiple rehabilitation hospitals across Ontario is recommended.

  18. Targeting the schizophrenia genome: a fast track strategy from GWAS to clinic

    PubMed Central

    Lencz, T; Malhotra, A K

    2015-01-01

    The Psychiatric Genomics Consortium–Schizophrenia Workgroup (PGC–SCZ) has recently published a genomewide association study (GWAS) identifying >100 genetic loci, encompassing a total of 341 protein-coding genes, attaining genomewide significance for susceptibility to schizophrenia. Given the extremely long time (12–15 years) and expense (>$1 billion) associated with the development of novel drug targets, repurposing of drugs with known and validated targets may be the most expeditious path toward deriving clinical utility from these GWAS findings. In the present study, we examined all genes within loci implicated by the PGC–SCZ GWAS against databases of targets of both approved and registered pharmaceutical compounds. We identified 20 potential schizophrenia susceptibility genes that encode proteins that are the targets of approved drugs. Of these, we prioritized genes/targets that are of clear neuropsychiatric interest and that are also sole members of the linkage disequilibrium block surrounding a PGC–SCZ GWAS hit. In addition to DRD2, 5 genes meet these criteria: CACNA1C, CACNB2, CACNA1I, GRIN2A and HCN1. An additional 20 genes coding for proteins that are the targets of drugs in registered clinical trials, but without approved indications, were also identified. Although considerable work is still required to fully explicate the biological implications of the PGC–SCZ GWAS results, pathways related to these known, druggable targets may represent a promising starting point. PMID:25869805

  19. Advances in clinical next-generation sequencing: target enrichment and sequencing technologies.

    PubMed

    Ballester, Leomar Y; Luthra, Rajyalakshmi; Kanagal-Shamanna, Rashmi; Singh, Rajesh R

    2016-01-01

    The huge parallel sequencing capabilities of next generation sequencing technologies have made them the tools of choice to characterize genomic aberrations for research and diagnostic purposes. For clinical applications, screening the whole genome or exome is challenging owing to the large genomic area to be sequenced, associated costs, complexity of data, and lack of known clinical significance of all genes. Consequently, routine screening involves limited markers with established clinical relevance. This process, referred to as targeted genome sequencing, requires selective enrichment of the genomic areas comprising these markers via one of several primer or probe-based enrichment strategies, followed by sequencing of the enriched genomic areas. Here, the authors review current target enrichment approaches and next generation sequencing platforms, focusing on the underlying principles, capabilities, and limitations of each technology along with validation and implementation for clinical testing.

  20. Inflammatory therapeutic targets in coronary atherosclerosis—from molecular biology to clinical application

    PubMed Central

    Linden, Fabian; Domschke, Gabriele; Erbel, Christian; Akhavanpoor, Mohammadreza; Katus, Hugo A.; Gleissner, Christian A.

    2014-01-01

    Atherosclerosis is the leading cause of death worldwide. Over the past two decades, it has been clearly recognized that atherosclerosis is an inflammatory disease of the arterial wall. Accumulating data from animal experiments have supported this hypothesis, however, clinical applications making use of this knowledge remain scarce. In spite of optimal interventional and medical therapy, the risk for recurrent myocardial infarction remains by about 20% over 3 years after acute coronary syndromes, novel therapies to prevent atherogenesis or treat atherosclerosis are urgently needed. This review summarizes selected potential molecular inflammatory targets that may be of clinical relevance. We also review recent and ongoing clinical trails that target inflammatory processes aiming at preventing adverse cardiovascular events. Overall, it seems surprising that translation of basic science into clinical practice has not been a great success. In conclusion, we propose to focus on specific efforts that promote translational science in order to improve outcome and prognosis of patients suffering from atherosclerosis. PMID:25484870

  1. Novel potential targets for prevention of arterial restenosis: insights from the pre-clinical research.

    PubMed

    Forte, Amalia; Rinaldi, Barbara; Berrino, Liberato; Rossi, Francesco; Galderisi, Umberto; Cipollaro, Marilena

    2014-12-01

    Restenosis is the pathophysiological process occurring in 10-15% of patients submitted to revascularization procedures of coronary, carotid and peripheral arteries. It can be considered as an excessive healing reaction of the vascular wall subjected to arterial/venous bypass graft interposition, endarterectomy or angioplasty. The advent of bare metal stents, drug-eluting stents and of the more recent drug-eluting balloons, have significantly reduced, but not eliminated, the incidence of restenosis, which remains a clinically relevant problem. Biomedical research in pre-clinical animal models of (re)stenosis, despite its limitations, has contributed enormously to the identification of processes involved in restenosis progression, going well beyond the initial dogma of a primarily proliferative disease. Although the main molecular and cellular mechanisms underlying restenosis have been well described, new signalling molecules and cell types controlling the progress of restenosis are continuously being discovered. In particular, microRNAs and vascular progenitor cells have recently been shown to play a key role in this pathophysiological process. In addition, the advanced highly sensitive high-throughput analyses of molecular alterations at the transcriptome, proteome and metabolome levels occurring in injured vessels in animal models of disease and in human specimens serve as a basis to identify novel potential therapeutic targets for restenosis. Molecular analyses are also contributing to the identification of reliable circulating biomarkers predictive of post-interventional restenosis in patients, which could be potentially helpful in the establishment of an early diagnosis and therapy. The present review summarizes the most recent and promising therapeutic strategies identified in experimental models of (re)stenosis and potentially translatable to patients subjected to revascularization procedures.

  2. Clinical benefit of drugs targeting mitochondrial function as an adjunct to reperfusion in ST-segment elevation myocardial infarction: A meta-analysis of randomized clinical trials.

    PubMed

    Campo, Gianluca; Pavasini, Rita; Morciano, Giampaolo; Lincoff, A Michael; Gibson, C Michael; Kitakaze, Masafumi; Lonborg, Jacob; Ahluwalia, Amrita; Ishii, Hideki; Frenneaux, Michael; Ovize, Michel; Galvani, Marcello; Atar, Dan; Ibanez, Borja; Cerisano, Giampaolo; Biscaglia, Simone; Neil, Brandon J; Asakura, Masanori; Engstrom, Thomas; Jones, Daniel A; Dawson, Dana; Ferrari, Roberto; Pinton, Paolo; Ottani, Filippo

    2017-10-01

    To perform a systematic review and meta-analysis of randomized clinical trials (RCT) comparing the effectiveness of drugs targeting mitochondrial function vs. placebo in patients with ST-segment elevation myocardial infarction (STEMI) undergoing mechanical coronary reperfusion. Inclusion criteria: RCTs enrolling STEMI patients treated with primary percutaneous coronary intervention (PCI) and comparing drugs targeting mitochondrial function vs. placebo. Odds ratios (OR) were computed from individual studies and pooled with random-effect meta-analysis. Fifteen studies were identified involving 5680 patients. When compared with placebo, drugs targeting mitochondrial component/pathway were not associated with significant reduction of cardiovascular and all-cause mortality (OR 0.9, 95% CI 0.7-1.17 and OR 0.92, 95% CI 0.69-1.23, respectively). However, these agents significantly reduced hospital admission for heart failure (HF) (OR 0.64; 95% CI 0.45-0.92) and increased left ventricular ejection fraction (LVEF) (OR 1.44; 95% CI 1.15-1.82). After analysis for subgroups according to the mechanism of action, drugs with direct/selective action did not reduce any outcome. Conversely, those with indirect/unspecific action showed a significant effect on cardiovascular mortality (0.65, 95% CI 0.46-0.92), all-cause mortality (OR 0.69, 95% CI 0.52-0.92), hospital readmission for HF (OR 0.41, 95% CI 0.28-0.6) and LVEF (OR 1.49, 95% CI 1.09-2.05). Administration of drugs targeting mitochondrial function in STEMI patients undergoing primary PCI appear to have no effect on mortality, but may reduce hospital readmission for HF. The drugs with a broad-spectrum mechanism of action seem to be more effective in reducing adverse events. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Targeting Kv1.3 channels to reduce white matter pathology after traumatic brain injury

    PubMed Central

    Reeves, Thomas M.; Trimmer, Patricia A.; Colley, Beverly S.; Phillips, Linda L.

    2016-01-01

    Axonal injury is present in essentially all clinically significant cases of traumatic brain injury (TBI). While no effective treatment has been identified to date, experimental TBI models have shown promising axonal protection using immunosuppressants FK506 and Cyclosporine-A, with treatment benefits attributed to calcineurin inhibition or protection of mitochondrial function. However, growing evidence suggests neuroprotective efficacy of these compounds may also involve direct modulation of ion channels, and in particular Kv1.3. The present study tested whether blockade of Kv1.3 channels, using Clofazimine (CFZ), would alleviate TBI-induced white matter pathology in rodents. Postinjury CFZ administration prevented suppression of compound action potential (CAP) amplitude in the corpus callosum of adult rats following midline fluid percussion TBI, with injury and treatment effects primarily expressed in unmyelinated CAPs. Kv1.3 protein levels in callosal tissue extracts were significantly reduced postinjury, but this loss was prevented by CFZ treatment. In parallel, CFZ also attenuated the injury-induced elevation in pro-inflammatory cytokine IL1-β. The effects of CFZ on glial function were further studied using mixed microglia/astrocyte cell cultures derived from P3-5 mouse corpus callosum. Cultures of callosal glia challenged with lipopolysaccharide exhibited a dramatic increase in IL1-β levels, accompanied by reactive morphological changes in microglia, both of which were attenuated by CFZ treatment. These results support a cell specific role for Kv1.3 signaling in white matter pathology after TBI, and suggest a treatment approach based on the blockade of these channels. This therapeutic strategy may be especially efficacious for normalizing neuro-glial interactions affecting unmyelinated axons after TBI. PMID:27302680

  4. Target Volume Delineation for Partial Breast Radiotherapy Planning: Clinical Characteristics Associated with Low Interobserver Concordance

    SciTech Connect

    Petersen, Ross P.; Truong, Pauline T. Kader, Hosam A.; Berthelet, Eric; Lee, Junella C.; Hilts, Michelle L.; Kader, Adam S.; Beckham, Wayne A.; Olivotto, Ivo A.

    2007-09-01

    Purpose: To examine variability in target volume delineation for partial breast radiotherapy planning and evaluate characteristics associated with low interobserver concordance. Methods and Materials: Thirty patients who underwent planning CT for adjuvant breast radiotherapy formed the study cohort. Using a standardized scale to score seroma clarity and consensus contouring guidelines, three radiation oncologists independently graded seroma clarity and delineated seroma volumes for each case. Seroma geometric center coordinates, maximum diameters in three axes, and volumes were recorded. Conformity index (CI), the ratio of overlapping volume and encompassing delineated volume, was calculated for each case. Cases with CI {<=}0.50 were analyzed to identify features associated with low concordance. Results: The median time from surgery to CT was 42.5 days. For geometric center coordinates, variations from the mean were 0.5-1.1 mm and standard deviations (SDs) were 0.5-1.8 mm. For maximum seroma dimensions, variations from the mean and SDs were predominantly <5 mm, with the largest SDs observed in the medial-lateral axis. The mean CI was 0.61 (range, 0.27-0.84). Five cases had CI {<=}0.50. Conformity index was significantly associated with seroma clarity (p < 0.001) and seroma volume (p < 0.002). Features associated with reduced concordance included tissue stranding from the surgical cavity, proximity to muscle, dense breast parenchyma, and benign calcifications that may be mistaken for surgical clips. Conclusion: Variability in seroma contouring occurred in three dimensions, with the largest variations in the medial-lateral axis. Awareness of clinical features associated with reduced concordance may be applied toward training staff and refining contouring guidelines for partial breast radiotherapy trials.

  5. Improved laser-to-proton conversion efficiency in isolated reduced mass targets

    SciTech Connect

    Morace, A.; Bellei, C.; Patel, P. K.; Bartal, T.; Kim, J.; Beg, F. N.; Willingale, L.; Maksimchuk, A.; Krushelnick, K.; Wei, M. S.; Batani, D.; Piovella, N.; Stephens, R. B.

    2013-07-29

    We present experimental results of laser-to-proton conversion efficiency as a function of lateral confinement of the refluxing electrons. Experiments were carried out using the T-Cubed laser at the Center for Ultrafast Optical Science, University of Michigan. We demonstrate that the laser-to-proton conversion efficiency increases by 50% with increased confinement of the target from surroundings with respect to a flat target of the same thickness. Three-dimensional hybrid particle-in-cell simulations using LSP code agree with the experimental data. The adopted target design is suitable for high repetition rate operation as well as for Inertial Confinement Fusion applications.

  6. Improved laser-to-proton conversion efficiency in isolated reduced mass targets

    NASA Astrophysics Data System (ADS)

    Morace, A.; Bellei, C.; Bartal, T.; Willingale, L.; Kim, J.; Maksimchuk, A.; Krushelnick, K.; Wei, M. S.; Patel, P. K.; Batani, D.; Piovella, N.; Stephens, R. B.; Beg, F. N.

    2013-07-01

    We present experimental results of laser-to-proton conversion efficiency as a function of lateral confinement of the refluxing electrons. Experiments were carried out using the T-Cubed laser at the Center for Ultrafast Optical Science, University of Michigan. We demonstrate that the laser-to-proton conversion efficiency increases by 50% with increased confinement of the target from surroundings with respect to a flat target of the same thickness. Three-dimensional hybrid particle-in-cell simulations using LSP code agree with the experimental data. The adopted target design is suitable for high repetition rate operation as well as for Inertial Confinement Fusion applications.

  7. Paclitaxel-coated balloon reduces target lesion revascularization compared with standard balloon angioplasty.

    PubMed

    Candy, Nicholas; Ng, Eugene; Velu, Ramesh

    2017-02-01

    Peripheral arterial disease (PAD) is a highly prevalent condition that contributes significantly to the morbidity and mortality of affected patients. PAD creates a significant economic burden on health care systems around the world. We reviewed all available literature to provide a meta-analysis assessing the outcome of patients treated with drug-eluting balloons (DEBs) compared with percutaneous transluminal balloon angioplasty (PTA) through measuring the rate of target lesion revascularization (TLR). An electronic search of the MEDLINE, Scopus, Embase, Web of Science, and Cochrane Library databases was performed. Articles reporting randomized controlled trials that compared treatment with DEBs vs PTA were selected for inclusion. A meta-analysis was performed by pooling data on rates of TLR, binary restenosis (BR), and late lumen loss (LLL). The 10 included articles comprised a sample size of 1292 patients. Meta-analysis demonstrated the rate of TLR in DEB-treated patients was significantly lower compared with patients treated with PTA at 6 months (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11-0.53; P = .0004), 12 months (OR, 0.28; 95% CI, 0.13-0.62; P = .002), and 24 months (OR, 0.25; 95% CI, 0.10-0.61; P = .002). Decreased LLL and BR was demonstrated at 6 months in patients treated with DEBs compared with patients treated with PTA (mean difference, -0.74; 95% CI, -0.97 to -0.51; P = .00001; OR, 0.34; 95% CI, 0.23-0.49; P = .00001). This meta-analysis demonstrates that treatment with DEBs compared with PTA results in reduced rates of reintervention in patients with PAD. Comparison of DEBs to other emerging treatments to determine which method results in the lowest reintervention rates and in the greatest improvement in quality of life should be the focus of future trials. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

  8. Targeted Myocardial Microinjections of a Biocomposite Material Reduces Infarct Expansion in Pigs

    PubMed Central

    Mukherjee, Rupak; Zavadzkas, Juozas A.; Saunders, Stuart M.; McLean, Julie E.; Jeffords, Laura B.; Beck (HTL), Christy; Stroud, Robert E.; Leone, Allyson M.; Koval, Christine N.; Rivers, William T.; Basu, Shubhayu; Sheehy, Alexander; Michal, Gene; Spinale, Francis G.

    2009-01-01

    Background Left ventricular (LV) remodeling after myocardial infarction (MI) commonly causes infarct expansion (IE). This study sought to interrupt IE through microinjections of a biocompatible composite material into the post-MI myocardium. Methods MI was created in 21 pigs (coronary ligation). Radiopaque markers (2-mm diameter) were placed for IE (fluoroscopy). Pigs were randomized for microinjections (25 injections; 2- × 2-cm array; 200 µL/injection) at 7 days post-MI of a fibrin-alginate composite (Fib-Alg; fibrinogen, fibronectin, factor XIII, gelatin-grafted alginate, thrombin; n = 11) or saline (n = 10). Results At 7 days after injection (14 days post-MI), LV posterior wall thickness was higher in the Fib-Alg group than in the saline group (1.07 ± 0.11 vs 0.69 ± 0.07 cm, respectively, p = 0.002). At 28 days post-MI, the area within the markers (IE) increased from baseline (1 cm2) in the saline (1.71 ± 0.13 cm2, p = 0.010) and Fib-Alg groups (1.44 ± 0.23 cm2, p < 0.001). However, the change in IE at 21 and 28 days post-MI was reduced in the Fib-Alg group (p=0.043 and p=0.019). Total collagen content within the MI region was similar in the saline and Fib-Alg groups (12.8 ± 1.7 and 11.6 ± 1.5 µg/mg, respectively, p = NS). However, extractable collagen, indicative of solubility, was lower in the Fib-Alg group than the saline group (59.1 ± 3.5 vs 71.0 ± 6.1 µg/mL, p = 0.020). Conclusions Targeted myocardial microinjection of the biocomposite attenuated the post-MI decrease in LV wall thickness and infarct expansion. Thus, intraoperative microinjections of biocompatible material may provide a novel approach for interrupting post-MI LV remodeling. PMID:18805174

  9. Access to a polymerase chain reaction assay method targeting 13 respiratory viruses can reduce antibiotics: a randomised, controlled trial

    PubMed Central

    2011-01-01

    Background Viral respiratory infections are common worldwide and range from completely benign disease to life-threatening illness. Symptoms can be unspecific, and an etiologic diagnosis is rarely established because of a lack of suitable diagnostic tools. Improper use of antibiotics is common in this setting, which is detrimental in light of the development of bacterial resistance. It has been suggested that the use of diagnostic tests could reduce antibiotic prescription rates. The objective of this study was to evaluate whether access to a multiplex polymerase chain reaction (PCR) assay panel for etiologic diagnosis of acute respiratory tract infections (ARTIs) would have an impact on antibiotic prescription rate in primary care clinical settings. Methods Adult patients with symptoms of ARTI were prospectively included. Nasopharyngeal and throat swabs were analysed by using a multiplex real-time PCR method targeting thirteen viruses and two bacteria. Patients were recruited at 12 outpatient units from October 2006 through April 2009, and samples were collected on the day of inclusion (initial visit) and after 10 days (follow-up visit). Patients were randomised in an open-label treatment protocol to receive a rapid or delayed result (on the following day or after eight to twelve days). The primary outcome measure was the antibiotic prescription rate at the initial visit, and the secondary outcome was the total antibiotic prescription rate during the study period. Results A total sample of 447 patients was randomised. Forty-one were excluded, leaving 406 patients for analysis. In the group of patients randomised for a rapid result, 4.5% (9 of 202) of patients received antibiotics at the initial visit, compared to 12.3% (25 of 204) (P = 0.005) of patients in the delayed result group. At follow-up, there was no significant difference between the groups: 13.9% (28 of 202) in the rapid result group and 17.2% (35 of 204) in the delayed result group (P = 0

  10. Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications.

    PubMed

    Li, Junjie; Oyen, Raymond; Verbruggen, Alfons; Ni, Yicheng

    2013-01-01

    Hitting the evasive tumor cells proves challenging in targeted cancer therapies. A general and unconventional anticancer approach namely small molecule sequential dual-targeting theragnostic strategy (SMSDTTS) has recently been introduced with the aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. This dual targeting approach works in two steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent, e.g., combretastatin A4 phosphate (CA4P), is injected to selectively cut off tumor blood supply and to cause massive necrosis, which nevertheless always leaves peripheral tumor residues. Secondly, a necrosis-avid radiopharmaceutical, namely (131)I-hypericin ((131)I-Hyp), is administered the next day, which accumulates in intratumoral necrosis and irradiates the residual cancer cells with beta particles. Theoretically, this complementary targeted approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the emitted gamma rays facilitate radio-scintigraphy to detect tumors and follow up the therapy, hence a simultaneous theragnostic approach. SMSDTTS has now shown promise from multicenter animal experiments and may demonstrate unique anticancer efficacy in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the rationale of SMSDTTS, its preclinical antitumor efficacy, multifocal targetability, simultaneous theragnostic property, and toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications.

  11. MET targeted therapy for lung cancer: clinical development and future directions.

    PubMed

    Feng, Yan; Ma, Patrick C

    2012-01-01

    MET, the receptor for hepatocyte growth factor, has been identified as a novel promising target in various human malignancies, including lung cancer. Research studies have demonstrated that MET signaling plays important physiologic roles in embryogenesis and early development, whereas its deregulation from an otherwise quiescent signaling state in mature adult tissues can lead to upregulated cell proliferation, survival, scattering, motility and migration, angiogenesis, invasion, and metastasis in tumorigenesis and tumor progression. The MET pathway can be activated through ligand (hepatocyte growth factor, HGF) or MET receptor overexpression, genomic amplification, MET mutations, and alternative splicing. A number of novel therapeutic agents that target the MET/hepatocyte growth factor pathway have been tested in early-phase clinical studies with promising results. Phase III studies of MET targeting agents have recently been initiated. This paper will review the MET signaling pathway and biology in lung cancer, and the recent clinical development and advances of MET/hepatocyte growth factor targeting agents. Emphasis will be placed on discussing various unanswered issues and key strategies needed to optimize further clinical development of MET targeting personalized lung cancer therapy.

  12. The impact of patient support programs on adherence, clinical, humanistic, and economic patient outcomes: a targeted systematic review

    PubMed Central

    Ganguli, Arijit; Clewell, Jerry; Shillington, Alicia C

    2016-01-01

    Background Patient support programs (PSPs), including medication management and counseling, have the potential to improve care in chronic disease states with complex therapies. Little is known about the program’s effects on improving clinical, adherence, humanistic, and cost outcomes. Purpose To conduct a targeted review describing medical conditions in which PSPs have been implemented; support delivery components (eg, face-to-face, phone, mail, and internet); and outcomes associated with implementation. Data sources MEDLINE – 10 years through March 2015 with supplemental handsearching of reference lists. Study selection English-language trials and observational studies of PSPs providing at minimum, counseling for medication management, measurement of ≥1 clinical outcome, and a 3-month follow-up period during which outcomes were measured. Data extraction Program characteristics and related clinical, adherence, humanistic, and cost outcomes were abstracted. Study quality and the overall strength of evidence were reviewed using standard criteria. Data synthesis Of 2,239 citations, 64 studies met inclusion criteria. All targeted chronic disease processes and the majority (48 [75%]) of programs offered in-clinic, face-to-face support. All but 9 (14.1%) were overseen by allied health care professionals (eg, nurses, pharmacists, paraprofessionals). Forty-one (64.1%) reported at least one significantly positive clinical outcome. The most frequent clinical outcome impacted was adherence, where 27 of 41 (66%) reported a positive outcome. Of 42 studies measuring humanistic outcomes (eg, quality of life, functional status), 27 (64%) reported significantly positive outcomes. Only 15 (23.4%) programs reported cost or utilization-related outcomes, and, of these, 12 reported positive impacts. Conclusion The preponderance of evidence suggests a positive impact of PSPs on adherence, clinical and humanistic outcomes. Although less often measured, health care utilization and

  13. Clinical Application of Targeted Deep Sequencing in Solid-Cancer Patients; Utility of Targeted Deep Sequencing for Biomarker-Selected Clinical Trial.

    PubMed

    Kim, Seung Tae; Kim, Kyoung-Mee; Kim, Nayoung K D; Park, Joon Oh; Ahn, Soomin; Yun, Jae-Won; Kim, Kyu-Tae; Park, Se Hoon; Park, Peter J; Kim, Hee Cheol; Sohn, Tae Sung; Choi, Dong Il; Cho, Jong Ho; Heo, Jin Seok; Kwon, Wooil; Lee, Hyuk; Min, Byung-Hoon; Hong, Sung No; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Park, Woong-Yang; Lee, Jeeyun

    2017-07-12

    Molecular profiling of actionable mutations in refractory cancer patients has the potential to enable "precision medicine," wherein individualized therapies are guided based on genomic profiling. The molecular-screening program was intended to route participants to different candidate drugs in trials based on clinical-sequencing reports. In this screening program, we used a custom target-enrichment panel consisting of cancer-related genes to interrogate single-nucleotide variants, insertions and deletions, copy number variants, and a subset of gene fusions. From August 2014 through April 2015, 654 patients consented to participate in the program at Samsung Medical Center. Of these patients, 588 passed the quality control process for the 381-gene cancer-panel test, and 418 patients were included in the final analysis as being eligible for any anticancer treatment (127 gastric cancer, 122 colorectal cancer, 62 pancreatic/biliary tract cancer, 67 sarcoma/other cancer, and 40 genitourinary cancer patients). Of the 418 patients, 55 (12%) harbored a biomarker that guided them to a biomarker-selected clinical trial, and 184 (44%) patients harbored at least one genomic alteration that was potentially targetable. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. © AlphaMed Press 2017.

  14. Use of clinical simulations for patient education: targeting an untapped audience.

    PubMed

    Siwe, Karin; Berterö, Carina; Pugh, Carla; Wijma, Barbro

    2009-01-01

    In most cases, the health professional has been the target for simulation based learning curricula. We have developed a simulation based curriculum for patient education. In our curriculum lay-women learn how to perform the clinical female pelvic examination using a manikin-based trainer. Learner assessments show that prior negative expectations turned into positive expectations regarding future pelvic examinations.

  15. Potential for reducing air-pollutants while achieving 2 °C global temperature change limit target.

    PubMed

    Hanaoka, Tatsuya; Akashi, Osamu; Fujiwara, Kazuya; Motoki, Yuko; Hibino, Go

    2014-12-01

    This study analyzes the potential to reduce air pollutants while achieving the 2 °C global temperature change limit target above pre-industrial levels, by using the bottom-up optimization model, AIM/Enduse[Global]. This study focuses on; 1) estimating mitigation potentials and costs for achieving 2 °C, 2.5 °C, and 3 °C target scenarios, 2) assessing co-benefits of reducing air pollutants such as NOx, SO2, BC, PM, and 3) analyzing features of sectoral attributions in Annex I and Non-Annex I groups of countries. The carbon tax scenario at 50 US$/tCO2-eq in 2050 can reduce GHG emissions more than the 3 °C target scenario, but a higher carbon price around 400 US$/tCO2-eq in 2050 is required to achieve the 2 °C target scenario. However, there is also a co-benefit of large reduction potential of air pollutants, in the range of 60-80% reductions in 2050 from the reference scenario while achieving the 2 °C target. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Pre-Clinical Studies of Epigenetic Therapies Targeting Histone Modifiers in Lung Cancer

    PubMed Central

    Huffman, Kenneth; Martinez, Elisabeth D.

    2013-01-01

    Treatment options for lung cancer patients have been generally limited to standard therapies or targeted interventions which involve a small number of known mutations. Although the targeted therapies are initially successful, they most often result in drug resistance, relapse, and mortality. We now know that the complexity of lung cancer comes not only from genomic changes, but also from aberrant epigenetic regulatory events. Epigenetic therapies have shown promise as single agents in the treatment of hematological malignancies but have yet to meet this expectation in solid tumors thus fostering researchers to pursue new approaches in the development and use of epigenetic interventions. Here, we review some recent pre-clinical findings involving the use of drugs targeting histone modifying enzymes both as single agents and as co-therapies against lung cancer. A greater understanding of the impact of these epigenetic compounds in lung cancer signaling is needed and further evaluation in vivo is warranted in several cases based on the pre-clinical activity of a subset of compounds discussed in this review, including drugs co-targeting HDACs and EGF receptor, targeting Brd4 and targeting Jumonji histone demethylases. PMID:24058902

  17. New Zealand's emergency department target - did it reduce ED length of stay, and if so, how and when?

    PubMed

    Tenbensel, Tim; Chalmers, Linda; Jones, Peter; Appleton-Dyer, Sarah; Walton, Lisa; Ameratunga, Shanthi

    2017-09-26

    In 2009, the New Zealand government introduced a hospital emergency department (ED) target - 95% of patients seen, treated or discharged within 6 h - in order to alleviate crowding in public hospital EDs. While these targets were largely met by 2012, research suggests that such targets can be met without corresponding overall reductions in ED length-of-stay (LOS). Our research explores whether the NZ ED time target actually reduced ED LOS, and if so, how and when. We adopted a mixed-methods approach with integration of data sources. After selecting four hospitals as case study sites, we collected all ED utilisation data for the period 2006 to 2012. ED LOS data was derived in two forms-reported ED LOS, and total ED LOS - which included time spent in short-stay units. This data was used to identify changes in the length of ED stay, and describe the timing of these changes to these indicators. Sixty-eight semi-structured interviews and two surveys of hospital clinicians and managers were conducted between 2011 and 2013. This data was then explored to identify factors that could account for ED LOS changes and their timing. Reported ED LOS reduced in all sites after the introduction of the target, and continued to reduce in 2011 and 2012. However, total ED LOS only decreased from 2008 to 2010, and did not reduce further in any hospital. Increased use of short-stay units largely accounted for these differences. Interview and survey data showed changes to improve patient flow were introduced in the early implementation period, whereas increased ED resources, better information systems to monitor target performance, and leadership and social marketing strategies mainly took throughout 2011 and 2012 when total ED LOS was not reducing. While the ED target clearly stimulated improvements in patient flow, our analysis also questions the value of ED targets as a long term approach. Increased use of short-stay units suggests that the target became less effective in 'standing

  18. A Preliminary Controlled Comparison of Programs Designed to Reduce Risk of Eating Disorders Targeting Perfectionism and Media Literacy

    ERIC Educational Resources Information Center

    Wilksch, Simon M.; Durbridge, Mitchell R.; Wade, Tracey D.

    2008-01-01

    The study aims to find out whether programs targeting perfectionism and media literacy are more effective than control classes in reducing eating disorder risk factors. Finding reveals that perfectionism programs are well suited to individuals of mid- to late adolescent age and shows the importune of making prevention programs developmentally…

  19. An Integrated Approach to Change the Outcome Part II: Targeted Neuromuscular Training Techniques to Reduce Identified ACL Injury Risk Factors

    PubMed Central

    Myer, Gregory D.; Ford, Kevin R.; Brent, Jensen L.; Hewett, Timothy E.

    2014-01-01

    Prior reports indicate that female athletes who demonstrate high knee abduction moments (KAMs) during landing are more responsive to neuromuscular training designed to reduce KAM. Identification of female athletes who demonstrate high KAM, which accurately identifies those at risk for noncontact anterior cruciate ligament (ACL) injury, may be ideal for targeted neuromuscular training. Specific neuromuscular training targeted to the underlying biomechanical components that increase KAM may provide the most efficient and effective training strategy to reduce noncontact ACL injury risk. The purpose of the current commentary is to provide an integrative approach to identify and target mechanistic underpinnings to increased ACL injury in female athletes. Specific neuromuscular training techniques will be presented that address individual algorithm components related to high knee load landing patterns. If these integrated techniques are employed on a widespread basis, prevention strategies for noncontact ACL injury among young female athletes may prove both more effective and efficient. PMID:22580980

  20. Targeting apoptosis: preclinical and early clinical experience with mapatumumab, an agonist monoclonal antibody targeting TRAIL-R1.

    PubMed

    Moretto, Patricia; Hotte, Sébastien J

    2009-03-01

    In spite of the advances in survival with chemotherapy and radiotherapy, many cancer patients continue to experience failure with treatments. Advances in molecular oncology and the development of numerous targeted therapies, used by themselves or in combination with at present available treatments such as chemotherapy and radiation, will hopefully improve the fate of these patients. It has been well understood for many years now that deregulation of apoptosis is a major hallmark of cancer cells. Mapatumumab, a fully human agonistic monoclonal antibody to TNF-related apoptosis-inducing ligand receptor 1, has been developed to induce apoptosis in cancer cells although having minimal effects on normal cells. This paper reviews the preclinical and early clinical data of this exciting new agent and discusses options for future development of mapatumumab, mostly in combinations with other therapies.

  1. Limbic, associative, and motor territories within the targets for deep brain stimulation: potential clinical implications.

    PubMed

    Sudhyadhom, Atchar; Bova, Frank J; Foote, Kelly D; Rosado, Christian A; Kirsch-Darrow, Lindsey; Okun, Michael S

    2007-07-01

    The use of deep brain stimulation (DBS) has recently been expanding for the treatment of many neurologic disorders such as Parkinson disease, dystonia, essential tremor, Tourette's syndrome, cluster headache, epilepsy, depression, and obsessive compulsive disorder. The target structures for DBS include specific segregated territories within limbic, associative, or motor regions of very small subnuclei. In this review, we summarize current clinical techniques for DBS, the cognitive/mood/motor outcomes, and the relevant neuroanatomy with respect to functional territories within specific brain targets. Future development of new techniques and technology that may include a more direct visualization of "motor" territories within target structures may prove useful for avoiding side effects that may result from stimulation of associative and limbic regions. Alternatively, newer procedures may choose and specifically target non-motor territories for chronic electrical stimulation.

  2. Two visual targets for the price of one? Pupil dilation shows reduced mental effort through temporal integration.

    PubMed

    Wolff, Michael J; Scholz, Sabine; Akyürek, Elkan G; van Rijn, Hedderik

    2015-02-01

    In dynamic sensory environments, successive stimuli may be combined perceptually and represented as a single, comprehensive event by means of temporal integration. Such perceptual segmentation across time is intuitively plausible. However, the possible costs and benefits of temporal integration in perception remain underspecified. In the present study pupil dilation was analyzed as a measure of mental effort. Observers viewed either one or two successive targets amidst distractors in rapid serial visual presentation, which they were asked to identify. Pupil dilation was examined dependent on participants' report: dilation associated with the report of a single target, of two targets, and of an integrated percept consisting of the features of both targets. There was a clear distinction between dilation observed for single-target reports and integrations on the one side, and two-target reports on the other. Regardless of report order, two-target reports produced increased pupil dilation, reflecting increased mental effort. The results thus suggested that temporal integration reduces mental effort and may thereby facilitate perceptual processing.

  3. NRDTD: a database for clinically or experimentally supported non-coding RNAs and drug targets associations

    PubMed Central

    Sun, Ya-Zhou; Zhang, De-Hong; Yan, Gui-Ying; An, Ji-Yong; You, Zhu-Hong

    2017-01-01

    Abstract In recent years, more and more non-coding RNAs (ncRNAs) have been identified and increasing evidences have shown that ncRNAs may affect gene expression and disease progression, making them a new class of targets for drug discovery. It thus becomes important to understand the relationship between ncRNAs and drug targets. For this purpose, an ncRNAs and drug targets association database would be extremely beneficial. Here, we developed ncRNA Drug Targets Database (NRDTD) that collected 165 entries of clinically or experimentally supported ncRNAs as drug targets, including 97 ncRNAs and 96 drugs. Moreover, we annotated ncRNA-drug target associations with drug information from KEGG, PubChem, DrugBank, CTD or Wikipedia, GenBank sequence links, OMIM disease ID, pathway and function annotation for ncRNAs, detailed description of associations between ncRNAs and diseases from HMDD or LncRNADisease and the publication PubMed ID. Additionally, we provided users a link to submit novel disease-ncRNA-drug associations and corresponding supporting evidences into the database. We hope NRDTD will be a useful resource for investigating the roles of ncRNAs in drug target identification, drug discovery and disease treatment. Database URL: http://chengroup.cumt.edu.cn/NRDTD

  4. Targeted ablation of cardiac sympathetic neurons reduces the susceptibility to ischemia-induced sustained ventricular tachycardia in conscious rats

    PubMed Central

    Lujan, Heidi L.; Palani, Gurunanthan; Zhang, Lijie

    2010-01-01

    The Cardiac Arrhythmia Suppression Trial demonstrated that antiarrhythmic drugs not only fail to prevent sudden cardiac death, but actually increase overall mortality. These findings have been confirmed in additional trials. The “proarrhythmic” effects of most currently available antiarrhythmic drugs makes it essential that we investigate novel strategies for the prevention of sudden cardiac death. Targeted ablation of cardiac sympathetic neurons may become a therapeutic option by reducing sympathetic activity. Thus cholera toxin B subunit (CTB) conjugated to saporin (a ribosomal inactivating protein that binds to and inactivates ribosomes; CTB-SAP) was injected into both stellate ganglia to test the hypothesis that targeted ablation of cardiac sympathetic neurons reduces the susceptibility to ischemia-induced, sustained ventricular tachycardia in conscious rats. Rats were randomly divided into three groups: 1) control (no injection); 2) bilateral stellate ganglia injection of CTB; and 3) bilateral stellate ganglia injection of CTB-SAP. CTB-SAP rats had a reduced susceptibility to ischemia-induced, sustained ventricular tachycardia. Associated with the reduced susceptibility to ventricular arrhythmias were a reduced number of stained neurons in the stellate ganglia and spinal cord (segments T1-T4), as well as a reduced left ventricular norepinephrine content and sympathetic innervation density. Thus CTB-SAP retrogradely transported from the stellate ganglia is effective at ablating cardiac sympathetic neurons and reducing the susceptibility to ventricular arrhythmias. PMID:20173045

  5. Reducing the Clinical and Socioeconomic Burden of Narcolepsy by Earlier Diagnosis and Effective Treatment.

    PubMed

    Thorpy, Michael; Morse, Anne Marie

    2017-03-01

    The burden of narcolepsy is likely the result of 2 main aspects: the clinical difficulties and disability incurred as a direct effect of the disorder and the socioeconomic burden. The clinical burden includes the symptoms, diagnosis, comorbidities, treatment, and even mortality that can be associated with narcolepsy. Lifelong therapy is necessary for these patients. Effective treatment results in long-term benefits from both patient and societal perspectives by improving clinical outcomes, potentially enabling improved education and increased employment and work productivity, and quality of life. Thus, reducing the time to appropriate management results in improved outcomes in these patients.

  6. Prostate bed target interfractional motion using RTOG consensus definitions and daily CT on rails : Does target motion differ between superior and inferior portions of the clinical target volume?

    PubMed

    Verma, Vivek; Chen, Shifeng; Zhou, Sumin; Enke, Charles A; Wahl, Andrew O

    2017-01-01

    Using high-quality CT-on-rails imaging, the daily motion of the prostate bed clinical target volume (PB-CTV) based on consensus Radiation Therapy Oncology Group (RTOG) definitions (instead of surgical clips/fiducials) was studied. It was assessed whether PB motion in the superior portion of PB-CTV (SUP-CTV) differed from the inferior PB-CTV (INF-CTV). Eight pT2-3bN0-1M0 patients underwent postprostatectomy intensity-modulated radiotherapy, totaling 300 fractions. INF-CTV and SUP-CTV were defined as PB-CTV located inferior and superior to the superior border of the pubic symphysis, respectively. Daily pretreatment CT-on-rails images were compared to the planning CT in the left-right (LR), superoinferior (SI), and anteroposterior (AP) directions. Two parameters were defined: "total PB-CTV motion" represented total shifts from skin tattoos to RTOG-defined anatomic areas; "PB-CTV target motion" (performed for both SUP-CTV and INF-CTV) represented shifts from bone to RTOG-defined anatomic areas (i. e., subtracting shifts from skin tattoos to bone). Mean (± standard deviation, SD) total PB-CTV motion was -1.5 (± 6.0), 1.3 (± 4.5), and 3.7 (± 5.7) mm in LR, SI, and AP directions, respectively. Mean (± SD) PB-CTV target motion was 0.2 (±1.4), 0.3 (±2.4), and 0 (±3.1) mm in the LR, SI, and AP directions, respectively. Mean (± SD) INF-CTV target motion was 0.1 (± 2.8), 0.5 (± 2.2), and 0.2 (± 2.5) mm, and SUP-CTV target motion was 0.3 (± 1.8), 0.5 (± 2.3), and 0 (± 5.0) mm in LR, SI, and AP directions, respectively. No statistically significant differences between INF-CTV and SUP-CTV motion were present in any direction. There are no statistically apparent motion differences between SUP-CTV and INF-CTV. Current uniform planning target volume (PTV) margins are adequate to cover both portions of the CTV.

  7. Reduced Toxicity Breast Cancer Therapy: Changing the Or to And in Dual Targeted Therapeutics

    DTIC Science & Technology

    2010-10-01

    targeted to a distin ct molecular m arker. The siRNA therapy can only be activa ted in cells expressing both m arkers since onl y one of the needed...improve adjuvant or system ic chemotherapy for superficial breast cancers and dim inish recurrence rates post tum or excision by treating tum or

  8. Long-Term Effects of a Personality-Targeted Intervention to Reduce Alcohol Use in Adolescents

    ERIC Educational Resources Information Center

    Conrod, Patricia J.; Castellanos-Ryan, Natalie; Mackie, Clare

    2011-01-01

    Objective: To examine the long-term effects of a personality-targeted intervention on drinking quantity and frequency (QF), problem drinking, and personality-specific motivations for alcohol use in early adolescence. Method: A randomized control trial was carried out with 364 adolescents (median age 14) recruited from 13 secondary schools with…

  9. Reduced performance of prey targeting in pit vipers with contralaterally occluded infrared and visual senses.

    PubMed

    Chen, Qin; Deng, Huanhuan; Brauth, Steven E; Ding, Li; Tang, Yezhong

    2012-01-01

    Both visual and infrared (IR) senses are utilized in prey targeting by pit vipers. Visual and IR inputs project to the contralateral optic tectum where they activate both multimodal and bimodal neurons. A series of ocular and pit organ occlusion experiments using the short-tailed pit viper (Gloydius brevicaudus) were conducted to investigate the role of visual and IR information during prey targeting. Compared with unoccluded controls, snakes with either both eyes or pit organs occluded performed more poorly in hunting prey although such subjects still captured prey on 75% of trials. Subjects with one eye and one pit occluded on the same side of the face performed as well as those with bilateral occlusion although these subjects showed a significant targeting angle bias toward the unoccluded side. Performance was significantly poorer when only a single eye or pit was available. Interestingly, when one eye and one pit organ were occluded on opposite sides of the face, performance was poorest, the snakes striking prey on no more than half the trials. These results indicate that, visual and infrared information are both effective in prey targeting in this species, although interference between the two modalities occurs if visual and IR information is restricted to opposite sides of the brain.

  10. Long-Term Effects of a Personality-Targeted Intervention to Reduce Alcohol Use in Adolescents

    ERIC Educational Resources Information Center

    Conrod, Patricia J.; Castellanos-Ryan, Natalie; Mackie, Clare

    2011-01-01

    Objective: To examine the long-term effects of a personality-targeted intervention on drinking quantity and frequency (QF), problem drinking, and personality-specific motivations for alcohol use in early adolescence. Method: A randomized control trial was carried out with 364 adolescents (median age 14) recruited from 13 secondary schools with…

  11. Dependable and Efficient Clinical Molecular Diagnosis of Chinese RP Patient with Targeted Exon Sequencing.

    PubMed

    Yang, Liping; Cui, Hui; Yin, Xiaobei; Dou, Hongliang; Zhao, Lin; Chen, Ningning; Zhang, Jinlu; Zhang, Huirong; Li, Genlin; Ma, Zhizhong

    2015-01-01

    Retinitis pigmentosa (RP) is the most common inherited retinal disease. It is a clinically and genetically heterogeneous disorder, which is why it is particularly challenging to diagnose. The aim of this study was to establish a targeted next-generation sequencing (NGS) approach for the comprehensive, rapid, and cost-effective clinical molecular diagnosis of RP. A specific hereditary eye disease enrichment panel (HEDEP) based on exome capture technology was used to collect the protein coding regions of 371 targeted hereditary eye disease genes, followed by high-throughput sequencing on the Illumina HiSeq2000 platform. From a cohort of 34 Chinese RP families, 13 families were successfully diagnosed; thus, the method achieves a diagnostic rate of approximately 40%. Of 16 pathogenic mutations identified, 11 were novel. Our study demonstrates that targeted capture sequencing offers a rapid and effective method for the molecular diagnosis of RP, which helps to provide a more accurate clinical diagnosis and paves the way for genetic counseling, family planning, and future gene-targeted treatment.

  12. Dependable and Efficient Clinical Molecular Diagnosis of Chinese RP Patient with Targeted Exon Sequencing

    PubMed Central

    Yin, Xiaobei; Dou, Hongliang; Zhao, Lin; Chen, Ningning; Zhang, Jinlu; Zhang, Huirong; Li, Genlin; Ma, Zhizhong

    2015-01-01

    Retinitis pigmentosa (RP) is the most common inherited retinal disease. It is a clinically and genetically heterogeneous disorder, which is why it is particularly challenging to diagnose. The aim of this study was to establish a targeted next-generation sequencing (NGS) approach for the comprehensive, rapid, and cost-effective clinical molecular diagnosis of RP. A specific hereditary eye disease enrichment panel (HEDEP) based on exome capture technology was used to collect the protein coding regions of 371 targeted hereditary eye disease genes, followed by high-throughput sequencing on the Illumina HiSeq2000 platform. From a cohort of 34 Chinese RP families, 13 families were successfully diagnosed; thus, the method achieves a diagnostic rate of approximately 40%. Of 16 pathogenic mutations identified, 11 were novel. Our study demonstrates that targeted capture sequencing offers a rapid and effective method for the molecular diagnosis of RP, which helps to provide a more accurate clinical diagnosis and paves the way for genetic counseling, family planning, and future gene-targeted treatment. PMID:26496393

  13. DSL prescriptive targets for bone conduction devices: adaptation and comparison to clinical fittings.

    PubMed

    Hodgetts, William E; Scollie, Susan D

    2017-07-01

    To develop an algorithm that prescribes targets for bone conduction frequency response shape, compression, and output limiting, along with a clinical method that ensures accurate transforms between assessment and verification stages of the clinical workflow. Technical report of target generation and validation. We recruited 39 adult users of unilateral percutaneous bone conduction hearing aids with a range of unilateral, bilateral, mixed and conductive hearing losses across the sample. The initial algorithm over-prescribed output compared to the user's own settings in the low frequencies, but provided a good match to user settings in the high frequencies. Corrections to the targets were derived and implemented as a low-frequency cut aimed at improving acceptance of the wearer's own voice during device use. The DSL-BCD prescriptive algorithm is compatible with verification of devices and fine-tuning to target for percutaneous bone conduction hearing devices that can be coupled to a skull simulator. Further study is needed to investigate the appropriateness of this prescriptive algorithm for other input levels, and for other clinical populations including those with single-sided deafness, bilateral devices, children and users of transcutaneous bone conduction hearing aids.

  14. Immunological and Clinical Effects of Vaccines Targeting p53-Overexpressing Malignancies

    PubMed Central

    Vermeij, R.; Leffers, N.; van der Burg, S. H.; Melief, C. J.; Daemen, T.; Nijman, H. W.

    2011-01-01

    Approximately 50% of human malignancies carry p53 mutations, which makes it a potential antigenic target for cancer immunotherapy. Adoptive transfer with p53-specific cytotoxic T-lymphocytes (CTL) and CD4+ T-helper cells eradicates p53-overexpressing tumors in mice. Furthermore, p53 antibodies and p53-specific CTLs can be detected in cancer patients, indicating that p53 is immunogenic. Based on these results, clinical trials were initiated. In this paper, we review immunological and clinical responses observed in cancer patients vaccinated with p53 targeting vaccines. In most trials, p53-specific vaccine-induced immunological responses were observed. Unfortunately, no clinical responses with significant reduction of tumor-burden have occurred. We will elaborate on possible explanations for this lack of clinical effectiveness. In the second part of this paper, we summarize several immunopotentiating combination strategies suitable for clinical use. In our opinion, future p53-vaccine studies should focus on addition of these immunopotentiating regimens to achieve clinically effective therapeutic vaccination strategies for cancer patients. PMID:21541192

  15. Targeting Carcinoembryonic Antigen with DNA Vaccination: On-Target Adverse Events Link with Immunological and Clinical Outcomes

    PubMed Central

    Chudley, Lindsey; Stasakova, Jana; Thirdborough, Stephen; King, Andrew; Lloyd-Evans, Paul; Buxton, Emily; Edwards, Ceri; Halford, Sarah; Bateman, Andrew; O’Callaghan, Ann; Clive, Sally; Anthoney, Alan; Jodrell, Duncan I.; Weinschenk, Toni; Simon, Petra; Sahin, Ugur; Thomas, Gareth J.; Stevenson, Freda K.; Ottensmeier, Christian H.

    2017-01-01

    Purpose We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201 binding peptide CAP-1 from carcinoembryonic antigen (CEA605–613) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin. Experimental Design Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (Arm-I) and 12 patients without radiological evidence of disease (Arm-II). Six intramuscular vaccinations of naked DNA (1mg/dose) were administered up to week 12. Clinical and immunological follow-up was to week 64 or clinical/radiological disease. Results DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared to 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8+ T-cells, respectively. CAP-1-specific T-cells were only detectable in the blood post-vaccination, but could also be identified in previously resected cancer tissue. The gastrointestinal adverse event diarrhea was reported by 48% of patients and linked to more frequent decreases in CEA (p<0.001) and improved global immunological responses (anti-DOM responses of greater magnitude (p<0.001), frequency (p=0.004) and duration) compared to patients without diarrhea. In advanced disease patients, decreases in CEA were associated with better overall survival (HR=0.14, p=0.017). CAP-1 peptide was detectable on MHC class I of normal bowel mucosa and primary colorectal cancer tissue by mass-spectrometry, offering a mechanistic explanation for diarrhea through CD8+ T-cell attack. Conclusions Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody. PMID:27091407

  16. Radiosensitizers in Pancreatic Cancer – Preclinical and Clinical Exploits with Molecularly Targeted Agents

    PubMed Central

    Walker, Amanda J.; Alcorn, Sara; Narang, Amol; Nugent, Katriana; Wild, Aaron T.; Herman, Joseph M.; Tran, Phuoc T.

    2013-01-01

    There has been an explosion in the number of molecularly targeted agents engineered to inhibit specific molecular pathways driving the tumorigenic phenotype in cancer cells. Some of these molecularly targeted agents have demonstrated robust clinical effects, but few result in meaningful durable responses. Therapeutic radiation is used to treat a majority of cancer patients with recent technologic and pharmacologic enhancements, leading to improvements in the therapeutic ratio for cancer care. Radiotherapy has a very specific role in select cases of postoperative and locally advanced pancreatic cancer patients, but control of metastatic disease still appears to be the major limiting factor behind improvements in cure. Recent rapid autopsy pathologic findings suggest a sub-group of advanced pancreatic cancer patients where death is caused from local disease progression and who would thus benefit from improved local control. One promising approach is to combine molecularly targeted agents with radiotherapy to improve tumor response rates and likelihood of durable local control. We review suggested recommendations on the investigation of molecularly targeted agents as radiosensitizers from preclinical studies to implementation in phase I–II clinical trials. We then discuss a select set of molecularly targeted therapies that we believe show promise as radiosensitizers in the treatment of pancreatic cancer. PMID:24331186

  17. Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

    PubMed Central

    Panaccione, Alexander; Chang, Michael T.; Ivanov, Sergey V.

    2016-01-01

    Objectives This review surveys trialed therapies and molecular defects in adenoid cystic carcinoma (ACC), with an emphasis on neural crest‐like stemness characteristics of newly discovered cancer stem cells (CSCs) and therapies that may target these CSCs. Data Sources Articles available on Pubmed or OVID MEDLINE databases and unpublished data. Review Methods Systematic review of articles pertaining to ACC and neural crest‐like stem cells. Results Adenoid cystic carcinoma of the salivary gland is a slowly growing but relentless cancer that is prone to nerve invasion and metastases. A lack of understanding of molecular etiology and absence of targetable drivers has limited therapy for patients with ACC to surgery and radiation. Currently, no curative treatments are available for patients with metastatic disease, which highlights the need for effective new therapies. Research in this area has been inhibited by the lack of validated cell lines and a paucity of clinically useful markers. The ACC research environment has recently improved, thanks to the introduction of novel tools, technologies, approaches, and models. Improved understanding of ACC suggests that neural crest‐like stemness is a major target in this rare tumor. New cell culture techniques and patient‐derived xenografts provide tools for preclinical testing. Conclusion Preclinical research has not identified effective targets in ACC, as confirmed by the large number of failed clinical trials. New molecular data suggest that drivers of neural crest‐like stemness may be required for maintenance of ACC; as such, CSCs are a target for therapy of ACC. PMID:28894804

  18. Return of target material ions leads to a reduced hysteresis in reactive high power impulse magnetron sputtering: Experiment

    NASA Astrophysics Data System (ADS)

    Čapek, Jiří; Kadlec, Stanislav

    2017-05-01

    Titanium and aluminum targets have been reactively sputtered in Ar +O2 or Ar +N2 gas mixtures in order to systematically investigate the effect of reduced hysteresis in reactive high power impulse magnetron sputtering (HiPIMS) as compared to other sputtering techniques utilizing low discharge target power density (e.g., direct current or pulsed direct current mid-frequency magnetron sputtering) operated at the same average discharge power. We found that the negative slope of the flow rate of the reactive gas gettered by the sputtered target material as a function of the reactive gas partial pressure is clearly lower in the case of HiPIMS. This results in a lower critical pumping speed, which implies a reduced hysteresis. We argue that the most important effect explaining the observed behavior is covering of the reacted areas of the target by the returning ionized metal, effectively lowering the target coverage at a given partial pressure. This explanation is supported by a calculation using an analytical model of reactive HiPIMS with time and space averaging (developed by us).

  19. CD40-targeted adenoviral cancer vaccines: the long and winding road to the clinic

    PubMed Central

    Hangalapura, Basav N.; Timares, Laura; Oosterhoff, Dinja; Scheper, Rik J.; Curiel, David T.; de Gruijl, Tanja D.

    2012-01-01

    Summary The ability of Dendritic Cells (DC) to orchestrate innate and adaptive immune responses has been exploited to develop potent anti-cancer immunotherapies. Recent clinical trials exploring the efficacy of ex vivo modified autologous DC-based vaccines have reported some promising results. However, in vitro generation of autologous DC for clinical administration, their loading with tumor associated antigens (TAA) and their activation, is laborious and expensive, and, due to interindividual variability in the personalized vaccines, poorly standardized. An attractive alternative approach is to load resident DC in vivo by targeted delivery of TAA , using viral vectors and activating them simultaneously. To this end we have constructed genetically modified Adenoviral (Ad) vectors and bispecific adaptor molecules to retarget Ad vectors encoding TAA to the CD40 receptor on DC. Preclinical human and murine studies conducted so far have clearly demonstrated the suitability of a “two-component”, i.e. Ad and adaptor molecule, configuration for targeted modification of DC in vivo for cancer immunotherapy. This review summarizes recent progress in the development of CD40-targeted Ad-based cancer vaccines and highlights pre-clinical issues in clinical translation of this approach. PMID:22228547

  20. Pilot study demonstrating effectiveness of targeted education to improve informed consent understanding in AIDS clinical trials.

    PubMed

    Sengupta, Sohini; Lo, Bernard; Strauss, Ronald P; Eron, Joseph; Gifford, Allen L

    2011-11-01

    Assessing and improving informed consent understanding is equally important as obtaining consent from participants in clinical trial research, but developing interventions to target gaps in participants' informed consent understanding remains a challenge. We used a randomized controlled study design to pilot test an educational intervention to improve actual informed consent understanding of new enrollees in the Adult AIDS Clinical Trial Group (AACTG). Questionnaires were administered to 24 enrollees to assess their baseline understanding on eight elements of informed consent associated with AIDS clinical trials. Enrollees who scored 18/21(85%) or less were randomly assigned to in-person, targeted education (intervention), or delayed education (control). Two follow-up assessments were administered. Repeated measures ANOVA was performed to determine intervention effectiveness in improving actual informed consent understanding over time. Actual understanding improved at the immediate post-intervention time point with a significant score difference of 2.5 when comparing the intervention and delayed groups. In addition, there was a significant score difference of 3.2 when comparing baseline to three-month follow-up for the two groups, suggesting a statistically significant intervention effect to improve actual understanding of the basic elements of informed consent. The findings demonstrated that one-time targeted education can improve actual informed consent understanding one week after the intervention, but retention of these concepts may require periodic monitoring to ensure comprehension throughout the course of a clinical trial.

  1. Detection of Gene Rearrangements in Targeted Clinical Next-Generation Sequencing

    PubMed Central

    Abel, Haley J.; Al-Kateb, Hussam; Cottrell, Catherine E.; Bredemeyer, Andrew J.; Pritchard, Colin C.; Grossmann, Allie H.; Wallander, Michelle L.; Pfeifer, John D.; Lockwood, Christina M.; Duncavage, Eric J.

    2015-01-01

    The identification of recurrent gene rearrangements in the clinical laboratory is the cornerstone for risk stratification and treatment decisions in many malignant tumors. Studies have reported that targeted next-generation sequencing assays have the potential to identify such rearrangements; however, their utility in the clinical laboratory is unknown. We examine the sensitivity and specificity of ALK and KMT2A (MLL) rearrangement detection by next-generation sequencing in the clinical laboratory. We analyzed a series of seven ALK rearranged cancers, six KMT2A rearranged leukemias, and 77 ALK/KMT2A rearrangement–negative cancers, previously tested by fluorescence in situ hybridization (FISH). Rearrangement detection was tested using publicly available software tools, including Breakdancer, ClusterFAST, CREST, and Hydra. Using Breakdancer and ClusterFAST, we detected ALK rearrangements in seven of seven FISH-positive cases and KMT2A rearrangements in six of six FISH-positive cases. Among the 77 ALK/KMT2A FISH-negative cases, no false-positive identifications were made by Breakdancer or ClusterFAST. Further, we identified one ALK rearranged case with a noncanonical intron 16 breakpoint, which is likely to affect its response to targeted inhibitors. We report that clinically relevant chromosomal rearrangements can be detected from targeted gene panel–based next-generation sequencing with sensitivity and specificity equivalent to that of FISH while providing finer-scale information and increased efficiency for molecular oncology testing. PMID:24813172

  2. RNA-targeted therapeutics in cancer clinical trials: Current status and future directions.

    PubMed

    Barata, Pedro; Sood, Anil K; Hong, David S

    2016-11-01

    Recent advances in RNA delivery and target selection provide unprecedented opportunities for cancer treatment, especially for cancers that are particularly hard to treat with existing drugs. Small interfering RNAs, microRNAs, and antisense oligonucleotides are the most widely used strategies for silencing gene expression. In this review, we summarize how these approaches were used to develop drugs targeting RNA in human cells. Then, we review the current state of clinical trials of these agents for different types of cancer and outcomes from published data. Finally, we discuss lessons learned from completed studies and future directions for this class of drugs.

  3. Targeting the Tumor Microenvironment: From Understanding Pathways to Effective Clinical Trials

    PubMed Central

    Fang, Hua; DeClerck, Yves A.

    2013-01-01

    It is clear that tumor cells do not act alone but in close interaction with the extracellular matrix and with stromal cells in the tumor microenvironment (TME). As our understanding of tumor cell-stroma interactions increased over the last two decades, significant efforts have been made to develop agents that interfere with these interactions. Here, we discuss four different therapeutic strategies that target the TME, focusing on agents that are at the most advanced stage of preclinical or clinical development. We end this review by outlining some of the lessons we have learned so far from the development of TME-targeting agents. PMID:23913938

  4. Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy.

    PubMed

    Bai, Huimin; Cao, Dongyan; Yang, Jiaxin; Li, Menghui; Zhang, Zhenyu; Shen, Keng

    2016-04-01

    Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and tumoural heterogeneity (TH) has been blamed for treatment failure. The genomic and epigenomic atlas of EOC varies significantly with tumour histotype, grade, stage, sensitivity to chemotherapy and prognosis. Rapidly accumulating knowledge about the genetic and epigenetic events that control TH in EOC has facilitated the development of molecular-targeted therapy. Poly (ADP-ribose) polymerase (PARP) inhibitors, designed to target homologous recombination, are poised to change how breast cancer susceptibility gene (BRCA)-related ovarian cancer is treated. Epigenetic treatment regimens being tested in clinical or preclinical studies could provide promising novel treatment approaches and hope for improving patient survival.

  5. Targeting medullary thyroid carcinomas with bispecific antibodies and bivalent haptens. Results and clinical perspectives.

    PubMed

    Rouvier, E; Gautherot, E; Meyer, P; Barbet, J

    1997-01-01

    The present article reviews the clinical trials that have been performed in recurrent medullary thyroid carcinoma patients with the Affinity Enhancement System. This technique uses bispecific antibodies to target radiolabelled bivalent haptens to tumour cells. Its sensitivity in the detection of known tumour sites is high (90%) and this technique also achieves good sensitivity (61%) in the detection of occult disease as revealed by abnormal thyrocalcitonin blood levels. Due to its high targeting capacity, this technique is now considered for use as a therapeutic agent in medullary thyroid carcinoma patients.

  6. Comparative results of an obesity clinic and a commercial weight-reducing organization.

    PubMed

    Willians, A E; Duncan, B

    1976-05-22

    Members of a commercial weight-reducing organization achieved, on average, almost double the weight loss of patients attending an obestiy clinic, where an extensive regime of drugs and other therapies was offered. It is suggested that medical expertise could be used to supplement the benefits for patients attending community groups, rather than in the individual treatment of obesity.

  7. Antibacterials Developed to Target a Single Organism: Mechanisms and Frequencies of Reduced Susceptibility to the Novel Anti-Clostridium difficile Compounds Fidaxomicin and LFF571.

    PubMed

    Leeds, Jennifer A

    2016-02-01

    Clostridium difficile is the most common cause of antibacterial-associated diarrhea. Clear clinical presentation and rapid diagnostics enable targeted therapy for C. difficile infection (CDI) to start quickly. CDI treatment includes metronidazole and vancomycin (VAN). Despite decades of use for CDI, no clinically meaningful resistance to either agent has emerged. Fidaxomicin (FDX), an RNA polymerase inhibitor, is also approved to treat CDI. Mutants with reduced susceptibility to FDX have been selected in vitro by single and multistep methods. Strains with elevated FDX minimum inhibitory concentrations (MICs) were also identified from FDX-treated patients in clinical trials. LFF571 is an exploratory agent that inhibits EF-Tu. In a proof-of-concept study, LFF571 was safe and effective for treating CDI. Spontaneous mutants with reduced susceptibility to LFF571 were selected in vitro in a single step, but not via serial passage. Although there are several agents in development for treatment of CDI, this review summarizes the frequencies and mechanisms of C. difficile mutants displaying reduced susceptibility to FDX or LFF71.

  8. OSHA targets reducing needlesticks among HCWs. Occupational Safety and Health Administration.

    PubMed

    1998-11-01

    The Occupational Safety and Health Administration (OSHA) set a deadline for receiving information on engineering practices that have reduced the number of percutaneous injuries among health care workers. California leads the nation in efforts to reduce these accidents; the State requires the use of safer needle devices whenever possible. OSHA estimates the number of occupational exposures to be 600,000 annually, but the number of exposures is vastly under reported. Accidental needle sticks remain a major occupational health concern.

  9. Target Salt 2025: A Global Overview of National Programs to Encourage the Food Industry to Reduce Salt in Foods

    PubMed Central

    Webster, Jacqui; Trieu, Kathy; Dunford, Elizabeth; Hawkes, Corinna

    2014-01-01

    Reducing population salt intake has been identified as a priority intervention to reduce non-communicable diseases. Member States of the World Health Organization have agreed to a global target of a 30% reduction in salt intake by 2025. In countries where most salt consumed is from processed foods, programs to engage the food industry to reduce salt in products are being developed. This paper provides a comprehensive overview of national initiatives to encourage the food industry to reduce salt. A systematic review of the literature was supplemented by key informant questionnaires to inform categorization of the initiatives. Fifty nine food industry salt reduction programs were identified. Thirty eight countries had targets for salt levels in foods and nine countries had introduced legislation for some products. South Africa and Argentina have both introduced legislation limiting salt levels across a broad range of foods. Seventeen countries reported reductions in salt levels in foods—the majority in bread. While these trends represent progress, many countries have yet to initiate work in this area, others are at early stages of implementation and further monitoring is required to assess progress towards achieving the global target. PMID:25195640

  10. Target salt 2025: a global overview of national programs to encourage the food industry to reduce salt in foods.

    PubMed

    Webster, Jacqui; Trieu, Kathy; Dunford, Elizabeth; Hawkes, Corinna

    2014-08-21

    Reducing population salt intake has been identified as a priority intervention to reduce non-communicable diseases. Member States of the World Health Organization have agreed to a global target of a 30% reduction in salt intake by 2025. In countries where most salt consumed is from processed foods, programs to engage the food industry to reduce salt in products are being developed. This paper provides a comprehensive overview of national initiatives to encourage the food industry to reduce salt. A systematic review of the literature was supplemented by key informant questionnaires to inform categorization of the initiatives. Fifty nine food industry salt reduction programs were identified. Thirty eight countries had targets for salt levels in foods and nine countries had introduced legislation for some products. South Africa and Argentina have both introduced legislation limiting salt levels across a broad range of foods. Seventeen countries reported reductions in salt levels in foods-the majority in bread. While these trends represent progress, many countries have yet to initiate work in this area, others are at early stages of implementation and further monitoring is required to assess progress towards achieving the global target.

  11. Mechanism of Reduced Susceptibility to Fosfomycin in Escherichia coli Clinical Isolates

    PubMed Central

    Ohkoshi, Yasuo; Sato, Toyotaka; Suzuki, Yuuki; Yamamoto, Soh; Shiraishi, Tsukasa; Ogasawara, Noriko

    2017-01-01

    In recent years, multidrug resistance of Escherichia coli has become a serious problem. However, resistance to fosfomycin (FOM) has been low. We screened E. coli clinical isolates with reduced susceptibility to FOM and characterized molecular mechanisms of resistance and reduced susceptibility of these strains. Ten strains showing reduced FOM susceptibility (MIC ≥ 8 μg/mL) in 211 clinical isolates were found and examined. Acquisition of genes encoding FOM-modifying enzyme genes (fos genes) and mutations in murA that underlie high resistance to FOM were not observed. We examined ability of FOM incorporation via glucose-6-phosphate (G6P) transporter and sn-glycerol-3-phosphate transporter. In ten strains, nine showed lack of growth on M9 minimum salt agar supplemented with G6P. Eight of the ten strains showed fluctuated induction by G6P of uhpT that encodes G6P transporter expression. Nucleotide sequences of the uhpT, uhpA, glpT, ptsI, and cyaA shared several deletions and amino acid mutations in the nine strains with lack of growth on G6P-supplemented M9 agar. In conclusion, reduction of uhpT function is largely responsible for the reduced sensitivity to FOM in clinical isolates that have not acquired FOM-modifying genes or mutations in murA. However, there are a few strains whose mechanisms of reduced susceptibility to FOM are still unclear. PMID:28197413

  12. Mechanism of Reduced Susceptibility to Fosfomycin in Escherichia coli Clinical Isolates.

    PubMed

    Ohkoshi, Yasuo; Sato, Toyotaka; Suzuki, Yuuki; Yamamoto, Soh; Shiraishi, Tsukasa; Ogasawara, Noriko; Yokota, Shin-Ichi

    2017-01-01

    In recent years, multidrug resistance of Escherichia coli has become a serious problem. However, resistance to fosfomycin (FOM) has been low. We screened E. coli clinical isolates with reduced susceptibility to FOM and characterized molecular mechanisms of resistance and reduced susceptibility of these strains. Ten strains showing reduced FOM susceptibility (MIC ≥ 8 μg/mL) in 211 clinical isolates were found and examined. Acquisition of genes encoding FOM-modifying enzyme genes (fos genes) and mutations in murA that underlie high resistance to FOM were not observed. We examined ability of FOM incorporation via glucose-6-phosphate (G6P) transporter and sn-glycerol-3-phosphate transporter. In ten strains, nine showed lack of growth on M9 minimum salt agar supplemented with G6P. Eight of the ten strains showed fluctuated induction by G6P of uhpT that encodes G6P transporter expression. Nucleotide sequences of the uhpT, uhpA, glpT, ptsI, and cyaA shared several deletions and amino acid mutations in the nine strains with lack of growth on G6P-supplemented M9 agar. In conclusion, reduction of uhpT function is largely responsible for the reduced sensitivity to FOM in clinical isolates that have not acquired FOM-modifying genes or mutations in murA. However, there are a few strains whose mechanisms of reduced susceptibility to FOM are still unclear.

  13. Setting cumulative emissions targets to reduce the risk of dangerous climate change

    PubMed Central

    Zickfeld, Kirsten; Eby, Michael; Matthews, H. Damon; Weaver, Andrew J.

    2009-01-01

    Avoiding “dangerous anthropogenic interference with the climate system” requires stabilization of atmospheric greenhouse gas concentrations and substantial reductions in anthropogenic emissions. Here, we present an inverse approach to coupled climate-carbon cycle modeling, which allows us to estimate the probability that any given level of carbon dioxide (CO2) emissions will exceed specified long-term global mean temperature targets for “dangerous anthropogenic interference,” taking into consideration uncertainties in climate sensitivity and the carbon cycle response to climate change. We show that to stabilize global mean temperature increase at 2 °C above preindustrial levels with a probability of at least 0.66, cumulative CO2 emissions from 2000 to 2500 must not exceed a median estimate of 590 petagrams of carbon (PgC) (range, 200 to 950 PgC). If the 2 °C temperature stabilization target is to be met with a probability of at least 0.9, median total allowable CO2 emissions are 170 PgC (range, −220 to 700 PgC). Furthermore, these estimates of cumulative CO2 emissions, compatible with a specified temperature stabilization target, are independent of the path taken to stabilization. Our analysis therefore supports an international policy framework aimed at avoiding dangerous anthropogenic interference formulated on the basis of total allowable greenhouse gas emissions. PMID:19706489

  14. Reduced-order model for underwater target identification using proper orthogonal decomposition

    NASA Astrophysics Data System (ADS)

    Ramesh, Sai Sudha; Lim, Kian Meng

    2017-03-01

    Research on underwater acoustics has seen major development over the past decade due to its widespread applications in domains such as underwater communication/navigation (SONAR), seismic exploration and oceanography. In particular, acoustic signatures from partially or fully buried targets can be used in the identification of buried mines for mine counter measures (MCM). Although there exist several techniques to identify target properties based on SONAR images and acoustic signatures, these methods first employ a feature extraction method to represent the dominant characteristics of a data set, followed by the use of an appropriate classifier based on neural networks or the relevance vector machine. The aim of the present study is to demonstrate the applications of proper orthogonal decomposition (POD) technique in capturing dominant features of a set of scattered pressure signals, and subsequent use of the POD modes and coefficients in the identification of partially buried underwater target parameters such as its location, size and material density. Several numerical examples are presented to demonstrate the performance of the system identification method based on POD. Although the present study is based on 2D acoustic model, the method can be easily extended to 3D models and thereby enables cost-effective representations of large-scale data.

  15. NCCN Work Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

    PubMed Central

    Venook, Alan P.; Arcila, Maria E.; Benson, Al B.; Berry, Donald A.; Camidge, David Ross; Carlson, Robert W.; Choueiri, Toni K.; Guild, Valerie; Kalemkerian, Gregory P.; Kurzrock, Razelle; Lovly, Christine M.; McKee, Amy E.; Morgan, Robert J.; Olszanski, Anthony J.; Redman, Mary W.; Stearns, Vered; McClure, Joan; Birkeland, Marian L.

    2016-01-01

    Defining treatment susceptible or resistant populations of cancer patients through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents both opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies because potential patient populations are divided into ever-smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists and information developers. PMID:25361808

  16. Peptidic Tumor Targeting Agents: The Road from Phage Display Peptide Selections to Clinical Applications

    PubMed Central

    Brown, Kathlynn C.

    2014-01-01

    Cancer has become the number one cause of death amongst Americans, killing approximately 1,600 people per day. Novel methods for early detection and the development of effective treatments are an eminent priority in medicine. For this reason, isolation of tumor-specific ligands is a growing area of research. Tumor-specific binding agents can be used to probe the tumor cell surface phenotype and customize treatment accordingly by conjugating the appropriate cell-targeting ligand to an anticancer drug. This refines the molecular diagnosis of the tumor and creates guided drugs that can target the tumor while sparing healthy tissues. Additionally, these targeting agents can be used as in vivo imaging agents that allow for earlier detection of tumors and micrometastasis. Phage display is a powerful technique for the isolation of peptides that bind to a particular target with high affinity and specificity. The biopanning of intact cancer cells or tumors in animals can be used to isolate peptides that bind to cancer-specific cell surface biomarkers. Over the past 10 years, unbiased biopanning of phage-displayed peptide libraries has generated a suite of cancer targeting peptidic ligands. This review discusses the recent advances in the isolation of cancer-targeting peptides by unbiased biopanning methods and highlights the use of the isolated peptides in clinical applications. PMID:20030617

  17. Molecular targets on blood vessels for cancer therapies in clinical trials.

    PubMed

    Sato, Masanori; Arap, Wadih; Pasqualini, Renata

    2007-10-01

    This review covers progress to date in the identification of molecular targets on blood vessels in cancers, as well as agents that act on those targets, with emphasis on those currently in clinical trials. Current vascular-targeting therapies comprise two general types--antiangiogenic therapy and antivascular therapy. Advances in antiangiogenic therapies, particularly inhibitors of vascular endothelial growth factors and their receptors, have clarified the capacity of these inhibitors to change tumor-associated vessel structure to a more normal state, thereby improving the ability of chemotherapeutics to access the tumors. The responses of other antiangiogenesis target molecules in humans are more complicated; for example, alphanubeta3 integrins are known to stimulate as well as inhibit angiogenesis, and cleavage of various extracellular proteins/proteoglycans by matrix metalloproteinases produces potent regulators of the angiogenic process. Antivascular therapies disrupt established blood vessels in solid tumors and often involve the use of ligand-based or small-molecule agents. Ligand-based agents, irrespective of the antiangiogenic capacity of the ligand, target antivascular effectors to molecules expressed specifically on blood vessels, such as aminopeptidase N, fibronectin extra-domain B, and prostate-specific membrane antigen. Small-molecule antivascular agents, which are not targeted to molecules on blood vessels, rely on physical differences between the vasculatures in tumors and those in normal tissues.

  18. Measurement of Neuropsychiatric Symptoms in Clinical Trials Targeting Alzheimer’s Disease and Related Disorders

    PubMed Central

    David, Renaud; Mulin, Emmanuel; Mallea, Patrick; Robert, Philippe H.

    2010-01-01

    Behavioral and psychological symptoms (BPSD) are now known to be frequently associated to cognitive and functional decline in Alzheimer‘s disease and related disorders. They are present since the early stages of the disease and have negative impact on the disease process. BPSD assessment is crucial in clinical practice and also in future clinical trials targeting disease-modifying therapies for dementia. In this article, we will first review current assessment tools for BPSD, mainly global and domain-specific scales, and new assessment methods, currently available or in development, including new scales, diagnostic criteria and new technologies such as ambulatory actigraphy. PMID:27713359

  19. Angiotensin II type 2-receptor: new clinically validated target in the treatment of neuropathic pain.

    PubMed

    Rice, A S C; Smith, M T

    2015-02-01

    Neuropathic pain is a large unmet medical need. The angiotensin II type 2 (AT2 ) receptor is a target with promising data in rodent models of peripheral neuropathic pain. The AT2 receptor has attracted attention on the basis of human data from a proof-of-concept clinical trial showing that oral EMA401, a highly selective, peripherally restricted, small molecule AT2 receptor antagonist, at 100 mg twice-daily for 4 weeks, alleviated postherpetic neuralgia, an often intractable type of peripheral neuropathic pain. © 2014 American Society for Clinical Pharmacology and Therapeutics.

  20. Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application.

    PubMed

    Maione, Paolo; Sacco, Paola Claudia; Sgambato, Assunta; Casaluce, Francesca; Rossi, Antonio; Gridelli, Cesare

    2015-09-01

    The discovery that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by druggable protein kinases has led to a revolutionary change in nonsmall cell lung cancer (NSCLC) treatment. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the targets of several tyrosine kinase inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. First-generation agents offer, in target populations, a substantial improvement of outcomes compared with standard chemotherapy in the treatment of advanced NSCLC. Unfortunately, drug resistance develops after initial benefit through a variety of mechanisms. Novel generation EGFR and ALK inhibitors are currently in advanced clinical development and are producing encouraging results in patients with acquired resistance to previous generation agents. The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations or ALK rearrangements is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC.

  1. Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application

    PubMed Central

    Sacco, Paola Claudia; Sgambato, Assunta; Casaluce, Francesca; Rossi, Antonio; Gridelli, Cesare

    2015-01-01

    The discovery that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by druggable protein kinases has led to a revolutionary change in nonsmall cell lung cancer (NSCLC) treatment. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the targets of several tyrosine kinase inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. First-generation agents offer, in target populations, a substantial improvement of outcomes compared with standard chemotherapy in the treatment of advanced NSCLC. Unfortunately, drug resistance develops after initial benefit through a variety of mechanisms. Novel generation EGFR and ALK inhibitors are currently in advanced clinical development and are producing encouraging results in patients with acquired resistance to previous generation agents. The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations or ALK rearrangements is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC. PMID:26327924

  2. Guidelines for delineation of lymphatic clinical target volumes for high conformal radiotherapy: head and neck region

    PubMed Central

    2011-01-01

    The success of radiotherapy depends on the accurate delineation of the clinical target volume. The delineation of the lymph node regions has most impact, especially for tumors in the head and neck region. The purpose of this article was the development an atlas for the delineation of the clinical target volume for patients, who should receive radiotherapy for a tumor of the head and neck region. Literature was reviewed for localisations of the adjacent lymph node regions and their lymph drain in dependence of the tumor entity. On this basis the lymph node regions were contoured on transversal CT slices. The probability for involvement was reviewed and a recommendation for the delineation of the CTV was generated. PMID:21854585

  3. Preparation of near-infrared-labeled targeted contrast agents for clinical translation

    NASA Astrophysics Data System (ADS)

    Olive, D. Michael

    2011-03-01

    Targeted fluorophore-labeled contrast agents are moving toward translation to human surgical use. To prepare for future clinical use, we examined the performance of potential ligands targeting the epidermal growth factor receptor, α5β3 integrins, and GLUT transporters for their suitability as directed contrast agents. Each agent was labeled with IRDye 800CW, and near-infrared dye with excitation/emission wavelengths of 789/805 nm, which we determined had favorable toxicity characteristics. The probe molecules examined consisted of Affibodies, nanobodies, peptides, and the sugar 2-deoxy-D-glucose. Each probe was tested for specific and non-specific binding in cell based assays. All probe types showed good performance in mouse models for detecting either spontaneous tumors or tumor xenografts in vivo. Each of the probes tested show promise for future human clinical studies.

  4. Reactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications.

    PubMed

    Casas, Ana I; Dao, V Thao-Vi; Daiber, Andreas; Maghzal, Ghassan J; Di Lisa, Fabio; Kaludercic, Nina; Leach, Sonia; Cuadrado, Antonio; Jaquet, Vincent; Seredenina, Tamara; Krause, Karl H; López, Manuela G; Stocker, Roland; Ghezzi, Pietro; Schmidt, Harald H H W

    2015-11-10

    Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear. We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach. Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired. Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic.

  5. Potential Therapeutic Strategies for Alzheimer's Disease Targeting or Beyond β-Amyloid: Insights from Clinical Trials

    PubMed Central

    Jia, Qiutian; Qing, Hong

    2014-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder with two hallmarks: β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer's disease. PMID:25136630

  6. Brain Malignancy Steering Committee clinical trials planning workshop: report from the Targeted Therapies Working Group.

    PubMed

    Alexander, Brian M; Galanis, Evanthia; Yung, W K Alfred; Ballman, Karla V; Boyett, James M; Cloughesy, Timothy F; Degroot, John F; Huse, Jason T; Mann, Bhupinder; Mason, Warren; Mellinghoff, Ingo K; Mikkelsen, Tom; Mischel, Paul S; O'Neill, Brian P; Prados, Michael D; Sarkaria, Jann N; Tawab-Amiri, Abdul; Trippa, Lorenzo; Ye, Xiaobu; Ligon, Keith L; Berry, Donald A; Wen, Patrick Y

    2015-02-01

    Glioblastoma is the most common primary brain malignancy and is associated with poor prognosis despite aggressive local and systemic therapy, which is related to a paucity of viable treatment options in both the newly diagnosed and recurrent settings. Even so, the rapidly increasing number of targeted therapies being evaluated in oncology clinical trials offers hope for the future. Given the broad range of possibilities for future trials, the Brain Malignancy Steering Committee convened a clinical trials planning meeting that was held at the Udvar-Hazy Center in Chantilly, Virginia, on September 19 and 20, 2013. This manuscript reports the deliberations leading up to the event from the Targeted Therapies Working Group and the results of the meeting.

  7. Network Analysis Reveals Sex- and Antibiotic Resistance-Associated Antivirulence Targets in Clinical Uropathogens

    PubMed Central

    2015-01-01

    Increasing antibiotic resistance among uropathogenic Escherichia coli (UPEC) is driving interest in therapeutic targeting of nonconserved virulence factor (VF) genes. The ability to formulate efficacious combinations of antivirulence agents requires an improved understanding of how UPEC deploy these genes. To identify clinically relevant VF combinations, we applied contemporary network analysis and biclustering algorithms to VF profiles from a large, previously characterized inpatient clinical cohort. These mathematical approaches identified four stereotypical VF combinations with distinctive relationships to antibiotic resistance and patient sex that are independent of traditional phylogenetic grouping. Targeting resistance- or sex-associated VFs based upon these contemporary mathematical approaches may facilitate individualized anti-infective therapies and identify synergistic VF combinations in bacterial pathogens. PMID:26985454

  8. Laser Coupling to Reduced-Scale Targets at the Early Light Program of the National Ignition Facility

    SciTech Connect

    Hinkel, D E; Schneider, M B; Baldis, H A; Bower, D; Campbell, K M; Celeste, J R; Compton, S; Costa, R; Dewald, E L; Dixit, S; Eckart, M J; Eder, D C; Edwards, M J; Ellis, A; Emig, J; Froula, D H; Glenzer, S H; Hargrove, D; Haynam, C A; Heeter, R F; Holder, J P; Holtmeier, G; James, L; Jancaitis, K S; Kalantar, D H; Kauffman, R L; Kimbrough, J; Kirkwood, R K; Koniges, A E; Kamperschroer, J; Landen, O L; Landon, M; Langdon, A B; Lee, F D; MacGowan, B J; MacKinnon, A J; Manes, K R; May, M J; McDonald, J W; Munro, D H; Murray, J R; Niemann, C; Pellinen, D; Rekow, V; Ruppe, J A; Schein, J; Shepherd, R; Singh, M S; Springer, P T; Still, C H; Suter, L J; Turner, R E; Wallace, R J; Warrick, A; Watts, P; Weber, F; Williams, E A; Young, B K; Young, P E

    2004-11-18

    A platform for analysis of material properties under extreme conditions, where a sample is bathed in radiation with a high temperature, is under development. This hot environment is produced with a laser by depositing maximum energy into a small, high-Z can. Such targets were recently included in an experimental campaign using the first four of the 192 beams of the National Ignition Facility, under construction at the University of California Lawrence Livermore National Laboratory. These targets demonstrate good laser coupling, reaching a radiation temperature of 340 eV. In addition, there is a unique wavelength dependence of the Raman backscattered light that is consistent with Brillouin backscatter of Raman forward scatter [A. B. Langdon and D. E. Hinkel, Physical Review Letters 89, 015003 (2002)]. Finally, novel diagnostic capabilities indicate that 20% of the direct backscatter from these reduced-scale targets is in the polarization orthogonal to that of the incident light.

  9. Hemodialysis in a satellite unit: clinical performance target attainment and health-related quality of life.

    PubMed

    Diamant, Michael J; Young, Ann; Gallo, Kerri; Xi, Wang; Suri, Rita S; Garg, Amit X; Moist, Louise M

    2011-07-01

    In Canada, patients are increasingly receiving hemodialysis (HD) in satellite units, which are closer to their community but further from tertiary care hospitals and their nephrologists. The process of care is different in the satellites with fewer visits from nephrologists and reliance on remote communication. The objective of this study is to compare clinical performance target attainment and health-related quality of life (HRQOL) in patients receiving HD in satellite versus in-center units. The London Health Sciences Centre in London, Ontario, Canada, has both tertiary care center and satellite HD units. All eligible patients who received dialysis treatment at one of these units as of July 24, 2008, were enrolled into a cross-sectional study (n = 522). Patient attainment of hemoglobin, albumin, calcium-phosphate (Ca-P) product, Kt/V, and vascular access targets were compared. Participants were also administered the Kidney Disease Quality of Life Short-Form questionnaire. Satellite patients were more likely to attain clinical performance targets for albumin (adjusted odds ratio [OR] = 4.87 [95% confidence interval [CI]: 2.13 to 11.14]), hemoglobin (OR = 1.59 [95% CI: 1.08 to 2.35]), and Ca-P product (OR = 2.02 [95% CI: 1.14 to 3.60]), as well as for multiple targets (P < 0.05). HRQOL scores were largely similar between groups. Patients receiving HD in a satellite unit were just as likely, or more likely, to demonstrate attainment of clinical performance targets as those dialyzing in-center, while maintaining a similar HRQOL. This supports the increased use of satellite units to provide care closer to the patient's community.

  10. Clinical Evaluation of Targeting Accuracy of Gamma Knife Radiosurgery in Trigeminal Neuralgia

    SciTech Connect

    Massager, Nicolas Abeloos, Laurence; Devriendt, Daniel; Op de Beeck, Marc; Levivier, Marc

    2007-12-01

    Purpose: The efficiency of radiosurgery is related to its highly precise targeting. We assessed clinically the targeting accuracy of radiosurgical treatment with the Leksell Gamma Knife for trigeminal neuralgia. We also studied the applied radiation dose within the area of focal contrast enhancement on the trigeminal nerve root following radiosurgery. Methods and Materials: From an initial group of 78 patients with trigeminal neuralgia treated with gamma knife radiosurgery using a 90-Gy dose, we analyzed a subgroup of 65 patients for whom 6-month follow-up MRI showed focal contrast enhancement of the trigeminal nerve. Follow-up MRI was spatially coregistered to the radiosurgical planning MRI. Target accuracy was assessed from deviation of the coordinates of the intended target compared with the center of enhancement on postoperative MRI. Radiation dose delivered at the borders of contrast enhancement was evaluated. Results: The median deviation of the coordinates between the intended target and the center of contrast enhancement was 0.91 mm in Euclidean space. The radiation doses fitting within the borders of the contrast enhancement of the trigeminal nerve root ranged from 49 to 85 Gy (median value, 77 {+-} 8.7 Gy). Conclusions: The median deviation found in clinical assessment of gamma knife treatment for trigeminal neuralgia is low and compatible with its high rate of efficiency. Focal enhancement of the trigeminal nerve after radiosurgery occurred in 83% of our patients and was not associated with clinical outcome. Focal enhancement borders along the nerve root fit with a median dose of 77 {+-} 8.7 Gy.

  11. Targeted Delivery System of Nanobiomaterials in Anticancer Therapy: From Cells to Clinics

    PubMed Central

    Jin, Su-Eon; Jin, Hyo-Eon; Hong, Soon-Sun

    2014-01-01

    Targeted delivery systems of nanobiomaterials are necessary to be developed for the diagnosis and treatment of cancer. Nanobiomaterials can be engineered to recognize cancer-specific receptors at the cellular levels and to deliver anticancer drugs into the diseased sites. In particular, nanobiomaterial-based nanocarriers, so-called nanoplatforms, are the design of the targeted delivery systems such as liposomes, polymeric nanoparticles/micelles, nanoconjugates, norganic materials, carbon-based nanobiomaterials, and bioinspired phage system, which are based on the nanosize of 1–100 nm in diameter. In this review, the design and the application of these nanoplatforms are discussed at the cellular levels as well as in the clinics. We believe that this review can offer recent advances in the targeted delivery systems of nanobiomaterials regarding in vitro and in vivo applications and the translation of nanobiomaterials to nanomedicine in anticancer therapy. PMID:24672796

  12. Immunology in the clinic review series; focus on cancer: glycolipids as targets for tumour immunotherapy.

    PubMed

    Durrant, L G; Noble, P; Spendlove, I

    2012-02-01

    Research into aberrant glycosylation and over-expression of glycolipids on the surface of the majority of cancers, coupled with a knowledge of glycolipids as functional molecules involved in a number of cellular physiological pathways, has provided a novel area of targets for cancer immunotherapy. This has resulted in the development of a number of vaccines and monoclonal antibodies that are showing promising results in recent clinical trials.

  13. Challenges in the design of clinically useful brain-targeted drug nanocarriers.

    PubMed

    Costantino, L; Boraschi, D; Eaton, M

    2014-01-01

    Nowadays, the delivery of drugs by means of intravenously administered nanosized drug carriers - polymerdrug conjugates, liposomes and micelles, is technically possible. These delivery systems are mainly designed for tumour therapy, and accumulate passively into tumours by means of the well known EPR effect. Targeted nanocarriers, that additionally contain ligands for receptors expressed on cell surfaces, are also widely studied but products of this kind are not marketed, and only a few are in clinical trial. Polymeric nanoparticles (Np) able to deliver drugs to the CNS were pioneered in 1995; a number of papers have been published dealing with brain-targeted drug delivery using polymeric Np able to cross the BBB, mainly for the treatment of brain tumours. At present, however, the translation potential of these Np seems to have been exceeded by targeted liposomes, a platform based on a proven technology. This drug delivery system entered clinical trials soon after its discovery, while the challenges in formulation, characterization and manufacturing of brain-targeted polymeric Np and the cost/benefit ratio could be the factors that have prevented their development. A key issue is that it is virtually impossible to define the in vivo fate of polymers, especially in the brain, which is a regulatory requirement; perhaps this is why no progress has been made. The most advanced Np for brain tumours treatment will be compared here with the published data available for those in clinical trial for tumours outside the CNS, to highlight the knowledge gaps that still penalise these delivery systems. At present, new approaches for brain tumours are emerging, such as lipid Np or the use of monoclonal antibody (mAb)-drug conjugates, which avoid polymers. The success or failure in the approval of the polymeric Np currently in clinical trials will certainly affect the field. At present, the chances of their approval appear to be very low.

  14. CPTAC Team Releases Targeted Proteomic Assays for Ovarian Cancer | Office of Cancer Clinical Proteomics Research

    Cancer.gov

    Pacific Northwest National Laboratory (PNNL) investigators in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute (NCI), announces the public release of 98 targeted mass spectrometry-based assays for ovarian cancer research studies.  Chosen based on proteogenomic observations from the recently published multi-institutional collaborative project between PNNL and Johns Hopkins University that comprehensively examined the collections of proteins in the tumors of ovarian cancer patients (highlighted in a paper in

  15. MicroRNA-141 Targets Sirt1 and Inhibits Autophagy to Reduce HBV Replication.

    PubMed

    Yang, Ying; Liu, Yanning; Xue, Jihua; Yang, Zhenggang; Shi, Yu; Shi, Yixian; Lou, Guohua; Wu, Shanshan; Qi, Jinjin; Liu, Weixia; Chen, Zhi; Wang, Jing

    2017-01-01

    About 400 million individuals are chronically infected with hepatitis B virus, at high risk of developing liver cirrhosis and hepatocellular carcinoma. Recent studies have demonstrated an interaction between hepatitis B virus replication and autophagy activity of hepatocytes. In the present study, we aimed to investigate the role of miR-141 in regulating autophagy and hepatitis B virus replication. The expression of HBV-DNA, miR-141 and Sirt1 mRNA was determined by quantitative real-time PCR analysis. The expression of HBsAg and HBeAg was determined by ELISA. Western blotting was performed to detect protein expression. The LC3 puncta was determined by immunofluorescence. To test whether miR-141 directly regulate the expression level of Sirt1 mRNA, dual-luciferase reporter gene assay was performed. In vitro studies showed that miR-141 mimic inhibited the autophagic response, hepatitis B virus and the expression of Sirt1 in hepatocytes. And transfection with miR-141 inhibitor enhanced autophagic response and Sirt1 expression. The autophagy induced by overexpression of Sirt1 was inhibited by miR-141 mimic. In addition, miR-141 mimic also decreased the expression of Sirt1 mRNA. Sirt1 was predicted as a potential miR-141 target by bioinformatic analysis of its 3'-UTR, and confirmed by luciferase reporter assays which analyzing the interaction of miR-141 with the wild- type or the mutated Sirt1 3'-UTR. We have therefore demonstrated a role of miR-141 in regulating autophagy-mediated hepatitis B virus inhibition by targeting Sirt1, and may provide potential targets for drug development. © 2017 The Author(s) Published by S. Karger AG, Basel.

  16. Does targeting key-containers effectively reduce Aedes aegypti population density?

    PubMed

    Maciel-de-Freitas, Rafael; Lourenço-de-Oliveira, Ricardo

    2011-08-01

    The elimination of Aedes aegypti breeding sites has been broadly adopted worldwide to keep vector population density below a critical threshold. We observed the effectiveness of targeting the most productive containers on adult A. aegypti females density, which was evaluated weekly. Adult mosquitoes were collected weekly over 55 weeks and pupal surveys were done in intervals of 4 months to determine container productivity and guidelines for interventions. Pupal surveys indicated that water tanks (72% of pupae in first survey) and metal drums (30.7% of pupae in second survey) were the most productive container types. We observed a dramatic but short-term decrease in weekly adult female A. aegypti density after covering 733 water tanks with nylon net. A long-term decrease in female adult population density was achieved only when we covered both water tanks and metal drums. Overall, pupae abundance and pupae standing crop diminished after netting water tanks and metal drums. Pupae per person, per hectare and per house decreased gradually between the first and the third pupal surveys, suggesting that targeting the most productive container types (water tanks and metal drums) produced a reduction in adult population density and infestation levels. Overall, targeting the most productive container types caused the adult mosquito density to decrease over time, supporting the assumption that this intervention is an effective tool for dengue control. However, this effect was observed only when both water tanks and metal drums were covered, possibly due to the functional similarity between these container types, which are large, often shaded, perennial water storage containers. © 2011 Blackwell Publishing Ltd.

  17. Calcineurin Inhibition at the Clinical Phase of Prion Disease Reduces Neurodegeneration, Improves Behavioral Alterations and Increases Animal Survival

    PubMed Central

    Mukherjee, Abhisek; Morales-Scheihing, Diego; Gonzalez-Romero, Dennisse; Green, Kristi; Taglialatela, Giulio; Soto, Claudio

    2010-01-01

    Prion diseases are fatal neurodegenerative disorders characterized by a long pre-symptomatic phase followed by rapid and progressive clinical phase. Although rare in humans, the unconventional infectious nature of the disease raises the potential for an epidemic. Unfortunately, no treatment is currently available. The hallmark event in prion diseases is the accumulation of a misfolded and infectious form of the prion protein (PrPSc). Previous reports have shown that PrPSc induces endoplasmic reticulum stress and changes in calcium homeostasis in the brain of affected individuals. In this study we show that the calcium-dependent phosphatase Calcineurin (CaN) is hyperactivated both in vitro and in vivo as a result of PrPSc formation. CaN activation mediates prion-induced neurodegeneration, suggesting that inhibition of this phosphatase could be a target for therapy. To test this hypothesis, prion infected wild type mice were treated intra-peritoneally with the CaN inhibitor FK506 at the clinical phase of the disease. Treated animals exhibited reduced severity of the clinical abnormalities and increased survival time compared to vehicle treated controls. Treatment also led to a significant increase in the brain levels of the CaN downstream targets pCREB and pBAD, which paralleled the decrease of CaN activity. Importantly, we observed a lower degree of neurodegeneration in animals treated with the drug as revealed by a higher number of neurons and a lower quantity of degenerating nerve cells. These changes were not dependent on PrPSc formation, since the protein accumulated in the brain to the same levels as in the untreated mice. Our findings contribute to an understanding of the mechanism of neurodegeneration in prion diseases and more importantly may provide a novel strategy for therapy that is beneficial at the clinical phase of the disease. PMID:20949081

  18. A Miniaturized Chemical Proteomic Approach for Target Profiling of Clinical Kinase Inhibitors in Tumor Biopsies

    PubMed Central

    Chamrád, Ivo; Rix, Uwe; Stukalov, Alexey; Gridling, Manuela; Parapatics, Katja; Müller, André C.; Altiok, Soner; Colinge, Jacques; Superti-Furga, Giulio; Haura, Eric B.; Bennett, Keiryn L.

    2014-01-01

    While targeted therapy based on the idea of attenuating the activity of a preselected, therapeutically relevant protein has become one of the major trends in modern cancer therapy, no truly specific targeted drug has been developed and most clinical agents have displayed a degree of polypharmacology. Therefore, the specificity of anticancer therapeutics has emerged as a highly important but severely underestimated issue. Chemical proteomics is a powerful technique combining postgenomic drug-affinity chromatography with high-end mass spectrometry analysis and bioinformatic data processing to assemble a target profile of a desired therapeutic molecule. Due to high demands on the starting material, however, chemical proteomic studies have been mostly limited to cancer cell lines. Herein, we report a down-scaling of the technique to enable the analysis of very low abundance samples, as those obtained from needle biopsies. By a systematic investigation of several important parameters in pull-downs with the multikinase inhibitor bosutinib, the standard experimental protocol was optimized to 100 µg protein input. At this level, more than 30 well-known targets were detected per single pull-down replicate with high reproducibility. Moreover, as presented by the comprehensive target profile obtained from miniaturized pull-downs with another clinical drug, dasatinib, the optimized protocol seems to be extendable to other drugs of interest. Sixty distinct human and murine targets were finally identified for bosutinib and dasatinib in chemical proteomic experiments utilizing core needle biopsy samples from xenotransplants derived from patient tumor tissue. Altogether, the developed methodology proves robust and generic and holds many promises for the field of personalized health care. PMID:23901793

  19. Neuron-targeted copolymers with sheddable shielding blocks synthesized using a reducible, RAFT-ATRP double-head agent.

    PubMed

    Wei, Hua; Schellinger, Joan G; Chu, David S H; Pun, Suzie H

    2012-10-10

    Adaptation of in vitro optimized polymeric gene delivery systems for in vivo use remains a significant challenge. Most in vivo applications require particles that are sterically stabilized, which significantly compromises transfection efficiency of materials shown to be effective in vitro. We present a multifunctional well-defined block copolymer that forms particles useful for cell targeting, reversible shielding, endosomal release, and DNA condensation. We show that targeted and stabilized particles retain transfection efficiencies comparable to the nonstabilized formulations. A novel, double-head agent that combines a reversible addition-fragmentation chain transfer agent and an atom transfer radical polymerization initiator through a disulfide linkage is used to synthesize a well-defined cationic block copolymer containing a hydrophilic oligoethyleneglycol and a tetraethylenepentamine-grafted polycation. This material effectively condenses plasmid DNA into salt-stable particles that deshield under intracellular reducing conditions. In vitro transfection studies show that the reversibly shielded polyplexes afford up to 10-fold higher transfection efficiencies than the analogous stably shielded polymer in four different mammalian cell lines. To compensate for reduced cell uptake caused by the hydrophilic particle shell, a neuron-targeting peptide is further conjugated to the terminus of the block copolymer. Transfection of neuron-like, differentiated PC-12 cells demonstrates that combining both targeting and deshielding in stabilized particles yields formulations that are suitable for in vivo delivery without compromising in vitro transfection efficiency and are thus promising carriers for in vivo gene delivery applications.

  20. CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts

    PubMed Central

    Marangoni, E; Lecomte, N; Durand, L; de Pinieux, G; Decaudin, D; Chomienne, C; Smadja-Joffe, F; Poupon, M-F

    2009-01-01

    CD44 is a marker of tumour-initiating cells and is upregulated in invasive breast carcinoma; however, its role in the cancer progression is unknown. Here, we show that antibody-mediated CD44-targeting in human breast cancer xenografts (HBCx) significantly reduces tumour growth and that this effect is associated to induction of growth-inhibiting factors. Moreover, treatment with this antibody prevents tumour relapse after chemotherapy-induced remission in a basal-like HBCx. PMID:19240712

  1. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update.

    PubMed

    Takebe, Naoko; Miele, Lucio; Harris, Pamela Jo; Jeong, Woondong; Bando, Hideaki; Kahn, Michael; Yang, Sherry X; Ivy, S Percy

    2015-08-01

    During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents.

  2. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

    PubMed Central

    Miele, Lucio; Harris, Pamela Jo; Jeong, Woondong; Bando, Hideaki; Kahn, Michael; Yang, Sherry X.

    2015-01-01

    During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents. PMID:25850553

  3. The Potential and Hurdles of Targeted Alpha Therapy – Clinical Trials and Beyond

    PubMed Central

    Elgqvist, Jörgen; Frost, Sofia; Pouget, Jean-Pierre; Albertsson, Per

    2013-01-01

    This article presents a general discussion on what has been achieved so far and on the possible future developments of targeted alpha (α)-particle therapy (TAT). Clinical applications and potential benefits of TAT are addressed as well as the drawbacks, such as the limited availability of relevant radionuclides. Alpha-particles have a particular advantage in targeted therapy because of their high potency and specificity. These features are due to their densely ionizing track structure and short path length. The most important consequence, and the major difference compared with the more widely used β−-particle emitters, is that single targeted cancer cells can be killed by self-irradiation with α-particles. Several clinical trials on TAT have been reported, completed, or are on-going: four using 213Bi, two with 211At, two with 225Ac, and one with 212Pb/212Bi. Important and conceptual proof-of-principle of the therapeutic advantages of α-particle therapy has come from clinical studies with 223Ra-dichloride therapy, showing clear benefits in castration-resistant prostate cancer. PMID:24459634

  4. The potential and hurdles of targeted alpha therapy - clinical trials and beyond.

    PubMed

    Elgqvist, Jörgen; Frost, Sofia; Pouget, Jean-Pierre; Albertsson, Per

    2014-01-14

    This article presents a general discussion on what has been achieved so far and on the possible future developments of targeted alpha (α)-particle therapy (TAT). Clinical applications and potential benefits of TAT are addressed as well as the drawbacks, such as the limited availability of relevant radionuclides. Alpha-particles have a particular advantage in targeted therapy because of their high potency and specificity. These features are due to their densely ionizing track structure and short path length. The most important consequence, and the major difference compared with the more widely used β(-)-particle emitters, is that single targeted cancer cells can be killed by self-irradiation with α-particles. Several clinical trials on TAT have been reported, completed, or are on-going: four using (213)Bi, two with (211)At, two with (225)Ac, and one with (212)Pb/(212)Bi. Important and conceptual proof-of-principle of the therapeutic advantages of α-particle therapy has come from clinical studies with (223)Ra-dichloride therapy, showing clear benefits in castration-resistant prostate cancer.

  5. Reducing mortality risk by targeting specific air pollution sources: Suva, Fiji.

    PubMed

    Isley, C F; Nelson, P F; Taylor, M P; Stelcer, E; Atanacio, A J; Cohen, D D; Mani, F S; Maata, M

    2017-08-29

    Health implications of air pollution vary dependent upon pollutant sources. This work determines the value, in terms of reduced mortality, of reducing ambient particulate matter (PM2.5: effective aerodynamic diameter 2.5μm or less) concentration due to different emission sources. Suva, a Pacific Island city with substantial input from combustion sources, is used as a case-study. Elemental concentration was determined, by ion beam analysis, for PM2.5 samples from Suva, spanning one year. Sources of PM2.5 have been quantified by positive matrix factorisation. A review of recent literature has been carried out to delineate the mortality risk associated with these sources. Risk factors have then been applied for Suva, to calculate the possible mortality reduction that may be achieved through reduction in pollutant levels. Higher risk ratios for black carbon and sulphur resulted in mortality predictions for PM2.5 from fossil fuel combustion, road vehicle emissions and waste burning that surpass predictions for these sources based on health risk of PM2.5 mass alone. Predicted mortality for Suva from fossil fuel smoke exceeds the national toll from road accidents in Fiji. The greatest benefit for Suva, in terms of reduced mortality, is likely to be accomplished by reducing emissions from fossil fuel combustion (diesel), vehicles and waste burning. Copyright © 2017. Published by Elsevier B.V.

  6. Impact of strategies to reduce polypharmacy on clinically relevant endpoints: a systematic review and meta‐analysis

    PubMed Central

    Abuzahra, Muna E.; Keller, Sophie; Mann, Eva; Faller, Barbara; Sommerauer, Christina; Höck, Jennifer; Löffler, Christin; Köchling, Anna; Schuler, Jochen; Flamm, Maria; Sönnichsen, Andreas

    2016-01-01

    Aim The aim of the present study was to explore the impact of strategies to reduce polypharmacy on mortality, hospitalization and change in number of drugs. Methods Systematic review and meta‐analysis: a systematic literature search targeting patients ≥65 years with polypharmacy (≥4 drugs), focusing on patient‐relevant outcome measures, was conducted. We included controlled studies aiming to reduce polypharmacy. Two reviewers independently assessed studies for eligibility, extracted data and evaluated study quality. Results Twenty‐five studies, including 10 980 participants, were included, comprising 21 randomized controlled trials and four nonrandomized controlled trials. The majority of the included studies aimed at improving quality or the appropriateness of prescribing by eliminating inappropriate and non‐evidence‐based drugs. These strategies to reduce polypharmacy had no effect on all‐cause mortality (odds ratio 1.02; 95% confidence interval 0.84, 1.23). Only single studies found improvements, in terms of reducing the number of hospital admissions, in favour of the intervention group. At baseline, patients were taking, on average, 7.4 drugs in both the intervention and the control groups. At follow‐up, the weighted mean number of drugs was reduced (−0.2) in the intervention group but increased (+0.2) in controls. Conclusions There is no convincing evidence that the strategies assessed in the present review are effective in reducing polypharmacy or have an impact on clinically relevant endpoints. Interventions are complex; it is still unclear how best to organize and implement them to achieve a reduction in inappropriate polypharmacy. There is therefore a need to develop more effective strategies to reduce inappropriate polypharmacy and to test them in large, pragmatic randomized controlled trials on effectiveness and feasibility. PMID:27059768

  7. Novel target for high-risk neuroblastoma identified in pre-clinical research | Center for Cancer Research

    Cancer.gov

    Pre-clinical research by investigators at the Center for Cancer Research and their colleagues have identified a number of novel epigenetic targets for high-risk neuroblastoma and validated a promising new targeted inhibitor in pre-clinical models.  Read more...

  8. Setting cumulative emissions targets to reduce the risk of dangerous climate change

    NASA Astrophysics Data System (ADS)

    Zickfeld, K.; Eby, M.; Matthews, D.; Weaver, A. J.

    2008-12-01

    Preventing "dangerous anthropogenic interference with the climate system" requires stabilization of atmospheric greenhouse gas concentrations and substantial reductions in anthropogenic emissions. Here we present a novel approach to coupled climate-carbon cycle modelling which allows one to estimate the probability that any given level of greenhouse gas emissions will exceed specified long-term global mean temperature targets for "dangerous anthropogenic interference", taking into consideration uncertainties in climate sensitivity and the carbon cycle response to climate change. Results obtained within this framework can serve as a basis for selecting a greenhouse gas emissions level given a global mean temperature target and an overshoot probability that society is willing to accept. For instance, we show that in order to stabilize global mean temperature at 2°C above pre-industrial levels with a probability of 0.66, cumulative CO2-equivalent emissions after 2000 must not exceed a best estimate of about 640 PgC (uncertainty range 280-930 PgC), independently of the path taken to stabilization.

  9. Dual actions of albumin packaging and tumor targeting enhance the antitumor efficacy and reduce the cardiotoxicity of doxorubicin in vivo

    PubMed Central

    Zheng, Ke; Li, Rui; Zhou, Xiaolei; Hu, Ping; Zhang, Yaxin; Huang, Yunmei; Chen, Zhuo; Huang, Mingdong

    2015-01-01

    Doxorubicin (DOX) is an effective chemotherapy drug used to treat different types of cancers. However, DOX has severe side effects, especially life-threatening cardiotoxicity. We herein report a new approach to reduce the toxicity of DOX by embedding DOX inside human serum albumin (HSA). HSA is further fused by a molecular biology technique with a tumor-targeting agent, amino-terminal fragment of urokinase (ATF). ATF binds with a high affinity to urokinase receptor, which is a cell-surface receptor overexpressed in many types of tumors. The as-prepared macromolecule complex (ATF–HSA:DOX) was not as cytotoxic as free DOX to cells in vitro, and was mainly localized in cell cytosol in contrast to DOX that was localized in cell nuclei. However, in tumor-bearing mice, ATF–HSA:DOX was demonstrated to have an enhanced tumor-targeting and antitumor efficacy compared with free DOX. More importantly, histopathological examinations of the hearts from the mice treated with ATF–HSA:DOX showed a significantly reduced cardiotoxicity compared with hearts from mice treated with free DOX. These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening its antitumor efficacy. Such a tumor-targeted albumin packaging strategy can also be applied to other antitumor drugs. PMID:26346331

  10. Targeting FAK in human cancer: from finding to first clinical trials

    PubMed Central

    Golubovskaya, Vita M

    2014-01-01

    It is twenty years since Focal Adhesion Kinase (FAK) was found to be overexpressed in many types of human cancer. FAK plays an important role in adhesion, spreading, motility, invasion, metastasis, survival, angiogenesis, and recently has been found to play an important role as well in epithelial to mesenchymal transition (EMT), cancer stem cells and tumor microenvironment. FAK has kinase-dependent and kinase independent scaffolding, cytoplasmic and nuclear functions. Several years ago FAK was proposed as a potential therapeutic target; the first clinical trials were just reported, and they supported further studies of FAK as a promising therapeutic target. This review discusses the main functions of FAK in cancer, and specifically focuses on recent novel findings on the role of FAK in cancer stem cells, microenvironment, epithelial-to-mesenchymal transition, invasion, metastasis, and also highlight new approaches of targeting FAK and critically discuss challenges that lie ahead for its targeted therapeutics. The review provides a summary of translational approaches of FAK-targeted and combination therapies and outline perspectives and future directions of FAK research. PMID:24389213

  11. Targeting and Reducing Noise Trauma-Induced Tinnitus and Hearing Loss

    DTIC Science & Technology

    2010-08-01

    various times (right away to several days) and with different regimens ( pulse or taper) to rats following noise-trauma. We report on the effect of...reliable presence of another stimulus just before the burst will reduce the startle reflex (this is called pre- pulse inhibition). In our case, a...randomly. For a rat with normal hearing the ratio of gap to nogap startle reflex (whether measured by maximal amplitude or RMS of the startle

  12. Clinical interventions to reduce secondhand smoke exposure among pregnant women: a systematic review.

    PubMed

    Tong, Van T; Dietz, Patricia M; Rolle, Italia V; Kennedy, Sara M; Thomas, William; England, Lucinda J

    2015-05-01

    To conduct a systematic review of clinical interventions to reduce secondhand smoke (SHS) exposure among non-smoking pregnant women. We searched 16 databases for publications from 1990 to January 2013, with no language restrictions. Papers were included if they met the following criteria: (1) the study population included non-smoking pregnant women exposed to SHS, (2) the clinical interventions were intended to reduce SHS exposure at home, (3) the study included a control group and (4) outcomes included either reduced SHS exposure of non-smoking pregnant women at home or quit rates among smoking partners during the pregnancy of the woman. Two coders independently reviewed each abstract or full text to identify eligible papers. Two abstractors independently coded papers based on US Preventive Services Task Force criteria for study quality (good, fair, poor), and studies without biochemically-verified outcome measures were considered poor quality. From 4670 papers, we identified five studies that met our inclusion criteria: four focused on reducing SHS exposure among non-smoking pregnant women, and one focused on providing cessation support for smoking partners of pregnant women. All were randomised controlled trials, and all reported positive findings. Three studies were judged poor quality because outcome measures were not biochemically-verified, and two were considered fair quality. Clinical interventions delivered in prenatal care settings appear to reduce SHS exposure, but study weaknesses limit our ability to draw firm conclusions. More rigorous studies, using biochemical validation, are needed to identify strategies for reducing SHS exposure in pregnant women. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. Carbonyl-reducing enzymes as targets of a drug-immobilised affinity carrier.

    PubMed

    Andrýs, Rudolf; Zemanová, Lucie; Lenčo, Juraj; Bílková, Zuzana; Wsól, Vladimír

    2015-06-05

    Proteins, peptides and nucleic acids are commonly isolated and purified in almost all bioscience laboratories. Methods based on molecular recognition are currently the most powerful tool in separation processes due to their selectivity and recovery. The aim of this study was to prove the versatility and the ability of an affinity carrier containing the immobilised ligand oracin (previously developed by our workgroup) to selectively bind carbonyl-reducing enzymes. These enzymes play an important role in metabolic pathways of various endogenic compounds and xenobiotics. Many important drugs, such as doxorubicin, daunorubicin, haloperidol and the model anticancer drug oracin, are metabolised by carbonyl-reducing enzymes. The functionality of the presented carrier was demonstrated with pure recombinant enzymes (AKR1A1, AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C3, AKR1C4, CBR1 and CBR3) as well as with two model biological samples (cell extract from genetically modified Escherichia coli and pre-purified human liver cytosol). Enzymes that show an affinity toward oracin were efficiently captured, gently eluted using 150 mM ammonium hydroxide and subsequently identified by MS. The method is highly selective and robust and may be applied to the purification and identification of various carbonyl-reducing enzymes from any biological sample. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Micro–RNA-126 Reduces the Blood Thrombogenicity in Diabetes Mellitus via Targeting of Tissue Factor

    PubMed Central

    Witkowski, Marco; Weithauser, Alice; Tabaraie, Termeh; Steffens, Daniel; Kränkel, Nicolle; Witkowski, Mario; Stratmann, Bernd; Tschoepe, Diethelm; Landmesser, Ulf

    2016-01-01

    Objective— Diabetes mellitus involves vascular inflammatory processes and is a main contributor to cardiovascular mortality. Notably, heightened levels of circulating tissue factor (TF) account for the increased thrombogenicity and put those patients at risk for thromboembolic events. Here, we sought to investigate the role of micro-RNA (miR)–driven TF expression and thrombogenicity in diabetes mellitus. Approach and Results— Plasma samples of patients with diabetes mellitus were analyzed for TF protein and activity as well as miR-126 expression before and after optimization of the antidiabetic treatment. We found low miR-126 levels to be associated with markedly increased TF protein and TF-mediated thrombogenicity. Reduced miR-126 expression was accompanied by increased vascular inflammation as evident from the levels of vascular adhesion molecule-1 and fibrinogen, as well as leukocyte counts. With optimization of the antidiabetic treatment miR-126 levels increased and thrombogenicity was reduced. Using a luciferase reporter system, we demonstrated miR-126 to directly bind to the F3-3′-untranslated region, thereby reducing TF expression both on mRNA and on protein levels in human microvascular endothelial cells as well as TF mRNA and activity in monocytes. Conclusions— Circulating miR-126 exhibits antithrombotic properties via regulating post-transcriptional TF expression, thereby impacting the hemostatic balance of the vasculature in diabetes mellitus. PMID:27127202

  15. Micro-RNA-126 Reduces the Blood Thrombogenicity in Diabetes Mellitus via Targeting of Tissue Factor.

    PubMed

    Witkowski, Marco; Weithauser, Alice; Tabaraie, Termeh; Steffens, Daniel; Kränkel, Nicolle; Witkowski, Mario; Stratmann, Bernd; Tschoepe, Diethelm; Landmesser, Ulf; Rauch-Kroehnert, Ursula

    2016-06-01

    Diabetes mellitus involves vascular inflammatory processes and is a main contributor to cardiovascular mortality. Notably, heightened levels of circulating tissue factor (TF) account for the increased thrombogenicity and put those patients at risk for thromboembolic events. Here, we sought to investigate the role of micro-RNA (miR)-driven TF expression and thrombogenicity in diabetes mellitus. Plasma samples of patients with diabetes mellitus were analyzed for TF protein and activity as well as miR-126 expression before and after optimization of the antidiabetic treatment. We found low miR-126 levels to be associated with markedly increased TF protein and TF-mediated thrombogenicity. Reduced miR-126 expression was accompanied by increased vascular inflammation as evident from the levels of vascular adhesion molecule-1 and fibrinogen, as well as leukocyte counts. With optimization of the antidiabetic treatment miR-126 levels increased and thrombogenicity was reduced. Using a luciferase reporter system, we demonstrated miR-126 to directly bind to the F3-3'-untranslated region, thereby reducing TF expression both on mRNA and on protein levels in human microvascular endothelial cells as well as TF mRNA and activity in monocytes. Circulating miR-126 exhibits antithrombotic properties via regulating post-transcriptional TF expression, thereby impacting the hemostatic balance of the vasculature in diabetes mellitus. © 2016 The Authors.

  16. Targeting Alcohol Misuse: A Promising Strategy for Reducing Military Sexual Assaults?

    PubMed

    Farris, Coreen; Hepner, Kimberly A

    2015-03-20

    On the 2012 Workplace and Gender Relations Survey on Active Duty Service Members, 23 percent of female and 4 percent of male service members indicated that they had experienced a completed or attempted sexual assault during their military service. In addition, official numbers show no decline in sexual assaults, despite the implementation of sexual assault prevention programs across the U.S. Department of Defense (DoD). Alcohol misuse is also a problem in the military: One-third of active-duty service members reported binge drinking, a rate that compares unfavorably with that of their civilian counterparts. DoD has invested considerable resources in universal sexual assault prevention programs and social media campaigns, but evaluation results are not yet available, and the effectiveness of these programs is unclear. Research on civilian populations-particularly college students, who share some characteristics with junior enlisted personnel-could provide insights for DoD. For example, the research indicates a connection between alcohol and aggression, including sexual aggression. Alcohol can also have a range of effects on the risk of victimization-from a reduced awareness of risk indicators to incapacitation or unconsciousness. An extensive review of the existing research provides some guidance for how DoD can implement and evaluate efforts to reduce alcohol misuse as part of a larger strategy to reduce the incidence of sexual assault among members of the armed forces.

  17. Clinical immunotherapy of B-cell malignancy using CD19-targeted CAR T-cells.

    PubMed

    Maher, John

    2014-02-01

    The CD19 molecule is ubiquitously expressed throughout all stages of B-cell differentiation, but is not found on haemopoietic stem cells. Since most B-cell leukaemias and lymphomas retain CD19 expression, it represents an excellent target for immunotherapy of these malignant disorders. Over the past 10 years, compelling pre-clinical evidence has accrued to indicate that expression of a CD19-targeted chimeric antigen receptor (CAR) in peripheral blood T-cells exerts therapeutic efficacy in diverse models of B-cell malignancy. Building on this, clinical studies are ongoing in several centres in which autologous CD19-specific CAR T-cells are undergoing evaluation in patients with acute and chronic B-cell leukaemia and refractory lymphoma. Early data have generated considerable excitement, providing grounds to speculate that CAR-based immunotherapy will radically alter existing management paradigms in B-cell malignancy. The focus of this mini-review is to evaluate these emerging clinical data and to speculate on clinical prospects for this new therapeutic modality.

  18. Neurooncology clinical trial design for targeted therapies: Lessons learned from the North American Brain Tumor Consortium

    PubMed Central

    Chang, Susan M.; Lamborn, Kathleen R.; Kuhn, John G.; Yung, W.K. Alfred; Gilbert, Mark R.; Wen, Patrick Y.; Fine, Howard A.; Mehta, Minesh P.; DeAngelis, Lisa M.; Lieberman, Frank S.; Cloughesy, Timothy F.; Robins, H. Ian; Abrey, Lauren E.; Prados, Michael D.

    2008-01-01

    The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study. PMID:18559968

  19. Reducing impaired driving through the identification of Repeat Target Vehicles: A case study.

    PubMed

    Stewart, James

    2012-02-01

    One of the most persistent groups of impaired drivers that are seemingly unaffected by social pressure, moral appeals, and the fear of arrest is that of the repeat impaired driver. This smaller group accounts for a disproportionate number of all impaired driving trips, often with high blood alcohol contents. New approaches are needed to identify and deal with the repeat impaired driver. We propose a method based on the discovery that almost 10% of all impaired driving calls for service involve repeat vehicles. Using the number of times a vehicle appears in our data, the average time to repeat, and the personality characteristics of the repeat impaired driver, we are able to create a comprehensive and predictive description of a Repeat Target Vehicle (RTV). Our method provides an opportunity to explore new and innovative crime reduction strategies that were never before possible. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. COX-2 – A Novel Target for Reducing Tumor Angiogenesis and Metastasis | Center for Cancer Research

    Cancer.gov

    Angiogenesis is essential for tumor growth and metastasis, by supplying a steady stream of nutrients, removing waste, and providing tumor cells access to other sites in the body. The vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a key role in tumor-mediated angiogenesis, and this pathway is the target of monoclonal antibodies and tyrosine kinase inhibitors (TKIs) that have been approved to treat patients with cancer. Unfortunately, tumors can use alternative angiogenesis mechanisms to escape VEGF pathway blockade, but these alternate pathways are not well understood. Brad St. Croix, Ph.D., of CCR’s Mouse Cancer Genetics Program, along with Lihong Xu, Ph.D., a Postdoctoral Fellow in the St. Croix laboratory, and colleagues set out to identify VEGF-independent mediators of tumor angiogenesis.

  1. Targeting of DNA Damage Signaling Pathway Induced Senescence and Reduced Migration of Cancer cells.

    PubMed

    Gao, Ran; Singh, Rumani; Kaul, Zeenia; Kaul, Sunil C; Wadhwa, Renu

    2015-06-01

    The heat shock 70 family protein, mortalin, has pancytoplasmic distribution pattern in normal and perinuclear in cancer human cells. Cancer cells when induced to senesce by either chemicals or stress showed shift in mortalin staining pattern from perinuclear to pancytoplasmic type. Using such shift in mortalin staining as a reporter, we screened human shRNA library and identified nine senescence-inducing siRNA candidates. An independent Comparative Genomic Hybridization analysis of 35 breast cancer cell lines revealed that five (NBS1, BRCA1, TIN2, MRE11A, and KPNA2) of the nine genes located on chromosome regions identified as the gain of locus in more than 80% cell lines. By gene-specific PCR, these five genes were found to be frequently amplified in cancer cell lines. Bioinformatics revealed that the identified targets were connected to MRN (MRE11-RAD50-NBS1) complex, the DNA damage-sensing complex. We demonstrate that the identified shRNAs triggered DNA damage response and induced the expression of tumor suppressor protein p16(INK4A) causing growth arrest of cancer cells. Furthermore, cells showed decreased migration, mediated by decrease in matrix metalloproteases. Taken together, we demonstrate that the MRN complex is a potential target of cancer cell proliferation and migration, and staining pattern of mortalin could serve as an assay to identify senescence-inducing/anticancer reagents. © The Author 2014. Published by Oxford University Press on behalf of the Gerontological Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. Clinical efforts to reduce myocardial infarct size--the next step.

    PubMed

    Braunwald, Eugene

    2011-01-01

    Prompt myocardial reperfusion reduces infarct size in patients experiencing coronary occlusion. However, its clinical value is limited because reperfusion also causes ischemic myocardial reperfusion injury (IMRI). Considerable research to reduce IMRI has been conducted. Three interventions appear to be promising: 1) myocardial conditioning, which consists of repetitive occlusions of coronary or other arteries prior to or at the time of myocardial reperfusion; 2) the administration of cyclosporine A; and 3) the administration of adenosine. A plan for the testing of these interventions in patients with acute myocardial infarction is described.

  3. Precision Medicine for Molecularly Targeted Agents and Immunotherapies in Early-Phase Clinical Trials

    PubMed Central

    Lopez, Juanita; Harris, Sam; Roda, Desam; Yap, Timothy A

    2015-01-01

    Precision medicine in oncology promises the matching of genomic, molecular, and clinical data with underlying mechanisms of a range of novel anticancer therapeutics to develop more rational and effective antitumor strategies in a timely manner. However, despite the remarkable progress made in the understanding of novel drivers of different oncogenic processes, success rates for the approval of oncology drugs remain low with substantial fiscal consequences. In this article, we focus on how recent rapid innovations in technology have brought greater clarity to the biological and clinical complexities of different cancers and advanced the development of molecularly targeted agents and immunotherapies in clinical trials. We discuss the key challenges of identifying and validating predictive biomarkers of response and resistance using both tumor and surrogate tissues, as well as the hurdles associated with intratumor heterogeneity. Finally, we outline evolving strategies employed in early-phase trial designs that incorporate omics-based technologies. PMID:26609214

  4. Clinical relevance of access targets for elective dental treatment under general anesthesia in pediatrics.

    PubMed

    Chung, Sonia S; Casas, Michael J; Kenny, David J; Barrett, Edward J

    2010-01-01

    To evaluate the clinical relevance of access targets for elective dental procedures performed under general anesthesia at The Hospital for Sick Children in Toronto, Ontario, by assessing incremental changes in the burden of dental disease over wait times for such procedures. Children scheduled for elective dental procedures under general anesthesia were assigned a priority according to the dental diagnosis and the medical risk status. Each priority level was defined by a specific diagnostic code and access target (maximum acceptable wait time). The dental records of children who underwent dental procedures with general anesthesia between June 2005 and December 2008 were assessed retrospectively. A novel assessment scale was used to measure the cumulative burden of dental disease during the waiting period. A total of 378 children (age range 10 months to 17 years) met the inclusion criteria. Statistically significant correlations were identified between disease burden and wait times for priority group IV (access target 90 days) (p=0.004), for the entire sample (p<0.001), for children with advanced dental caries and low medical risk (p=0.005), for patients with comorbidities (p=0.036), for healthy patients (p<0.001), for females (p=0.014) and for males (p=0.008). The mean cumulative burden of disease over time did not differ between matched groups with and without comorbidity (p=0.38). A trend suggestive of increasing burden of dental disease for children with longer wait times for elective dental procedures involving general anesthesia was found, but it was not clinically significant. Refinements in the assessment scale and a better understanding of the natural history of dental disease will likely be useful in developing clinically relevant access targets.

  5. Rapid molecular determination of methicillin resistance in staphylococcal bacteraemia improves early targeted antibiotic prescribing: a randomized clinical trial.

    PubMed

    Emonet, S; Charles, P G; Harbarth, S; Stewardson, A J; Renzi, G; Uckay, I; Cherkaoui, A; Rougemont, M; Schrenzel, J

    2016-11-01

    Empiric therapy of methicillin-susceptible Staphylococcus aureus (MSSA) infections with vancomycin is associated with poorer outcome than targeted therapy with β-lactams. Our objective was to evaluate whether rapid determination of methicillin resistance shortens the time from Gram stain to targeted antimicrobial therapy in staphylococcal bacteraemia, thereby reducing vancomycin overuse. This was a single-centre open parallel RCT. Gram-positive cocci in clusters in positive blood culture underwent real-time PCR for rapid species and methicillin resistance determination parallel to conventional microbiology. Patients were randomized 1:1 so that clinicians would be informed of PCR results (intervention group) or not (control group). Eighty-nine patients (intervention 48, control 41) were analysed. MRSA was identified in seven patients, MSSA in 46, and CoNS in 36. PCR results were highly concordant (87/89) with standard microbiology. Median time (hours) from Gram stain to transmission of methicillin-susceptibility was 3.9 (2.8-4.3) vs. 25.4 (24.4-26-7) in intervention vs. control groups (p <0.001). Median time (hours) from Gram stain to targeted treatment was similar for 'all staphylococci' [6 (3.8-10) vs. 8 (1-36) p 0.13] but shorter in the intervention group when considering S. aureus only [5 (3-7) vs. 25.5 (3.8-54) p <0.001]. When standard susceptibility testing was complete, 41/48 (85.4%) patients in the intervention group were already receiving targeted therapy compared with 23/41 (56.1%) in the control group (p 0.004). There was no significant effect on clinical outcomes. Rapid determination of methicillin resistance in staphylococcal bacteraemia is accurate and reduces significantly the time to targeted antibiotic therapy in the subgroup of S. aureus, thereby avoiding unnecessary exposure to vancomycin. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  6. Evaluation of Peritumoral Edema in the Delineation of Radiotherapy Clinical Target Volumes for Glioblastoma

    SciTech Connect

    Chang, Eric L. . E-mail: echang@mdanderson.org; Akyurek, Serap; Avalos, Tedde C; Rebueno, Neal C; Spicer, Chris C; Garcia, John C; Famiglietti, Robin; Allen, Pamela K.; Chao, K.S. Clifford; Mahajan, Anita; Woo, Shiao Y.; Maor, Moshe H.

    2007-05-01

    Purpose: To evaluate the spatial relationship between peritumoral edema and recurrence pattern in patients with glioblastoma (GBM). Methods and Materials: Forty-eight primary GBM patients received three-dimensional conformal radiotherapy that did not intentionally include peritumoral edema within the clinical target volume between July 2000 and June 2001. All 48 patients have subsequently recurred, and their original treatment planning parameters were used for this study. New theoretical radiation treatment plans were created for the same 48 patients, based on Radiation Therapy Oncology Group (RTOG) target delineation guidelines that specify inclusion of peritumoral edema. Target volume and recurrent tumor coverage, as well as percent volume of normal brain irradiated, were assessed for both methods of target delineation using dose-volume histograms. Results: A comparison between the location of recurrent tumor and peritumoral edema volumes from all 48 cases failed to show correlation by linear regression modeling (r {sup 2} 0.0007; p = 0.3). For patients with edema >75 cm{sup 3}, the percent volume of brain irradiated to 46 Gy was significantly greater in treatment plans that intentionally included peritumoral edema compared with those that did not (38% vs. 31%; p = 0.003). The pattern of failure was identical between the two sets of plans (40 central, 3 in-field, 3 marginal, and 2 distant recurrence). Conclusion: Clinical target volume delineation based on a 2-cm margin rather than on peritumoral edema did not seem to alter the central pattern of failure for patients with GBM. For patients with peritumoral edema >75 cm{sup 3}, using a constant 2-cm margin resulted in a smaller median percent volume of brain being irradiated to 30 Gy, 46 Gy, and 50 Gy compared with corresponding theoretical RTOG plans that deliberately included peritumoral edema.

  7. Nasal Methicillin-Resistant Staphylococcus aureus (MRSA) PCR Testing Reduces the Duration of MRSA-Targeted Therapy in Patients with Suspected MRSA Pneumonia.

    PubMed

    Baby, Nidhu; Faust, Andrew C; Smith, Terri; Sheperd, Lyndsay A; Knoll, Laura; Goodman, Edward L

    2017-04-01

    The objective of this study was to evaluate the impact of pharmacist-ordered methicillin-resistant Staphylococcus aureus (MRSA) PCR testing on the duration of empirical MRSA-targeted antibiotic therapy in patients with suspected pneumonia. This is a retrospective analysis of patients who received vancomycin or linezolid for suspected pneumonia before and after the implementation of a pharmacist-driven protocol for nasal MRSA PCR testing. Patients were included if they were adults of >18 years of age and initiated on vancomycin or linezolid for suspected MRSA pneumonia. The primary endpoint was the duration of vancomycin or linezolid therapy. After screening 368 patients, 57 patients met inclusion criteria (27 pre-PCR and 30 post-PCR). Baseline characteristics were similar between the two groups, with the majority of patients classified as having health care-associated pneumonia (68.4%). The use of the nasal MRSA PCR test reduced the mean duration of MRSA-targeted therapy by 46.6 h (74.0 ± 48.9 h versus 27.4 ± 18.7 h; 95% confidence interval [CI], 27.3 to 65.8 h; P < 0.0001). Fewer patients in the post-PCR group required vancomycin serum levels and dose adjustment (48.1% versus 16.7%; P = 0.02). There were no significant differences between the pre- and post-PCR groups regarding days to clinical improvement (1.78 ± 2.52 versus 2.27 ± 3.34; P = 0.54), length of hospital stay (11.04 ± 9.5 versus 8.2 ± 7.8; P = 0.22), or hospital mortality (14.8% versus 6.7%; P = 0.41). The use of nasal MRSA PCR testing in patients with suspected MRSA pneumonia reduced the duration of empirical MRSA-targeted therapy by approximately 2 days without increasing adverse clinical outcomes.

  8. Epigenetic Changes Modulate Schistosome Egg Formation and Are a Novel Target for Reducing Transmission of Schistosomiasis

    PubMed Central

    Carneiro, Vitor Coutinho; de Abreu da Silva, Isabel Caetano; Torres, Eduardo José Lopes; Caby, Stephany; Lancelot, Julien; Vanderstraete, Mathieu; Furdas, Silviya D.; Jung, Manfred; Pierce, Raymond J.; Fantappié, Marcelo Rosado

    2014-01-01

    Treatment and control of schistosomiasis relies on the only available drug, praziquantel, and the search for alternative chemotherapeutic agents is therefore urgent. Egg production is required for the transmission and immunopathology of schistosomiasis and females of S. mansoni lay 300 eggs daily. A large fraction of the total mRNA in the mature female worm encodes one eggshell protein, Smp14. We report that the nuclear receptors SmRXR1 and SmNR1 regulate Smp14 transcription through the recruitment of two histone acetyltransferases (HATs), SmGCN5 and SmCBP1. The treatment of HEK293 cells with histone deacetylase (HDAC) inhibitors (NaB or TSA) produced an 8-fold activation of the SmRXR1/SmNR1-mediated Smp14 promoter activity. Incubation with synthetic HAT inhibitors, including PU139, significantly impaired the Smp14 promoter activity in these cells. Worm pairs cultivated in the presence of PU139 exhibited limited expression of Smp14 mRNA and protein. ChIP analysis demonstrated chromatin condensation at the Smp14 promoter site in worms treated with PU139. ChIP also revealed the presence of H3K27me3 and the absence of RNA Pol II at the Smp14 promoter region in the PU139-treated worms. Most significantly, the PU139-mediated inhibition of Smp14 expression resulted in a significant number of abnormal eggs as well as defective eggs within the ootype. In addition, scanning electron microscopy revealed structural defects and unformed eggshells, and vitelline cell leakage was apparent. The dsRNAi-targeting of SmGCN5 or SmCBP1 significantly decreased Smp14 transcription and protein synthesis, which compromised the reproductive system of mature female worms, egg-laying and egg morphology. Our data strongly suggest that the inhibition of Smp14 expression targeting SmGCN5 and/or SmCBP1 represents a novel and effective strategy to control S. mansoni egg development. PMID:24809504

  9. Reduced nighttime transpiration is a relevant breeding target for high water-use efficiency in grapevine

    PubMed Central

    Coupel-Ledru, Aude; Lebon, Eric; Christophe, Angélique; Gallo, Agustina; Gago, Pilar; Pantin, Florent; Doligez, Agnès; Simonneau, Thierry

    2016-01-01

    Increasing water scarcity challenges crop sustainability in many regions. As a consequence, the enhancement of transpiration efficiency (TE)—that is, the biomass produced per unit of water transpired—has become crucial in breeding programs. This could be achieved by reducing plant transpiration through a better closure of the stomatal pores at the leaf surface. However, this strategy generally also lowers growth, as stomatal opening is necessary for the capture of atmospheric CO2 that feeds daytime photosynthesis. Here, we considered the reduction in transpiration rate at night (En) as a possible strategy to limit water use without altering growth. For this purpose, we carried out a genetic analysis for En and TE in grapevine, a major crop in drought-prone areas. Using recently developed phenotyping facilities, potted plants of a cross between Syrah and Grenache cultivars were screened for 2 y under well-watered and moderate soil water deficit scenarios. High genetic variability was found for En under both scenarios and was primarily associated with residual diffusion through the stomata. Five quantitative trait loci (QTLs) were detected that underlay genetic variability in En. Interestingly, four of them colocalized with QTLs for TE. Moreover, genotypes with favorable alleles on these common QTLs exhibited reduced En without altered growth. These results demonstrate the interest of breeding grapevine for lower water loss at night and pave the way to breeding other crops with this underexploited trait for higher TE. PMID:27457942

  10. Reduced nighttime transpiration is a relevant breeding target for high water-use efficiency in grapevine.

    PubMed

    Coupel-Ledru, Aude; Lebon, Eric; Christophe, Angélique; Gallo, Agustina; Gago, Pilar; Pantin, Florent; Doligez, Agnès; Simonneau, Thierry

    2016-08-09

    Increasing water scarcity challenges crop sustainability in many regions. As a consequence, the enhancement of transpiration efficiency (TE)-that is, the biomass produced per unit of water transpired-has become crucial in breeding programs. This could be achieved by reducing plant transpiration through a better closure of the stomatal pores at the leaf surface. However, this strategy generally also lowers growth, as stomatal opening is necessary for the capture of atmospheric CO2 that feeds daytime photosynthesis. Here, we considered the reduction in transpiration rate at night (En) as a possible strategy to limit water use without altering growth. For this purpose, we carried out a genetic analysis for En and TE in grapevine, a major crop in drought-prone areas. Using recently developed phenotyping facilities, potted plants of a cross between Syrah and Grenache cultivars were screened for 2 y under well-watered and moderate soil water deficit scenarios. High genetic variability was found for En under both scenarios and was primarily associated with residual diffusion through the stomata. Five quantitative trait loci (QTLs) were detected that underlay genetic variability in En Interestingly, four of them colocalized with QTLs for TE. Moreover, genotypes with favorable alleles on these common QTLs exhibited reduced En without altered growth. These results demonstrate the interest of breeding grapevine for lower water loss at night and pave the way to breeding other crops with this underexploited trait for higher TE.

  11. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice.

    PubMed

    Zannad, Faiez; Gattis Stough, Wendy; Rossignol, Patrick; Bauersachs, Johann; McMurray, John J V; Swedberg, Karl; Struthers, Allan D; Voors, Adriaan A; Ruilope, Luis M; Bakris, George L; O'Connor, Christopher M; Gheorghiade, Mihai; Mentz, Robert J; Cohen-Solal, Alain; Maggioni, Aldo P; Beygui, Farzin; Filippatos, Gerasimos S; Massy, Ziad A; Pathak, Atul; Piña, Ileana L; Sabbah, Hani N; Sica, Domenic A; Tavazzi, Luigi; Pitt, Bertram

    2012-11-01

    Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HF-REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifibrotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplerenone and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the drugs, which may be relevant for therapeutic decision making in individual patients. Although serious hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HF-REF.

  12. [Cardiovascular prevention: could the polypill reduce the risk of clinical inertia and poor compliance?].

    PubMed

    Scheen, A J; Lefebvre, P J; Kulbertus, H

    2010-01-01

    The concept of "polypill" for cardiovascular prevention was introduced in 2003 in a landmark paper of the British Medical Journal. A model based on results provided by evidence-based medicine suggested that a "polypill", that contains a statin, three blood pressure lowering drugs (each at half standard dose), aspirin and folic acid, would result in an 80% reduction in the incidence of coronary and cerebrovascular events, while being associated with a good tolerance profile and offering a favourable cost-effectiveness ratio. The present paper aims at presenting the new advances dealing with this new paradigm in cardiovascular prevention. We will present the progresses of the "polypill" concept since 2003, the results of a first controlled clinical trial, the pharmaceutical feasibility for routine clinical use and the potential pharmaco-economical impacts of such a strategy. The "polypill" may offer a solution to avoid physician's clinical inertia and reduce patients's lack of compliance, two drawbacks in the field of cardiovascular prevention.

  13. Targeted ablation of mesenteric projecting sympathetic neurons reduces the hemodynamic response to pain in conscious, spinal cord-transected rats.

    PubMed

    Lujan, Heidi L; Palani, Gurunanthan; Peduzzi, Jean D; DiCarlo, Stephen E

    2010-05-01

    Individuals with spinal cord injuries above thoracic level 6 (T(6)) experience episodic bouts of life-threatening hypertension as part of a condition termed autonomic dysreflexia. The paroxysmal hypertension can be caused by a painful stimulus below the level of the injury. Targeted ablation of mesenteric projecting sympathetic neurons may reduce the severity of autonomic dysreflexia by reducing sympathetic activity. Therefore, cholera toxin B subunit (CTB) conjugated to saporin (SAP; a ribosomal inactivating protein that binds to and inactivates ribosomes) was injected into the celiac ganglion to test the hypothesis that targeted ablation of mesenteric projecting sympathetic neurons reduces the pressor response to pain in conscious, spinal cord-transected rats. Nine Sprague-Dawley male rats underwent a spinal cord transection between thoracic vertebrae 4 and 5. Following recovery (5 wk), all rats were instrumented with a radio telemetry device for recording arterial pressure and bilateral catheters in the gluteus maximus muscles for the infusion of hypertonic saline (hNa(+)Cl(-)). Subsequently, the hemodynamic responses to intramuscular injection of hNa(+)Cl(-) (100 microl and 250 microl, in random order) were determined. Following the experiments in the no celiac ganglia injected condition (NGI), rats received injections of CTB-SAP (n = 5) or CTB (n = 3) into the celiac ganglia. CTB-SAP rats, compared with NGI and CTB rats, had reduced pressor responses to hNa(+)Cl(-). Furthermore, the number of stained neurons in the celiac ganglia and spinal cord (segments T(6)-T(12)), was reduced in CTB-SAP rats. Thus, CTB-SAP retrogradely transported from the celiac ganglia is effective at ablating mesenteric projecting sympathetic neurons and reducing the pressor response to pain in spinal cord-transected rats.

  14. Lean mean fat reducing "ghrelin" machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity.

    PubMed

    Schellekens, Harriët; Dinan, Timothy G; Cryan, John F

    2010-01-01

    Obesity has reached epidemic proportions not only in Western societies but also in the developing world. Current pharmacological treatments for obesity are either lacking in efficacy and/or are burdened with adverse side effects. Thus, novel strategies are required. A better understanding of the intricate molecular pathways controlling energy homeostasis may lead to novel therapeutic intervention. The circulating hormone, ghrelin represents a major target in the molecular signalling regulating food intake, appetite and energy expenditure and its circulating levels often display aberrant signalling in obesity. Ghrelin exerts its central orexigenic action mainly in the hypothalamus and in particular in the arcuate nucleus via activation of specific G-protein coupled receptors (GHS-R). In this review we describe current pharmacological models of how ghrelin regulates food intake and how manipulating ghrelin signalling may give novel insight into developing better and more selective anti-obesity drugs. Accumulating data suggests multiple ghrelin variants and additional receptors exist to play a role in energy metabolism and these may well play an important role in obesity. In addition, the recent findings of hypothalamic GHS-R crosstalk and heterodimerization may add to the understanding of the complexity of bodyweight regulation.

  15. Mycobacterium avium MAV2054 protein induces macrophage apoptosis by targeting mitochondria and reduces intracellular bacterial growth

    PubMed Central

    Lee, Kang-In; Whang, Jake; Choi, Han-Gyu; Son, Yeo-Jin; Jeon, Haet Sal; Back, Yong Woo; Park, Hye-Soo; Paik, Seungwha; Park, Jeong-Kyu; Choi, Chul Hee; Kim, Hwa-Jung

    2016-01-01

    Mycobacterium avium complex induces macrophage apoptosis. However, the M. avium components that inhibit or trigger apoptosis and their regulating mechanisms remain unclear. We recently identified the immunodominant MAV2054 protein by fractionating M. avium culture filtrate protein by multistep chromatography; this protein showed strong immuno-reactivity in M. avium complex pulmonary disease and in patients with tuberculosis. Here, we investigated the biological effects of MAV2054 on murine macrophages. Recombinant MAV2054 induced caspase-dependent macrophage apoptosis. Enhanced reactive oxygen species production and JNK activation were essential for MAV2054-mediated apoptosis and MAV2054-induced interleukin-6, tumour necrosis factor, and monocyte chemoattractant protein-1 production. MAV2054 was targeted to the mitochondrial compartment of macrophages treated with MAV2054 and infected with M. avium. Dissipation of the mitochondrial transmembrane potential (ΔΨm) and depletion of cytochrome c also occurred in MAV2054-treated macrophages. Apoptotic response, reactive oxygen species production, and ΔΨm collapse were significantly increased in bone marrow-derived macrophages infected with Mycobacterium smegmatis expressing MAV2054, compared to that in M. smegmatis control. Furthermore, MAV2054 expression suppressed intracellular growth of M. smegmatis and increased the survival rate of M. smegmatis-infected mice. Thus, MAV2054 induces apoptosis via a mitochondrial pathway in macrophages, which may be an innate cellular response to limit intracellular M. avium multiplication. PMID:27901051

  16. Multivoxel pattern analysis reveals increased memory targeting and reduced use of retrieved details during single-agenda source monitoring.

    PubMed

    McDuff, Susan G R; Frankel, Hillary C; Norman, Kenneth A

    2009-01-14

    We used multivoxel pattern analysis (MVPA) of functional MRI (fMRI) data to gain insight into how subjects' retrieval agendas influence source memory judgments (was item X studied using source Y?). In Experiment 1, we used a single-agenda test where subjects judged whether items were studied with the targeted source or not. In Experiment 2, we used a multiagenda test where subjects judged whether items were studied using the targeted source, studied using a different source, or nonstudied. To evaluate the differences between single- and multiagenda source monitoring, we trained a classifier to detect source-specific fMRI activity at study, and then we applied the classifier to data from the test phase. We focused on trials where the targeted source and the actual source differed, so we could use MVPA to track neural activity associated with both the targeted source and the actual source. Our results indicate that single-agenda monitoring was associated with increased focus on the targeted source (as evidenced by increased targeted-source activity, relative to baseline) and reduced use of information relating to the actual, nontarget source. In the multiagenda experiment, high levels of actual-source activity were associated with increased correct rejections, suggesting that subjects were using recollection of actual-source information to avoid source memory errors. In the single-agenda experiment, there were comparable levels of actual-source activity (suggesting that recollection was taking place), but the relationship between actual-source activity and behavior was absent (suggesting that subjects were failing to make proper use of this information).

  17. The majority of accredited continuing professional development activities do not target clinical behavior change.

    PubMed

    Légaré, France; Freitas, Adriana; Thompson-Leduc, Philippe; Borduas, Francine; Luconi, Francesca; Boucher, Andrée; Witteman, Holly O; Jacques, André

    2015-02-01

    Continually improving patient outcomes requires that physicians start new behaviors, stop old behaviors, or adjust how they practice medicine. Continuing professional development (CPD) is the method most commonly used by physicians to improve their knowledge and skills. However, despite regular physician attendance at these activities, change in clinical behavior is rarely observed. The authors sought to identify which of Bloom's domains (cognitive, affective, or psychomotor) are targeted by the learning objectives of CPD activities offered by medical associations, regulatory bodies, and academic institutions in the province of Quebec, Canada. The authors evaluated the objectives of 110 accredited CPD activities offered to physicians and other health professionals from November 2012 to March 2013. The objectives of each activity were extracted and classified into learning domains using Bloom's taxonomy. Ninety-six percent of the learning objectives analyzed targeted the cognitive domain, which consists of six levels of increasing complexity: knowledge, comprehension, application, analysis, synthesis, and evaluation. Half (47%) targeted knowledge and comprehension, whereas only 26% aimed to improve skills in analysis, synthesis, and evaluation. Most accredited CPD activities within this sample were generally not designed to promote clinical behavior change because the focus of these activities was on remembering and understanding information instead of preparing physicians to put knowledge into practice by analyzing information, evaluating new evidence, and planning operations that lead to behavior change. Educators and CPD providers should take advantage of well-established theories of health professional behavior change, such as sociocognitive theories, to develop their activities.

  18. Pediatric Targeted Therapy: Clinical Feasibility of Personalized Diagnostics in Children with Relapsed and Progressive Tumors.

    PubMed

    Selt, Florian; Deiß, Alica; Korshunov, Andrey; Capper, David; Witt, Hendrik; van Tilburg, Cornelis M; Jones, David T W; Witt, Ruth; Sahm, Felix; Reuss, David; Kölsche, Christian; Ecker, Jonas; Oehme, Ina; Hielscher, Thomas; von Deimling, Andreas; Kulozik, Andreas E; Pfister, Stefan M; Witt, Olaf; Milde, Till

    2016-07-01

    The "pediatric targeted therapy" (PTT) program aims to identify the presence and activity of druggable targets and evaluate the clinical benefit of a personalized treatment approach in relapsed or progressive tumors on an individual basis. 10 markers (HDAC2, HR23B, p-AKT, p-ERK, p-S6, p-EGFR, PDGFR-alpha/beta, p53 and BRAFV600E) were analyzed by immunohistochemistry. Pediatric patients with tumors independent of the histological diagnosis, with relapse or progression after treatment according to standard protocols were included. N = 61/145 (42%) cases were eligible for analysis between 2009 and 2013, the most common entities being brain tumors. Immunohistochemical stainings were evaluated by the H-Score (0-300). In 93% of the cases potentially actionable targets were identified. The expressed or activated pathways were histone deacetylase (HDACs; 83.0% of cases positive), EGFR (87.2%), PDGFR (75.9%), p53 (50.0%), MAPK/ERK (43.3%) and PI3K/mTOR (36.1%). Follow-up revealed partial or full implementation of PTT results in treatment decision-making in 41% of the cases. Prolonged disease stabilization responses in single cases were noticed, however, response rates did not differ from cases treated with other modalities. Further studies evaluating the feasibility and clinical benefit of personalized diagnostic approaches using paraffin material are warranted.

  19. FDG-PET/CT during concomitant chemo radiotherapy for esophageal cancer: Reducing target volumes to deliver higher radiotherapy doses.

    PubMed

    Nkhali, Lamyaa; Thureau, Sébastien; Edet-Sanson, Agathe; Doyeux, Kaya; Benyoucef, Ahmed; Gardin, Isabelle; Michel, Pierre; Vera, Pierre; Dubray, Bernard

    2015-06-01

    A planning study investigated whether reduced target volumes defined on FDG-PET/CT during radiotherapy allow total dose escalation without compromising normal tissue tolerance in patients with esophageal cancer. Ten patients with esophageal squamous cell carcinoma (SCC), candidate to curative-intent concomitant chemo-radiotherapy (CRT), had FDG-PET/CT performed in treatment position, before and during (Day 21) radiotherapy (RT). Four planning scenarios were investigated: 1) 50 Gy total dose with target volumes defined on pre-RT FDG-PET/CT; 2) 50 Gy with boost target volume defined on FDG-PET/CT during RT; 3) 66 Gy with target volumes from pre-RT FDG-PET/CT; and 4) 66 Gy with boost target volume from during-RT FDG-PET/CT. The median metabolic target volume decreased from 12.9 cm3 (minimum 3.7-maximum 44.8) to 5.0 cm3 (1.7-13.5) (p=0.01) between pre- and during-RCT FDG-PET/CT. The median PTV66 was smaller on during-RT than on baseline FDG-PET/CT [108 cm3 (62.5-194) vs. 156 cm3 (68.8-251), p=0.02]. When total dose was set to 50 Gy, planning on during-RT FDG-PET/CT was associated with a marginal reduction in normal tissues irradiation. When total dose was increased to 66 Gy, planning on during-RT PET yielded significantly lower doses to the spinal cord [Dmax=44.1Gy (40.8-44.9) vs. 44.7Gy (41.5-45.0), p=0.007] and reduced lung exposure [V20Gy=23.2% (17.3-27) vs. 26.8% (19.7-30.2), p=0.006]. This planning study suggests that adaptive RT based on target volume reduction assessed on FDG-PET/CT during treatment could facilitate dose escalation up to 66 Gy in patients with esophageal SCC.

  20. The efficacy of targeted health agents education to reduce the duration of untreated psychosis in a rural population.

    PubMed

    Padilla, Eduardo; Molina, Juan; Kamis, Danielle; Calvo, Maria; Stratton, Lee; Strejilevich, Sergio; Aleman, Gabriela Gonzalez; Guerrero, Gonzalo; Bourdieu, Mercedes; Conesa, Horacio A; Escobar, Javier I; de Erausquin, Gabriel A

    2015-02-01

    The duration of untreated psychosis (DUP) is a key determinant in the severity of symptoms in patients with schizophrenia. DUP is a modifiable factor that if reduced can improve patient outcome and treatment response. We sought to decrease DUP in rural Argentina by instituting annual training of local health agents to better identify signs of mental illness and offer earlier intervention. DUP was estimated using Schedules of Clinical Assessment in Neuropsychiatry (SCAN). Ongoing training was correlated with a reduction in DUP. Reducing DUP through better screening can decrease the psychosocial burden of disease and improve the trajectory of psychosis. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. The efficacy of targeted Health Agents education to reduce the duration of untreated psychosis in a rural population

    PubMed Central

    Padilla, Eduardo; Molina, Juan; Kamis, Danielle; Calvo, Maria; Stratton, Lee; Strejilevich, Sergio; Aleman, Gabriela Gonzalez; Guerrero, Gonzalo; Bourdieu, Mercedes; Conesa, Horacio A.; Escobar, Javier I.; de Erausquin, Gabriel A.

    2014-01-01

    The duration of untreated psychosis (DUP) is a key determinant in the severity of symptoms in patients with schizophrenia. DUP is a modifiable factor that if reduced can improve patient outcome and treatment response. We sought to decrease DUP in rural Argentina by instituting annual training of local health agents to better identify signs of mental illness and offer earlier intervention. DUP was estimated using Schedules of Clinical Assessment in Neuropsychiatry (SCAN). Ongoing training was correlated with a reduction in DUP. Reducing DUP through better screening can decrease the psychosocial burden of disease and improve the trajectory of psychosis. PMID:25439394

  2. Long circulating reduced graphene oxide-iron oxide nanoparticles for efficient tumor targeting and multimodality imaging.

    PubMed

    Xu, Cheng; Shi, Sixiang; Feng, Liangzhu; Chen, Feng; Graves, Stephen A; Ehlerding, Emily B; Goel, Shreya; Sun, Haiyan; England, Christopher G; Nickles, Robert J; Liu, Zhuang; Wang, Taihong; Cai, Weibo

    2016-07-07

    Polyethylene glycol (PEG) surface modification is one of the most widely used approaches to improve the solubility of inorganic nanoparticles, prevent their aggregation and prolong their in vivo blood circulation half-life. Herein, we developed double-PEGylated biocompatible reduced graphene oxide nanosheets anchored with iron oxide nanoparticles (RGO-IONP-(1st)PEG-(2nd)PEG). The nanoconjugates exhibited a prolonged blood circulation half-life (∼27.7 h) and remarkable tumor accumulation (>11 %ID g(-1)) via an enhanced permeability and retention (EPR) effect. Due to the strong near-infrared absorbance and superparamagnetism of RGO-IONP-(1st)PEG-(2nd)PEG, multimodality imaging combining positron emission tomography (PET) imaging with magnetic resonance imaging (MRI) and photoacoustic (PA) imaging was successfully achieved. The promising results suggest the great potential of these nanoconjugates for multi-dimensional and more accurate tumor diagnosis and therapy in the future.

  3. Long circulating reduced graphene oxide-iron oxide nanoparticles for efficient tumor targeting and multimodality imaging

    NASA Astrophysics Data System (ADS)

    Xu, Cheng; Shi, Sixiang; Feng, Liangzhu; Chen, Feng; Graves, Stephen A.; Ehlerding, Emily B.; Goel, Shreya; Sun, Haiyan; England, Christopher G.; Nickles, Robert J.; Liu, Zhuang; Wang, Taihong; Cai, Weibo

    2016-06-01

    Polyethylene glycol (PEG) surface modification is one of the most widely used approaches to improve the solubility of inorganic nanoparticles, prevent their aggregation and prolong their in vivo blood circulation half-life. Herein, we developed double-PEGylated biocompatible reduced graphene oxide nanosheets anchored with iron oxide nanoparticles (RGO-IONP-1stPEG-2ndPEG). The nanoconjugates exhibited a prolonged blood circulation half-life (~27.7 h) and remarkable tumor accumulation (>11 %ID g-1) via an enhanced permeability and retention (EPR) effect. Due to the strong near-infrared absorbance and superparamagnetism of RGO-IONP-1stPEG-2ndPEG, multimodality imaging combining positron emission tomography (PET) imaging with magnetic resonance imaging (MRI) and photoacoustic (PA) imaging was successfully achieved. The promising results suggest the great potential of these nanoconjugates for multi-dimensional and more accurate tumor diagnosis and therapy in the future.

  4. Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis

    PubMed Central

    Kusminski, Christine M.; Sun, Kai; Sharma, Ankit X.; Pearson, Mackenzie J.; Sifuentes, Angelika J.; McDonald, Jeffrey G.; Gordillo, Ruth; Scherer, Philipp E.

    2015-01-01

    Sphingolipids have garnered attention for their role in insulin resistance and lipotoxic cell death. Aberrant accumulation of ceramides correlates with hepatic insulin resistance and steatosis. To further investigate the tissue-specific effects of local changes in ceramidase activity, we have developed transgenic mice inducibly expressing acid ceramidase, to trigger the deacylation of ceramides. This represents the first inducible genetic model that acutely manipulates ceramides in adult mouse tissues. Hepatic overexpression of acid ceramidase prevents hepatic steatosis and prompts improvements in insulin action in liver and adipose tissue. Conversely, overexpression of acid ceramidase within adipose tissue prevents hepatic steatosis and insulin resistance. Induction of ceramidase activity in either tissue promotes a lowering of hepatic ceramides and reduced activation of the ceramide-activated protein kinase C isoform PKC-zeta. These observations suggest the existence of a rapidly acting "crosstalk" between liver and adipose tissue sphingolipids, critically regulating glucose metabolism and hepatic lipid uptake. PMID:26190650

  5. One-pot synthesis of dextran decorated reduced graphene oxide nanoparticles for targeted photo-chemotherapy.

    PubMed

    Hu, Yanfang; He, Liang; Ding, Jianxun; Sun, Diankui; Chen, Li; Chen, Xuesi

    2016-06-25

    Graphene-based nanocarriers show great potential in photo-chemotherapy, however, to prepare desired reduced graphene oxide (rGO) nanoparticles in a facile way is still a challenge. Herein, a novel strategy has been presented to prepare rGO nanoparticle using dextran (Dex) as a reducing agent. In this strategy, Dex was directly conjugated on rGO by hydrogen bond and then self-assemble to form rGO/Dex nanoparticles. After decorated by dextran, rGO-based nanoparticles not only show excellent biocompatibility but also can load anticancer drug for photo-chemotherapy. The data of fourier transform infrared (FT-IR) analysis, Raman spectrum analysis, thermos-gravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), the transmission electron microscope (TEM) image and dynamic light scattering (DLS) measurements powerfully proved that the stable rGO-based nanoparticles with desired nanosize have been successfully prepared. To verify the photo-chemotherapy, anticancer drug, doxorubicin (DOX), has been loaded on rGO/Dex nanoparticles (rGO/DOX/Dex). And RGD, a kind of oligopeptide which can improve the intracellular uptake by αvβ3 recognition, also has been introduced (rGO/DOX/RDex). Compared with single chemotherapy, rGO/DOX/Dex and rGO/DOX/RDex combining the local specific chemotherapy and external near-infrared (NIR) photo-thermal therapy show higher therapeutic efficacy, endowing the desired rGO-based nanoparticle with great potential for cancer treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Clinical efficacy of local targeted chemotherapy for triple-negative breast cancer.

    PubMed

    He, Jinsong; Wang, Xianming; Guan, Hong; Chen, Weicai; Wang, Ming; Wu, Huisheng; Wang, Zun; Zhou, Ruming; Qiu, Shuibo

    2011-06-01

    The aim of the study was to evaluate the clinical efficacy of superselective intra-arterial targeted neo-adjuvant chemotherapy in the treatment of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative (triple-negative) breast cancer. PATIENTS AND METHODS.: A total of 47 triple-negative breast cancer patients (29 at stage II, 13 at stage III and 5 at stage IV) were randomly assigned to two groups: targeted chemotherapy group (n=24) and control group (n=23). Patients in the targeted chemotherapy group received preoperative superselective intra-arterial chemotherapy with CEF regimen (C: cyclophosphamide [600 mg/m(2)]; E: epirubicin [90 mg/m(2)]; F: 5-fluorouracil [600 mg/m(2)]), and those in the control group received routine neoadjuvant chemotherapy with CEF. The duration of the treatment, changes in lesions and the prognosis were determined. The average course of the treatment was 15 days in the targeted chemotherapy group which was significantly shorter than that in the control group (31 days) (P<0.01). The remission rate of lesions was 91.6% in the targeted chemotherapy group and 60.9% in the control group, respectively. Among these patients, 9 died within two years, including 2 (both at IV stage) in the targeted chemotherapy group and 7 (2 at stage II, 4 at stage III and 1 at stage IV) in the control group. As an neoadjuvant therapy, the superselective intra-arterial chemotherapy is effective for triple-negative breast cancer, with advantages of the short treatment course and favourable remission rates as well as prognoses.

  7. Oligoclonal antibody targeting ghrelin increases energy expenditure and reduces food intake in fasted mice.

    PubMed

    Zakhari, Joseph S; Zorrilla, Eric P; Zhou, Bin; Mayorov, Alexander V; Janda, Kim D

    2012-02-06

    Ghrelin, an enteric peptide hormone linked to the pathophysiology of obesity has been a therapeutic target of great interest over the past decade. Many research efforts have focused on the antagonism of ghrelin's endogenous receptor GHSR1a, which is found along ascending vagal afferent fibers, as well as in the arcuate nucleus of the hypothalamus. Additionally, peptidic inhibitors of ghrelin O-acyltransferase, the enzyme responsible for the paracrine activation of ghrelin, have recently been studied. Our research has taken an alternative immunological approach, studying both active and passive vaccination as a means to sequester ghrelin in the periphery, with the original discovery in rat of decreased feed efficiency and adiposity, as well as increased metabolic activity. Using our previous hapten designs as a stepping-stone, three monoclonal antibodies (JG2, JG3, and JG4) were procured against ghrelin and tested in vivo. While mAb JG4 had the highest affinity for ghrelin, it failed to attenuate the orexigenic effects of food deprivation on energy metabolism or food intake in mice. However, animals that were administered a combination of JG3:JG4 (termed a doublet) or JG2:JG3:JG4 (termed a triplet) demonstrated higher heat dispersion and rate of respiration (higher CO(2) emission and O(2) consumption) during a 24 h fast refeed. Mice administered the triplet cocktail of JG2:JG3:JG4 also demonstrated decreased food intake upon refeeding as compared to control animals. Recently, Lu and colleagues reported that a passive approach using a single, high affinity N-terminally directed monoclonal antibody did not abrogate the effects of endogenous ghrelin. Our current report corroborates this finding, yet, refutes that a monoclonal antibody approach cannot be efficacious. Rather, we find that a multiple monoclonal antibody (oligoclonal) approach can reproduce the underlying logic to previously reported efficacies using active vaccinations.

  8. Risks and benefits of reducing target volume margins in breast tangent radiotherapy.

    PubMed

    Basaula, Deepak; Quinn, Alexandra; Walker, Amy; Batumalai, Vikneswary; Kumar, Shivani; Delaney, Geoff P; Holloway, Lois

    2017-02-27

    This study investigates the potential benefits of planning target volume (PTV) margin reduction for whole breast radiotherapy in relation to dose received by organs at risk (OARs), as well as reductions in radiation-induced secondary cancer risk. Such benefits were compared to the increased radiation-induced secondary cancer risk attributed from increased ionizing radiation imaging doses. Ten retrospective patients' computed tomography datasets were considered. Three computerized treatment plans with varied PTV margins (0, 5 and 10 mm) were created for each patient complying with the Radiation Therapy Oncology Group (RTOG) 1005 protocol requirements. The BEIR VII lifetime attributable risk (LAR) model was used to estimate secondary cancer risk to OARs. The LAR was assessed for all treatment plans considering (a) doses from PTV margin variation and (b) doses from two (daily and weekly) kilovoltage cone beam computed tomography (kV CBCT) imaging protocols during the course of treatment. We found PTV margins from largest to smallest resulted in a mean OAR relative dose reduction of 31% (heart), 28% (lung) and 23% (contralateral breast) and the risk of radiation-induced secondary cancer by a relative 23% (contralateral breast) and 22% (contralateral lung). Daily image-guidance using kV CBCT increased the risk of radiation induced secondary cancer to the contralateral breast and contralateral lung by a relative 1.6-1.9% and 1.9-2.5% respectively. Despite the additional dose from kV CBCT for the two considered imaging protocols, smaller PTV margins would still result in an overall reduction in secondary cancer risk.

  9. Reducing isozyme competition increases target fatty acid accumulation in seed triacylglycerols of transgenic Arabidopsis.

    PubMed

    van Erp, Harrie; Shockey, Jay; Zhang, Meng; Adhikari, Neil D; Browse, John

    2015-05-01

    One goal of green chemistry is the production of industrially useful fatty acids (FAs) in crop plants. We focus on hydroxy fatty acids (HFAs) and conjugated polyenoic FAs (α-eleostearic acids [ESAs]) using Arabidopsis (Arabidopsis thaliana) as a model. These FAs are found naturally in seed oils of castor (Ricinus communis) and tung tree (Vernicia fordii), respectively, and used for the production of lubricants, nylon, and paints. Transgenic oils typically contain less target FA than that produced in the source species. We hypothesized that competition between endogenous and transgenic isozymes for substrates limits accumulation of unique FAs in Arabidopsis seeds. This hypothesis was tested by introducing a mutation in Arabidopsis diacylglycerol acyltransferase1 (AtDGAT1) in a line expressing castor FA hydroxylase and acyl-Coenzyme A:RcDGAT2 in its seeds. This led to a 17% increase in the proportion of HFA in seed oil. Expression of castor phospholipid:diacylglycerol acyltransferase 1A in this line increased the proportion of HFA by an additional 12%. To determine if our observations are more widely applicable, we investigated if isozyme competition influenced production of ESA. Expression of tung tree FA conjugase/desaturase in Arabidopsis produced approximately 7.5% ESA in seed lipids. Coexpression of VfDGAT2 increased ESA levels to approximately 11%. Overexpression of VfDGAT2 combined with suppression of AtDGAT1 increased ESA accumulation to 14% to 15%. Our results indicate that isozyme competition is a limiting factor in the engineering of unusual FAs in heterologous plant systems and that reduction of competition through mutation and RNA suppression may be a useful component of seed metabolic engineering strategies.

  10. Bridging academic science and clinical research in the search for novel targeted anti-cancer agents.

    PubMed

    Matter, Alex

    2015-12-01

    This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.

  11. Bridging academic science and clinical research in the search for novel targeted anti-cancer agents

    PubMed Central

    Matter, Alex

    2015-01-01

    This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials. PMID:26779369

  12. Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions.

    PubMed

    Curry, Jonathan L; Torres-Cabala, Carlos A; Kim, Kevin B; Tetzlaff, Michael T; Duvic, Madeleine; Tsai, Kenneth Y; Hong, David S; Prieto, Victor G

    2014-03-01

    Dermatologic toxicities (DT) to targeted cancer therapy may present as inflammatory dermatoses, keratoses, and as benign and malignant squamous proliferations. Published reports of DT with cancer therapy with epidermal growth factor receptor (EGFR), tyrosine kinase (TK), MEK, PI3K, AKT, and BRAF inhibitors were reviewed. DT associated with targeted cancer therapy demonstrated similar reactions and may be grouped as (i) DT as cutaneous inflammation, and (ii) DT as cutaneous epithelial proliferation. EGFR inhibitor, cetuximab, and MEK inhibitors, selumetinib and trametinib, demonstrated papulopustular rash with a suppurative folliculitis in 83%, 93%, and 80% of the patients on therapy, respectively. Common DT with EGFR inhibitors erlotinib and tyrosine kinase inhibitor sorafenib were hand-foot skin reactions in 30-60% of patients on therapy. PI3K inhibitor BKM-120 and AKT inhibitor MK2206 produced maculopapular eruptions seen as dermal hypersensitivity reaction on the skin biopsy. RAF inhibitors vemurafenib and sorafenib were associated with a variety of cutaneous epithelial proliferations (keratosis pilaris, seborrheic keratosis, verruca vulgaris, actinic keratosis, keratoacanthoma, and squamous cell carcinoma. Various anticancer agents may target similar cellular compounds and/or cell signaling pathways thus share similar clinical and histologic features of DT. The knowledge of the overlap of DT with different types of targeted cancer therapy will assist in evaluation of cutaneous reactions. © 2013 The International Society of Dermatology.

  13. Genetic profiling of intrahepatic cholangiocarcinoma and its clinical implication in targeted therapy.

    PubMed

    Xie, Diyang; Ren, Zhenggang; Fan, Jia; Gao, Qiang

    2016-01-01

    Intrahepatic cholangiocarcinoma (iCCA) is a treatment-refractory primary liver cancer with an increasing incidence and mortality worldwide in recent years. Lack of a stereotyped genetic signature and limited understanding of genomic landscape make the development of effective targeted therapies challenging. Recent application of advanced technologies such as next-generation sequencing (NGS) has broadened our understanding of genetic heterogeneity in iCCA and many potentially actionable genetic alterations have been identified. This review explores the recent advances in defining genetic alterations in iCCAs, which may present potent therapeutic targets. Chromatin remodeling genes and genes encoding isocitrate dehydrogenase and tyrosine kinase receptors as well as their downstream effectors are among the most frequently altered genes. Clinical trials testing the effect of new targeted agents on iCCA patients, especially those with the above genetic markers are under way. However, the complex interplay of environmental and evolutionary factors contributing to the genetic variability in iCCA calls for a more cautionary use of NGS in tailoring targeted regimen to the patients. Next-generation functional testing may complement NGS to execute precision medicine in future.

  14. Clinical roundtable monograph: unmet needs in the treatment of chronic lymphocytic leukemia: integrating a targeted approach.

    PubMed

    O'Brien, Susan M; Furman, Richard R; Byrd, John C; Smith, Ashbel

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is the most frequently diagnosed hematologic malignancy in the United States. Although several features can be useful in the diagnosis of CLL, the most important is the immunophenotype.Two staging systems--the Binet system and the Rai classification--are used to assess risk. After diagnosis, the first major therapeutic decision is when to initiate therapy, as a watchful waiting approach is often appropriate for patients with asymptomatic disease. Once a patient has met the criteria for treatment, the choice of therapy is the next major decision. Younger patients (<65 years) often receive more aggressive treatment that typically consists of cytotoxic chemotherapy. There is a great unmet need concerning treatment of older patients with CLL, who often present with more comorbid conditions that can decrease their ability to tolerate particular regimens. The current standard of care for older patients with CLL is rituximab plus chlorambucil. The concept of targeted agents is currently an area of intense interest in CLL. The Bruton’s tyrosine kinase inhibitor ibrutinib is the targeted agent that is furthest along in clinical development. It is associated with an overall survival rate of 83%. Idelalisib targets the phosphatidyl inositol 3-kinase and is under evaluation in pivotal trials. Targeted agents offer much promise in terms of efficacy, toxicity, and oral availability. They will change the management of patients with CLL.

  15. [Impact on evaluation of clinical efficacy of traditional Chinese medicine for level in soft targets of processing technology].

    PubMed

    Shao, Ming-Yi; Wei, Ming; Yan, Bo-Hua

    2014-04-01

    Traditional Chinese medicine (TCM) is a very practical subject, which has its unique theoretical system and clinical characteristics. In the course of clinical practice, the exact clinical efficacy is the key of existence and development. But the existing evaluation system is difficult to objectively evaluate the clinical efficacy of TCM. Therefore, how to objectively evaluate the clinical efficacy and get definitive evidence is the focus of the evaluation of clinical efficacy of TCM. Relative to modern medicine, TCM is more concerned about the changes of feelings and clinical symptoms of the patient in the course of the evolution of the disease. Soft targets mainly used for the evaluation of the clinical efficacy of symptoms and functional activity of the disease. The level in soft targets of processing technology is often used methods in clinical evaluation. But it has often produced the phenomenon which the results of the evaluation is mutual contradiction, which will ultimately affect the effect of evaluation of clinical efficacy of TCM. In order to better evaluate the clinical efficacy of TCM, in the process of adoption of soft targets, it clearly identify it's role, highlighting the characteristics of interventions on disease, and as much as possibly avoid the level in soft targets of processing technology to real assess clinical efficacy of TCM.

  16. Current HER2 Testing Recommendations and Clinical Relevance as a Predictor of Response to Targeted Therapy.

    PubMed

    Ballinger, Tarah J; Sanders, Melinda E; Abramson, Vandana G

    2015-06-01

    Clinical decision-making in the treatment of breast cancer depends on an accurate determination and understanding of human epidermal growth factor receptor 2 (HER2) status. The guidelines for HER2 testing were recently updated in late 2013, but limitations continue to exist in the interpretation and clinical application of results when the tumor specimens do not fall neatly into positive or negative categories with immunohistochemistry and fluorescence in situ hybridization testing. The issues, including discordance between pathologists or laboratories, polysomy, and genetic heterogeneity, present challenging situations that are difficult to translate into clinical significance. The present review discussed the changes in the updated American Society of Clinical Oncology/College of American Pathologists guidelines, the clinical relevance of complex issues in HER2 testing, and the implications of the results on the response to HER2-targeted therapies. Great advances have been made in the treatment of HER2-positive breast cancer; however, the challenge remains to determine the best testing analysis that will identify patients who will benefit the most from these therapies.

  17. Targeted mass media interventions promoting healthy behaviours to reduce risk of non-communicable diseases in adult, ethnic minorities.

    PubMed

    Mosdøl, Annhild; Lidal, Ingeborg B; Straumann, Gyri H; Vist, Gunn E

    2017-02-17

    Physical activity, a balanced diet, avoidance of tobacco exposure, and limited alcohol consumption may reduce morbidity and mortality from non-communicable diseases (NCDs). Mass media interventions are commonly used to encourage healthier behaviours in population groups. It is unclear whether targeted mass media interventions for ethnic minority groups are more or less effective in changing behaviours than those developed for the general population. To determine the effects of mass media interventions targeting adult ethnic minorities with messages about physical activity, dietary patterns, tobacco use or alcohol consumption to reduce the risk of NCDs. We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, ERIC, SweMed+, and ISI Web of Science until August 2016. We also searched for grey literature in OpenGrey, Grey Literature Report, Eldis, and two relevant websites until October 2016. The searches were not restricted by language. We searched for individual and cluster-randomised controlled trials, controlled before-and-after studies (CBA) and interrupted time series studies (ITS). Relevant interventions promoted healthier behaviours related to physical activity, dietary patterns, tobacco use or alcohol consumption; were disseminated via mass media channels; and targeted ethnic minority groups. The population of interest comprised adults (≥ 18 years) from ethnic minority groups in the focal countries. Primary outcomes included indicators of behavioural change, self-reported behavioural change and knowledge and attitudes towards change. Secondary outcomes were the use of health promotion services and costs related to the project. Two authors independently reviewed the references to identify studies for inclusion. We extracted data and assessed the risk of bias in all included studies. We did not pool the results due to heterogeneity in comparisons made, outcomes, and study designs. We describe the results narratively and present them in 'Summary of findings

  18. Reducing blood volume requirements for clinical pathology testing in toxicologic studies-points to consider.

    PubMed

    Poitout-Belissent, Florence; Aulbach, Adam; Tripathi, Niraj; Ramaiah, Lila

    2016-12-01

    In preclinical safety assessment, blood volume requirements for various endpoints pose a major challenge. The goal of this working group was to review current practices for clinical pathology (CP) testing in preclinical toxicologic studies, and to discuss advantages and disadvantages of methods for reducing blood volume requirements. An industry-wide survey was conducted to gather information on CP instrumentation and blood collection practices for hematology, clinical biochemistry, and coagulation evaluation in laboratory animals involved in preclinical studies. Based on the survey results and collective experience of the authors, the working group proposes the following "points to consider" for CP testing: (1) For most commercial analyzers, 0.5 mL and 0.8 mL of whole blood are sufficient for hematology and biochemistry evaluation, respectively. (2) Small analyzers with low volume requirements and low throughput have limited utility in preclinical studies. (3) Sample pooling or dilution is inappropriate for many CP methods. (4) Appropriate collection sites should be determined based on blood volume requirements and technical expertise. (5) Microsampling does not provide sufficient volume given current analyzer and quality assurance requirements. (6) Study design considerations include: the use of older/larger animals (rodents), collection of CP samples before toxicokinetic samples, use of separate subsets of mice for hematology and clinical biochemistry testing, use of a priority list for clinical biochemistry, and when possible, eliminating coagulation testing. © 2016 American Society for Veterinary Clinical Pathology.

  19. Health Outcomes in Acromegaly: Depression and Anxiety are Promising Targets for Improving Reduced Quality of Life

    PubMed Central

    Geraedts, Victor Jacobus; Dimopoulou, Christina; Auer, Matthias; Schopohl, Jochen; Stalla, Günter Karl; Sievers, Caroline

    2015-01-01

    Introduction: Remission criteria of acromegaly are based on biochemical variables, i.e., normalization of increased hormone levels. However, the established reduction in Quality of Life (QoL) is suggested to be independent of biochemical control. The aim of this study was to test which aspects predict QoL best in acromegaly. Methods/design: This is a prospective cohort study in 80 acromegalic patients, with a cross-sectional and longitudinal part. The main outcome measure was health-related QoL, measured by a generic and a disease-specific questionnaire (the SF-36 and AcroQoL). Main predictors were age, gender, biochemical control, disease characteristics, treatment modalities, and psychopathology. Results: Our cohort of 80 acromegalics had a mean age 54.7 ± 12.3 years with an average disease duration of 10.8 ± 10.0 years. Ratio macro-/microadenoma was 54/26. In adjusted mixed method models, we found that psychopathology significantly predicts QoL in acromegaly (in models including the variables age, gender, disease duration, tumor size, basal hormone levels, relevant treatment modalities, and relevant comorbidities), with a higher degree of psychopathology indicating a lower QoL (depression vs. AcroQoL: B = −1.175, p < 0.001, depression vs. SF-36: B = −1.648, p < 0.001, anxiety vs. AcroQoL: B = −0.399, p < 0.001, anxiety vs. SF-36: B = −0.661, p < 0.001). The explained variances demonstrate superiority of psychopathology over biochemical control and other variables in predicting QoL in our models. Discussion: Superiority of psychopathology over biochemical control calls for a more extensive approach regarding diagnosing depression and anxiety in pituitary adenomas to improve QoL. Depressive symptoms and anxiety are modifiable factors that might provide valuable targets for possible future treatment interventions. PMID:25610427

  20. Personalized medicine in metastatic non-small-cell lung cancer: promising targets and current clinical trials

    PubMed Central

    Black, A.; Morris, D.

    2012-01-01

    Non-small-cell lung cancer (nsclc) remains the leading cause of cancer-related death globally, with most patients presenting with non-curable disease. Platinum-based doublet chemotherapy has been the cornerstone of treatment for patients with advanced-stage disease and has resulted in a modest increase in overall survival (on the order of an incremental 2 months increased survival per decade) and quality of life. Improved knowledge of the molecular signalling pathways found in nsclc has led to the development of biomarkers with associated targeted therapeutics, thus changing the treatment paradigm for many nsclc patients. In this review, we present a summary of many of the currently investigated nsclc targets, discuss their current clinical trial status, and provide commentary as to the likelihood of their success making a positive impact for nsclc patients. PMID:22787415

  1. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges

    PubMed Central

    Hoshida, Yujin; Fuchs, Bryan C.; Tanabe, Kenneth K.

    2013-01-01

    Chronic fibrotic liver diseases such as viral hepatitis eventually develop liver cirrhosis, which causes occurrence of hepatocellular carcinoma (HCC). Given the limited therapeutic efficacy in advanced HCC, prevention of HCC development could be an effective strategy for improving patient prognosis. However, there is still no established therapy to meet the goal. Studies have elucidated a wide variety of molecular mechanisms and signaling pathways involved in HCC development. Genetically-engineered or chemically-treated experimental models of cirrhosis and HCC have been developed and shown their potential value in investigating molecular therapeutic targets and diagnostic biomarkers for HCC prevention. In this review, we overview potential targets of prevention and currently available experimental models, and discuss strategies to translate the findings into clinical practice. PMID:22873223

  2. Targeting HIV clinical training with maps: lessons from the Pacific AIDS Education and Training Center.

    PubMed

    Myers, Janet; Bernstein, Mona; Morin, Stephen F; Reyes, Michael

    2007-12-01

    Public health providers are increasingly called on to do more with fewer resources. Aiming to help HIV clinical training providers in 15 local sites to better target their efforts, the Pacific AIDS Education and Training Center (PAETC) implemented a method for integrating disparate information, such as program-level evaluation and publicly available health services data, into one combined and useful format. The resulting local area profiles were distributed to each training site and were updated annually for 2 years. As a result, local training teams adopted data-based approaches to doing their work. Training managers and faculty reported that data presented in spatial formats (i.e., maps) were most helpful for targeting their outreach and training. In addition to achieving the aim of supporting better programs, the project increased capacity for using data to support all aspects of training and education, from grant writing to strategic planning.

  3. Mitochondria-Targeted Antioxidant Mitoquinone Reduces Cisplatin-Induced Ototoxicity in Guinea Pigs.

    PubMed

    Tate, Alan D; Antonelli, Patrick J; Hannabass, Kyle R; Dirain, Carolyn O

    2017-03-01

    Objective To determine if mitoquinone (MitoQ) attenuates cisplatin-induced hearing loss in guinea pigs. Study Design Prospective and controlled animal study. Setting Academic, tertiary medical center. Subjects and Methods Guinea pigs were injected subcutaneously with either 5 mg/kg MitoQ (n = 9) or normal saline (control, n = 9) for 7 days and 1 hour before receiving a single dose of 10 mg/kg cisplatin. Auditory brainstem response thresholds were measured before MitoQ or saline administration and 3 to 4 days after cisplatin administration. Results Auditory brainstem response threshold shifts after cisplatin treatment were smaller by 28 to 47 dB in guinea pigs injected with MitoQ compared with those in the control group at all tested frequencies (4, 8, 16, and 24 kHz, P = .0002 to .04). Scanning electron microscopy of cochlear hair cells showed less outer hair cell loss and damage in the MitoQ group. Conclusion MitoQ reduced cisplatin-induced hearing loss in guinea pigs. MitoQ appears worthy of further investigation as a means of preventing cisplatin ototoxicity in humans.

  4. KGF-2 targets alveolar epithelia and capillary endothelia to reduce high altitude pulmonary oedema in rats

    PubMed Central

    She, Jun; Goolaerts, Arnaud; Shen, Jun; Bi, Jing; Tong, Lin; Gao, Lei; Song, Yuanlin; Bai, Chunxue

    2012-01-01

    High altitude pulmonary oedema (HAPE) severely affects non-acclimatized individuals and is characterized by alveolar flooding with protein- rich oedema as a consequence of blood-gas barrier disruption. Limited choice for prophylactic treatment warrants effective therapy against HAPE. Keratinocyte growth factor-2 (KGF-2) has shown efficiency in preventing alveolar epithelial cell DNA damages in vitro. In the current study, the effects of KGF-2 intratracheal instillation on mortality, lung liquid balance and lung histology were evaluated in our previously developed rat model of HAPE. We found that pre-treatment with KGF-2 (5 mg/kg) significantly decreased mortality, improved oxygenation and reduced lung wet-to-dry weight ratio by preventing alveolar-capillary barrier disruption demonstrated by histological examination and increasing alveolar fluid clearance up to 150%. In addition, KGF-2 significantly inhibited decrease of transendothelial permeability after exposure to hypoxia, accompanied by a 10-fold increase of Akt activity and inhibited apoptosis in human pulmonary microvascular endothelial cells, demonstrating attenuated endothelial apoptosis might contribute to reduction of endothelial permeability. These results showed the efficacy of KGF-2 on inhibition of endothelial cell apoptosis, preservation of alveolar-capillary barrier integrity and promotion of pulmonary oedema absorption in HAPE. Thus, KGF-2 may represent a potential drug candidate for the prevention of HAPE. PMID:22568566

  5. Targeting the chemotactic function of CD147 reduces collagen-induced arthritis.

    PubMed

    Damsker, Jesse M; Okwumabua, Ifeanyi; Pushkarsky, Tatiana; Arora, Kamalpreet; Bukrinsky, Michael I; Constant, Stephanie L

    2009-01-01

    CD147 is a type I transmembrane glycoprotein expressed on a wide variety of cell types, including all leucocytes. While CD147 is best known as a potent inducer of matrix metalloproteinases, it can also function as a regulator of leucocyte migration through its cell surface interaction with chemotactic extracellular cyclophilins. A potential role for CD147-cyclophilin interactions during inflammatory diseases, including rheumatoid arthritis (RA), is suggested from several studies. For example, CD147 expression is increased on reactive leucocytes in the synovial fluid and tissues of patients with arthritis. In addition, the synovial fluid of patients with RA contains high levels of extracellular cyclophilin A. In the current studies we investigated the contribution of the chemotactic function of CD147-cyclophilin interactions to joint inflammation using the mouse model of collagen-induced arthritis. Our data demonstrate that proinflammatory leucocytes, specifically neutrophils, monocytes and activated CD4(+) T cells, lose their ability to migrate in response to cyclophilin A in vitro when treated with anti-CD147 monoclonal antibody. Furthermore, in vivo treatment with anti-CD147 monoclonal antibody can reduce the development of collagen-induced arthritis in mice by >75%. Such findings suggest that CD147-cyclophilin interactions might contribute to the pathogenesis of RA by promoting the recruitment of leucocytes into joint tissues.

  6. Targeting the chemotactic function of CD147 reduces collagen-induced arthritis

    PubMed Central

    Damsker, Jesse M; Okwumabua, Ifeanyi; Pushkarsky, Tatiana; Arora, Kamalpreet; Bukrinsky, Michael I; Constant, Stephanie L

    2009-01-01

    CD147 is a type I transmembrane glycoprotein expressed on a wide variety of cell types, including all leucocytes. While CD147 is best known as a potent inducer of matrix metalloproteinases, it can also function as a regulator of leucocyte migration through its cell surface interaction with chemotactic extracellular cyclophilins. A potential role for CD147–cyclophilin interactions during inflammatory diseases, including rheumatoid arthritis (RA), is suggested from several studies. For example, CD147 expression is increased on reactive leucocytes in the synovial fluid and tissues of patients with arthritis. In addition, the synovial fluid of patients with RA contains high levels of extracellular cyclophilin A. In the current studies we investigated the contribution of the chemotactic function of CD147–cyclophilin interactions to joint inflammation using the mouse model of collagen-induced arthritis. Our data demonstrate that proinflammatory leucocytes, specifically neutrophils, monocytes and activated CD4+ T cells, lose their ability to migrate in response to cyclophilin A in vitro when treated with anti-CD147 monoclonal antibody. Furthermore, in vivo treatment with anti-CD147 monoclonal antibody can reduce the development of collagen-induced arthritis in mice by > 75%. Such findings suggest that CD147–cyclophilin interactions might contribute to the pathogenesis of RA by promoting the recruitment of leucocytes into joint tissues. PMID:18557953

  7. Neuron-targeted copolymers with sheddable shielding blocks synthesized using a reducible, RAFT-ATRP double-head agent

    PubMed Central

    Wei, Hua; Schellinger, Joan G.; Chu, David S.H.

    2012-01-01

    Successful adaptation of in vitro optimized polymeric gene delivery systems for in vivo use remains a significant challenge. Most in vivo applications require particles that are sterically stabilized but doing so significantly compromises transfection efficiency of materials shown to be effective in vitro. In this communication, we present a multi-functional well-defined block copolymer that forms particles with the following properties: cell targeting, reversible shielding, endosomal release, and DNA condensation. We show that targeted and stabilized particles retain transfection efficiencies comparable to the non-stabilized formulations. The block copolymers are synthesized using a novel, double-head agent (CPADB-SS-iBuBr) that combines a RAFT CTA and an ATRP initiator through a disulfide linkage. Using this double-head agent, a well-defined cationic block copolymer P(OEGMA)15-SS-P(GMA-TEPA)50 containing a hydrophilic oligoethyleneglycol (OEG) block and a tetraethylenepentamine (TEPA)-grafted polycation block was synthesized. This material effectively condenses plasmid DNA into salt-stable particles that deshield under intracellular reducing conditions. In vitro transfection studies showed that the reversibly shielded polyplexes afforded up 10-fold higher transfection efficiencies compared to the analogous stably-shielded polymer in four different mammalian cell lines. To compensate for reduced cell uptake caused by the hydrophilic particle shell, a neuron-targeting peptide was further conjugated to the terminus of theP(OEGMA) block. Transfection of neuron-like, differentiated PC-12 cells demonstrated that combining both targeting and deshielding in stabilized particles yields formulations that are suitable for in vivo delivery without compromising in vitro transfection efficiency. These materials are therefore promising carriers for in vivo gene delivery applications. PMID:23013485

  8. Reducing the blame culture through clinical audit in nuclear medicine: a mixed methods study

    PubMed Central

    Ross, P; Hubert, J

    2017-01-01

    Objectives To identify the barriers and facilitators of doctors’ engagement with clinical audit and to explore how and why these factors influenced doctors’ decisions to engage with the NHS National Clinical Audit Programme. Design A single-embedded case study. Mixed methods sequential approach with explorative pilot study and follow-up survey. Pilot study comprised 13 semi-structured interviews with purposefully selected consultant doctors over a six-month period. Interview data coded and analysed using directed thematic content analysis with themes compared against the study’s propositions. Themes derived from the pilot study informed the online survey question items. Exploratory factor analysis using STATA and descriptive statistical methods applied to summarise findings. Data triangulation techniques used to corroborate and validate findings across the different methodological techniques. Setting NHS National PET-CT Clinical Audit Programme. Participants Doctors reporting on the Audit Programme. Main Outcome measures Extent of engagement with clinical audit, factors that influence engagement with clinical audit. Results Online survey: 58/59 doctors responded (98.3%). Audit was found to be initially threatening (79%); audit was reassuring (85%); audit helped validate professional competence (93%); participation in audit improved reporting skills (76%). Three key factors accounted for 97.6% of the variance in survey responses: (1) perception of audit’s usefulness, (2) a common purpose, (3) a supportive blame free culture of trust. Factor 1 influenced medical engagement most. Conclusions The study documents performance feedback as a key facilitator of medical engagement with clinical audit. It found that medical engagement with clinical audit was associated with reduced levels of professional anxiety and higher levels of perceived self-efficacy. PMID:28210493

  9. Reducing the blame culture through clinical audit in nuclear medicine: a mixed methods study.

    PubMed

    Ross, P; Hubert, J; Wong, W L

    2017-02-01

    To identify the barriers and facilitators of doctors' engagement with clinical audit and to explore how and why these factors influenced doctors' decisions to engage with the NHS National Clinical Audit Programme. A single-embedded case study. Mixed methods sequential approach with explorative pilot study and follow-up survey. Pilot study comprised 13 semi-structured interviews with purposefully selected consultant doctors over a six-month period. Interview data coded and analysed using directed thematic content analysis with themes compared against the study's propositions. Themes derived from the pilot study informed the online survey question items. Exploratory factor analysis using STATA and descriptive statistical methods applied to summarise findings. Data triangulation techniques used to corroborate and validate findings across the different methodological techniques. NHS National PET-CT Clinical Audit Programme. Doctors reporting on the Audit Programme. Extent of engagement with clinical audit, factors that influence engagement with clinical audit. Online survey: 58/59 doctors responded (98.3%). Audit was found to be initially threatening (79%); audit was reassuring (85%); audit helped validate professional competence (93%); participation in audit improved reporting skills (76%). Three key factors accounted for 97.6% of the variance in survey responses: (1) perception of audit's usefulness, (2) a common purpose, (3) a supportive blame free culture of trust. Factor 1 influenced medical engagement most. The study documents performance feedback as a key facilitator of medical engagement with clinical audit. It found that medical engagement with clinical audit was associated with reduced levels of professional anxiety and higher levels of perceived self-efficacy.

  10. Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1

    PubMed Central

    Schessl, Joachim; Taratuto, Ana L.; Sewry, Caroline; Battini, Roberta; Chin, Steven S.; Maiti, Baijayanta; Dubrovsky, Alberto L.; Erro, Marcela G.; Espada, Graciela; Robertella, Monica; Saccoliti, Maria; Olmos, Patricia; Bridges, Leslie R.; Standring, Peter; Hu, Ying; Zou, Yaqun; Swoboda, Kathryn J.; Scavina, Mena; Goebel, Hans-Hilmar; Mitchell, Christina A.; Flanigan, Kevin M.; Muntoni, Francesco

    2009-01-01

    We recently identified the X-chromosomal four and a half LIM domain gene FHL1 as the causative gene for reducing body myopathy, a disorder characterized by progressive weakness and intracytoplasmic aggregates in muscle that exert reducing activity on menadione nitro-blue-tetrazolium (NBT). The mutations detected in FHL1 affected highly conserved zinc coordinating residues within the second LIM domain and lead to the formation of aggregates when transfected into cells. Our aim was to define the clinical and morphological phenotype of this myopathy and to assess the mutational spectrum of FHL1 mutations in reducing body myopathy in a larger cohort of patients. Patients were ascertained via the detection of reducing bodies in muscle biopsy sections stained with menadione-NBT followed by clinical, histological, ultrastructural and molecular genetic analysis. A total of 11 patients from nine families were included in this study, including seven sporadic patients with early childhood onset disease and four familial cases with later onset. Weakness in all patients was progressive, sometimes rapidly so. Respiratory failure was common and scoliosis and spinal rigidity were significant in some of the patients. Analysis of muscle biopsies confirmed the presence of aggregates of FHL1 positive material in all biopsies. In two patients in whom sequential biopsies were available the aggregate load in muscle sections appeared to increase over time. Ultrastructural analysis revealed that cytoplasmic bodies were regularly seen in conjunction with the reducing bodies. The mutations detected were exclusive to the second LIM domain of FHL1 and were found in both sporadic as well as familial cases of reducing body myopathy. Six of the nine mutations affected the crucial zinc coordinating residue histidine 123. All mutations in this residue were de novo and were associated with a severe clinical course, in particular in one male patient (H123Q). Mutations in the zinc coordinating residue

  11. Effectiveness of physical exercise to reduce cardiovascular risk factors in youths: a randomized clinical trial.

    PubMed

    Cesa, Claudia Ciceri; Barbiero, Sandra Mari; Petkowicz, Rosemary de Oliveira; Martins, Carla Correa; Marques, Renata das Virgens; Andreolla, Allana Abreu Martins; Pellanda, Lucia Campos

    2015-05-01

    The aim of the current study was to test the effectiveness of a physical activity and exercise-based program in a clinical context to reduce cardiovascular risk factors in children and adolescents. A randomized clinical trial was conducted in a pediatric preventive outpatient clinic. Intervention was 14 weeks of exercise for the intervention group or general health advice for the control group. The primary and the secondary outcomes were reduction of cardiovascular risk factors and the feasibility and the effectiveness of clinical advice plan to practice physical exercises at home. A total of 134 children were screened; 26 met eligibility criteria. Of these, 10 were allocated in the exercise intervention group and nine were included in the control group until the end of the intervention. Those patients who discontinued the intervention had the lowest scores of z-BMI (P = 0.033) and subscapular skin fold (P = 0.048). After 14 weeks of intervention, no statistical differences were found between the groups. High-density lipoprotein cholesterol (HDL-C) was higher in the exercise group, with a mild tendency to be significant (P = 0.066). Patients who adhere to treatment had diastolic blood pressure decreased from baseline to the end of the follow-up period in the control group (P = 0.013). Regardless of this result, the other comparisons within the group were not statistically different between T0 and T14. A low-cost physical activity advice intervention presented many barriers for implementation in routine clinical care, limiting its feasibility and evaluation of effectiveness to reduce cardiovascular risk factors.

  12. Targeting the NLRP3 Inflammasome to Reduce Diet-Induced Metabolic Abnormalities in Mice

    PubMed Central

    Chiazza, Fausto; Couturier-Maillard, Aurélie; Benetti, Elisa; Mastrocola, Raffaella; Nigro, Debora; Cutrin, Juan C; Serpe, Loredana; Aragno, Manuela; Fantozzi, Roberto; Ryffel, Bernard; Collino, Massimo

    2015-01-01

    Although the molecular links underlying the causative relationship between chronic low-grade inflammation and insulin resistance are not completely understood, compelling evidence suggests a pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Here we tested the hypothesis that either a selective pharmacological inhibition or a genetic downregulation of the NLRP3 inflammasome results in reduction of the diet-induced metabolic alterations. Male C57/BL6 wild-type mice and NLRP3−/− littermates were fed control diet or high-fat, high-fructose diet (HD). A subgroup of HD-fed wild-type mice was treated with the NLRP3 inflammasome inhibitor BAY 11-7082 (3 mg/kg intraperitoneally [IP]). HD feeding increased plasma and hepatic lipids and impaired glucose homeostasis and renal function. Renal and hepatic injury was associated with robust increases in profibrogenic markers, while only minimal fibrosis was recorded. None of these metabolic abnormalities were detected in HD-fed NLRP3−/− mice, and they were dramatically reduced in HD-mice treated with the NLRP3 inflammasome inhibitor. BAY 11-7082 also attenuated the diet-induced increase in NLRP3 inflammasome expression, resulting in inhibition of caspase-1 activation and interleukin (IL)-1β and IL-18 production (in liver and kidney). Interestingly, BAY 11-7082, but not gene silencing, inhibited nuclear factor (NF)-κB nuclear translocation. Overall, these results demonstrate that the selective pharmacological modulation of the NLRP3 inflammasome attenuates the metabolic abnormalities and the related organ injury/dysfunction caused by chronic exposure to HD, with effects similar to those obtained by NLRP3 gene silencing. PMID:26623925

  13. Magnetic Nanoparticle-Mediated Targeting of Cell Therapy Reduces In-Stent Stenosis in Injured Arteries.

    PubMed

    Polyak, Boris; Medved, Mikhail; Lazareva, Nina; Steele, Lindsay; Patel, Tirth; Rai, Ahmad; Rotenberg, Menahem Y; Wasko, Kimberly; Kohut, Andrew R; Sensenig, Richard; Friedman, Gary

    2016-09-19

    Although drug-eluting stents have dramatically reduced the recurrence of restenosis after vascular interventions, the nonselective antiproliferative drugs released from these devices significantly delay reendothelialization and vascular healing, increasing the risk of short- and long-term stent failure. Efficient repopulation of endothelial cells in the vessel wall following injury may limit complications, such as thrombosis, neoatherosclerosis, and restenosis, through reconstitution of a luminal barrier and cellular secretion of paracrine factors. We assessed the potential of magnetically mediated delivery of endothelial cells (ECs) to inhibit in-stent stenosis induced by mechanical injury in a rat carotid artery stent angioplasty model. ECs loaded with biodegradable superparamagnetic nanoparticles (MNPs) were administered at the distal end of the stented artery and localized to the stent using a brief exposure to a uniform magnetic field. After two months, magnetic localization of ECs demonstrated significant protection from stenosis at the distal part of the stent in the cell therapy group compared to both the proximal part of stent in the cell therapy group and the control (stented, nontreated) group: 1.7-fold (p < 0.001) less reduction in lumen diameter as measured by B-mode and color Doppler ultrasound, 2.3-fold (p < 0.001) less reduction in the ratios of peak systolic velocities as measured by pulsed wave Doppler ultrasound, and 2.1-fold (p < 0.001) attenuation of stenosis as determined through end point morphometric analysis. The study thus demonstrates that magnetically assisted delivery of ECs is a promising strategy for prevention of vessel lumen narrowing after stent angioplasty procedure.

  14. Total renal denervation reduces sympathoexcitation to different target organs in a model of chronic kidney disease.

    PubMed

    Veiga, Glaucia L; Nishi, Erika E; Estrela, Heder F; Lincevicius, Gisele S; Gomes, Guiomar N; Simões Sato, Alex Y; Campos, Ruy R; Bergamaschi, Cássia T

    2017-05-01

    It is known that increased sympathetic nerve activity in chronic kidney disease (CKD) progressively worsens kidney function and hypertension. We tested the hypothesis that total renal denervation contributes to reduce sympathetic activation to different beds and improves renal function in 5/6 nephrectomy model of CKD in male Wistar rats. After eight weeks of 5/6 nephrectomy surgery there was an increase in mean arterial pressure (CKD 179±22mmHg, n=6 vs. control animals 108±9; p<0.05, n=6) with no changes in heart rate (HR). Sympathetic nerve activity was increased at different levels to the remaining kidney, splanchnic and lumbar beds compared to control (CTL) group (CKD rSNA: 150±50, n=9 vs. CTL 96±15, n=9; CKD sSNA: 129±51, n=5 vs. CTL 34±14, n=6; CKD lSNA: 203±35, n=8 vs. CTL 146±21, spikes/s, n=7, p<0.05). Three weeks after total renal denervation (DNX) MAP was normalized in the CKD rats (124±19mmHg, n=5, p<0.05), with no change in HR. The lSNA was normalized (151±40, n=5, vs. CKD 203±35 spikes/s, n=8) and sSNA was decreased in 49% (64±34, n=5 vs. CKD 129±51 spikes/s, n=5, p<0.05). Renal function, assessed by creatinine plasma levels was improved after renal denervation (CKD 1.50±0.64, n=8; vs. CKD+DNX 0.82±0.22mg/mL, n=8, p<0.05). These findings demonstrate that renal nerves contribute to the maintenance of hypertension in CKD by increasing sympathoexcitation to other beds.

  15. Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels

    PubMed Central

    Jiang, Xian-cheng; Bruce, Can; Mar, Jefferson; Lin, Min; Ji, Yong; Francone, Omar L.; Tall, Alan R.

    1999-01-01

    It has been proposed that the plasma phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids and cholesterol from triglyceride-rich lipoproteins (TRL) into high-density lipoproteins (HDL). To evaluate the in vivo role of PLTP in lipoprotein metabolism, we used homologous recombination in embryonic stem cells and produced mice with no PLTP gene expression. Analysis of plasma of F2 homozygous PLTP–/– mice showed complete loss of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, and partial loss of free cholesterol transfer activities. Moreover, the in vivo transfer of [3H]phosphatidylcholine ether from very-low-density proteins (VLDL) to HDL was abolished in PLTP–/– mice. On a chow diet, PLTP–/– mice showed marked decreases in HDL phospholipid (60%), cholesterol (65%), and apo AI (85%), but no significant change in non-HDL lipid or apo B levels, compared with wild-type littermates. On a high-fat diet, HDL levels were similarly decreased, but there was also an increase in VLDL and LDL phospholipids (210%), free cholesterol (60%), and cholesteryl ester (40%) without change in apo B levels, suggesting accumulation of surface components of TRL. Vesicular lipoproteins were shown by negative-stain electron microscopy of the free cholesterol– and phospholipid-enriched IDL/LDL fraction. Thus, PLTP is the major factor facilitating transfer of VLDL phospholipid into HDL. Reduced plasma PLTP activity causes markedly decreased HDL lipid and apoprotein, demonstrating the importance of transfer of surface components of TRL in the maintenance of HDL levels. Vesicular lipoproteins accumulating in PLTP–/– mice on a high-fat diet could influence the development of atherosclerosis. PMID:10079112

  16. Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence.

    PubMed

    Russo, Antonio; Fratto, Maria E; Bazan, Viviana; Schiró, Valentina; Agnese, Valentina; Cicero, Giuseppe; Vincenzi, Bruno; Tonini, Giuseppe; Santini, Daniele

    2007-12-01

    The ubiquitin-proteasome pathway is the main proteolytic system present in the nucleus and cytoplasm of all eukaryotic cells. Apoptosis activation induced by ubiquitin-proteasome pathway inhibition makes the proteasome a new target of anticancer therapy. Bortezomib is the first proteasome inhibitor to be approved by the US FDA; in 2003 as a third line and in 2005 as a second line therapy for the treatment of multiple myeloma only. This review focuses on the use of bortezomib, not only in its therapeutic role but also, more specifically, in its biologic role and discusses the most recent applications of the drug in solid tumors, both at a preclinical and clinical level.

  17. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer.

    PubMed

    Scheiermann, Julia; Klinman, Dennis M

    2014-11-12

    Synthetic oligonucleotides (ODN) that express unmethylated "CpG motifs" trigger cells that express Toll-like receptor 9. In humans this includes plasmacytoid dendritic cells and B cells. CpG ODN induce an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. Their utility as vaccine adjuvants was evaluated in a number of clinical trials. Results indicate that CpG ODN improve antigen presentation and the generation of vaccine-specific cellular and humoral responses. This work provides an up-to-date overview of the utility of CpG ODN as adjuvants for vaccines targeting infectious agents and cancer.

  18. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer

    PubMed Central

    Scheiermann, Julia; Klinman, Dennis M.

    2014-01-01

    Synthetic oligonucleotides (ODN) that express unmethylated “CpG motifs” trigger cells that express Toll-like receptor 9. In humans this includes plasmacytoid dendritic cells and B cells. CpG ODN induce an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. Their utility as vaccine adjuvants was evaluated in a number of clinical trials. Results indicate that CpG ODN improve antigen presentation and the generation of vaccine-specific cellular and humoral responses. This work provides an up-to-date overview of the utility of CpG ODN as adjuvants for vaccines targeting infectious agents and cancer. PMID:24975812

  19. Peroxisome proliferator-activated receptor (PPAR α/γ) agonists as a potential target to reduce cardiovascular risk in diabetes.

    PubMed

    Nicholls, Stephen J; Uno, Kiyoko

    2012-04-01

    The disappointing results of glucose lowering studies have highlighted the ongoing need to develop new therapeutic strategies to reduce cardiovascular risk in patients with type 2 diabetes. The presence of a range of metabolic abnormalities in diabetic patients presents a number of potential targets for therapeutic intervention. While modulation of peroxisome proliferator activated receptors (PPARs) represents an attractive approach, the results of studies of pharmacological agonists have been variable. The findings of these studies and rationale for development of dual PPAR-α/γ agonists will be reviewed.

  20. Intravenous Paracetamol Reduces Postoperative Opioid Consumption after Orthopedic Surgery: A Systematic Review of Clinical Trials

    PubMed Central

    Khanna, Puneet

    2013-01-01

    Postoperative pain management is one of the most challenging jobs in orthopedic surgical population as it comprises of patients from extremes of ages and with multiple comorbidities. Though effective, opioids may contribute to serious adverse effects particularly in old age patients. Intravenous paracetamol is widely used in the postoperative period with the hope that it may reduce opioid consumption and produce better pain relief. A brief review of human clinical trials where intravenous paracetamol was compared with placebo or no treatment in postoperative period in orthopedic surgical population has been done here. We found that four clinical trials reported that there is a significant reduction in postoperative opioid consumption. When patients received an IV injection of 2 g propacetamol, reduction of morphine consumption up to 46% has been reported. However, one study did not find any reduction of opioid requirement after spinal surgery in children and adolescent. Four clinical trials reported better pain scores when paracetamol has been used, but other three trials denied. We conclude that postoperative intravenous paracetamol is a safe and effective adjunct to opioid after orthopedic surgery, but at present there is no data to decide whether paracetamol reduces opioid related adverse effects or not. PMID:24307945

  1. Perspectives on the design of clinical trials for targeted therapies and immunotherapy in veterinary oncology.

    PubMed

    Marconato, Laura; Buracco, Paolo; Aresu, Luca

    2015-08-01

    The field of oncology research has undergone major changes in recent years. Progress in molecular and cellular biology has led to a greater understanding of the cellular pathways and mechanisms of cell proliferation and tissue invasion associated with cancer. New classes of cancer therapies are becoming available or are in development but these new agents require a paradigm shift in the design of oncology clinical trials. This review provides an overview of clinical trial designs for the development of tumour vaccines and targeted therapeutic agents. In addition, some of the successes, limitations and challenges of these trials are discussed, with a special emphasis on the difficulties and particularities that are encountered in veterinary medicine compared to similar work in human patients. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

    PubMed Central

    Bittner, Stefan; Ruck, Tobias; Wiendl, Heinz; Grauer, Oliver M.; Meuth, Sven G.

    2016-01-01

    Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that is caused by an autoimmune response against central nervous system (CNS) structures. Traditionally considered a T-cell-mediated disorder, the contribution of B cells to the pathogenesis of MS has long been debated. Based on recent promising clinical results from CD20-depleting strategies by three therapeutic monoclonal antibodies in clinical phase II and III trials (rituximab, ocrelizumab and ofatumumab), targeting B cells in MS is currently attracting growing interest among basic researchers and clinicians. Many questions about the role of B and plasma cells in MS remain still unanswered, ranging from the role of specific B-cell subsets and functions to the optimal treatment regimen of B-cell depletion and monitoring thereafter. Here, we will assess our current knowledge of the mechanisms implicating B cells in multiple steps of disease pathology and examine current and future therapeutic approaches for the treatment of MS. PMID:28450895

  3. Clinical applications of quantitative proteomics using targeted and untargeted data-independent acquisition techniques.

    PubMed

    Meyer, Jesse G; Schilling, Birgit

    2017-05-01

    While selected/multiple-reaction monitoring (SRM or MRM) is considered the gold standard for quantitative protein measurement, emerging data-independent acquisition (DIA) using high-resolution scans have opened a new dimension of high-throughput, comprehensive quantitative proteomics. These newer methodologies are particularly well suited for discovery of biomarker candidates from human disease samples, and for investigating and understanding human disease pathways. Areas covered: This article reviews the current state of targeted and untargeted DIA mass spectrometry-based proteomic workflows, including SRM, parallel-reaction monitoring (PRM) and untargeted DIA (e.g., SWATH). Corresponding bioinformatics strategies, as well as application in biological and clinical studies are presented. Expert commentary: Nascent application of highly-multiplexed untargeted DIA, such as SWATH, for accurate protein quantification from clinically relevant and disease-related samples shows great potential to comprehensively investigate biomarker candidates and understand disease.

  4. How do CARs work?: Early insights from recent clinical studies targeting CD19.

    PubMed

    Davila, Marco L; Brentjens, Renier; Wang, Xiuyan; Rivière, Isabelle; Sadelain, Michel

    2012-12-01

    Second-generation chimeric antigen receptors (CARs) are powerful tools to redirect antigen-specific T cells independently of HLA-restriction. Recent clinical studies evaluating CD19-targeted T cells in patients with B-cell malignancies demonstrate the potency of CAR-engineered T cells. With results from 28 subjects enrolled by five centers conducting studies in patients with chronic lymphocytic leukemia (CLL) or lymphoma, some insights into the parameters that determine T-cell function and clinical outcome of CAR-based approaches are emerging. These parameters involve CAR design, T-cell production methods, conditioning chemotherapy as well as patient selection. Here, we discuss the potential relevance of these findings and in particular the interplay between the adoptive transfer of T cells and pre-transfer patient conditioning.

  5. Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors.

    PubMed

    Pincez, Thomas; Clément, Nathalie; Lapouble, Eve; Pierron, Gaëlle; Kamal, Maud; Bieche, Ivan; Bernard, Virginie; Fréneaux, Paul; Michon, Jean; Orbach, Daniel; Aerts, Isabelle; Pacquement, Hélène; Bourdeaut, Franck; Jiménez, Irene; Thébaud, Estelle; Oudot, Caroline; Vérité, Cécile; Taque, Sophie; Owens, Cormac; Doz, François; Le Tourneau, Christophe; Delattre, Olivier; Schleiermacher, Gudrun

    2017-06-01

    The role of tumor molecular profiling in directing targeted therapy utilization remains to be defined for pediatric tumors. We aimed to evaluate the feasibility of a sequencing and molecular biology tumor board (MBB) program, and its clinical impact on children with solid tumors. We report on a single-center MBB experience of 60 pediatric patients with a poor prognosis or relapsed/refractory solid tumors screened between October 2014 and November 2015. Tumor molecular profiling was performed with panel-based next-generation sequencing and array comparative genomic hybridization. Mean age was 12 ± 5.7 years (range 0.1-21.5); main tumor types were high-grade gliomas (n = 14), rare sarcomas (n = 9), and neuroblastomas (n = 8). The indication was a poor prognosis tumor at diagnosis for 16 patients and relapsed (n = 26) or refractory disease (n = 18) for the remaining 44 patients. Molecular profiling was feasible in 58 patients. Twenty-three patients (40%) had a potentially actionable finding. Patients with high-grade gliomas had the highest number of targetable alterations (57%). Six of the 23 patients subsequently received a matched targeted therapy for a period ranging from 16 days to 11 months. The main reasons for not receiving targeted therapy were poor general condition (n = 5), pursuit of conventional therapy (n = 6), or lack of pediatric trial (n = 4). Pediatric molecular profiling is feasible, with more than a third of patients being eligible to receive targeted therapy, yet only a small proportion were treated with these therapies. Analysis at diagnosis may be useful for children with very poor prognosis tumsors. © 2016 Wiley Periodicals, Inc.

  6. Clinical impact of a targeted next-generation sequencing gene panel for autoinflammation and vasculitis

    PubMed Central

    Standing, Ariane; Keylock, Annette; Price-Kuehne, Fiona; Melo Gomes, Sonia; Rowczenio, Dorota; Nanthapisal, Sira; Cullup, Thomas; Nyanhete, Rodney; Ashton, Emma; Murphy, Claire; Clarke, Megan; Ahlfors, Helena; Jenkins, Lucy; Gilmour, Kimberly; Eleftheriou, Despina; Lachmann, Helen J.; Hawkins, Philip N.; Klein, Nigel; Brogan, Paul A.

    2017-01-01

    Background Monogenic autoinflammatory diseases (AID) are a rapidly expanding group of genetically diverse but phenotypically overlapping systemic inflammatory disorders associated with dysregulated innate immunity. They cause significant morbidity, mortality and economic burden. Here, we aimed to develop and evaluate the clinical impact of a NGS targeted gene panel, the “Vasculitis and Inflammation Panel” (VIP) for AID and vasculitis. Methods The Agilent SureDesign tool was used to design 2 versions of VIP; VIP1 targeting 113 genes, and a later version, VIP2, targeting 166 genes. Captured and indexed libraries (QXT Target Enrichment System) prepared for 72 patients were sequenced as a multiplex of 16 samples on an Illumina MiSeq sequencer in 150bp paired-end mode. The cohort comprised 22 positive control DNA samples from patients with previously validated mutations in a variety of the genes; and 50 prospective samples from patients with suspected AID in whom previous Sanger based genetic screening had been non-diagnostic. Results VIP was sensitive and specific at detecting all the different types of known mutations in 22 positive controls, including gene deletion, small INDELS, and somatic mosaicism with allele fraction as low as 3%. Six/50 patients (12%) with unclassified AID had at least one class 5 (clearly pathogenic) variant; and 11/50 (22%) had at least one likely pathogenic variant (class 4). Overall, testing with VIP resulted in a firm or strongly suspected molecular diagnosis in 16/50 patients (32%). Conclusions The high diagnostic yield and accuracy of this comprehensive targeted gene panel validate the use of broad NGS-based testing for patients with suspected AID. PMID:28750028

  7. Topical photodynamic therapy significantly reduces epidermal Langerhans cells during clinical treatment of basal cell carcinoma.

    PubMed

    Evangelou, G; Farrar, M D; Cotterell, L; Andrew, S; Tosca, A D; Watson, R E B; Rhodes, L E

    2012-05-01

    Topical photodynamic therapy (PDT) is a widely applied treatment for basal cell carcinoma (BCC). PDT-induced immunosuppression leading to reduced antitumour immune responses may be a factor in treatment failure. To examine the impact of topical PDT on leucocyte trafficking following clinical treatment of BCC. Superficial BCCs in eight white caucasian patients were treated with methyl aminolaevulinate (MAL)-PDT. Biopsies for immunohistochemical assessment were taken from BCCs pre-PDT, 1 h and 24 h post-PDT and from untreated healthy skin. Treatment of BCC with MAL-PDT produced a rapid neutrophil infiltration, commencing by 1 h and significantly increased at 24 h post-PDT (P < 0·05 compared with baseline). An associated increase in the number of blood vessels expressing E-selectin was observed at 1 h and 24 h post-PDT (both P < 0·05 compared with baseline). In contrast, the number of epidermal Langerhans cells fell sharply by 1 h post-PDT, and remained significantly reduced at 24 h post-PDT (both P < 0·05 compared with baseline). Reduction of Langerhans cells during clinical treatment of BCC might potentially impact negatively on antitumour responses through reduced activation of tumour-specific effector cells. Investigation of modified PDT protocols with the aim to minimize immunosuppressive effects while maintaining antitumour efficacy is warranted. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.

  8. [How to reduce health inequities by targeting social determinants: the role of the health sector in Mexico].

    PubMed

    Martínez Valle, Adolfo; Terrazas, Paulina; Alvarez, Fernando

    2014-04-01

    To study lines of action implemented in Mexico by the health sector from 2007 to 2012 in order to combat health inequities by targeting social determinants. To contribute to better understanding and knowledge of how health system inequalities in the Region of the Americas can be reduced. To formulate recommendations for designing a future public policy agenda to address the social determinants associated with health inequities in Mexico. The policies and programs established in the National Health Program (PRONASA) 2007 - 2012 were reviewed, and those that met four criteria were selected: i) they affected the social determinants of health (SDH); ii) they developed specific lines of action aimed at reducing health inequities; iii) they set concrete goals; and iv) they had been evaluated to determine whether those goals had been met. Three programs were selected: Seguro Popular, Programa de Desarrollo Humano Oportunidades (PDHO), and Caravanas de la Salud. Once each program's specific lines of action targeting SDH had been identified, the monitoring and evaluation indicators established in PRONASA 2007 - 2012, along with other available evaluations and empirical evidence, were used to measure the extent to which the goals were met. The findings showed that Seguro Popular had had a positive impact in terms of the financial protection of lower-income households. Moreover, the reduction in the gap between workers covered by the social security system and those who were not was more evident. By reducing poverty among its beneficiaries, the PDHO also managed to reduce health inequities. The indicators for Caravanas de la Salud, on the other hand, did not show statistically significant differences between the control localities and the localities covered by the program, except in the case of Pap tests. These findings have important public policy implications for designing an agenda that promotes continued targeting of SDH and heightening its impact in terms of reducing

  9. Late-stage clinical development in lower urogenital targets: sexual dysfunction

    PubMed Central

    Azam, Usman

    2006-01-01

    In recent years, late-stage clinical drug development that primarily focuses on urogenital targets has centered around four areas of medical need (both unmet need and aiming to improve on existing therapies). These include male sexual dysfunction (MSD), female sexual dysfunction (FSD), prostatic pathology (neoplastic, pre-neoplasitic, and non-neoplastic), and improvement in lower urinary tract symptoms. Despite the regulatory approval of compounds to treat erectile dysfunction (ED), benign prostatic hyperplasia, a number of treatments for overactive bladder, and stress urinary incontinence, there remains a deficiency in addressing a number of conditions that arise out of pathophysiological dysfunction resulting in lower urogenital tract sexual conditions. In terms of late-stage clinical development, significant progress has most recently been made in MSD development, especially in understanding further a common and complex sexual dysfunction – that of premature ejaculation. The search also continues for compounds that improve ED in terms of better efficacy and superior safety profile compared to the currently marketed phosphodiesterase-5-inhibitors. Whilst there are no approved medications to treat the subtypes of FSD, there has been significant progress in attempting to better understand how to appropriately assess treatment benefit in clinical trial settings for this difficult to diagnose and treat condition. This review will focus on late-stage human clinical development pertaining to MSD and FSD. PMID:16465180

  10. Mat Pilates training reduced clinical and ambulatory blood pressure in hypertensive women using antihypertensive medications.

    PubMed

    Martins-Meneses, Daniele Tavares; Antunes, Hanna Karen Moreira; de Oliveira, Nara Rejane Cruz; Medeiros, Alessandra

    2015-01-20

    Physical exercise has been used in the treatment of hypertension. However, there are few methods researched and shown beneficial for treatment of hypertension. The objective was to evaluate the effect of Mat Pilates training (MP) on blood pressure (BP) of hypertensive women medicated with antihypertensive drugs. 44 hypertensive women (50.5 ± 6.3 years age), treated with medication for blood pressure and, uninvolved in structured exercise program were distributed into two groups: Training Group (TG) and Control Group (CG). TG performed 60-minute sessions of MP, twice a week for 16 weeks. CG was requested to maintain daily activities without exercise training. The following variables were evaluated during the pre- and post-experimental periods: clinical and ambulatory BP, heart rate (HR) and double product (DP), besides body mass, height, body mass index, waist and hip circumferences, flexibility, and right and left hand strengths. TG showed statistically significant improvements (p<0.05) within and between-groups for the systolic, diastolic and mean BP in all moments evaluated (clinical, 24h, awake and asleep). Besides that, TG showed improvements in height, waist and hip circumferences, flexibility, right and left hand strengths and clinical DP. The other variables in TG, as well as all variables in the CG didn't show significant changes. In hypertensive women using antihypertensive medications, MP reduces clinical and ambulatory BP. These results support the recommendation of MP as a non-drug treatment for hypertension. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Optimizing Smart Pump Technology by Increasing Critical Safety Alerts and Reducing Clinically Insignificant Alerts

    PubMed Central

    Mansfield, Jennifer; Jarrett, Steven

    2015-01-01

    Background: Alerts generated by intravenous (IV) infusion pump safety software prevent life-threatening situations that might otherwise go unnoticed. However, when alerts are often clinically insignificant, health care workers may become desensitized and discount their importance, resulting in potentially dangerous situations. Little research has been devoted to visual alert desensitization. Method: This paper describes how the Carolinas HealthCare System decreased the number of nonclinically relevant infusion pump alerts by analyzing alert data that were formatted into scatter plots. This in turn enabled the identification of the medications associated with the most meaningful alerts and those associated with the least meaningful alerts. Conclusion: By revising drug library limits for specific medications, it was possible to decrease the number of less clinically meaningful alerts, reduce alert fatigue, and thereby increase the effectiveness of the smart infusion pumps. This added another layer of safety to patient care. PMID:25717206

  12. Adjuvant treatment with tumor-targeting Salmonella typhimurium A1-R reduces recurrence and increases survival after liver metastasis resection in an orthotopic nude mouse model.

    PubMed

    Murakami, Takashi; Hiroshima, Yukihiko; Zhao, Ming; Zhang, Yong; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2015-12-08

    Colon cancer liver metastasis is often the lethal aspect of this disease. Well-isolated metastases are candidates for surgical resection, but recurrence is common. Better adjuvant treatment is therefore needed to reduce or prevent recurrence. In the present study, HT-29 human colon cancer cells expressing red fluorescent protein (RFP) were used to establish liver metastases in nude mice. Mice with a single liver metastasis were randomized into bright-light surgery (BLS) or the combination of BLS and adjuvant treatment with tumor-targeting S. typhimurium A1-R. Residual tumor fluorescence after BLS was clearly visualized at high magnification by fluorescence imaging. Adjuvant treatment with S. typhimurium A1-R was highly effective to increase survival and disease-free survival after BLS of liver metastasis. The results suggest the future clinical potential of adjuvant S. typhimurium A1-R treatment after liver metastasis resection.

  13. Education research: a new system for reducing patient nonattendance in residents' clinic.

    PubMed

    Price, Raymond S; Balcer, Laura J; Galetta, Steven L

    2010-03-09

    Patient nonattendance in neurology and other subspecialty clinics is closely linked to longer waiting times for appointments. We developed a new scheduling system for residents' clinic that reduced average waiting times from >4 months to < or =3 weeks. The purpose of this study was to compare nonattendance for clinics scheduled using the new model (termed "rapid access") vs those scheduled using the traditional system. In the rapid access system, nonestablished (new) patients are scheduled on a first-come, first-served basis for appointments that must occur within 2 weeks of their telephone request. Nonattendance for new patient appointments (cancellations plus no-shows) was compared for patients scheduled under the traditional vs the rapid access scheduling systems. Nonattendance was compared for periods of 6, 12, and 18 months following change in scheduling system using the chi2 test and logistic regression. Compared to the traditional scheduling system, the rapid access system was associated with a 50% reduction in nonattendance over 18 months (64% [812/1,261 scheduled visits] vs 31% [326/1,059 scheduled visits], p < 0.0001). In logistic regression models, appointment waiting time was a major factor in the relation between rapid access scheduling and nonattendance. Demographics, diagnoses, and likelihood of scheduling follow-up visits were similar between the 2 systems. A new scheduling system that minimizes waiting times for new patient appointments has been effective in substantially reducing nonattendance in our neurology residents' clinic. This rapid access system should be considered for implementation and will likely enhance the outpatient educational experience for trainees in neurology.

  14. Enteric Glial Cells: A New Frontier in Neurogastroenterology and Clinical Target for Inflammatory Bowel Diseases

    PubMed Central

    Ochoa-Cortes, Fernando; Turco, Fabio; Linan-Rico, Andromeda; Soghomonyan, Suren; Whitaker, Emmett; Wehner, Sven; Cuomo, Rosario

    2015-01-01

    Abstract: The word “glia” is derived from the Greek word “γλοια,” glue of the enteric nervous system, and for many years, enteric glial cells (EGCs) were believed to provide mainly structural support. However, EGCs as astrocytes in the central nervous system may serve a much more vital and active role in the enteric nervous system, and in homeostatic regulation of gastrointestinal functions. The emphasis of this review will be on emerging concepts supported by basic, translational, and/or clinical studies, implicating EGCs in neuron-to-glial (neuroglial) communication, motility, interactions with other cells in the gut microenvironment, infection, and inflammatory bowel diseases. The concept of the “reactive glial phenotype” is explored as it relates to inflammatory bowel diseases, bacterial and viral infections, postoperative ileus, functional gastrointestinal disorders, and motility disorders. The main theme of this review is that EGCs are emerging as a new frontier in neurogastroenterology and a potential therapeutic target. New technological innovations in neuroimaging techniques are facilitating progress in the field, and an update is provided on exciting new translational studies. Gaps in our knowledge are discussed for further research. Restoring normal EGC function may prove to be an efficient strategy to dampen inflammation. Probiotics, palmitoylethanolamide (peroxisome proliferator-activated receptor–α), interleukin-1 antagonists (anakinra), and interventions acting on nitric oxide, receptor for advanced glycation end products, S100B, or purinergic signaling pathways are relevant clinical targets on EGCs with therapeutic potential. PMID:26689598

  15. Targeting notch signaling pathway in cancer: clinical development advances and challenges.

    PubMed

    Takebe, Naoko; Nguyen, Dat; Yang, Sherry X

    2014-02-01

    Notch signaling plays an important role in development and cell fate determination, and it is deregulated in human hematologic malignancies and solid tumors. This review includes a brief introduction of the relevant pathophysiology of Notch signaling pathway and primarily focuses on the clinical development of promising agents that either obstruct Notch receptor cleavages such as γ-secretase inhibitors (GSIs) or interfere with the Notch ligand-receptor interaction by monoclonal antibodies (mAbs). Antitumor activity by GSIs and mAbs administered as single agent in early phases of clinical trials has been observed in advanced or metastatic thyroid cancer, non-small cell lung cancer, intracranial tumors, sarcoma or desmoid tumors, colorectal cancer with neuroendocrine features, melanoma and ovarian cancer. A number of mechanism-based adverse events particularly gastrointestinal toxicities emerged and mitigation strategies are developed after testing multiple GSIs and Notch targeting mAbs. We also discuss pharmacodynamic biomarkers in conjunction with methods of assessment of the molecular target inhibition validation. Biomarkers of efficacy or benefit may be of importance for a successful development of this class of drugs.

  16. Reactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications

    PubMed Central

    Daiber, Andreas; Maghzal, Ghassan J.; Di Lisa, Fabio; Kaludercic, Nina; Leach, Sonia; Cuadrado, Antonio; Jaquet, Vincent; Seredenina, Tamara; Krause, Karl H.; López, Manuela G.; Stocker, Roland

    2015-01-01

    Abstract Significance: Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear. Recent Advances: We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach. Critical Issues: Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired. Future Directions: Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic. Antioxid. Redox Signal. 23, 1171–1185. PMID:26583264

  17. Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma

    PubMed Central

    Richter, Joshua; Neparidze, Natalia; Zhang, Lin; Nair, Shiny; Monesmith, Tamara; Sundaram, Ranjini; Miesowicz, Fred; Dhodapkar, Kavita M.

    2013-01-01

    Natural killer T (iNKT) cells can help mediate immune surveillance against tumors in mice. Prior studies targeting human iNKT cells were limited to therapy of advanced cancer and led to only modest activation of innate immunity. Clinical myeloma is preceded by an asymptomatic precursor phase. Lenalidomide was shown to mediate antigen-specific costimulation of human iNKT cells. We treated 6 patients with asymptomatic myeloma with 3 cycles of combination of α-galactosylceramide–loaded monocyte-derived dendritic cells and low-dose lenalidomide. Therapy was well tolerated and led to reduction in tumor-associated monoclonal immunoglobulin in 3 of 4 patients with measurable disease. Combination therapy led to activation-induced decline in measurable iNKT cells and activation of NK cells with an increase in NKG2D and CD56 expression. Treatment also led to activation of monocytes with an increase in CD16 expression. Each cycle of therapy was associated with induction of eosinophilia as well as an increase in serum soluble IL2 receptor. Clinical responses correlated with pre-existing or treatment-induced antitumor T-cell immunity. These data demonstrate synergistic activation of several innate immune cells by this combination and the capacity to mediate tumor regression. Combination therapies targeting iNKT cells may be of benefit toward prevention of cancer in humans (trial registered at clinicaltrials.gov: NCT00698776). PMID:23100308

  18. Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma.

    PubMed

    Richter, Joshua; Neparidze, Natalia; Zhang, Lin; Nair, Shiny; Monesmith, Tamara; Sundaram, Ranjini; Miesowicz, Fred; Dhodapkar, Kavita M; Dhodapkar, Madhav V

    2013-01-17

    Natural killer T (iNKT) cells can help mediate immune surveillance against tumors in mice. Prior studies targeting human iNKT cells were limited to therapy of advanced cancer and led to only modest activation of innate immunity. Clinical myeloma is preceded by an asymptomatic precursor phase. Lenalidomide was shown to mediate antigen-specific costimulation of human iNKT cells. We treated 6 patients with asymptomatic myeloma with 3 cycles of combination of α-galactosylceramide-loaded monocyte-derived dendritic cells and low-dose lenalidomide. Therapy was well tolerated and led to reduction in tumor-associated monoclonal immunoglobulin in 3 of 4 patients with measurable disease. Combination therapy led to activation-induced decline in measurable iNKT cells and activation of NK cells with an increase in NKG2D and CD56 expression. Treatment also led to activation of monocytes with an increase in CD16 expression. Each cycle of therapy was associated with induction of eosinophilia as well as an increase in serum soluble IL2 receptor. Clinical responses correlated with pre-existing or treatment-induced antitumor T-cell immunity. These data demonstrate synergistic activation of several innate immune cells by this combination and the capacity to mediate tumor regression. Combination therapies targeting iNKT cells may be of benefit toward prevention of cancer in humans.

  19. Enteric Glial Cells: A New Frontier in Neurogastroenterology and Clinical Target for Inflammatory Bowel Diseases.

    PubMed

    Ochoa-Cortes, Fernando; Turco, Fabio; Linan-Rico, Andromeda; Soghomonyan, Suren; Whitaker, Emmett; Wehner, Sven; Cuomo, Rosario; Christofi, Fievos L

    2016-02-01

    The word "glia" is derived from the Greek word "γλoια," glue of the enteric nervous system, and for many years, enteric glial cells (EGCs) were believed to provide mainly structural support. However, EGCs as astrocytes in the central nervous system may serve a much more vital and active role in the enteric nervous system, and in homeostatic regulation of gastrointestinal functions. The emphasis of this review will be on emerging concepts supported by basic, translational, and/or clinical studies, implicating EGCs in neuron-to-glial (neuroglial) communication, motility, interactions with other cells in the gut microenvironment, infection, and inflammatory bowel diseases. The concept of the "reactive glial phenotype" is explored as it relates to inflammatory bowel diseases, bacterial and viral infections, postoperative ileus, functional gastrointestinal disorders, and motility disorders. The main theme of this review is that EGCs are emerging as a new frontier in neurogastroenterology and a potential therapeutic target. New technological innovations in neuroimaging techniques are facilitating progress in the field, and an update is provided on exciting new translational studies. Gaps in our knowledge are discussed for further research. Restoring normal EGC function may prove to be an efficient strategy to dampen inflammation. Probiotics, palmitoylethanolamide (peroxisome proliferator-activated receptor-α), interleukin-1 antagonists (anakinra), and interventions acting on nitric oxide, receptor for advanced glycation end products, S100B, or purinergic signaling pathways are relevant clinical targets on EGCs with therapeutic potential.

  20. Targeted Next-Generation Sequencing for Clinical Diagnosis of 561 Mendelian Diseases

    PubMed Central

    Kong, Xiangdong; Guo, Xueqin; Sun, Yan; Man, Jianfen; Du, Lique; Zhu, Hui; Qu, Zelan; Tian, Ping; Mao, Bing; Yang, Yun

    2015-01-01

    Background Targeted next-generation sequencing (NGS) is a cost-effective approach for rapid and accurate detection of genetic mutations in patients with suspected genetic disorders, which can facilitate effective diagnosis. Methodology/Principal Findings We designed a capture array to mainly capture all the coding sequence (CDS) of 2,181 genes associated with 561 Mendelian diseases and conducted NGS to detect mutations. The accuracy of NGS was 99.95%, which was obtained by comparing the genotypes of selected loci between our method and SNP Array in four samples from normal human adults. We also tested the stability of the method using a sample from normal human adults. The results showed that an average of 97.79% and 96.72% of single-nucleotide variants (SNVs) in the sample could be detected stably in a batch and different batches respectively. In addition, the method could detect various types of mutations. Some disease-causing mutations were detected in 69 clinical cases, including 62 SNVs, 14 insertions and deletions (Indels), 1 copy number variant (CNV), 1 microdeletion and 2 microduplications of chromosomes, of which 35 mutations were novel. Mutations were confirmed by Sanger sequencing or real-time polymerase chain reaction (PCR). Conclusions/Significance Results of the evaluation showed that targeted NGS enabled to detect disease-causing mutations with high accuracy, stability, speed and throughput. Thus, the technology can be used for the clinical diagnosis of 561 Mendelian diseases. PMID:26274329

  1. Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review.

    PubMed

    King, Jordan B; Bress, Adam P; Reese, Austin D; Munger, Mark A

    2015-09-01

    There has been a 10-year hiatus in the approval of a new pharmacotherapy for patients with chronic heart failure with a reduced ejection fraction (HFrEF). Combining an angiotensin receptor blocker, valsartan, with sacubitril, an inhibitor of neprilysin, results in increasing levels of natriuretic peptides that counterbalance high circulating levels of neurohormones in HFrEF. This has resulted in the development of a new agent, LCZ696. A comprehensive overview of LCZ696, its pharmacology, its role in the pathophysiology of HFrEF, completed and future clinical trial information, specific critical issues, and the place of LCZ696 in HFrEF therapy are presented.

  2. Clinical use of virtual reality distraction system to reduce anxiety and pain in dental procedures.

    PubMed

    Wiederhold, Mark D; Gao, Kenneth; Wiederhold, Brenda K

    2014-06-01

    Virtual reality (VR) has been used by clinicians to manage pain in clinical populations. This study examines the use of VR as a form of distraction for dental patients using both subjective and objective measures to determine how a VR system affects patients' reported anxiety level, pain level, and physiological factors. As predicted, results of self-evaluation questionnaires showed that patients experienced less anxiety and pain after undergoing VR treatment. Physiological data reported similar trends in decreased anxiety. Overall, the favorable subjective and objective responses suggest that VR distraction systems can reduce discomfort and pain for patients with mild to moderate fear and anxiety.

  3. Clinical Use of Virtual Reality Distraction System to Reduce Anxiety and Pain in Dental Procedures

    PubMed Central

    Gao, Kenneth; Wiederhold, Brenda K.

    2014-01-01

    Abstract Virtual reality (VR) has been used by clinicians to manage pain in clinical populations. This study examines the use of VR as a form of distraction for dental patients using both subjective and objective measures to determine how a VR system affects patients' reported anxiety level, pain level, and physiological factors. As predicted, results of self-evaluation questionnaires showed that patients experienced less anxiety and pain after undergoing VR treatment. Physiological data reported similar trends in decreased anxiety. Overall, the favorable subjective and objective responses suggest that VR distraction systems can reduce discomfort and pain for patients with mild to moderate fear and anxiety. PMID:24892198

  4. Sevoflurane reduces clinical disease in a mouse model of multiple sclerosis

    PubMed Central

    2012-01-01

    Background Inhalational anesthetics have been shown to influence T cell functions both in vitro and in vivo, in many cases inducing T cell death, suggesting that exposure to these drugs could modify the course of an autoimmune disease. We tested the hypothesis that in mice immunized to develop experimental autoimmune encephalomyelitis (EAE), a well established model of multiple sclerosis (MS), treatment with the commonly used inhalational anesthetic sevoflurane would attenuate disease symptoms. Methods C57Bl6 female mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide residues 35 to 55 to induce a chronic demyelinating disease. At day 10 after immunization, the mice were subjected to 2 h of 2.5% sevoflurane in 100% oxygen, or 100% oxygen, alone. Following treatment, clinical scores were monitored up to 4 weeks, after which brain histology was performed to measure the effects on astrocyte activation and lymphocyte infiltration. Effects of sevoflurane on T cell activation were studied using splenic T cells isolated from MOG peptide-immunized mice, restimulated ex vivo with MOG peptide or with antibodies to CD3 and CD28, and in the presence of different concentrations of sevoflurane. T cell responses were assessed 1 day later by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for proliferation, lactate dehydrogenase (LDH) release for cell death, and inflammatory activation by production of interleukin (IL)-17 and interferon (IFN)γ. Results Clinical scores in the oxygen-treated group increased until day 28 at which time they showed moderate to severe disease (average clinical score of 2.9). In contrast, disease progression in the sevoflurane-treated group increased to 2.1 at day 25, after which it remained unchanged until the end of the study. Immunohistochemical analysis revealed reduced numbers of infiltrating leukocytes and CD4+ cells in the CNS of the sevoflurane-treated mice, as well as reduced glial cell activation

  5. Targeting services to reduce social inequalities in utilisation: an analysis of breast cancer screening in New South Wales

    PubMed Central

    Birch, Stephen; Haas, Marion; Savage, Elizabeth; Van Gool, Kees

    2007-01-01

    Background Many jurisdictions have used public funding of health care to reduce or remove price at the point of delivery of services. Whilst this reduces an important barrier to accessing care, it does nothing to discriminate between groups considered to have greater or fewer needs. In this paper, we consider whether active targeted recruitment, in addition to offering a 'free' service, is associated with a reduction in social inequalities in self-reported utilization of the breast screening services in NSW, Australia. Methods Using the 1997 and 1998 NSW Health Surveys we estimated probit models on the probability of having had a screening mammogram in the last two years for all women aged 40–79. The models examined the relative importance of socio-economic and geographic factors in predicting screening behaviour in three different needs groups – where needs were defined on the basis of a woman's age. Results We find that women in higher socio-economic groups are more likely to have been screened than those in lower groups for all age groups. However, the socio-economic effect is significantly less among women who were in the actively targeted age group. Conclusion This indicates that recruitment and follow-up was associated with a modest reduction in social inequalities in utilisation although significant income differences remain. PMID:17550622

  6. Targeted gene transfer of hepatocyte growth factor to alveolar type II epithelial cells reduces lung fibrosis in rats.

    PubMed

    Gazdhar, Amiq; Temuri, Almas; Knudsen, Lars; Gugger, Mathias; Schmid, Ralph A; Ochs, Matthias; Geiser, Thomas

    2013-01-01

    Inefficient alveolar wound repair contributes to the development of pulmonary fibrosis. Hepatocyte growth factor (HGF) is a potent growth factor for alveolar type II epithelial cells (AECII) and may improve repair and reduce fibrosis. We studied whether targeted gene transfer of HGF specifically to AECII improves lung fibrosis in bleomycin-induced lung fibrosis. A plasmid encoding human HGF expressed from the human surfactant protein C promoter (pSpC-hHGF) was designed, and extracorporeal electroporation-mediated gene transfer of HGF specifically to AECII was performed 7 days after bleomycin-induced lung injury in the rat. Animals were killed 7 days after hHGF gene transfer. Electroporation-mediated HGF gene transfer resulted in HGF expression specifically in AECII at biologically relevant levels. HGF gene transfer reduced pulmonary fibrosis as assessed by histology, hydroxyproline determination, and design-based stereology compared with controls. Our results indicate that the antifibrotic effect of HGF is due in part to a reduction of transforming growth factor-β(1), modulation of the epithelial-mesenchymal transition, and reduction of extravascular fibrin deposition. We conclude that targeted HGF gene transfer specifically to AECII decreases bleomycin-induced lung fibrosis and may therefore represent a novel cell-specific gene transfer technology to treat pulmonary fibrosis.

  7. Return of target material ions leads to a reduced hysteresis in reactive high power impulse magnetron sputtering: Model

    NASA Astrophysics Data System (ADS)

    Kadlec, Stanislav; Čapek, Jiří

    2017-05-01

    A tendency to disappearing hysteresis in reactive High Power Impulse Magnetron Sputtering (HiPIMS) has been reported previously without full physical explanation. An analytical model of reactive pulsed sputtering including HiPIMS is presented. The model combines a Berg-type model of reactive sputtering with the global HiPIMS model of Christie-Vlček. Both time and area averaging is used to describe the macroscopic steady state, especially the reactive gas balance in the reactor. The most important effect in the presented model is covering of reacted parts of target by the returning ionized metal, effectively lowering the target coverage by reaction product at a given partial pressure. The return probability of ionized sputtered metal has been selected as a parameter to quantify the degree of HiPIMS effects. The model explains the reasons for reduced hysteresis in HiPIMS. The critical pumping speed was up to a factor of 7 lower in reactive HiPIMS compared to the mid-frequency magnetron sputtering. The model predicts reduced hysteresis in HiPIMS due to less negative slope of metal flux to substrates and of reactive gas sorption as functions of reactive gas partial pressure. Higher deposition rate of reactive HiPIMS compared to standard reactive sputtering is predicted for some parameter combinations. Comparison of the model with experiment exhibits good qualitative and quantitative agreement for three material combinations, namely, Ti-O2, Al-O2, and Ti-N2.

  8. Densification of tube-shaped transparent conducting oxide target at reduced temperature via initial heat treatment under pressure

    NASA Astrophysics Data System (ADS)

    Lee, Sung-Pyo; Lee, Jong-Rak; Chung, Tai-Joo; Paek, Yeong-Kyeun; Yang, Seung-Ho; Hong, Gil-Su; Oh, Kyung-Sik

    2015-11-01

    Transparent conducting oxide such as aluminum doped ZnO (Al-ZnO) needs to be prepared in a tube-shaped target for prolonged life time during sputtering. To prevent warping and coarsening during preparation, the densification of tube-shaped target need to be achieved at reduced temperature. In this study, tube-shaped 2 wt% Al-ZnO was prepared via two-step sintering route, consisted with initial heat treatment (IHT) at 700 °C or 800 °C under mild external pressure (1 MPa) and subsequent pressureless sintering at 1300 °C or 1350 °C. By applying pressure during the IHT, the density obtained by sintering at 1300 °C increased by 2.38% and reached the same level of density as material sintered at 1350 °C. The reduced sintering temperature rendered a fine grained tube, suitable for prevention of nodules during sputtering. The IHT under external pressure had limited effects for tall tubes, where loss of pressure was anticipated due to the difficulty in fine filling the pressing medium within the mold.

  9. Targeting atypical protein kinase C iota reduces viability in glioblastoma stem-like cells via a notch signaling mechanism.

    PubMed

    Phillips, Emma; Lang, Verena; Bohlen, Jonathan; Bethke, Frederic; Puccio, Laura; Tichy, Diana; Herold-Mende, Christel; Hielscher, Thomas; Lichter, Peter; Goidts, Violaine

    2016-10-15

    In a previous study, Protein Kinase C iota (PRKCI) emerged as an important candidate gene for glioblastoma (GBM) stem-like cell (GSC) survival. Here, we show that PKCι is overexpressed and activated in patient derived GSCs compared with normal neural stem cells and normal brain lysate, and that silencing of PRKCI in GSCs causes apoptosis, along with loss of clonogenicity and reduced proliferation. Notably, PRKCI silencing reduces tumor growth in vivo in a xenograft mouse model. PKCι has been intensively studied as a therapeutic target in non-small cell lung cancer, resulting in the identification of an inhibitor, aurothiomalate (ATM), which disrupts the PKCι/ERK signaling axis. However, we show that, although sensitive to pharmacological inhibition via a pseudosubstrate peptide inhibitor, GSCs are much less sensitive to ATM, suggesting that PKCι acts along a different signaling axis in GSCs. Gene expression profiling of PRKCI-silenced GSCs revealed a novel role of the Notch signaling pathway in PKCι mediated GSC survival. A proximity ligation assay showed that Notch1 and PKCι are in close proximity in GSCs. Targeting PKCι in the context of Notch signaling could be an effective way of attacking the GSC population in GBM.

  10. Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets

    PubMed Central

    Martin, Pauline L; Bugelski, Peter J

    2012-01-01

    Monoclonal antibodies (mAbs) and fusion proteins directed towards soluble targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 14 currently approved mAbs and fusion proteins targeted to soluble targets. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency ‘Scientific Discussions’ and United States Food and Drug Administration ‘Pharmacology/Toxicology Reviews’ and package inserts (United States Prescribing Information). Data on the following approved biopharmaceuticals were included: adalimumab, anakinra, bevacizumab, canakinumab, certolizumab pegol, denosumab, eculizumab, etanercept, golimumab, infliximab, omalizumab, ranibizumab, rilonacept and ustekinumab. Some related biopharmaceuticals in late-stage development were also included for comparison. Good concordance with human pharmacodynamics was found for both non-human primates (NHPs) receiving the human biopharmaceutical and mice receiving rodent homologues (surrogates). In contrast, there was limited concordance for human adverse effects in genetically deficient mice, mice receiving surrogates or NHPs receiving the human pharmaceutical. In summary, the results of this survey show that although both mice and NHPs have good predictive value for human pharmacodynamics, neither species have good predictive value for human adverse effects. No evidence that NHPs have superior predictive value was found. PMID:22168335

  11. New Developments in Salivary Gland Pathology: Clinically Useful Ancillary Testing and New Potentially Targetable Molecular Alterations.

    PubMed

    Griffith, Christopher C; Schmitt, Alessandra C; Little, James L; Magliocca, Kelly R

    2017-03-01

    Accurate diagnosis of salivary gland tumors can be challenging because of the many diagnostic entities, the sometimes extensive morphologic overlap, and the rarity of most tumor types. Ancillary testing is beginning to ameliorate some of these challenges through access to newer immunohistochemical stains and fluorescence in situ hybridization probes, which can limit differential diagnostic considerations in some cases. These ancillary testing strategies are especially useful in small biopsy samples, including aspiration cytology. Molecular techniques are also expanding our understanding of salivary gland tumor pathology and are helping to identify potential targets that may improve treatment for some of these tumors. Here, we summarize the clinical use of new immunohistochemical markers in our practice and review the current understanding of chromosomal rearrangements in salivary gland tumor pathology, emphasizing the prospects for exploiting molecular alterations in salivary gland tumors for diagnosis and targeted therapy. We find that immunohistochemistry and fluorescence in situ hybridization are powerful tools toward the diagnosis of salivary gland tumors, especially when used in a systematic manner based on morphologic differential-diagnostic considerations. As new targeted therapies emerge, it will become increasingly vital to incorporate appropriate molecular testing into the pathologic evaluation of salivary gland cancers.

  12. A clinical interactive technique for MR-CT image registration for target delineation of intracranial tumors.

    PubMed

    Luu, Q T; Levy, R P; Miller, D W; Shahnazi, K; Yonemoto, L T; Slater, J M; Slater, J D

    2005-06-01

    Replacement of current CT-based, three-dimensional (3D) treatment planning systems by newer versions capable of automated multi-modality image registration may be economically prohibitive for most radiation oncology clinics. We present a low-cost technique for MR-CT image registration on a "first generation" CT-based, 3D treatment planning system for intracranial tumors. The technique begins with fabrication of a standard treatment mask. A second truncated mask, the "minimask," is then made, using the standard mask as a mold. Two orthogonal leveling vials glued onto the minimask detect angular deviations in pitch and roll. Preservation of yaw is verified by referencing a line marked according to the CT laser on the craniocaudal axis. The treatment mask immobilizes the patient's head for CT. The minimask reproduces this CT-based angular treatment position, which is then maintained by taping the appropriately positioned head to the MR head coil for MR scanning. All CT and MR images, in DICOM 3.0 format, are entered into the treatment planning system via a computer network. Interactive registration of MR to CT images is controlled by real-time visual feedback on the computer monitor. Translational misalignments at the target are eliminated or minimized by iterative use of qualitative visual inspection. In this study, rotational errors were measured in a retrospective series of 20 consecutive patients who had undergone CT-MR image registration using this technique. Anatomic structures defined the three CT orthogonal axes from which angular errors on MR image were measured. Translational errors at the target isocenter were within pixel size, as judged by visual inspection. Clinical setup using the minimask resulted in overall average angular deviation of 3 degrees +/-2 degrees (mean +/- SD) and translational deviation within the edges of the target volume of typically less than 2 mm. The accuracy of this registration technique for target delineation of intracranial

  13. Photoresponsive fluorescent reduced graphene oxide by spiropyran conjugated hyaluronic acid for in vivo imaging and target delivery.

    PubMed

    Nahain, Abdullah-Al; Lee, Jung-Eun; Jeong, Ji Hoon; Park, Sung Young

    2013-11-11

    This present article demonstrates the strategy to prepare photoresponsive reduced graphene oxide with mussel inspired adhesive material dopamine (DN) and photochromic dye spiropyran (SP) conjugated to the backbone of the targeting ligand hyaluronic acid (HA; HA-SP). Graphene oxide (GO) was reduced by prepared HA-SP accepting the advantages of catechol chemistry under mildly alkaline condition enabling to achieve functionalized graphene (rGO/HA-SP) as fluorescent nanoparticles. Due to containing HA, rGO/HA-SP can bind to the CD44 cell receptors. The prepared rGO/HA-SP is able to retain its photochromic features and can be converted to merocyanine (MC) form upon irradiation with UV light (wavelength: 365 nm) displaying purple color. Photochromic behavior of rGO/HA-SP was monitored by UV-vis and fluorescence spectroscopy. In vitro fluorescence behavior, examined by confocal laser scanning microscope (CLSM), of rGO/HA-SP in cancerous A549 cell lines assured that efficient delivery of rGO/HA-SP was gained due to HA as targeting ligand. In this work, we have shown that in vivo fluorescence image of spiropyran is possible by administrating MC form solution of rGO/HA-SP using Balb/C mice as in vivo modal. Accumulation of rGO/HA-SP in tumor tissue from biodistribution analysis strongly supports the specific delivery of prepared graphene to the target destination. The well tuned drug release manner from the surface of rGO/HA-SP strongly recommends the developed material not only as fluorescent probe for diagnosis but also as a drug carrier in drug delivery system.

  14. Clinical roundtable monograph: CD30 in lymphoma: its role in biology, diagnostic testing, and targeted therapy.

    PubMed

    Sotomayor, Eduardo M; Young, Ken H; Younes, Anas

    2014-04-01

    CD30, a member of the tumor necrosis factor receptor superfamily, is a transmembrane glycoprotein receptor consisting of an extracellular domain, a transmembrane domain, and an intracellular domain. CD30 has emerged as an important molecule in the field of targeted therapy because its expression is generally restricted to specific disease types and states. The major cancers with elevated CD30 expression include Hodgkin lymphoma and anaplastic large T-cell lymphoma, and CD30 expression is considered essential to the differential diagnosis of these malignancies. Most commonly, CD30 expression is detected and performed by immunohistochemical staining of biopsy samples. Alternatively, flow cytometry analysis has also been developed for fresh tissue and cell aspiration specimens, including peripheral blood and bone marrow aspirate. Over the past several years, several therapeutic agents were developed to target CD30, with varying success in clinical trials. A major advance in the targeting of CD30 was seen with the development of the antibody-drug conjugate brentuximab vedotin, which consists of the naked anti-CD30 antibody SGN-30 conjugated to the synthetic antitubulin agent monomethyl auristatin E. In 2011, brentuximab vedotin was approved by the US Food and Drug Administration for use in Hodgkin lymphoma and anaplastic large cell lymphoma based on clinical trial data showing high response rates in these indications. Ongoing trials are examining brentuximab vedotin after autologous stem cell transplantation, as part of chemotherapy combination regimens, and in other CD30-expressing malignancies, including primary mediastinal large B-cell lymphomas, diffuse large B-cell lymphoma, lymphoma positive for Epstein-Barr virus, peripheral T-cell lymphoma not otherwise specified, and cutaneous anaplastic large cell lymphoma.

  15. Receptor activator of nuclear factor kappa B ligand/osteoprotegerin pathway is a promising target to reduce atherosclerotic plaque calcification.

    PubMed

    Quercioli, Alessandra; Luciano Viviani, Giorgio; Dallegri, Franco; Mach, François; Montecucco, Fabrizio

    2010-12-01

    Atherosclerotic plaque calcification represents a common pathophysiologic process in the advanced phases of the disease. Both inflammatory and vascular cells (such as osteoblast-like cells, osteoclast-like cells, dendritic cells, macrophages, smooth muscle cells, and endothelial cells) are active players in the balance between intraplaque bone deposition and resorption. Inflammatory processes underlying plaque calcification are regulated by soluble mediators that also contribute to plaque destabilization and increased vulnerability. Among different mediators, the receptor activator of nuclear factor-kappa B (NF-kappa B) ligand (RANKL)/osteoprogerin (OPG) system is a major determinant in inflammatory cell differentiation toward osteoclast-like cells. Thus, this system might be a promising parameter to be investigated as a marker of calcification-related cardiovascular risk and a therapeutic target. Despite some promising results, several limitations have been shown in the potential clinical use of serum RANKL/OPG to better assess the cardiovascular risk. At present, the potential relationship between RANKL/OPG and the content of calcium within the intima of the coronary arteries (CAC score, assessed by computed tomography) needs to be explored in large clinical studies. On the other hand, the antiatherosclerotic relevance of treatments antagonizing RANKL is still under investigation. Despite that clinical evidence is needed, this therapeutic approach might be of particular benefit in selective populations (such as rheumatoid arthritis patients) with an increased cardiovascular risk.

  16. Clinically relevant HOCl concentrations reduce clot retraction rate via the inhibition of energy production in platelet mitochondria.

    PubMed

    Misztal, T; Rusak, T; Tomasiak, M

    2014-12-01

    Using porcine blood, we examined the impact of hypochlorite, product of activated inflammatory cells, on clot retraction (CR), an important step of hemostasis. We found that, in vitro, HOCl is able to reduce CR rate and enlarge final clot size in whole blood (t.c. 100 μM), platelet-rich plasma (PRP) threshold concentration (t.c. 50 μM), and an artificial system (washed platelets and fibrinogen) (t.c. 25 nM). Combination of low HOCl and peroxynitrite concentrations resulted in synergistic inhibition of CR by these stressors. Concentrations of HOCl completely inhibiting CR failed to affect the kinetics of coagulation measured in PRP and in platelet-free plasma. Concentrations of HOCl reducing CR rate in PRP augmented production of lactate, inhibited consumption of oxygen by platelets, and decreased total adenosine triphosphate (ATP) content in PRP-derived clots. In an artificial system, concentrations of HOCl resulting in inhibition of CR (25-100 nM) reduced mitochondrial transmembrane potential and did not affect actin polymerization in thrombin-stimulated platelets. These concentrations of HOCl failed to affect the adhesion of washed platelets to fibrinogen and to evoke sustained calcium signal, thus excluding stressor action on glycoprotein IIb/IIIa receptors. Exogenously added Mg-ATP almost completely recovered HOCl-mediated retardation of CR. Concentrations of HOCl higher than those affecting CR reduced thromboelastometric variables (maximum clot firmness and α angle). We conclude that low clinically relevant HOCl concentrations may evoke the inhibition of CR via the reduction of platelet contractility resulted from malfunction of platelet mitochondria. At the inflammatory conditions, CR may be the predominant HOCl target.

  17. Study of the dissociation of a charge-reduced phosphopeptide formed by electron transfer from an alkali metal target.

    PubMed

    Hayakawa, Shigeo; Hashimoto, Mami; Nagao, Hirofumi; Awazu, Kunio; Toyoda, Michisato; Ichihara, Toshio; Shigeri, Yasushi

    2008-01-01

    Doubly protonated phosphopeptide (YGGMHRQET(p)VDC) ions obtained by electrospray ionization were collided with Xe and Cs targets to give singly and doubly charged positive ions via collision-induced dissociation (CID). The resulting ions were analyzed and detected by using an electrostatic analyzer (ESA). Whereas doubly charged fragment ions resulting from collisionally activated dissociation (CAD) were dominant in the CID spectrum with the Xe target, singly charged fragment ions resulting from electron transfer dissociation (ETD) were dominant in the CID spectrum with the Cs target. The most intense peak resulting from ETD was estimated to be associated with the charge-reduced ion with H2 lost from the precursor. Five c-type fragment ions with amino acid residues detached consecutively from the C-terminal were clearly observed without a loss of the phosphate group. These ions must be formed by N--Calpha bond cleavage, in a manner similar to the cases of electron capture dissociation (ECD) and ETD from negative ions. Although the accuracy in m/z of the CID spectra was about +/-1 Th because of the mass analysis using the ESA, it is supposed from the m/z values of the c-type ions that these ions were accompanied by the loss of a hydrogen atom. Four z-type (or y--NH3, or y--H2O) ions analogously detached consecutively from the N-terminal were also observed. The fragmentation processes took place within the time scale of 4.5 micros in the high-energy collision. The present results demonstrated that high-energy ETD with the alkali metal target allowed determination of the position of phosphorylation and the amino acid sequence of post-translational peptides.

  18. Clinical and economic burden of postoperative pulmonary complications: patient safety summit on definition, risk-reducing interventions, and preventive strategies.

    PubMed

    Shander, Aryeh; Fleisher, Lee A; Barie, Philip S; Bigatello, Luca M; Sladen, Robert N; Watson, Charles B

    2011-09-01

    Postoperative pulmonary complications are a major contributor to the overall risk of surgery. We convened a patient safety summit to discuss ways to enhance physician awareness of postoperative pulmonary complications, advance postoperative pulmonary complications as a substantive public health concern demanding national attention, recommend strategies to reduce the deleterious impact of postoperative pulmonary complications on clinical outcomes and healthcare costs, and establish an algorithm that will help identify patients who are at increased risk for postoperative pulmonary complications. We conducted PubMed searches for relevant literature on postoperative pulmonary complications in addition to using the summit participants' experience in the management of patients with postoperative pulmonary complications. Postoperative pulmonary complications are common, are associated with increased morbidity and mortality, and adversely affect financial outcomes in health care. A multifaceted approach is necessary to reduce the incidence of postoperative pulmonary complications. Identifying a measurable marker of risk will facilitate the targeted implementation of risk-reduction strategies. The most practicable marker that identifies patients at highest risk for postoperative pulmonary complications is the need for postoperative mechanical ventilation of a cumulative duration >48 hrs.

  19. Survey and Rapid Detection of Bordetella pertussis in Clinical Samples Targeting the BP485 in China.

    PubMed

    Liu, Wei; Xu, Yinghua; Dong, Derong; Li, Huan; Zhao, Xiangna; Li, Lili; Zhang, Ying; Wei, Xiao; Wang, Xuesong; Huang, Simo; Zeng, Ming; Huang, Liuyu; Zhang, Shumin; Yuan, Jing

    2015-01-01

    Bordetella pertussis is an important human respiratory pathogen. Here, we describe a loop-mediated isothermal amplification (LAMP) method for the rapid detection of B. pertussis in clinical samples based on a visual test. The LAMP assay detected the BP485 target sequence within 60 min with a detection limit of 1.3 pg/μl, a 10-fold increase in sensitivity compared with conventional PCR. All 31 non-pertussis respiratory pathogens tested were negative for LAMP detection, indicating the high specificity of the primers for B. pertussis. To evaluate the application of the LAMP assay to clinical diagnosis, of 105 sputum and nasopharyngeal samples collected from the patients with suspected respiratory infections in China, a total of 12 B. pertussis isolates were identified from 33 positive samples detected by LAMP-based surveillance targeting BP485. Strikingly, a 4.5 months old baby and her mother were found to be infected with B. pertussis at the same time. All isolates belonged to different B. pertussis multilocus sequence typing groups with different alleles of the virulence-related genes including four alleles of ptxA, six of prn, four of tcfA, two of fim2, and three of fim3. The diversity of B. pertussis carrying toxin genes in clinical strains indicates a rapid and continuing evolution of B. pertussis. This combined with its high prevalence will make it difficult to control. In conclusion, we have developed a visual detection LAMP assay, which could be a useful tool for rapid B. pertussis detection, especially in situations where resources are poor and in point-of-care tests.

  20. Survey and Rapid Detection of Bordetella pertussis in Clinical Samples Targeting the BP485 in China

    PubMed Central

    Liu, Wei; Xu, Yinghua; Dong, Derong; Li, Huan; Zhao, Xiangna; Li, Lili; Zhang, Ying; Wei, Xiao; Wang, Xuesong; Huang, Simo; Zeng, Ming; Huang, Liuyu; Zhang, Shumin; Yuan, Jing

    2015-01-01

    Bordetella pertussis is an important human respiratory pathogen. Here, we describe a loop-mediated isothermal amplification (LAMP) method for the rapid detection of B. pertussis in clinical samples based on a visual test. The LAMP assay detected the BP485 target sequence within 60 min with a detection limit of 1.3 pg/μl, a 10-fold increase in sensitivity compared with conventional PCR. All 31 non-pertussis respiratory pathogens tested were negative for LAMP detection, indicating the high specificity of the primers for B. pertussis. To evaluate the application of the LAMP assay to clinical diagnosis, of 105 sputum and nasopharyngeal samples collected from the patients with suspected respiratory infections in China, a total of 12 B. pertussis isolates were identified from 33 positive samples detected by LAMP-based surveillance targeting BP485. Strikingly, a 4.5 months old baby and her mother were found to be infected with B. pertussis at the same time. All isolates belonged to different B. pertussis multilocus sequence typing groups with different alleles of the virulence-related genes including four alleles of ptxA, six of prn, four of tcfA, two of fim2, and three of fim3. The diversity of B. pertussis carrying toxin genes in clinical strains indicates a rapid and continuing evolution of B. pertussis. This combined with its high prevalence will make it difficult to control. In conclusion, we have developed a visual detection LAMP assay, which could be a useful tool for rapid B. pertussis detection, especially in situations where resources are poor and in point-of-care tests. PMID:25798436

  1. The Clinical Development of Molecularly Targeted Agents in Combination With Radiation Therapy: A Pharmaceutical Perspective

    SciTech Connect

    Ataman, Ozlem U.; Sambrook, Sally J.; Wilks, Chris; Lloyd, Andrew; Taylor, Amanda E.; Wedge, Stephen R.

    2012-11-15

    Summary: This paper explores historical and current roles of pharmaceutical industry sponsorship of clinical trials testing radiation therapy combinations with molecularly targeted agents and attempts to identify potential solutions to expediting further combination studies. An analysis of clinical trials involving a combination of radiation therapy and novel cancer therapies was performed. Ongoing and completed trials were identified by searching the (clinicaltrials.gov) Web site, in the first instance, with published trials of drugs of interest identified through American Society of Clinical Oncology, European CanCer Organisation/European Society for Medical Oncology, American Society for Radiation Oncology/European Society for Therapeutic Radiology and Oncology, and PubMed databases and then cross-correlated with (clinicaltrials.gov) protocols. We examined combination trials involving radiation therapy with novel agents and determined their distribution by tumor type, predominant molecular mechanisms examined in combination to date, timing of initiation of trials relative to a novel agent's primary development, and source of sponsorship of such trials. A total of 564 studies of targeted agents in combination with radiation therapy were identified with or without concomitant chemotherapy. Most studies were in phase I/II development, with only 36 trials in phase III. The tumor site most frequently studied was head and neck (26%), followed by non-small cell lung cancer. Pharmaceutical companies were the sponsors of 33% of studies overall and provided support for only 16% of phase III studies. In terms of pharmaceutical sponsorship, Genentech was the most active sponsor of radiation therapy combinations (22%), followed by AstraZeneca (14%). Most radiation therapy combination trials do not appear to be initiated until after drug approval. In phase III studies, the most common (58%) primary endpoint was overall survival. Collectively, this analysis suggests that such

  2. A Pharmacist-Staffed, Virtual Gout Management Clinic for Achieving Target Serum Uric Acid Levels: A Randomized Clinical Trial

    PubMed Central

    Goldfien, Robert; Pressman, Alice; Jacobson, Alice; Ng, Michele; Avins, Andrew

    2016-01-01

    Context: Relatively few patients with gout receive appropriate treatment. Objective: To determine whether a pharmacist-staffed gout management program is more effective than usual care in achieving target serum uric acid (sUA) levels in gout patients. Design: A parallel-group, randomized controlled trial of a pharmacist-staffed, telephone-based program for managing hyperuricemia vs usual care. Trial duration was 26 weeks. Main Outcome Measures: Primary outcome measure was achieving sUA levels at or below 6 mg/dL at the 26-week visit. Secondary outcome was mean change in sUA levels in the control and intervention groups. Participants were adults with recurrent gout and sUA levels above 6.0 mg/dL. Participants were randomly assigned to management by a clinical pharmacist following protocol or to monitoring of sUA levels but management of their gout by their usual treating physician. Results: Of 102 patients who met eligibility criteria, 77 subjects obtained a baseline sUA measurement and were entered into the trial. Among 37 participants in the intervention group, 13 (35%) had sUA levels at or below 6.0 mg/dL at 26 weeks, compared with 5 (13%) of 40 participants in the control group (risk ratio = 2.8, 95% confidence interval [CI] = 1.1 to 7.1, p = 0.03). The mean change in sUA levels among controls was +0.1 mg/dL compared with −1.5 mg/dL in the intervention group (sUA difference = −1.6, 95% CI = −0.9 to −2.4, p < 0.001). Conclusions: A structured pharmacist-staffed program was more effective than usual care for achieving target sUA levels. These results suggest a structured program could greatly improve gout management. PMID:27352414

  3. Proposed definition of the vaginal cuff and paracolpium clinical target volume in postoperative uterine cervical cancer.

    PubMed

    Murakami, Naoya; Norihisa, Yoshiki; Isohashi, Fumiaki; Murofushi, Keiko; Ariga, Takuro; Kato, Tomoyasu; Inaba, Koji; Okamoto, Hiroyuki; Ito, Yoshinori; Toita, Takafumi; Itami, Jun

    2016-01-01

    The aim of this study was to develop an appropriate definition for vaginal cuff and paracolpium clinical target volume (CTV) for postoperative intensity modulated radiation therapy in patients with uterine cervical cancer. A working subgroup was organized within the Radiation Therapy Study Group of the Japan Clinical Oncology Group to develop a definition for the postoperative vaginal cuff and paracolpium CTV in December 2013. The group consisted of 5 radiation oncologists who specialized in gynecologic oncology and a gynecologic oncologist. A comprehensive literature review that included anatomy, surgery, and imaging fields was performed and was followed by multiple discreet face-to-face discussions and e-mail messages before a final consensus was reached. Definitions for the landmark structures in all directions that demarcate the vaginal cuff and paracolpium CTV were decided by consensus agreement of the working group. A table was created that showed boundary structures of the vaginal cuff and paracolpium CTV in each direction. A definition of the postoperative cervical cancer vaginal cuff and paracolpium CTV was developed. It is expected that this definition guideline will serve as a template for future radiation therapy clinical trial protocols, especially protocols involving intensity modulated radiation therapy. Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

  4. Radium-223: From Radiochemical Development to Clinical Applications in Targeted Cancer Therapy

    SciTech Connect

    Bruland, Oyvind S.; Jonasdottir, Thora J.; Fisher, Darrell R.; Larsen, Roy H.

    2008-09-15

    The radiochemical properties of radium-223 (223Ra, T1/2 = 11.4 d) render this alpha-emitting radionuclide promising for targeted cancer therapy. Together with its short-lived daughters, each 223Ra decay produces four alpha-particle emissions—which enhance therapy effectiveness at the cellular level. In this paper, we review the recently published data reported for pre-clinical and clinical use of 223Ra in cancer treatment. We have evaluated two distinct chemical forms of 223Ra in vivo: 1) cationic 223Ra as dissolved RaCl2, and 2) liposome-encapsulated 223Ra. Cationic 223Ra seeks metabolically active osteoblastic bone and tumor lesions with high uptake and strong binding affinity based on its similarities to calcium. Based on these properties, we have advanced the clinical use of 223Ra for treating bone metastases from late-stage breast and prostate cancer. The results show impressive anti-tumor activity and improved overall survival in hormone-refractory prostate cancer patients with bone metastases. In other studies, we have evaluated the biodistribution and tumor uptake of liposomally encapsulated 223Ra in mice with human osteosarcoma xenografts, and in dogs with spontaneous osteosarcoma and associated soft tissue metastases. Results indicate excellent biodistributions in both species. In dogs, we found considerable uptake of liposomal 223Ra in cancer metastases in multiple organs, resulting in favorable tumor-to-normal soft tissue ratios. Collectively, these findings show an outstanding potential for 223Ra as a therapeutic agent.

  5. Neurosteroid Binding Sites on the GABAA Receptor Complex as Novel Targets for Therapeutics to Reduce Alcohol Abuse and Dependence

    PubMed Central

    Hulin, Mary W.; Amato, Russell J.; Porter, Johnny R.; Filipeanu, Catalin M.; Winsauer, Peter J.

    2011-01-01

    Despite the prevalence of alcohol abuse and dependence in the US and Europe, there are only five approved pharmacotherapies for alcohol dependence. Moreover, these pharmacotherapeutic options have limited clinical utility. The purpose of this paper is to present pertinent literature suggesting that both alcohol and the neurosteroids interact at the GABAA receptor complex and that the neurosteroid sites on this receptor complex could serve as new targets for the development of novel therapeutics for alcohol abuse. This paper will also present data collected by our laboratory showing that one neurosteroid in particular, dehydroepiandrosterone (DHEA), decreases ethanol intake in rats under a variety of conditions. In the process, we will also mention relevant studies from the literature suggesting that both particular subtypes and subunits of the GABAA receptor play an important role in mediating the interaction of neurosteroids and ethanol. PMID:22110489

  6. Pegylated Trastuzumab Fragments Acquire an Increased in Vivo Stability but Show a Largely Reduced Affinity for the Target Antigen

    PubMed Central

    Selis, Fabio; Focà, Giuseppina; Sandomenico, Annamaria; Marra, Carla; Di Mauro, Concetta; Saccani Jotti, Gloria; Scaramuzza, Silvia; Politano, Annalisa; Sanna, Riccardo; Ruvo, Menotti; Tonon, Giancarlo

    2016-01-01

    PEGylation of biomolecules is a major approach to increase blood stream half-life, stability and solubility of biotherapeutics and to reduce their immunogenicity, aggregation potential and unspecific interactions with other proteins and tissues. Antibodies have generally long half-lives due to high molecular mass and stability toward proteases, however their size lowers to some extent their potential because of a reduced ability to penetrate tissues, especially those of tumor origin. Fab or otherwise engineered smaller fragments are an alternative but are less stable and are much less well retained in circulation. We have here investigated the effects of various PEGylations on the binding properties and in vivo half-life of Fab fragments derived from the enzymatic splitting of Trastuzumab. We find that PEGylation increases the half-life of the molecules but also strongly affects the ability to recognize the target antigen in a way that is dependent on the extent and position of the chemical modification. Data thus support the concept that polyethylene glycol (PEG) conjugation on Trastuzumab Fabs increases half-life but reduces their affinity and this is a fine balance, which must be carefully considered for the design of strategies based on the use of antibody fragments. PMID:27043557

  7. Clinical Utility of Exercise Training in Heart Failure with Reduced and Preserved Ejection Fraction

    PubMed Central

    Asrar Ul Haq, Muhammad; Goh, Cheng Yee; Levinger, Itamar; Wong, Chiew; Hare, David L

    2015-01-01

    Reduced exercise tolerance is an independent predictor of hospital readmission and mortality in patients with heart failure (HF). Exercise training for HF patients is well established as an adjunct therapy, and there is sufficient evidence to support the favorable role of exercise training programs for HF patients over and above the optimal medical therapy. Some of the documented benefits include improved functional capacity, quality of life (QoL), fatigue, and dyspnea. Major trials to assess exercise training in HF have, however, focused on heart failure with reduced ejection fraction (HFREF). At least half of the patients presenting with HF have heart failure with preserved ejection fraction (HFPEF) and experience similar symptoms of exercise intolerance, dyspnea, and early fatigue, and similar mortality risk and rehospitalization rates. The role of exercise training in the management of HFPEF remains less clear. This article provides a brief overview of pathophysiology of reduced exercise tolerance in HFREF and heart failure with preserved ejection fraction (HFPEF), and summarizes the evidence and mechanisms by which exercise training can improve symptoms and HF. Clinical and practical aspects of exercise training prescription are also discussed. PMID:25698883