Miracle-dz/UniFAR-FTUs huggingface dataset:
Matrix Metalloproteinase-activated Anthrax Lethal Toxin Demonstrates High Potency in Targeting Tumor Vasculature*

Anthrax lethal toxin (LT), a virulence factor secreted by Bacillus anthracis, is selectively toxic to human melanomas with the BRAF V600E activating mutation because of its proteolytic activities toward the mitogen-activated protein kinase kinases (MEKs). To develop LT variants with lower in vivo toxicity and high tumor specificity, and therefore greater potential for clinical use, we generated a mutated LT that requires activation by matrix metalloproteinases (MMPs). This engineered toxin was less toxic than wild-type LT to mice because of the limited expression of MMPs by normal cells. Moreover, the systemically administered toxin produced greater anti-tumor effects than wild-type LT toward human xenografted tumors. This was shown to result from its greater bioavailability, a consequence of the limited uptake and clearance of the modified toxin by normal cells. Furthermore, the MMP-activated LT had very potent anti-tumor activity not only to human melanomas containing the BRAF mutation but also to other tumor types, including lung and colon carcinomas regardless of their BRAF status. Tumor histology and in vivo angiogenesis assays showed that this anti-tumor activity is due largely to the indirect targeting of tumor vasculature and angiogenic processes. Thus, even tumors genetically deficient in anthrax toxin receptors were still susceptible to the toxin therapy in vivo. Moreover, the modified toxin also displayed lower immunogenicity compared with the wild-type toxin. All these properties suggest that this MMP-activated anti-tumor toxin has potential for use in cancer therapy.
Potential Use of Modulators of Oxidative Stress as Add-on Therapy in Patients with Anxiety Disorders.

BACKGROUND It is known that an increased oxidative stress is present in a wide range of diseases and, given the vulnerability of the central nervous system, its involvement has been in particular investigated in neurological and psychiatric diseases, including anxiety disorders. OBJECTIVE In this review, we analyse the studies that have been conducted on the effects of oxidative stress modulators in anxiety, focusing on their possible clinical use. DISCUSSION AND CONCLUSION While preclinical studies have shown a clear anxiolytic-like effect of different oxidative stress modulators, less significant results have been obtained from clinical studies. After having reviewed the possible reasons for the discrepancy between preclinical and clinical data, we encourage further studies aimed at better investigating the utility of the modulation of oxidative stress in humans, as an adjunctive therapy of the traditional integrated psychotherapeutic and pharmacological approach.
Employment and work schedule are related to telomere length in women

Objectives To examine the association of employment and work schedule with shorter DNA telomeres, a marker of cellular ageing and disease risk factor, and consider whether differences were related to health, behaviours and sociodemographic factors, or varied by stress levels or menopausal status. Methods This cross-sectional analysis of 608 women aged 35–74 in the Sister Study examined determinants of relative telomere length (rTL) measured by quantitative PCR in leucocyte DNA. Age-adjusted regression models estimated base pair (bp) rTL differences for current and lifetime schedule characteristics (ie, part-time, full-time or overtime hours; multiple jobs; irregular hours; shiftwork; work at night). Covariates included race, smoking, perceived stress, sleep, physical activity, health and menopausal status, education, marital status, live births, children under 18, measured body mass index and urinary stress hormones. Results Compared with non-employed women with moderate or substantial past work histories (n=190), those currently working full-time (n=247; median 40 h/week) had a shorter rTL, an age-adjusted difference of −329 bp (95% CI −110 to −548). Longer-duration full-time work was also associated with shorter rTL (age-adjusted difference of −472 bp, 95% CI −786 to −158 for 20+ vs 1–5 years). Findings were not explained by health and demographic covariates. However, rTL differences for working at least full-time were greater in women with higher stress and epinephrine levels. Conclusions Current and long-term full-time work were associated with shorter rTL, with differences of similar magnitude to smoking and history of heart disease or diabetes. Longitudinal data with specific stress measures are needed to further evaluate the impact of work schedule on rTL.
University of Glasgow at CLEF 2013: Experiments in eHealth Task 3 with Terrier

In our participation in the CLEF 2013 eHealth task 3, we in- vestigate (1) the effectiveness of our Divergence from Randomness (DFR) framework on retrieving medical webpages, (2) the adoption of classi- cal pseudo-relevance feedback for improving the representation of the queries, and (3) the exploitation of a collection enrichment technique for alleviating the mismatches between the terms in documents and queries, all within the context of our Terrier information retrieval platform.
Treatment of nonsmall cell lung cancer: overcoming the resistance to epidermal growth factor receptor inhibitors

Purpose of review Testing for epidermal growth factor receptor (EGFR) mutations has become standard practice in treating patients with advanced nonsmall cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are being offered as first-line therapy in patients with EGFR activating mutations. These drugs offer an increased progression-free survival and response rate compared with standard chemotherapy in this setting; however, resistance invariably occurs. This review discusses the development of resistance to EGFR TKIs and the progress that is being made to better understand how to overcome this resistance. Recent findings Results from recently published articles dealing with resistance to EGFR TKIs are allowing for a better understanding of this mechanism. No one treatment allows for overcoming this resistance. Understanding this resistance will likely become an individualized patient/tumor approach. Selecting which drug or drugs that may be suitable can only be determined based on the molecular mechanism of resistance. Summary Progress is being made in our understanding of the multiple pathways of resistance. Using a tumor molecular signature at the time of progression can determine the best treatment option.
Risk Factors for Active Trachoma and Ocular Chlamydia trachomatis Infection in Treatment-Naïve Trachoma-Hyperendemic Communities of the Bijagós Archipelago, Guinea Bissau

Background Trachoma, caused by ocular infection with Chlamydia trachomatis, is hyperendemic on the Bijagós Archipelago of Guinea Bissau. An understanding of the risk factors associated with active trachoma and infection on these remote and isolated islands, which are atypical of trachoma-endemic environments described elsewhere, is crucial to the implementation of trachoma elimination strategies. Methodology/Principal Findings A cross-sectional population-based trachoma prevalence survey was conducted on four islands. We conducted a questionnaire-based risk factor survey, examined participants for trachoma using the World Health Organization (WHO) simplified grading system and collected conjunctival swab samples for 1507 participants from 293 randomly selected households. DNA extracted from conjunctival swabs was tested using the Roche Amplicor CT/NG PCR assay. The prevalence of active (follicular and/or inflammatory) trachoma was 11% (167/1508) overall and 22% (136/618) in 1–9 year olds. The prevalence of C. trachomatis infection was 18% overall and 25% in 1–9 year olds. There were strong independent associations of active trachoma with ocular and nasal discharge, C. trachomatis infection, young age, male gender and type of household water source. C. trachomatis infection was independently associated with young age, ocular discharge, type of household water source and the presence of flies around a latrine. Conclusions/Significance In this remote island environment, household-level risk factors relating to fly populations, hygiene behaviours and water usage are likely to be important in the transmission of ocular C. trachomatis infection and the prevalence of active trachoma. This may be important in the implementation of environmental measures in trachoma control.
Colon cancer screening practices and disclosure after receipt of positive or inconclusive genetic test results for hereditary nonpolyposis colorectal cancer

Patients who receive conclusive genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) tend to adopt appropriate colorectal cancer screening behaviors and disclose their test results. However, little is known about the disclosure processes or screening behaviors of individuals who receive inconclusive genetic test results. This study compared endoscopy use and disclosure between individuals with positive and inconclusive genetic test results, within a year after results were received.
Induction of CD4+ Th1 Lymphocytes That Recognize Known and Novel Class II MHC Restricted Epitopes from the Melanoma Antigen gp100 by Stimulation with Recombinant Protein

CD4+ T helper cells may play a critical role in the induction and maintenance of a therapeutic immune response to cancer. To evaluate the efficacy with which a recombinant tumor-associated protein can induce antigen-reactive CD4+ T cells, we stimulated peripheral blood lymphocytes from patients with melanoma in vitro with the purified melanoma antigen gp100 produced in Escherichia coli. In preliminary experiments, we observed that peripheral blood mononuclear cells could process and present known HLA-DR&bgr;1*0401 and HLA-DR&bgr;1*0701 restricted epitopes to gp100-reactive CD4+ T cell lines after being loaded exogenously with protein. Therefore, we used autologous protein-loaded peripheral blood mononuclear cells as antigen presenting cells. From four of nine patients who expressed both HLA-DR&bgr;1*0401 and HLA-DR&bgr;1*0701, we raised five gp100-reactive CD4+ T cell populations that secreted TH1 type cytokines in response to exogenously loaded protein as well as target cells that endogenously expressed gp100 and MHC class II molecules, including transfectants and melanoma cells. Four of the five cultures specifically recognized the known HLA-DR&bgr;1*0401 and HLA-DR&bgr;1*0701 restricted epitopes gp100:44-59 and gp100:170-190, respectively. The fifth culture, and 30 T cell clones derived from it, specifically recognized a new peptide, gp100:420-435, in the context of HLA-DR&bgr;1*0701. These results suggest that recombinant tumor-associated proteins may be clinically applicable for the generation of CD4+ T helper cells in active vaccination strategies or adoptive cellular immunotherapies.
COSMOLOGICAL CONCORDANCE OR CHEMICAL COINCIDENCE? DEUTERATED MOLECULAR HYDROGEN ABUNDANCES AT HIGH REDSHIFT

We report two detections of deuterated molecular hydrogen (HD) in QSO absorption-line systems at z>2. Toward J2123−0500, we find N(HD) =13.84 ± 0.2 for a sub-Damped Lyman Alpha system (DLA) with metallicity ≃0.5Z☉ and N(H2) = 17.64 ± 0.15 at z = 2.0594. Toward FJ0812+32, we find N(HD) =15.38 ± 0.3 for a solar-metallicity DLA with N(H2) = 19.88 ± 0.2 at z = 2.6265. These systems have ratios of HD to H2 above that observed in dense clouds within the Milky Way disk and apparently consistent with a simple conversion from the cosmological ratio of D/H. These ratios are not readily explained by any available model of HD chemistry, and there are no obvious trends with metallicity or molecular content. Taken together, these two systems and the two published z>2 HD-bearing DLAs indicate that HD is either less effectively dissociated or more efficiently produced in high-redshift interstellar gas, even at low molecular fraction and/or solar metallicity. It is puzzling that such diverse systems should show such consistent HD/H2 ratios. Without clear knowledge of all the aspects of HD chemistry that may help determine the ratio HD/H2, we conclude that these systems are potentially more revealing of gas chemistry than of D/H itself and that it is premature to use such systems to constrain D/H at high redshift.
RECONSTRUCTION OF RADIATION DOSES IN A CASE-CONTROL STUDY OF THYROID CANCER FOLLOWING THE CHERNOBYL ACCIDENT

A population-based case-control study of thyroid cancer was carried out in contaminated regions of Belarus and Russia among persons who were exposed during childhood and adolescence to fallout from the Chernobyl accident. For each study subject, individual thyroid doses were reconstructed for the following pathways of exposure: (1) intake of 131I via inhalation and ingestion; (2) intake of short-lived radioiodines (132I, 133I, and 135I) and radiotelluriums (131mTe, 132Te) via inhalation and ingestion; (3) external dose from radionuclides deposited on the ground; and (4) ingestion of 134Cs and 137Cs. A series of intercomparison exercises validated the models used for reconstruction of average doses to populations of specific age groups as well as of individual doses. Median thyroid doses from all factors for study subjects were estimated to be 0.37 and 0.034 Gy in Belarus and Russia, respectively. The highest individual thyroid doses among the subjects were 10.2 Gy in Belarus and 5.3 Gy in Russia. Iodine-131 intake was the main pathway for thyroid exposure. Estimated doses from short-lived radioiodines and radiotelluriums ranged up to 0.53 Gy. Reconstructed individual thyroid doses from external exposure ranged up to 0.1 Gy, while those from internal exposure due to ingested cesium did not exceed 0.05 Gy. The uncertainty of the reconstructed individual thyroid doses, characterized by the geometric standard deviation, varies from 1.7 to 4.0 with a median of 2.2.
Turning the pump handle: evolving methods for integrating the evidence on gene-disease association.

Julian P. T. Higgins, Julian Little, John P. A. Ioannidis, Molly S. Bray, Teri A. Manolio, Liam Smeeth, Jonathan A. Sterne, Betsy Anagnostelis, Adam S. Butterworth, John Danesh, Carol Dezateux, John E. Gallacher, Marta Gwinn, Sarah J. Lewis, Cosetta Minelli, Paul D. Pharoah, Georgia Salanti, Simon Sanderson, Lesley A. Smith, Emanuela Taioli, John R. Thompson, Simon G. Thompson, Neil Walker, Ron L. Zimmern, and Muin J. Khoury
Genesis and Emanations of Deviant Workplace Behaviour: A Case e Study in IT Industry

Objective: The objective of this paper is to evaluate the genesis and emanations of Deviant workplace behaviour in IT enterprise. And in addition it emphasises on the various parameters of how to transform the negative deviant behaviour into positive deviant behaviour. Statistical Analysis: The study at proceeds in following manner. It starts off evolved with a literature evaluation of Deviant workplace behaviour in IT enterprise and its elements this is based on organising a statistics-established statistical courting between the genesis and emanations of the Deviant workplace behaviour. Then followed by way of the assessment of the probability the use of the Predictive business intelligence equipment like ‘endconsumer query, reporting, and evaluation’. lastly, implementation of predictive packaged analytic strategies that included predictive technologies, inclusive of a ‘Fraud detection application’, ‘Multilayer Perceptron (MLP)’ and ‘K-Nearest neighbour’ that studies the same unit in a distinct sample will show off the particular performance. Findings: From this study, using a sample of 250 operational staff in Tata Consultancy Services (TCS) in India and US, the results show that: a) Motive to Quit, organization Disdain and Dissatisfaction have constructive outcome on Deviant workplace behaviour b) Motive to Quit have beneficial outcome on Dissatisfaction and c) Deviant workplace behaviour has poor impact on Individual’s overall Performance. Novelty: This study at can further increases to different service primarily based industries that outlines the strength of interpersonal affectivity that moderates the connection between organisational reactions and deviant behaviours. It also can be prolonged to define how business enterprise is acting relative to their peers and pinpoints development opportunities—and, these days, areas wherein sturdy body of workers analytics can contribute sport-changing insights.
Estimation of ROC curves based on stably distributed biomarkers subject to measurement error and pooling mixtures

Additive measurement errors and pooling design are objectively two different issues, which have been separately and extensively dealt with in the biostatistics literature. However, these topics usually correspond to problems of reconstructing a summand's distribution of the biomarker by the distribution of the convoluted observations. Thus, we associate the two issues into one stated problem. The integrated approach creates an opportunity to investigate new fields, e.g. a subject of pooling errors, issues regarding pooled data affected by measurement errors. To be specific, we consider the stated problem in the context of the receiver operating characteristic (ROC) curves analysis, which is the well‐accepted tool for evaluating the ability of a biomarker to discriminate between two populations. The present paper considers a wide family of biospecimen distributions. In addition, applied assumptions, which are related to distribution functions of biomarkers, are mainly conditioned by the reconstructing problem. We propose and examine maximum likelihood techniques based on the following data: a biomarker with measurement error; pooled samples; and pooled samples with measurement error. The obtained methods are illustrated by applications to real data studies. Published in 2007 by John Wiley & Sons, Ltd.
Molecular Methods for Detection of Beta-and Gamma-Papillomaviruses: AReview

Accumulating evidence on beta and gamma Human Papillomavirus (HPV) genera, show its association with nonmelanoma skin cancers (NMSC). Current methods for detection of HPV in clinical specimens are molecular based. A variety of molecular techniques developed for diagnosis of HPV; focus more on detection of mucosal HPV types. A limited number of assays have been developed to detect and genotype cutaneous HPVs. These assays detect a proportion of the HPV types implicated in skin lesions with differing sensitivities and specificities. Conflicting literature on the prevalence of HPV in NMSC has resulted from the inconsistent diagnostic standards. This review discusses the methods available for detection and genotyping of HPVs with emphasis on cutaneous HPV genotypes. This information will provide researchers the relevant choices of molecular methods applicable to epidemiological surveys. The ultimate objective is to make automated, rapid and cheaper molecular approaches for resource poor settings.
West Nile Virus Capsid Degradation of Claudin Proteins Disrupts Epithelial Barrier Function

ABSTRACT During acute infection, West Nile virus (WNV) has been reported to infect a variety of cell types in various tissues of both experimentally and naturally infected hosts. Virus infects epithelial cells in the skin, kidney, intestine, and testes, although the importance of these findings is unclear. In the current study, we have observed that WNV infection of kidney tubules in mice coincides with the loss of expression of several members of the claudin family. Proteins of this family are often involved in epithelial barrier formation and function. WNV infection of epithelial cells in culture resulted in a decrease in the transepithelial electrical resistance, an increase in the efflux of mannitol across the monolayer, and a loss of intracellular levels of claudin-1 to -4. WNV capsid alone was sufficient for the degradation event, which was mediated through lysosomal proteases. Since epithelial cells are frequent sites of WNV infection, these observations imply a potential mechanism for virus dissemination and extraneural pathogenesis.
Postoperative Analgesia by a Transversus Abdominis Plane Block Using Different Concentrations of Ropivacaine for Abdominal Surgery: A Meta-Analysis

Background: Transversus abdominis plane block (TAPB) has been proven to be an effective means of postoperative anesthesia, but the optimum effective concentration of ropivacaine warrants further research. Objective: This study aimed to identify the optimal ropivacaine concentration of TAPB using a meta-analysis. Materials and Methods: This study consisted of a meta-analysis of randomized controlled trials (RCTs). We searched online databases, including PubMed, Embase, the Cochrane Database of Systematic Reviews, and Web of Science. RCTs investigating the 24-hour postoperative opioid consumption and the rest and dynamic pain scores 2, 12, and 24 hours after surgery were included in this analysis. We also assessed opioid-related side-effects and patient satisfaction 24 hours after surgery. Results: Nineteen RCTs (1217 patients) were included in this meta-analysis, which showed that only TAPB with 0.375% and 0.5% ropivacaine was able to reduce opioid consumption 24 hours after surgery by weighted mean differences of −6.55 and −4.44 mg (morphine IV equivalents), respectively (P<0.05). A meta-regression analysis did not reveal an association between the local anesthetic dose (in mg), surgery, anesthesia, block timing, and the TAPB effect on opioid consumption. Ropivacaine concentrations of 0.375% and 0.5% reduced the 2-hour postoperative pain score and reduced the incidence of nausea and vomiting, but this analgesic effect disappeared at 12 and 24 hours. Only TAPB with 0.375% ropivacaine improved the degree of satisfaction 24 hours after surgery (weighted mean difference of 0.87 [0.08-1.66], P=0.03). Conclusion: In terms of efficacy and safety, the use of 0.375% ropivacaine for TAPB is preferred in the clinical work.
Tec kinases regulate T‐lymphocyte development and function: new insights into the roles of Itk and Rlk/Txk

Summary: The Tec (tyrosine kinase expressed in hepatocellular carcinoma) family of non‐receptor tyrosine kinases consists of five members: Tec, Bruton’s tyrosine kinase (Btk), inducible T‐cell kinase (Itk), resting lymphocyte kinase (Rlk/Txk), and bone marrow‐expressed kinase (Bmx/Etk). Although their functions are probably best understood in antigen receptor signaling, where they participate in the phosphorylation and regulation of phospholipase C‐γ (PLC‐γ), it is now appreciated that these kinases contribute to signaling from many receptors and that they participate in multiple downstream pathways, including regulation of the actin cytoskeleton. In T cells, three Tec kinases are expressed, Itk, Rlk/Txk, and Tec. Itk is expressed at highest amounts and plays the major role in regulating signaling from the T‐cell receptor. Recent studies provide evidence that these kinases contribute to multiple aspects of T‐cell biology and have unique roles in T‐cell development that have revealed new insight into the regulation of conventional and innate T‐cell development. We review new findings on the Tec kinases with a focus on their roles in T‐cell development and mature T‐cell differentiation.