Probing Mechanical Properties of Jurkat Cells under the Effect of ART Using Oscillating Optical Tweezers

Acute lymphoid leukemia is a common type of blood cancer and chemotherapy is the initial treatment of choice. Quantifying the effect of a chemotherapeutic drug at the cellular level plays an important role in the process of the treatment. In this study, an oscillating optical tweezer was employed to characterize the frequency-dependent mechanical properties of Jurkat cells exposed to the chemotherapeutic agent, artesunate (ART). A motion equation for a bead bound to a cell was applied to describe the mechanical characteristics of the cell cytoskeleton. By comparing between the modeling results and experimental results from the optical tweezer, the stiffness and viscosity of the Jurkat cells before and after the ART treatment were obtained. The results demonstrate a weak power-law dependency of cell stiffness with frequency. Furthermore, the stiffness and viscosity were increased after the treatment. Therefore, the cytoskeleton cell stiffness as the well as power-law coefficient can provide a useful insight into the chemo-mechanical relationship of drug treated cancer cells and may serve as another tool for evaluating therapeutic performance quantitatively

Projected effects of disruptions to human immunodeficiency virus (HIV) prevention services during the coronavirus disease 2019 pandemic among Black/African American men who have sex with men in an Ending the HIV Epidemic priority jurisdiction

BACKGROUND: Disruptions in access to in-person human immunodeficiency virus (HIV) preventive care during the coronavirus disease 2019 (COVID-19) pandemic may have a negative impact on our progress towards the Ending the HIV Epidemic goals in the United States. METHODS: We used an agent-based model to simulate HIV transmission among Black/African American men who have sex with men in Mississippi over 5 years to estimate how different reductions in access affected the number of undiagnosed HIV cases, new pre-exposure prophylaxis (PrEP) starts, and HIV incidence. RESULTS: We found that each additional 25% decrease in HIV testing and PrEP initiation was associated with decrease of 20% in the number of cases diagnosed and 23% in the number of new PrEP starts, leading to a 15% increase in HIV incidence from 2020 to 2022. CONCLUSIONS: Unmet need for HIV testing and PrEP prescriptions during the COVID-19 pandemic may temporarily increase HIV incidence in the years immediately after the disruption period

Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol

Prognostic stratification is critical for making therapeutic decisions and maximizing survival of patients with acute myeloid leukemia. Advances in the genomics of acute myeloid leukemia have identified several recurrent gene mutations whose prognostic impact is being deciphered. We used HaloPlex target enrichment and Illumina-based next generation sequencing to study 24 recurrently mutated genes in 42 samples of acute myeloid leukemia with a normal karyotype. Read depth varied between and within genes for the same sample, but was predictable and highly consistent across samples. Consequently, we were able to detect copy number changes, such as an interstitial deletion of BCOR, three MLL partial tandem duplications, and a novel KRAS amplification. With regards to coding mutations, we identified likely oncogenic variants in 41 of 42 samples. NPM1 mutations were the most frequent, followed by FLT3, DNMT3A and TET2. NPM1 and FLT3 indels were reported with good efficiency. We also showed that DNMT3A mutations can persist post-chemotherapy and in 2 cases studied at diagnosis and relapse, we were able to delineate the dynamics of tumor evolution and give insights into order of acquisition of variants. HaloPlex is a quick and reliable target enrichment method that can aid diagnosis and prognostic stratification of acute myeloid leukemia patients.This project was funded by the Wellcome Trust. NB is a fellow of the European Hematology Association and was supported by the Academy of Medical Sciences. EP is a European Hematology Association Advanced Research Fellow. GV is a Wellcome Trust Senior Fellow in Clinical Science. IV is funded by Spanish Ministerio de Economía y Competitividad subprograma Ramón y Cajal

Two new ArrayTrack libraries for personalized biomedical research

<p>Abstract</p> <p>Background</p> <p>Recent advances in high-throughput genotyping technology are paving the way for research in personalized medicine and nutrition. However, most of the genetic markers identified from association studies account for a small contribution to the total risk/benefit of the studied phenotypic trait. Testing whether the candidate genes identified by association studies are causal is critically important to the development of personalized medicine and nutrition. An efficient data mining strategy and a set of sophisticated tools are necessary to help better understand and utilize the findings from genetic association studies. </p> <p>Description</p> <p>SNP (single nucleotide polymorphism) and QTL (quantitative trait locus) libraries were constructed and incorporated into ArrayTrack, with user-friendly interfaces and powerful search features. Data from several public repositories were collected in the SNP and QTL libraries and connected to other domain libraries (genes, proteins, metabolites, and pathways) in ArrayTrack. Linking the data sets within ArrayTrack allows searching of SNP and QTL data as well as their relationships to other biological molecules. The SNP library includes approximately 15 million human SNPs and their annotations, while the QTL library contains publically available QTLs identified in mouse, rat, and human. The QTL library was developed for finding the overlap between the map position of a candidate or metabolic gene and QTLs from these species. Two use cases were included to demonstrate the utility of these tools. The SNP and QTL libraries are freely available to the public through ArrayTrack at <url>http://www.fda.gov/ArrayTrack</url>. </p> <p>Conclusions</p> <p>These libraries developed in ArrayTrack contain comprehensive information on SNPs and QTLs and are further cross-linked to other libraries. Connecting domain specific knowledge is a cornerstone of systems biology strategies and allows for a better understanding of the genetic and biological context of the findings from genetic association studies. </p

We are ready to sock it to ‘em! The ‘STOPCUTS’ pilot study. It is possible to do a full trial of protective socks for skin tears.

Conference poster presented at Clinical Trials Symposium, RD&E 5/11/15This poster summarises independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit Programme (Grant Reference Number PB-PG-0711-25129). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health

Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational cohort study

Background: Guideline-recommended doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), and β blockers are similar for men and women with heart failure with reduced ejection fraction (HFrEF), even though there are known sex differences in pharmacokinetics of these drugs. We hypothesised that there might be sex differences in the optimal dose of ACE inhibitors or ARBs and β blockers in patients with HFrEF. Methods: We did a post-hoc analysis of BIOSTAT-CHF, a prospective study in 11 European countries of patients with heart failure in whom initiation and up-titration of ACE inhibitors or ARBs and β blockers was encouraged by protocol. We included only patients with left ventricular ejection fraction less than 40%, and excluded those who died within the first 3 months. Primary outcome was a composite of time to all-cause mortality or hospitalisation for heart failure. Findings were validated in ASIAN-HF, an independent cohort of 3539 men and 961 women with HFrEF. Findings: Among 1308 men and 402 women with HFrEF from BIOSTAT-CHF, women were older (74 [12] years vs 70 [12] years, p&lt;0·0001) and had lower bodyweights (72 [16] kg vs 85 [18] kg, p&lt;0·0001) and heights (162 [7] cm vs 174 [8] cm, p&lt;0·0001) than did men, although body-mass index did not differ significantly. A similar number of men and women reached guideline-recommended target doses of ACE inhibitors or ARBs (99 [25%] vs 304 [23%], p=0·61) and β blockers (57 [14%] vs 168 [13%], p=0·54). In men, the lowest hazards of death or hospitalisation for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and β blockers, but women showed approximately 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels. These sex differences were still present after adjusting for clinical covariates, including age and body surface area. In the ASIAN-HF registry, similar patterns were observed for both ACE inhibitors or ARBs and β blockers, with women having approximately 30% lower risk at 50% of the recommended doses, with no further benefit at higher dose levels. Interpretation: This study suggests that women with HFrEF might need lower doses of ACE inhibitors or ARBs and β blockers than men, and brings into question what the true optimal medical therapy is for women versus men

Towards an Intelligent Tutor for Mathematical Proofs

Computer-supported learning is an increasingly important form of study since it allows for independent learning and individualized instruction. In this paper, we discuss a novel approach to developing an intelligent tutoring system for teaching textbook-style mathematical proofs. We characterize the particularities of the domain and discuss common ITS design models. Our approach is motivated by phenomena found in a corpus of tutorial dialogs that were collected in a Wizard-of-Oz experiment. We show how an intelligent tutor for textbook-style mathematical proofs can be built on top of an adapted assertion-level proof assistant by reusing representations and proof search strategies originally developed for automated and interactive theorem proving. The resulting prototype was successfully evaluated on a corpus of tutorial dialogs and yields good results.Comment: In Proceedings THedu'11, arXiv:1202.453

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology