Attenuation of HIV-Specific T Cell Responses Among People with HIV on art Following Dipyridamole Treatment.

Twelve weeks of dipyridamole increased extracellular adenosine levels and decreased T cell activation in people with HIV. In this analysis, we investigated the effect of dipyridamole on HIV-specific T cell responses. We compared changes in Gag- and Env-specific T cell responses using intracellular cytokine staining, following 12 weeks of dipyridamole treatment vs placebo.

YAP1 Status Defines Two Intrinsic Subtypes of LCNEC with Distinct Molecular Features and Therapeutic Vulnerabilities.

Purpose: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non-small cell lung cancer approaches.

Experimental Design: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models.

Interpretable representation learning for 3D multi-piece intracellular structures using point clouds.

A key challenge in understanding subcellular organization is quantifying interpretable measurements of intracellular structures with complex multi-piece morphologies in an objective, robust and generalizable manner. Here we introduce a morphology-appropriate representation learning framework that uses 3D rotation invariant autoencoders and point clouds. This framework is used to learn representations of complex multi-piece morphologies that are independent of orientation, compact, and easy to interpret.

IFNγ Production by Functionally Reprogrammed Tregs Promotes Antitumor Efficacy of OX40/CD137 Bispecific Agonist Therapy.

Unlabelled: Regulatory T cells (Treg) are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Tregs to contribute to antitumor immunity. OX40 and CD137 are expressed highly on Tregs, activated and memory T cells, and NK cells.

Colony context and size-dependent compensation mechanisms give rise to variations in nuclear growth trajectories.

To investigate the fundamental question of how cellular variations arise across spatiotemporal scales in a population of identical healthy cells, we focused on nuclear growth in hiPS cell colonies as a model system. We generated a 3D timelapse dataset of thousands of nuclei over multiple days, and developed open-source tools for image and data analysis and an interactive timelapse viewer for exploring quantitative features of nuclear size and shape. We performed a data-driven analysis of nuclear growth variations across timescales.

Brief Report: Comprehensive Clinicogenomic Profiling of Small Cell Transformation From -Mutant NSCLC Informs Potential Therapeutic Targets.

Introduction: NSCLC transformation to SCLC has been best characterized with -mutant NSCLC, with emerging case reports seen in , , and -altered NSCLC. Previous reports revealed transformed SCLC from -mutant NSCLC portends very poor prognosis and lack effective treatment. Genomic analyses revealed and loss of function increase the risk of SCLC transformation.

Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes.

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes.

Prospective Assessment of Humoral and Cellular Immune Responses to a Third COVID-19 mRNA Vaccine Dose Among Immunocompromised Individuals.

Background: Improved coronavirus disease 2019 (COVID-19) prevention is needed for immunocompromised individuals.

Methods: A prospective study was performed of health care workers (HCW) and immunocompromised participants with baseline serology following 2 mRNA vaccine doses and who were retested after dose 3 (D3); multivariable regression was used to identify predictors of serological responses. IFN-γ/TNF-α T-cell responses were assessed in a subset.

Unfolding the secrets of small cell lung cancer progression: Novel approaches and insights through rapid autopsies.

The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms.

Barriers and facilitators of the adoption and use of assistive technology for adults with an intellectual disability who live in supported accommodation: a mixed methods systematic review protocol.

Objective: The objective of this review is to identify the barriers and facilitators of assistive technology adoption and use in adults with intellectual disabilities living in supported accommodation. This will inform the development of an assistive technology adoption framework for these settings.

Introduction: Assistive technology has the potential to increase the independence and well-being of people with intellectual disabilities; however, it is often not adopted.

Combining targeted DNA repair inhibition and immune-oncology approaches for enhanced tumor control.

Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses.

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes.

PiSpy: An affordable, accessible, and flexible imaging platform for the automated observation of organismal biology and behavior.

A great deal of understanding can be gleaned from direct observation of organismal growth, development, and behavior. However, direct observation can be time consuming and influence the organism through unintentional stimuli. Additionally, video capturing equipment can often be prohibitively expensive, difficult to modify to one's specific needs, and may come with unnecessary features.

Veno-Arterial Extracorporeal Membrane Oxygenation in Patients with Fulminant Myocarditis: A Review of Contemporary Literature.

Fulminant myocarditis is characterized by life threatening heart failure presenting as cardiogenic shock requiring inotropic or mechanical circulatory support to maintain tissue perfusion. There are limited data on the role of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in the management of fulminant myocarditis. This review seeks to evaluate the management of fulminant myocarditis with a special emphasis on the role and outcomes with VA-ECMO use.

Annexin A1 Tripeptide Mimetic Increases Sirtuin-3 and Augments Mitochondrial Function to Limit Ischemic Kidney Injury.

Acute kidney injury (AKI) is one of the most common organ failures following surgery. We have developed a tripeptide mimetic (ANXA1sp) of the parent annexin A1 molecule that shows promise as an organ protectant limiting cellular stress; however, its potential as a kidney protective agent remains unexplored, and its mechanism of action is poorly understood. Our hypothesis was that ANXA1sp would limit kidney injury following surgical ischemic kidney injury.

Aluminum and Tau in Neurofibrillary Tangles in Familial Alzheimer's Disease.

Background: Familial Alzheimer's disease (fAD) is driven by genetic predispositions affecting the expression and metabolism of the amyloid-β protein precursor. Aluminum is a non-essential yet biologically-reactive metal implicated in the etiology of AD. Recent research has identified aluminum intricately and unequivocally associated with amyloid-β in senile plaques and, more tentatively, co-deposited with neuropil-like threads in the brains of a Colombian cohort of donors with fAD.

Mixing indistinguishable systems leads to a quantum Gibbs paradox.

The classical Gibbs paradox concerns the entropy change upon mixing two gases. Whether an observer assigns an entropy increase to the process depends on their ability to distinguish the gases. A resolution is that an "ignorant" observer, who cannot distinguish the gases, has no way of extracting work by mixing them.

Measurement of the three-axis vibration, temperature, and relative humidity profiles of commercial transport trailers for pigs.

The objective of this study was to collect and interpret three-axis acceleration, temperature, and relative humidity data from six locations within commercial transport trailers shipping market-weight pigs. Transport was observed in Kansas (n = 15) and North Carolina (n = 20). Prior to loading, three-axis accelerometers were affixed to six locations on the trailers: top fore (TF), top center (TC), top aft (TA), bottom fore (BF), bottom center (BC), and bottom aft (BA) compartments.

MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma.

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2).