Sex hormones, the anticancer immune response, and therapeutic opportunities.

Sex-based differences have been observed in the incidence and prognosis of various cancers, as well as in the response to immune check point inhibitors (ICIs). These disparities are partially attributed to sex-based differences in the molecular characteristics of the anticancer immune response, which are largely influenced by sex hormones. Here, we provide a comprehensive overview on how sex hormones affect innate and adaptive immunity and contribute to shaping the features of tumor immune microenvironment and response to anticancer immunotherapy.

Overcoming melanoma therapy resistance with RAF-MEK and FAK inhibition.

Cutaneous melanoma, frequently driven by BRAF (V600X) mutations, often develops resistance to mitogen-activated protein kinase (MAPK)-targeted therapies and immune checkpoint inhibitors. In this issue of Cancer Cell, Lubrano et al. identify RhoA-FAK-AKT signaling as a resistance mechanism and demonstrate that combining RAF-MEK glue with a FAK inhibitor enhances tumor regression and immune response.

Efficient protein quantification in drug metabolism and pharmacokinetics with an accelerated proteomic workflow.

Quantifying proteins involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs is essential to improve understanding of their disposition and pharmacokinetics. Proteomics, because of its great versatility, is a widely used approach for protein analysis. However, existing protocols face challenges, such as poor peptide identification in liquid chromatography with tandem mass spectrometry under multiple reaction monitoring mode as well as the time- and labor-intensive nature of detergent-engaged workflows.

Unraveling the role of the IL-20 cytokine family in neurodegenerative diseases: Mechanisms and therapeutic insights.

The IL-20 cytokine family, comprising IL-19, IL-20, IL-22, IL-24, and IL-26, has emerged as a critical player in the pathogenesis of neurodegenerative diseases due to its multiple roles in inflammation, tissue repair, and immune modulation. These cytokines signal through IL-20 receptor complexes (IL-20RA/IL-20RB and IL-22RA1/IL-20RB), triggering diverse immune processes. Recent evidence highlights their significant contributions to neuroinflammation and neurodegeneration in central nervous system disorders.

The utility of coagulation factor testing in non-anticoagulated elderly patients presenting with low-risk mechanical falls in the emergency department.

Introduction: Data on the utility of coagulation factor testing (INR, aPTT) in non-anticoagulated patients with low-risk trauma is limited. In this study, we describe the rate in which coagulation studies are ordered this population and report the frequency in which these tests were abnormal and resulted in intervention.

Methods: This was a multi-center retrospective observational study evaluating patients aged 65 years and older with low-risk mechanical falls not on chronic oral anticoagulation.

Retrospective analysis of low-dose versus higher-dose haloperidol in older emergency department patients.

Background: A reduced initial dose of injectable haloperidol is recommended in older patients for treatment of acute agitation based on limited studies.

Objective: Assess the effectiveness and safety of higher-dose versus low-dose injectable haloperidol in older patients presenting to the emergency department (ED).

Methods: This was a retrospective, propensity-score matched, cohort analysis conducted at a two-campus healthcare system.

Familial chylomicronemia syndrome and treatments to target hepatic APOC3 mRNA.

Familial chylomicronemia syndrome (FCS) is a rare, recessive monogenic disorder characterized by severely elevated plasma triglyceride (TG) levels due to absent or markedly impaired lipoprotein lipase activity, leading to a greatly increased risk of acute pancreatitis. Naturally occurring very low levels of apoC-III are associated with low TG levels; thus, apoC-III is a target for TG lowering, and therapies have been developed to reduce apoC-III. Strategies to inhibit hepatic apoC-III synthesis include antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs).

Claudin 1 dysregulation disrupts coronary microvascular integrity and impairs cardiac function.

Background And Aims: Claudin 1 (Cldn1) is a tight junction protein primarily known for its role in epithelial and endothelial barrier function. However, the role of Cldn1 in coronary microvascular barrier remain unclear. The aim of this study is to investigate the biological effects of Cldn1 dysregulation on coronary vascular permeability, inflammation, fibrosis, and left ventricular function.

Relations of temporoparietal connectivity with neighborhood social fragmentation in youth at clinical high-risk for psychosis.

Temporoparietal brain areas comprise a candidate set of regions for interrogating the brain functional correlates of socioenvironmental factors in people at clinical high-risk for psychosis (CHR-P). Temporal lobe abnormalities have been shown to be common among people with schizophrenia spectrum conditions. Further, temporoparietal brain regions are implicated in tasks relevant to psychosocial outcomes, including coherent autobiographical memory recall and multimodal integration.

Retrieval-Augmented Generation: Advancing personalized care and research in oncology.

Retrieval-Augmented Generation (RAG) pairs large language models (LLMs) with recent data to produce more accurate, context-aware outputs. By converting text into numeric embeddings, RAG locates and retrieves relevant "chunks" of data, that along with the query, ground the model's responses in current, specific information. This process helps reduce outdated or fabricated answers.

Efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal cancer.

Background: Larotrectinib is the first-in-class, highly selective TRK inhibitor with demonstrated efficacy in various TRK fusion solid tumours. We report the efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal (GI) cancer.

Methods: Patients with TRK fusion GI cancer from NAVIGATE (NCT02576431) were included.

Real-World Treatment Patterns and Outcomes in Patients With Bacillus Calmette-Guérin-Unresponsive High-Risk Non-Muscle-Invasive Bladder Cancer: A Multicountry Medical Chart Review.

Introduction: Treatment patterns for patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC) who are ineligible for or decline radical cystectomy (RC) are inconsistently reported. We retrospectively described demographic, clinical, and treatment characteristics for these patients and assessed their clinical outcomes.

Patients And Methods: Medical charts of patients with BCG-unresponsive high-risk NMIBC (carcinoma in situ [cohort A] or T1/high-grade Ta [cohort B]) who were ineligible for or declined RC documented between January 1, 2011, and December 31, 2018, at 15 academic centers were reviewed.

Unplanned extubation prevention in the neuroscience ICU at a High Reliability Organization.

Background: Intubated neuroscience ICU patients are at risk for unplanned extubation (premature removal of the endotracheal tube by the patient or during patient care). The incidence of unplanned extubation is an indicator of the quality of ICU care. Unplanned extubation is a risk factor for pneumonia, increased ventilator days, the need for tracheostomy and increased ICU and hospital length-of-stay.

Aging and senescence: Key players in brain tumor progression and drug resistance.

Aging plays a critical role in the development, progression, and therapeutic challenges associated with brain tumors, particularly glioblastomas (GBM). As the population ages, the incidence of brain tumors, including GBM, increases, with aging emerging as a significant prognostic factor influencing survival outcomes. This review examines the molecular mechanisms linking aging and brain tumor progression, with a specific focus on glioblastomas.

Patient and healthcare provider perspectives on treatment patterns and patient satisfaction of seborrheic dermatitis in the United States.

Introduction: Seborrheic dermatitis (SD) affects a large, diverse population and is associated with significant morbidity/burden.

Methods: The Harris Poll conducted online surveys to understand the perceptions, preferences, and experiences regarding treatments of US patients with SD and dermatology healthcare providers (HCPs) from December 2021 to January 2022.

Results: In this survey, patients using SD treatment invested on average 34 min/d treating SD with 5.

Effects of the COVID-19 Pandemic on New Physician Job Market Outcomes.

Objective: To evaluate the pandemic's impacts on new physician job market outcomes.

Design: We conducted a retrospective, repeated cross-sectional analysis using an interrupted time series approach on graduating residents and fellows from New York. We estimated linear probability models to examine binary outcomes and a generalized estimating equations model to analyze the base salary (measured in 2022 dollars).

Changes in Vasectomy Practice Patterns After-Dobbs: A Multi-Institutional Study.

Importance: Following the Dobbs decision overruling Roe vs. Wade, public interest in vasectomies increased. This ruling directly impacted urologic practice patterns, and warrants further investigation.

Cryo-ET reveals the in situ architecture of the polar tube invasion apparatus from microsporidian parasites.

Microsporidia are divergent fungal pathogens that employ a unique harpoon-like apparatus called the polar tube (PT) to invade host cells. The long PT is fired out of the microsporidian spore over the course of just a few hundred milliseconds. Once fired, the PT is thought to pierce the plasma membrane of a target cell and act as a conduit for the transfer of the parasite into the host cell, which initiates infection.

Bacterial motility depends on a critical flagellum length and energy-optimized assembly.

The flagellum is the most complex macromolecular structure known in bacteria and is composed of around two dozen distinct proteins. The main building block of the long, external flagellar filament, flagellin, is secreted through the flagellar type-III secretion system at a remarkable rate of several tens of thousands of amino acids per second, significantly surpassing the rates achieved by other pore-based protein secretion systems. The evolutionary implications and potential benefits of this high secretion rate for flagellum assembly and function, however, have remained elusive.

Large increases in public R&D investment are needed to avoid declines of US agricultural productivity.

Increasing agricultural productivity is a gradual process with significant time lags between research and development (R&D) investment and the resulting gains. We estimate the response of US agricultural Total Factor Productivity to both R&D investment and weather and quantify the public R&D spending required to offset the emerging impacts of climate change. We find that offsetting the climate-induced productivity slowdown by 2050 will require R&D spending over 2021 to 2050 to grow at 5.

Expansion and pathogenic activation of skeletal muscle-resident macrophages in mice.

Infiltrating macrophages contribute to muscle dystrophic changes in Duchenne muscular dystrophy (DMD). In a DMD mouse model, mice, CC chemokine receptor type 2 (CCR2) deficiency diminishes Ly6C macrophage infiltration by blocking blood Ly6C inflammatory monocyte recruitment. This is accompanied by transient improvement of muscle damage, fibrosis, and regeneration.

"Kids and Girls": Parents convey a male default in child-directed speech.

Adults tend to view men (more so than women) as default , with numerous real-world consequences for gender equity. In the United States, the tendency to center men in concepts of develops across middle childhood, yet the specific mechanisms that contribute to it remain unknown. Here, we investigate one subtle but potentially powerful social mechanism: the category labels that parents use to describe boys/men and girls/women in conversations with their children.

ALS molecular subtypes are a combination of cellular and pathological features learned by deep multiomics classifiers.

Amyotrophic lateral sclerosis (ALS) is a complex syndrome with multiple genetic causes and wide variation in disease presentation. Despite this heterogeneity, large-scale genomics studies revealed that ALS postmortem samples can be grouped into a small number of subtypes, defined by transcriptomic signatures of mitochondrial dysfunction and oxidative stress (ALS-Ox), microglial activation and neuroinflammation (ALS-Glia), or TDP-43 pathology and associated transposable elements (ALS-TE). In this study, we present a deep ALS neural net classifier (DANCer) for ALS molecular subtypes.

Neurophysiological correlates of subjective cognitive decline in perimenopausal and postmenopausal midlife women at risk for Alzheimer's disease.

Objective: This study aimed to investigate neurophysiological correlates of subjective cognitive decline (SCD) among midlife women at risk for Alzheimer's disease (AD).

Methods: We examined 156 cognitively normal perimenopausal and postmenopausal women aged 40 to 65 years, with an AD family history and/or apolipoprotein E epsilon 4 genotype, who were not on menopause hormone therapy. Participants underwent neuropsychological testing, health and menopausal symptom questionnaires, and brain volumetric magnetic resonance imaging, arterial spin labeling-magnetic resonance (MR) measuring cerebral blood flow, and 31phosphorus magnetic resonance spectroscopy (31P-MRS) measuring mitochondria high-energy phosphates (adenosine triphosphate [ATP], phosphocreatine [PCr], inorganic phosphate [Pi]).