Breast Cancer MRI Screening of Patients After Multiplex Gene Panel Testing.

Importance: Enhanced breast cancer screening with magnetic resonance imaging (MRI) is recommended to women with elevated risk of breast cancer, yet uptake of screening remains unclear after genetic testing.

Objective: To evaluate uptake of MRI after genetic results disclosure and counseling.

Design, Setting, And Participants: This multicenter cohort study was conducted at the University of Southern California Norris Cancer Hospital, the Los Angeles General Medical Center, and the Stanford University Cancer Institute.

HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells.

Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-γ is instrumental for anti-tumor immunity. HIF1α has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-γ induction in hypoxic T cells is unknown. Here, we show that the HIF1α-glycolysis axis controls IFN-γ induction in both human and mouse T cells, activated under hypoxia.

(Two) Wheels on the Bus: Road User Perceptions of a Bike Bus and How This Links to Addressing Global Health Challenges.

Background: Excessive car use hampers progress toward tackling global health challenges, including climate and sustainability issues, and is linked to lower physical activity. Local communities have been developing solutions through bike buses. This paper, one of the first on bike buses, explores how a bike bus is perceived by other road and place users.

House Dust Mite Proteins Adsorb on Multiwalled Carbon Nanotubes Forming an Allergen Corona That Intensifies Allergic Lung Disease in Mice.

The increasing use of multiwalled carbon nanotubes (MWCNTs) could increase the risk of allergic lung disease in occupational or consumer settings. We previously reported that MWCNTs exacerbated allergic lung disease in mice induced by extract from house dust mites (HDM), a common cause of asthma in humans. Because MWCNTs avidly bind biomolecules to form protein coronas that can modify immunotoxicity, we hypothesized that exacerbation of allergic lung disease in mice caused by coexposure to MWCNTs and HDM extract was due to the formation of an allergen corona.

Should they stay or should they go? Stroke transfers across a hospital network pre- and post-implementation of an automated image interpretation and communication platform.

Background: A key decision facing nonthrombectomy capable (spoke) hospitals is whether to transfer a suspected large vessel occlusion (LVO) patient to a comprehensive stroke center (CSC). In a retrospective cohort study, we investigated the rate of transfers resulting in endovascular thrombectomy (EVT) and associated costs before and after implementation of an artificial intelligence (AI)-based software.

Methods: All patients with a final diagnosis of acute ischemic stroke presenting across a five-spoke community hospital network in affiliation with a CSC were included.

PBPK-led assessment of antimalarial drugs as candidates for Covid-19: Simulating concentrations at the site of action to inform repurposing strategies.

The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID-19) prompted a global effort to evaluate drug repurposing opportunities. Pyronaridine and amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro activity does not always translate to clinical efficacy across a therapeutic dose range.

Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances.

Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase the risk of Alzheimer's disease (odds ratio ∼2), yet the pathogenic mechanisms and the neural cell types affected by these variants remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 human samples from the prefrontal cortex of 12 ABCA7 LoF carriers and 24 matched non-carrier control individuals. ABCA7 LoF was associated with gene expression changes in all major cell types.

A Novel Summer Camp Integrating Physical, Psychological, and Educational Health in Youth: The THINK Program.

Numerous youth summer programs focus upon physical fitness, nutritional health, psychological well-being, or education. Few, however, have integrated all of these elements into a single program. The Translational Health in Nutrition and Kinesiology (THINK) program provides an integrative nutrition and exercise science curriculum that is interfaced with social emotional learning (SEL) and STEM education to enhance healthy behaviors in youth.

Differences in tumor-associated T-cell receptor repertoires between early-onset and average-onset colorectal cancer.

The incidence of colorectal cancer (CRC) among individuals younger than age 50 (early-onset CRC [EOCRC]) has substantially increased, and yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. We compared tumor-associated T-cell repertoires between EOCRC and average-onset CRC (AOCRC) to uncover potentially unique immune microenvironment-related features by age of onset. Our discovery cohort included 242 patients who underwent surgical resection at Cleveland Clinic from 2000 to 2020.

Type I Interferon: Monkeypox/Mpox Viruses Achilles Heel?

Poxviruses are notorious for having acquired/evolved numerous genes to counteract host innate immunity. Chordopoxviruses have acquired/evolved at least three different inhibitors of host necroptotic death: E3, which blocks ZBP1-dependent necroptotic cell death, and vIRD and vMLKL that inhibit necroptosis downstream of initial cell death signaling. While this suggests the importance of the necroptotic cell death pathway in inhibiting chordopoxvirus replication, several chordopoxviruses have lost one or more of these inhibitory functions.

Germline genetic regulation of the colorectal tumor immune microenvironment.

Objective: To evaluate the contribution of germline genetics to regulating the briskness and diversity of T cell responses in CRC, we conducted a genome-wide association study to examine the associations between germline genetic variation and quantitative measures of T cell landscapes in 2,876 colorectal tumors from participants in the Molecular Epidemiology of Colorectal Cancer Study (MECC).

Methods: Germline DNA samples were genotyped and imputed using genome-wide arrays. Tumor DNA samples were extracted from paraffin blocks, and T cell receptor clonality and abundance were quantified by immunoSEQ (Adaptive Biotechnologies, Seattle, WA).

Gfi1 controls the formation of effector CD8 T cells during chronic infection and cancer.

During chronic infections and tumor progression, CD8 T cells gradually lose their effector functions and become exhausted. These exhausted CD8 T cells are heterogeneous and comprised of different subsets, including self-renewing progenitors that give rise to Ly108 CX3CR1 effector-like cells. Generation of these effector-like cells is essential for the control of chronic infections and tumors, albeit limited.

House Dust Mite Extract Forms a Der p 2 Corona on Multi-Walled Carbon Nanotubes: Implications for Allergic Airway Disease.

Multi-walled carbons nanotubes (MWCNTs) are used in materials for the construction, automotive, and aerospace industries. Workers and consumers are exposed to these materials via inhalation. Existing recommended exposure limits are based on MWCNT exposures that do not take into account more realistic co-exposures.

Surrogate endpoints in clinical trials of p16-positive squamous cell carcinoma of the oropharynx: an individual patient data meta-analysis.

Background: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy.

HIF1α-glycolysis engages activation-induced cell death to drive IFN-γ induction in hypoxic T cells.

The role of HIF1α-glycolysis in regulating IFN-γ induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-γ is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1α-glycolysis controls IFN-γ induction in both human and mouse T cells activated under hypoxia.

Nanoparticle-Mediated Delivery of Anti-PU.1 siRNA via Localized Intracisternal Administration Reduces Neuroinflammation.

Neuroinflammation is a hallmark of neurodegenerative disorders including Alzheimer's disease (AD). Microglia, the brain's immune cells, express many of the AD-risk loci identified in genome wide association studies and present a promising target for anti-inflammatory RNA therapeutics but are difficult to transfect with current methods. Here, several lipid nanoparticle (LNP) formulations are examined, and a lead candidate that supports efficient RNA delivery in cultures of human stem cell-derived microglia-like cells (iMGLs) and animal models of neuroinflammation is identified.

Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer.

Objective: Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC).

Methods: We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC).

Leading indicators of readiness among the general Army and Special Operations Forces: Predictive and psychometric analysis of the Global Assessment Tool.

Self-assessments are commonly used to track Army readiness in specialized communities, but they are rarely analyzed for reliability and predictive validity. Before introducing new assessments, existing ones should be reevaluated. We examined the Global Assessment Tool (GAT), an annual Army-required self-assessment with multiple psychosocial and health behavior short scales.

Transformer-based biomarker prediction from colorectal cancer histology: A large-scale multicentric study.

Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation.

Development and application of a PBPK modeling strategy to support antimalarial drug development.

As part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically-based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5 years. During this time, a strategy for their impactful use has evolved.

Role of the protease-activated receptor-2 (PAR2) in the exacerbation of house dust mite-induced murine allergic lung disease by multi-walled carbon nanotubes.

Background: Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been reported to exert strong pro-inflammatory and pro-fibrotic adjuvant effects in mouse models of allergic lung disease. However, the molecular mechanisms through which MWCNTs exacerbate allergen-induced lung disease remain to be elucidated. We hypothesized that protease-activated receptor 2 (PAR2), a G-protein coupled receptor previously implicated in the pathogenesis of various diseases including pulmonary fibrosis and asthma, may play an important role in the exacerbation of house dust mite (HDM) allergen-induced lung disease by MWCNTs.

A Monoclonal Antibody Produced in Glycoengineered Plants Potently Neutralizes Monkeypox Virus.

The 2022 global outbreaks of monkeypox virus (MPXV) and increased human-to-human transmission calls for the urgent development of countermeasures to protect people who cannot benefit from vaccination. Here, we describe the development of glycovariants of 7D11, a neutralizing monoclonal IgG antibody (mAb) directed against the L1 transmembrane protein of the related vaccinia virus, in a plant-based system as a potential therapeutic against the current MPVX outbreak. Our results indicated that 7D11 mAb quickly accumulates to high levels within a week after gene introduction to plants.

Assessment of Differences in Academic Rank and Compensation by Gender and Race/Ethnicity Among Academic Radiation Oncologists in the United States.

Purpose: Advancing equity, diversity, and inclusion in the physician workforce is essential to providing high-quality and culturally responsive patient care and has been shown to improve patient outcomes. To better characterize equity in the field of radiation oncology, we sought to describe the current academic radiation oncology workforce, including any contemporary differences in compensation and rank by gender and race/ethnicity.

Methods And Materials: We conducted a retrospective cohort study using data from the Society of Chairs of Academic Radiation Oncology Programs (SCAROP) 2018 Financial Survey.