Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers.

Interleukin-15 (IL-15) promotes the survival of T lymphocytes and enhances the antitumour properties of chimeric antigen receptor (CAR) T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy. Glypican-3 (GPC3) is expressed in a group of solid cancers, and here we report the evaluation in humans of the effects of IL-15 co-expression on GPC3-expressing CAR T cells (hereafter GPC3 CAR T cells). Cohort 1 patients ( NCT02905188 and NCT02932956 ) received GPC3 CAR T cells, which were safe but produced no objective antitumour responses and reached peak expansion at 2 weeks.

Metabolism of inorganic arsenic in mice carrying the human AS3MT gene and fed folate deficient or folate supplemented diet.

Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes the S-adenosylmethionine (SAM)-dependent methylation of inorganic arsenic (iAs), yielding monomethyl‑arsenic (MAs) and dimethyl‑arsenic (DMAs) metabolites. The formation of DMAs in this pathway is considered a key mechanism for iAs detoxification. Availability of SAM for iAs methylation depends in part on dietary intake of folate.

Apoptotic Caspases Suppress Expression of Endogenous Retroviruses in HPV31+ Cells That Are Associated with Activation of an Innate Immune Response.

Avoidance of an immune response is critical to completion of the human papillomavirus (HPV) life cycle, which occurs in the stratified epithelium and is linked to epithelial differentiation. We previously demonstrated that high-risk HPVs use apoptotic caspases to suppress an antiviral innate immune response during the productive phase of the life cycle. We found that caspase-8 and caspase-3 suppress a type I IFN-β and type III IFN-λ response by disabling the MDA5/MAVS double-stranded RNA (dsRNA) sensing pathway, indicating that immunogenic RNAs increase upon differentiation in HPV+ cells.

The impact of culturally-informed messages to reduce sugar-sweetened beverage consumption: An experiment among Black women in the United States.

Objective: Sugar-sweetened beverage (i.e., sugary drink) consumption is associated with chronic health issues that disproportionately affect Black women.

ARID1A governs the silencing of sex-linked transcription during male meiosis in the mouse.

We present evidence implicating the BAF (BRG1/BRM Associated Factor) chromatin remodeler in meiotic sex chromosome inactivation (MSCI). By immunofluorescence (IF), the putative BAF DNA binding subunit, ARID1A (AT-rich Interaction Domain 1 a), appeared enriched on the male sex chromosomes during diplonema of meiosis I. Germ cells showing a Cre-induced loss of ARID1A arrested in pachynema and failed to repress sex-linked genes, indicating a defective MSCI.

Associations of social vulnerability index with patient-reported outcomes in women treated with chemotherapy for early-stage breast cancer.

Background: In a convenience sample of women scheduled for chemotherapy for early-stage breast cancer, we investigated associations of the Center for Disease Control and Prevention's neighborhood-level social vulnerability index (SVI) with pretreatment demographics and patient-reported outcome (PRO) measures (health behavior, function and quality of life, treatment toxicities during chemotherapy).

Methods: The SVI Overall score is comprised of 4 themes: socioeconomic, household composition, minority status/language, and household type/transportation, with scores ranging from 0 = lowest to 1 = highest vulnerability neighborhoods. Participant SVI scores were derived from zip codes listed in the patient's address within the electronic medical record (EMR).

Meiotic Drive and Speciation.

Meiotic drive is the biased transmission of alleles from heterozygotes, contrary to Mendel's laws, and reflects intragenomic conflict rather than organism-level Darwinian selection. Theory has been developed as to how centromeric properties can promote female meiotic drive and how conflict between the X and Y chromosomes in males can promote male meiotic drive. There are empirical data that fit both the centromere drive and sex chromosome drive models.

Centralized Colorectal Cancer Screening Outreach in Federally Qualified Health Centers: A Randomized Clinical Trial.

Importance: Colorectal cancer (CRC) screening is effective but remains underused in federally qualified health centers (FQHCs).

Objective: To assess the effectiveness of a centralized CRC screening outreach intervention involving mailed fecal immunochemical testing (FIT) outreach and patient navigation to colonoscopy after abnormal results of FIT.

Design, Setting, And Participants: A pragmatic randomized clinical trial was conducted, using intention-to-treat analysis.

A High-Throughput Workflow to Analyze Sequence-Conformation Relationships and Explore Hydrophobic Patterning in Disordered Peptoids.

Understanding how a macromolecule's primary sequence governs its conformational landscape is crucial for elucidating its function, yet these design principles are still emerging for macromolecules with intrinsic disorder. Herein, we introduce a high-throughput workflow that implements a practical colorimetric conformational assay, introduces a semi-automated sequencing protocol using MALDI-MS/MS, and develops a generalizable sequence-structure algorithm. Using a model system of 20mer peptidomimetics containing polar glycine and hydrophobic -butylglycine residues, we identified nine classifications of conformational disorder and isolated 122 unique sequences across varied compositions and conformations.

Barcoding of viable peripheral blood mononuclear cells with selenium and tellurium isotopes for mass cytometry experiments.

Barcoding viable cells combined with pooled sample staining is an effective technique that eliminates batch effects from serial cell staining and facilitates uninterrupted data acquisition. We describe three novel and isotopically pure selenium-containing compounds (SeMals) that are useful cellular labeling tools. The maleimide-functionalized selenophenes (SeMal, SeMal, and SeMal) covalently react with cellular sulfhydryl groups and uniquely label cell samples.

Brief Report: Phase II Clinical Trial of Atezolizumab in Advanced Nonsmall Cell Lung Cancer Patients Previously Treated With PD-1-Directed Therapy.

Background:: Prospective data of sequencing PD-L1 inhibition after PD-1 inhibition is limited in non-small cell lung cancer (NSCLC). We report a phase II clinical trial of atezolizumab following PD-1 directed therapy (NCT03014648).

Methods:: Previously treated advanced NSCLC patients were enrolled in cohorts based on response to prior nivolumab or pembrolizumab therapy; progressive disease (Cohort 1); stable disease (Cohort 2), or partial or complete response (Cohort 3).

Efficacy of Inpatient, Evidence-Based Tobacco Use Treatment of Patients With Bladder Cancer After Radical Cystectomy.

Purpose: Despite a 3-fold increase in risks of bladder cancer (BC) among current smokers, smoking cessation therapy for patients undergoing treatment is significantly underutilized. Inpatient admission after surgery provides a teachable moment to pursue tobacco treatment. We conducted a 12-month prospective quality improvement initiative to increase tobacco treatment program (TTP) consultations with BC patients who smoke and underwent radical cystectomy (RC).

Longer travel times to acute hospitals are associated with lower likelihood of cancer screening receipt among rural-dwelling adults in the U.S. South.

Purpose: Given rural hospitals' role in providing outpatient services, we examined the association between travel burdens and receipt of cancer screening among rural-dwelling adults in the U.S. South region.

"It was not normal, and I had to find a doctor and tell him." Kenyan Women's Response to Cervical Cancer Symptoms.

This study aimed to characterize the cervical cancer diagnosis experience of Kenyan women undergoing treatment for cervical cancer. We analyzed qualitative interviews with 29 women living in rural Kenya who were currently undergoing cervical cancer treatment at Machakos Cancer Care and Research Centre at Machakos Level 5 Referral Hospital in eastern Kenya. Semistructured qualitative interviews were conducted in Kiswahili and English and then de-identified and translated to English during transcription.

Proximity proteomics provides a new resource for exploring the function of Afadin and the complexity of cell-cell adherens junctions.

The network of proteins at the interface between cell-cell adherens junctions and the actomyosin cytoskeleton provides robust yet dynamic connections that facilitate cell shape change and motility. While this was initially thought to be a simple linear connection via classic cadherins and their associated catenins, we now have come to appreciate that many more proteins are involved, providing robustness and mechanosensitivity. Defining the full network of proteins in this network remains a key objective in our field.

Epstein-Barr virus-associated B-cell lymphoproliferative disorders and lymphomas: Diagnostic overlaps and defining features.

This review explores four Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders (LPD) and lymphomas with significant diagnostic overlap: EBV(+) mucocutaneous ulcer (EBVMCU), EBV(+) polymorphic LPD, EBV(+) classic Hodgkin lymphoma (CHL), and EBV(+) diffuse large B-cell lymphoma (DLBCL). Each entity is compared for both overlapping and defining features of clinical presentation, morphology, immunohistochemical profile and EBV expression pattern and latency. Our aims for this review are to provide useful guidance to the practicing pathologist in the diagnosis of these EBV-associated entities.

Women's experiences and acceptability of self-administered, home delivered, intravaginal 5-Fluorouracil cream for cervical precancer treatment in Kenya.

Background: Innovative strategies are essential to meet the World Health Organization's 90/70/90 cervical cancer elimination targets, aiming for 90% access to precancer treatment globally by 2030. In low-and middle-income countries (LMICs) where most cervical cancer cases occur, access to precancer treatment is severely limited. Scalable solutions like self-administered topical therapies can help close this gap.

Hepatovirus translation requires PDGFA-associated protein 1, an eIF4E-binding protein regulating endoplasmic reticulum stress responses.

The overexpression and misfolding of viral proteins in the endoplasmic reticulum (ER) may cause cellular stress, thereby inducing a cytoprotective, proteostatic host response involving phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2α). Here, we show that hepatitis A virus, a positive-strand RNA virus responsible for infectious hepatitis, adopts a stress-resistant, eIF2α-independent mechanism of translation to ensure the synthesis of viral proteins within the infected liver. Cap-independent translation directed by the hepatovirus internal ribosome entry site and productive hepatovirus infection of mice both require platelet-derived growth factor subunit A (PDGFA)-associated protein 1 (PDAP1), a small phosphoprotein of unknown function with eIF4E-binding activity.

Enabling systemic identification and functionality profiling for Cdc42 homeostatic modulators.

Maintaining body homeostasis is the ultimate key to health. There are rich resources of bioactive materials for the functionality of homeostatic modulators (HMs) from both natural and synthetic chemical repertories. HMs are powerful modern therapeutics for human diseases including neuropsychiatric diseases, mental disorders, and drug addiction (e.

Evidence for dual roles of histone H3 lysine 4 in antagonizing Polycomb group function and promoting target gene expression.

Tight control over cell identity gene expression is necessary for proper adult form and function. The opposing activities of Polycomb and trithorax complexes determine the on/off state of cell identity genes such as the Hox factors. Polycomb group complexes repress target genes, whereas trithorax group complexes are required for their expression.

The role of Nef in the long-term persistence of the replication-competent HIV reservoir in South African women.

HIV-1 Nef mediates immune evasion and viral pathogenesis in part through downregulation of cell surface cluster of differentiation 4 (CD4) and major histocompatibility complex class I (MHC-I) on infected cells. While Nef function of circulating viral populations found early in infection has been associated with reservoir size in early-treated cohorts, there is limited research on how its activity impacts reservoir size in people initiating treatment during chronic infection. In addition, there is little research on its role in persistence of viral variants during long-term antiretroviral therapy (ART).