Mitochondria and NLRP3: To die or inflame.

Mitochondria play critical roles in intrinsic apoptosis and NLRP3 inflammasome activation, but how these processes are interconnected remains unclear. In this issue of Immunity, Saller et al. unveiled the complexity of NLRP3 activators, highlighting mitochondria's roles in switching apoptosis to NLRP3 inflammasome activation.

Feasibility trial of STRONG: A digital intervention to improve nutritional management for individuals with esophageal and gastroesophageal junction cancer.

Introduction: Individuals with esophageal and gastroesophageal junction (GEJ) cancers are at especially high risk of malnutrition. However, most patients with malnutrition do not receive adequate nutritional support. We conducted a single-arm trial to test the implementation of Support Through Remote Observation and Nutrition Guidance (STRONG), a multilevel digital intervention to improve nutritional outcomes for patients with locally advanced esophageal and gastroesophageal junction cancer.

Work-related Fatigue: Relationship between Perceived and Performance Fatigability in Career Firefighters.

Objective: The purpose of this study was to 1) examine the relationship between perceived work-related fatigue and performance fatigability, and 2) assess the impact of percent body fat (%BF) on perceived fatigue constructs in career firefighters.

Methods: Thirty-nine career firefighters completed body composition testing, the Occupational Fatigue Exhaustion Recovery (OFER15) scale assessing three subscales of work-related fatigue (acute fatigue, chronic fatigue, and inter-shift recovery), and maximal leg extensor isometric strength testing prior to and following an isotonic fatiguing protocol.

Results: Performance fatigability was not associated with any of the OFER15 perceived work-related fatigue variables ( P ≥ 0.

Modulation of Cell Cycle Kinases by Kaposi's Sarcoma-Associated Herpesvirus.

The cell cycle is governed by kinase activity that coordinates progression through a series of regulatory checkpoints, preventing the division of damaged cells. The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes multiple genes that modulate or co-opt the activity of these kinases, shaping the cellular environment to promote viral persistence. By advancing the cell cycle, KSHV facilitates latent replication and subsequent transmission of viral genomes to daughter cells, while also contributing to the establishment of multiple cancer types.

Evaluation of End-of-Life Quality Care Between American Indian and White North Carolina Decedents Diagnosed With Lung Cancer, 2003-2020.

Purpose: Lung cancer mortality rates for American Indians (AIs) are the highest among US race groups. End-of-life (EOL) care presents opportunities to limit aggressive and potentially unnecessary treatment. We evaluated differences in EOL quality of care between AI and White (WH) decedents with lung cancer.

Solar elastosis correlates with high tumor mutation burden and better 5-year disease-specific survival in patients with stage II/III melanoma.

Objective: To evaluate the relation between solar elastosis and tumor mutation burden (TMB) in a large clinically annotated cohort of stage II and III melanoma patients.

Methods: Primary cutaneous melanomas from 469 AJCC (8 edition) stage II and III patients with clinical annotation including outcome at 5 years of diagnosis were histopathologically evaluated for solar elastosis. Next-generation sequencing assay MSK-IMPACT was employed to determine TMB.

Fluctuations in mHealth engagement following receipt of goal-discrepant feedback messages.

Objective: Digital behavior change interventions can successfully promote change in behavioral outcomes, but often suffer from steep decreases in engagement over time, which hampers their effectiveness. Providing feedback on goal performance is an established technique to promote goal attainment; however, theory indicates that sending goal-discrepant feedback messages could cause some users to respond more negatively than others. This analysis assessed whether goal-discrepant messaging was negatively associated with participant engagement, and if this relationship was exacerbated by baseline depressive symptoms within the context of a three-month weight loss pilot mHealth intervention.

A conserved switch to less catalytically active Polycomb repressive complexes in non-dividing cells.

Polycomb repressive complex 2 (PRC2), composed of the core subunits EED, SUZ12, and either EZH1 or EZH2, is critical for maintaining cellular identity in multicellular organisms. PRC2 deposits H3K27me3, which is thought to recruit the canonical form of PRC1 (cPRC1) to promote gene repression. Here, we show that EZH1-PRC2 and cPRC1 are the primary Polycomb complexes on target genes in non-dividing, quiescent cells.

Sex Differences in Melanoma Survival-a GEM study.

Sex differences in melanoma are prominent, with females having a significant survival advantage. However, it is unclear why we see this survival advantage. Here we investigate the relationship between sex, clinicopathologic variables, and melanoma specific survival in 1,753 single primary melanomas from patients in the GEM study.

Development and Validation of a Simplified Financial Toxicity Screening Tool for Use in Clinical Practice.

Purpose: Cancer-related financial toxicity occurs frequently and is a key driver of inequities in access to care and disparities in treatment outcomes. Current practices to screen for financial toxicity are inconsistent because of the lack of a validated and clinically integrated screening tool. This analysis aimed to create and assess an abbreviated version of the validated Comprehensive Score for Financial Toxicity (COST) tool, a measure of financial toxicity used for research purposes, which could easily be added into often-lengthy clinical screening workflows.

Interventions to Address Cancer-Related Financial Hardship: A Scoping Review and Call to Action.

Purpose: As oncology practices implement routine screening for financial hardship (FH) and health-related social needs, interventions that address these needs must be implemented. A growing body of literature has reported on FH interventions.

Methods: We conducted a scoping review of the literature using PubMed, EMBASE, PsychInfo, and CINAHL to identify key studies (2000-2024) reporting on interventions to address cancer-related FH.

Functions of the Bloom Syndrome Helicase N-terminal Intrinsically Disordered Region.

Bloom Syndrome helicase (Blm) is a RecQ family helicase involved in DNA repair, cell-cycle progression, and development. Pathogenic variants in human BLM cause the autosomal recessive disorder Bloom Syndrome, characterized by predisposition to numerous types of cancer. Prior studies of Drosophila Blm mutants lacking helicase activity or protein have shown sensitivity to DNA damaging agents, defects in repairing DNA double-strand breaks (DSBs), female sterility, and improper segregation of chromosomes in meiosis.

Response eQTLs, chromatin accessibility, and 3D chromatin structure in chondrocytes provide mechanistic insight into osteoarthritis risk.

Osteoarthritis (OA) poses a significant healthcare burden with limited treatment options. While genome-wide association studies (GWASs) have identified over 100 OA-associated loci, translating these findings into therapeutic targets remains challenging. To address this gap, we mapped gene expression, chromatin accessibility, and 3D chromatin structure in primary human articular chondrocytes in both resting and OA-mimicking conditions.

Registry versus claims-based index dates for studies of cancer diagnosis in administrative data.

Purpose: Studies of healthcare encounters leading to cancer diagnosis have increased over recent years. While some studies examine healthcare utilization before the cancer registry date of diagnosis, relevant pre-diagnosis interactions are not always immediately prior to this date due to date abstraction guidelines. We evaluated agreement of a registry date with a claims-based index and examined Emergency Department (ED) involvement in cancer diagnosis as an example of possible pre-diagnostic healthcare misclassification that could arise from improper date choice.

Insights into conformational ensembles of compositionally identical disordered peptidomimetics.

While the conformational ensembles of disordered peptides and peptidomimetics are complex and challenging to characterize, they are a critical component in the paradigm connecting macromolecule sequence, structure, and function. In molecules that do not adopt a single predominant conformation, the conformational ensemble contains rich structural information that, if accessible, can provide a fundamental understanding related to desirable functions such as cell penetration of a therapeutic or the generation of tunable enzyme-mimetic architecture. To address the fundamental challenge of describing broad conformational ensembles, we developed a model system of peptidomimetics comprised of polar glycine and hydrophobic -butylglycine to characterize using a suite of analytical techniques.

Gene signatures derived from transcriptomic-causal networks stratify colorectal cancer patients for effective targeted therapy.

Background: Gene signatures derived from transcriptomic-causal networks offer potential for tailoring clinical care in cancer treatment by identifying predictive and prognostic biomarkers. This study aimed to uncover such signatures in metastatic colorectal cancer (CRC) patients to aid treatment decisions.

Methods: We constructed transcriptomic-causal networks and integrated gene interconnectivity into overall survival (OS) analysis to control for confounding genes.

A multi-kinase inhibitor screen identifies inhibitors preserving stem-cell-like chimeric antigen receptor T cells.

Chimeric antigen receptor T cells (CAR T cells) with T stem (T) cell-like phenotypic characteristics promote sustained antitumor effects. We performed an unbiased and automated high-throughput screen of a kinase-focused compound set to identify kinase inhibitors (KIs) that preserve human T cell-like CAR T cells. We identified three KIs, UNC10225387B, UNC10225263A and UNC10112761A, that combined in vitro increased the frequency of CD45RACCR7TCF1 T cell-like CAR T cells from both healthy donors and patients with cancer.

Differential impact of TIM-3 ligands on NK cell function.

Background: The transmembrane protein T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM-3) is an immune checkpoint receptor that is expressed by a variety of leukocyte subsets, particularly in the tumor microenvironment. An effective TIM-3-targeting therapy should account for multiple biological factors, including the disease setting, the specific cell types involved and their varying sensitivities to the four putative TIM-3 ligands (galectin-9, phosphatidylserine, high mobility group protein B1 and carcinoembryonic antigen cell adhesion molecule 1), each of which engages a unique binding site on the receptor's variable immunoglobulin domain. The primary objectives of this study were to assess the prevalence and function of TIM-3 natural killer (NK) cells in patients with head and neck squamous cell carcinoma (HNSCC), determine whether the four TIM-3 ligands differentially affect TIM-3 NK cell functions, identify the most immunosuppressive ligand, and evaluate whether targeting ligand-mediated TIM-3 signaling enhances NK cell effector functions.

Structures of ATP-binding cassette transporter ABCC1 reveal the molecular basis of cyclic dinucleotide cGAMP export.

Cyclic nucleotide GMP-AMP (cGAMP) plays a critical role in mediating the innate immune response through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Recent studies showed that ATP-binding cassette subfamily C member 1 (ABCC1) is a cGAMP exporter. The exported cGAMP can be imported into uninfected cells to stimulate a STING-mediated innate immune response.

Linking tumor immune infiltration to enhanced longevity in recurrence-free breast cancer.

Background: The infiltration of tumor-infiltrating B cells and plasma cells in early-stage breast cancer has been associated with a reduced risk of distant metastasis. However, the influence of B-cell tumor infiltration on overall patient survival remains unclear.

Materials And Methods: This study explored the relationship between an antitumor immune response, measured by a 14-gene B-cell/immunoglobulin (IGG) signature, and mortality risk in 9638 breast cancer patients across three datasets.

CD24-Fc resolves inflammation and rescues CD8 T cells with polyfunctionality in humanized mice infected with HIV-1 under cART.

The persistence of HIV-1 reservoirs during combination anti-retroviral therapy (cART) leads to chronic immune activation and systemic inflammation in people with HIV (PWH), associating with a suboptimal immune reconstitution as well as an increased risk of non-AIDS events. This highlights the needs to develop novel therapy for HIV-1 related diseases in PWH. In this study, we assessed the therapeutic effect of CD24-Fc, a fusion protein with anti-inflammatory properties that interacts with danger-associated molecular patterns (DAMPs) and siglec-10, in chronic HIV-1 infection model using humanized mice undergoing suppressive cART.

Cell cycle-regulated transcriptional pausing of replication-dependent histone genes.

Coordinated expression of replication-dependent (RD) histones genes occurs within the Histone Locus Body (HLB) during S phase, but the molecular steps in transcription that are cell cycle regulated are unknown. We report that RNA Pol II promotes HLB formation and is enriched in the HLB outside of S phase, including G1-arrested cells that do not transcribe RD histone genes. In contrast, the transcription elongation factor Spt6 is enriched in HLBs only during S phase.

A Pilot Randomized Controlled Trial of Families Addressing Cancer Together for Parents With Cancer: Feasibility, Acceptability, and Preliminary Effects.

Objective: To evaluate the feasibility, acceptability, and preliminary efficacy of Families Addressing Cancer Together (FACT), a web-based, individually tailored, psychoeducational intervention for parents with cancer to improve illness-related communication with their minor children.

Methods: Parents with stage I-IV solid tumors who had children ages 3-17 were randomized to 6 weeks of FACT versus waitlist control. Feasibility was assessed by rates of recruitment and retention.

Assessment of the functional and health-related needs of patients with metastatic breast cancer prior to initiation of cancer treatment.

Purpose: To identify needs of metastatic breast cancer patients prior to starting a new systemic treatment.

Methods: Fifty patients with newly diagnosed, recurrent, or progressive metastatic breast cancer completed an electronic survey which included patient-reported outcome measures of function (PROMIS Cancer Function Brief 3D profile), quality of life (FACT-G), exercise (Godin Leisure-Time exercise questionnaire), and diet (REAP-S); demographic information; and self-reported use of or referral to specific resources at the cancer center prior to beginning a new systemic oncologic treatment.

Results: Prior to starting a new treatment for metastatic breast cancer, patients reported mild functional impairment (PROMIS Cancer Function Brief 3D profile mean score:42.

Discrimination, Violence, Mental Health, and Substance Use by Age and Cancer History Among LGBTQ+ Individuals.

Young adult (YA) LGBTQ+ cancer survivors face inequities and unmet needs that impact their well-being. However, the impact of age and cancer among LGBTQ+ individuals have not been adequately assessed. The North Carolina LGBTQ+ Health Needs Assessment survey, conducted at local Pride events, aimed to collect data to describe the well-being of LGBTQ+ people in NC.