NEK7 phosphorylation amplifies NLRP3 inflammasome activation downstream of potassium efflux and gasdermin D.

The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory diseases. NIMA-related kinase 7 (NEK7) is essential for inflammasome activation, and its interaction with NLRP3 is enhanced by K efflux. However, the mechanism by which K efflux promotes this interaction remains unknown.

Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers.

SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective SMARCA2 PROTAC degraders, as exemplified by SMD-3236, which was designed using a new, high-affinity SMARCA ligand and a potent VHL-1 ligand. SMD-3236 achieves DC < 1 nM and > 95% against SMARCA2 and >2000-fold degradation selectivity over SMARCA4.

Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders.

In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands.

mRNA decay pre-complex assembly drives timely cell-state transitions during differentiation.

Complexes that control mRNA stability and translation promote timely cell-state transitions during differentiation by ensuring appropriate expression patterns of key developmental regulators. The Drosophila RNA-binding protein brain tumor (Brat) promotes the degradation of target transcripts during the maternal-to-zygotic transition in syncytial embryos and uncommitted intermediate neural progenitors (immature INPs). We identify ubiquitin-specific protease 5 (Usp5) as a candidate Brat interactor essential for the degradation of Brat target mRNAs.

Engineering immunity using metabolically active polymeric nanoparticles.

Immune system functions play crucial roles in both health and disease, and these functions are regulated by their metabolic programming. The field of immune engineering has emerged to develop therapeutic strategies, including polymeric nanoparticles (NPs), that can direct immune cell phenotype and function by directing immunometabolic changes. Precise control of bioenergetic processes may offer the opportunity to prevent undesired immune activity and improve disease-specific outcomes.

Genome-scale modeling identifies dynamic metabolic vulnerabilities during the epithelial to mesenchymal transition.

Epithelial-to-mesenchymal transition (EMT) is a conserved cellular process critical for embryogenesis, wound healing, and cancer metastasis. During EMT, cells undergo large-scale metabolic reprogramming that supports multiple functional phenotypes including migration, invasion, survival, chemo-resistance and stemness. However, the extent of metabolic network rewiring during EMT is unclear.

Universal Genetic Counseling and Testing for Black Women: A Risk-Stratified Approach to Addressing Breast Cancer Disparities.

Black women experience disproportionate breast cancer-related mortality, with similar overall incidence to White women. Approaches to address these racial health disparities should be multifaceted. Universal genetic counseling and testing for Black women could represent one dimension of a comprehensive approach in guiding early identification of those more likely to experience higher breast cancer-related mortality.

Molecular characterization of archival adrenal tumor tissue from patients with ACTH-independent Cushing syndrome.

Cushing syndrome represents a multitude of signs and symptoms associated with long-term and excessive exposure to glucocorticoids. Solitary cortisol-producing adenomas (CPAs) account for most cases of ACTH-independent Cushing syndrome (CS). Technological advances in next-generation sequencing have significantly increased our understanding about the genetic landscape of CPAs.

Complement C3d enables cell-mediated immunity capable of distinguishing spontaneously transformed from nontransformed cells.

Immune surveillance depends in part on the recognition of peptide variants by T cell antigen receptors. Given that both normal B cells and malignant B cells accumulate mutations we chose a murine model of multiple myeloma to test conditions to induce cell-mediated immunity targeting malignant plasma cell (PC) clones but sparing of normal PCs. Revealing a previously unknown function for intracellular C3d, we found that C3d engaged T cell responses against malignant PC in the bone marrow of mice that had developed multiple myeloma spontaneously.

Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024, NCCN Clinical Practice Guidelines In Oncology.

Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing.

NCCN Guidelines® Insights: Survivorship, Version 2.2024.

The NCCN Guidelines for Survivorship include recommendations for screening, evaluation, and treatment of psychosocial and physical problems resulting from adult-onset cancer and its treatment. They also include recommendations to promote healthy behaviors and immunizations in survivors and provide a framework for care coordination. These NCCN Guidelines Insights summarize the panel's current recommendations regarding sexual health and fertility.

Psychological Considerations Associated with Lobular Breast Cancer.

Purpose Of Review: Through an overview of invasive lobular carcinoma (ILC), this review highlights the unique complexities the diagnosis and treatment of this disease represents, followed by psychological considerations for both patients and providers. Perspectives from members of the multidisciplinary treatment team are included.

Recent Findings: A cancer diagnosis can be difficult for patients and their families and can also have a significant impact on the treatment team.

Olaparib and Radiotherapy Induce Type I Interferon- and CD8+ T Cell-Dependent Sensitization to Immunotherapy in Pancreatic Cancer.

PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN)-mediated antitumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote antitumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy.

"Share the Fear": Communication Concerns of Parents With Cancer With Dependents and Coparents: A Qualitative Needs Assessment Study.

Background: The estimated 1.6 million adults in the United States with cancer who also have dependents face unique challenges given the profound impact of cancer on their families, such as increased psychological distress, decreased quality of life, and altered family functioning. Unfortunately, little is known about the mutual cancer-related communication concerns from the perspectives of the parents with cancer or the coparents.

Three-Year Overall Survival With Nivolumab Plus Relatlimab in Advanced Melanoma From RELATIVITY-047.

Nivolumab plus relatlimab demonstrated a statistically significant improvement in progression-free survival (PFS), along with a clinically meaningful, but not statistically significant improvement in overall survival (OS) and a numerically higher objective response rate (ORR) compared with nivolumab in the RELATIVITY-047 trial (ClinicalTrials.gov identifier: NCT03470922). We report updated descriptive efficacy and safety results from RELATIVITY-047 with a median follow-up of 33.

Household income and county income inequality are associated with financial hardship among cancer survivors in New Jersey.

Purpose: To examine how household income and county income inequality are linked to financial hardship among cancer survivors.

Methods: Cancer survivors (n = 864) identified through the New Jersey State Cancer Registry were surveyed from August 2018 to January 2022. Local area income inequality was reflected by the Gini index a measure of income inequality at the county level.

: regulatory roles, cancer-associated signaling pathway disruptions, and therapeutic potential.

Introduction: () is a crucial post-transcriptional regulator of many mRNA transcripts and noncoding-RNAs, influencing cell proliferation, cancer cell stemness, apoptosis, and immune responses. Its abnormal expression is well-characterized in numerous cancers, establishing it as a significant genomic vulnerability and biomarker in cancer research.

Areas Covered: Here, we summarize 's correlation with poor patient outcomes across numerous cancers and the mechanisms governing 's activity and processing.

Nivolumab plus relatlimab and nivolumab plus ipilimumab for patients with advanced renal cell carcinoma: results from the open-label, randomised, phase II FRACTION-RCC trial.

Background: The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) was designed to assess new immuno-oncology (IO) combinations in patients with advanced renal cell carcinoma (aRCC). We present results in IO-naive patients treated with nivolumab (NIVO) + relatlimab (RELA) or NIVO + ipilimumab (IPI) in track 1.

Methods: The open-label, randomised, phase II FRACTION-RCC trial enrolled patients with aRCC from 32 hospitals and cancer centres across six countries.

Oncology and Primary Care Involvement in Breast Cancer Survivorship Care More Than 5 Years After Initial Treatment.

Purpose: Very little is known about primary care involvement in the care of cancer survivors beyond the initial 5 years post-treatment when transitioning to primary care is guideline-recommended for many survivors.

Methods: The ICanCare study is a longitudinal survey of women diagnosed with breast cancer in 2014-2015 identified in the Georgia and Los Angeles SEER registries. Women were surveyed during initial treatment and again approximately 6 years later in survivorship (2021-2022; n = 1,412, 60% response rate).

Spatial Transcriptomic Profiling to Characterize the Nature of Peripheral- Versus Transition-zone Prostate Cancer.

Background And Objective: Prostate cancer (PC) in the transition zone (TZ) has better prognosis than peripheral-zone (PZ) PC despite higher prostate-specific antigen (PSA) in patients with TZ tumors. Our aim was to characterize molecular differences between TZ and PZ tumors and their clinical implications.

Methods: We performed spatial whole-transcriptome analyses of 50 regions of interest (ROIs) from three patients with PZ and/or TZ PC.

Discovery of ERD-12310A as an Exceptionally Potent and Orally Efficacious PROTAC Degrader of Estrogen Receptor α (ERα).

Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evaluation of ERD-12310A as an exceptionally potent and orally efficacious PROTAC degrader of ERα. ERD-12310A achieved a DC value of 47 pM and is 10 times more potent than ARV-471.

Reducing Information and Selection Bias in EHR-Linked Biobanks via Genetics-Informed Multiple Imputation and Sample Weighting.

Electronic health records (EHRs) are valuable for public health and clinical research but are prone to many sources of bias, including missing data and non-probability selection. Missing data in EHRs is complex due to potential non-recording, fragmentation, or clinically informative absences. This study explores whether polygenic risk score (PRS)-informed multiple imputation for missing traits, combined with sample weighting, can mitigate missing data and selection biases in estimating disease-exposure associations.