TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.

Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency.

Towards designing improved cancer immunotherapy targets with a peptide-MHC-I presentation model, HLApollo.

Based on the success of cancer immunotherapy, personalized cancer vaccines have emerged as a leading oncology treatment. Antigen presentation on MHC class I (MHC-I) is crucial for the adaptive immune response to cancer cells, necessitating highly predictive computational methods to model this phenomenon. Here, we introduce HLApollo, a transformer-based model for peptide-MHC-I (pMHC-I) presentation prediction, leveraging the language of peptides, MHC, and source proteins.

Cancer-specific innate and adaptive immune rewiring drives resistance to PD-1 blockade in classic Hodgkin lymphoma.

Hodgkin Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL), like many solid tumors, elicit ineffective immune responses. However, patients with cHL are highly responsive to PD-1 blockade, which largely depends on HRS cell-specific retention of MHC class II and implicates CD4 T cells and additional MHC class I-independent immune effectors. Here, we utilize single-cell RNA sequencing and spatial analysis to define shared circulating and microenvironmental features of the immune response to PD-1 blockade in cHL.

Substitution of liposomal bupivacaine for lidocaine reduces incidence of injection-emergent adverse events after intraarticular therapies for knee osteoarthritis: a prospective cohort study.

Abstract: Local anesthetics as a part of intraarticular therapies (IATs) are widely used for treating knee osteoarthritis (KOA). Whether substitution of liposomal bupivacaine (LB) for lidocaine is safe and effective in reducing incidence of injection-emergent adverse events after IATs remains unclear.

Methods: We recruited outpatients who had a clinical diagnosis of KOA and decided to receive IATs from November 2023 to April 2024.

Reproducibility of proton density fat fraction assessment of thigh muscle in a multi-site, multi-vendor cohort study at 10 years after anterior cruciate ligament reconstruction.

Background: Dixon-based magnetic resonance imaging (MRI) intramuscular proton density fat fraction (PDFF) is a potentially useful imaging biomarker of muscle quality. However, multi-vendor, multi-site reproducibility of intramuscular PDFF quantification, required for large clinical studies, can be strongly dependent on acquisition and processing. The purpose of this study was (I) to develop a 6-point Dixon MRI-based acquisition and processing technique for reproducible multi-vendor, multi-site quantification of thigh intramuscular PDFF; and (II) to evaluate the ability of the technique to detect differences in thigh muscle status between operated .

Sphingolipid Levels and Processing of the Retinyl Chromophore in the Retina of a Mouse Model of Niemann-Pick Disease.

Purpose: Mutations in the gene that encodes the enzyme acid sphingomyelinase (ASMase) are associated with Niemann-Pick disease, a lysosomal storage disorder. Mice that lack ASMase (ASMase-/-) exhibit age-related retinal degeneration and large increases in accumulation of lipofuscin in the retinal pigment epithelium (RPE). We examined which lipid species accumulate in the retina and the RPE of ASMase-/- mice and whether the retinal degeneration is associated with impaired photoreceptor metabolism and retinyl chromophore processing.

A metagenome-assembled genome inventory for children reveals early-life gut bacteriome and virome dynamics.

Existing microbiota databases are biased toward adult samples, hampering accurate profiling of the infant gut microbiome. Here, we generated a metagenome-assembled genome inventory for children (MAGIC) from a large collection of bulk and viral-like particle-enriched metagenomes from 0 to 7 years of age, encompassing 3,299 prokaryotic and 139,624 viral species-level genomes, 8.5% and 63.

Vaccination Against Androgen Receptor Splice Variants to Immunologically Target Prostate Cancer.

: Androgen receptor (AR) expression and signaling are critical for the progression of prostate cancer and have been the therapeutic focus of prostate cancer for over 50 years. While a variety of agents have been developed to target this axis, many of these fail due to the emergent expression of AR RNA splice variants, such as AR-V7, that can signal independently of ligand binding. Other therapies, such as vaccination against prostate-specific antigens, have achieved FDA approvals but have fallen short of being incorporated as standard-of-care therapies for advanced prostate cancer.

Functional annotation of the Hippo pathway somatic mutations in human cancers.

The Hippo pathway is commonly altered in cancer initiation and progression; however, exactly how this pathway becomes dysregulated to promote human cancer development remains unclear. Here we analyze the Hippo somatic mutations in the human cancer genome and functionally annotate their roles in targeting the Hippo pathway. We identify a total of 85 loss-of-function (LOF) missense mutations for Hippo pathway genes and elucidate their underlying mechanisms.

Imaging Transcriptomics of Brain Functional Alterations in MS and Neuromyelitis Optica Spectrum Disorder.

Background And Purpose: The underlying transcriptomic signatures driving brain functional alterations in MS and neuromyelitis optica spectrum disorder (NMOSD) are still unclear.

Materials And Methods: Regional fractional amplitude of low-frequency fluctuation (fALFF) values were obtained and compared among 209 patients with MS, 90 patients with antiaquaporin-4 antibody (AQP4)+ NMOSD, 49 with AQP4- NMOSD, and 228 healthy controls from a discovery cohort. We used partial least squares (PLS) regression to identify the gene transcriptomic signatures associated with disease-related fALFF alterations.

5'-tRNA halves generated by IRE1α are linked to the ER stress response.

Transfer RNA halves (tRHs) have various biological functions. However, the biogenesis of specific 5'-tRHs under certain conditions remains unknown. Here, we report that inositol-requiring enzyme 1α (IRE1α) cleaves the anticodon stem-loop region of tRNA to produce 5'-tRHs (5'-tRH-Gly) with highly selective target discrimination upon endoplasmic reticulum (ER) stress.

Hippo pathway in cancer cells induces NCAM1αSMA fibroblasts to modulate tumor microenvironment.

Cancer cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of cancer cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in cancer cells orchestrates the TME by influencing the composition of cancer-associated fibroblasts (CAFs).

Patient-Reported Racial and Ethnic Disparities in Patients With Ulcerative Colitis: Results From the National Health and Wellness Survey.

Background: Ulcerative colitis (UC) is an inflammatory condition characterized by chronic, disabling gastrointestinal symptoms that can have detrimental effects on psychological, social, and professional quality of life. Few studies have examined patient-reported outcomes (PROs) and economic outcomes among individuals with varying UC severity and across different racial/ethnic groups.

Methods: This cross-sectional study assessed sociodemographic data, PROs, and economic outcomes for participants from the National Health and Wellness Survey (2018, 2019, and 2020) with UC.

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution.

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue.

Visualizing Immune Checkpoint Inhibitors Derived Inflammation in Atherosclerosis.

Background: Immune checkpoint inhibitor (ICI) usage has resulted in immune-related adverse events in patients with cancer, such as accelerated atherosclerosis. Of immune cells involved in atherosclerosis, the role of CCR2+ (CC motif chemokine receptor 2-positive) proinflammatory macrophages is well documented. However, there is no noninvasive approach to determine the changes of these cells in vivo following ICI treatment and explore the underlying mechanisms of immune-related adverse events.