Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.

Background: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability.

The X-Age Project to construct a Chinese aging clock.

The global surge in the population of people 60 years and older, including that in China, challenges healthcare systems with rising age-related diseases. To address this demographic change, the Aging Biomarker Consortium (ABC) has launched the X-Age Project to develop a comprehensive aging evaluation system tailored to the Chinese population. Our goal is to identify robust biomarkers and construct composite aging clocks that capture biological age, defined as an individual's physiological and molecular state, across diverse Chinese cohorts.

NEK9-mediated Wnt signalling repressor TLE3 rewires Docetaxel resistance in cancer cells by inducing pyroptosis.

Background: Docetaxel is the most common chemotherapy regimen for several neoplasms, including advanced OSCC (Oral Squamous Cell Carcinoma). Unfortunately, chemoresistance leads to relapse and adverse disease outcomes.

Methods: We performed CRISPR-based kinome screening to identify potential players of Docetaxel resistance.

Intestinal taurine acts as a novel immunometabolic modulator of IBD by degrading redundant mitochondrial RNA.

Anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD) is hampered by issues of nonresponse and resistance, highlighting the urgent need for alternative or complementary treatments. Our study revealed significant upregulation of taurine in the intestinal tissues of IBD patients, which was inversely related to the severity of the disease. A key discovery was that TNF directly induced taurine synthesis in intestinal epithelial cells and increased the production of angiogenin, a nuclease that degrades mitochondrial RNA, which is known to amplify inflammatory responses.

The molecular blueprint of targeted radionuclide therapy.

Targeted radionuclide therapy (TRT) is a cutting-edge treatment approach in oncology that combines the molecular precision of targeted agents with the effect of radiotherapy to selectively deliver cytotoxic radiation to cancer cells. Research efforts from the past few decades have led to a diverse molecular landscape of TRT and have provided lessons for further rational development of targeted radiopharmaceuticals and expansion of the clinical applications of this treatment modality. In this Review, we discuss TRT in the context of therapeutic approaches currently available in oncology, describe the broad range of established and emerging targets for TRT including innovative approaches to exploit vulnerabilities presented by the tumour microenvironment, and address the challenges for clinical translation and molecular optimization.

CD160 dictates anti-PD-1 immunotherapy resistance by regulating CD8 T cell exhaustion in colorectal cancer.

The colon exhibits higher propensity for tumour development than ileum. However, the role of immune microenvironment differences in driving this disparity remains unclear. Here, by comparing paired ileum and colon samples from patients with colorectal cancer (CRC) and healthy donors, we identified ileum-enriched CD160CD8 T cells with previously unrecognized characteristics, including resistance to terminal exhaustion and strong clonal expansion.

Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer.

Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer.

Computational pathology annotation enhances the resolution and interpretation of breast cancer spatial transcriptomics data.

Breast cancer is a highly heterogeneous disease with diverse outcomes, and intra-tumoral heterogeneity plays a significant role in both diagnosis and treatment. Despite its importance, the spatial distribution of intra-tumoral heterogeneity is not fully elucidated. Spatial transcriptomics has emerged as a promising tool to study the molecular mechanisms behind many diseases.

Characterization of the extrinsic and intrinsic signatures and therapeutic vulnerability of small cell lung cancers.

Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor strongly associated with exposure to tobacco carcinogens, is characterized by early dissemination and dismal prognosis with a five-year overall survival of less than 7%. High-frequency gain-of-function mutations in oncogenes are rarely reported, and intratumor heterogeneity (ITH) remains to be determined in SCLC. Here, via multiomics analyses of 314 SCLCs, we found that the ASCL1/MKI67 and ASCL1/CRIP2 clusters accounted for 74.

Silencing CD151 Gene in Donor Triple-Negative Breast Cancer Cells Attenuates Exosome-Driven Functions of Recipient Cells.

CD151 is a tetraspanin, abnormally expressed in triple negative breast cancer (TNBC). It is a prominent component of exosomes, facilitating the secretion of proteins that promote metastasis and drug resistance. We have previously demonstrated that silencing the CD151 gene reduces metastasis in TNBC.

Novel role of MKRN2 in regulating tumor growth through host microenvironment and macrophage M1 to M2 switch.

The tumor microenvironment (TME) plays a pivotal role in cancer progression, though the molecular regulators governing its immunosuppressive properties remain incompletely characterized. In this study, we identify Makorin-2 (MKRN2) as a novel modulator of TME remodeling through integrated analyses of genetically engineered mouse models and human clinical data. Utilizing MKRN2 knockout mice, we observed significantly accelerated tumor growth compared to wild-type control, which was associated with profound alterations in immune cell composition, especially M2 macrophages.

Immunomodulatory microbubbles targeting integrin αvβ3 in combination with immunotherapy for the theranostic of anaplastic thyroid cancer in mice.

Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid malignancy and currently lacks effective treatment options. While anti-PD1 therapy has shown remarkable clinical results in some cases, only a subset of ATC patients responds to it. Eganelisib (IPI549), a highly selective PI3Kγ inhibitor, can alleviate the tumor immunosuppressive state by reducing the proportion of M2-like tumor associated macrophages, partially overcoming patient resistance to anti-PD1 therapy and synergizing with its efficacy.

Single-cell analysis of Barrett's esophagus and carcinoma reveals cell types conferring risk via genetic predisposition.

Inherited genetic variants contribute to Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), but it is unknown which cell types are involved in this process. We performed single-cell RNA sequencing of BE, EAC, and paired normal tissues and integrated genome-wide association data to determine cell-type-specific genetic risk and cellular processes that contribute to BE and EAC. The analysis reveals that EAC development is driven to a greater extent by local cellular processes than BE development and suggests that one cell type of BE origin (intestinal metaplasia cells) and cellular processes that control the differentiation of columnar cells are of particular relevance for EAC development.

Availability of benign missense variant "truthsets" for validation of functional assays: Current status and a systematic approach.

Multiplex assays of variant effect (MAVEs) provide promising new sources of functional evidence, potentially empowering improved classification of germline genomic variants, particularly rare missense variants, which are commonly assigned as variants of uncertain significance (VUSs). However, paradoxically, quantification of clinically applicable evidence strengths for MAVEs requires construction of "truthsets" comprising missense variants already robustly classified as pathogenic and benign. In this study, we demonstrate how benign truthset size is the primary driver of applicable functional evidence toward pathogenicity (PS3).

Pan-carcinoma sialyl-Tn-targeting expands CAR therapy to solid tumors.

Accurate identification of tumor-specific markers is vital for developing chimeric antigen receptor (CAR)-based therapies. While cell surface antigens are seldom cancer-restricted, their post-translational modifications (PTMs), particularly aberrant carbohydrate structures, offer attractive alternatives. Among these, the sialyl-Tn (STn) antigen stands out for its prevalent presence in various epithelial tumors.

Modulation of fibronectin extracellular matrix enhances anti-tumor efficacy of immune checkpoint blockade.

The success of immune checkpoint inhibitors is limited by multiple factors, including poor T cell infiltration and function within tumors, partly due to a dense extracellular matrix (ECM). Here, we investigate modulating the ECM by targeting integrin α5β1, a major fibronectin-binding and organizing integrin, to improve immunotherapy outcomes. Use of a function-blocking murinized α5β1 antibody reduces fibronectin fibril formation, enhances CD8 T cell transendothelial migration, increases vascular permeability, and decreases vessel-associated collagen.

Rapid and sensitive acute leukemia classification and diagnosis platform using deep learning-assisted SERS detection.

Rapid identification and accurate diagnosis are critical for individuals with acute leukemia (AL). Here, we propose a combined deep learning and surface-enhanced Raman scattering (DL-SERS) classification strategy to achieve rapid and sensitive identification of AL with various subtypes and genetic abnormalities. More than 390 of cerebrospinal fluid (CSF) samples are collected as targets, encompassing healthy control, AL patients, and individuals with other diseases.

Defining breast epithelial cell types in the single-cell era.

Single-cell studies on breast tissue have contributed to a change in our understanding of breast epithelial diversity that has, in turn, precipitated a lack of consensus on breast cell types. The confusion surrounding this issue highlights a possible challenge for advancing breast atlas efforts. In this perspective, we present our consensus on the identities, properties, and naming conventions for breast epithelial cell types and propose goals for future atlas endeavors.

Discovery of 2-tetrahydroisoquinoline substituted quinazoline derivatives as lysine methyltransferase G9a inhibitors with in vivo antitumor efficacy.

Overexpression of protein lysine methyltransferase G9a, which catalyzes mono- and di-methylation of histone H3K9 and non-histone proteins, is closely associated with poor prognosis and metastasis of various cancers. Here, we designed and synthesized a series of novel G9a inhibitors bearing 2-tetrahydroisoquinoline substituted quinazoline scaffold. Among them, compound 31 with 2-dioxole fused tetrahydroisoquinoline exhibited the most potent inhibitory effects against G9a with an IC value of 0.

Monitoring ferroptosis in vivo: Iron-driven volatile oxidized lipids as breath biomarkers.

Ferroptosis, an iron-dependent cell death mechanism characterized by excessive lipid peroxidation, has been implicated in numerous human diseases and organ pathologies. However, current detection methods necessitate invasive tissue sampling to assess lipid peroxidation, making noninvasive detection of ferroptosis in human subjects extremely challenging. In this study, we employed oxidative volatolomics to comprehensively characterize the volatile oxidized lipids (VOLs) produced during ferroptosis.

Mechanisms of C5ORF13 in promoting epithelial-mesenchymal transition in hepatocellular carcinoma via eIF6 and the intervention of valproic acid.

Objective: To investigate the mechanism by which C5ORF13 promotes epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) through interaction with eukaryotic translation initiation factor 6 (eIF6) and its clinical significance, and to identify the potential use of valproic acid (VPA) as an eIF6 inhibitor in HCC.

Methods: The expression of C5ORF13 in HCC and its prognostic impact were analyzed using GEPIA, UALCAN, and The HUMAN PROTEIN ATLAS databases. Lentiviral transfection technology was used to knock down or overexpress C5ORF13 and eIF6.

Unraveling complex karyotype clonal architecture: co-existing double TP53 mutations alongside DNMT3A, TET2, and NF1 mutations - a case study.

Complex chromosomal changes in Acute Myeloid Leukemia (AML) are highly heterogeneous, with disease progression shaped by both the number and nature of abnormalities. Rarely do, multiple unrelated clones with independent chromosomal changes coexist at diagnosis. Present study showcases a comprehensive characterization of two cytogenetically distinct complex clones in AML, driven by non-cyclic and chromoplexy mechanisms, highlighting their co-existence with key molecular alterations (TP53, NF1, DNMT3A, TET2) along with their potential contribution to clonal evolution.

Identification of poor prognostic factors using circulating extracellular vesicles in durvalumab consolidation therapy for locally advanced non-small cell lung cancer.

Background: The risk factors associated with treatment resistance to consolidation durvalumab following chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (NSCLC) have not been well established.

Methods: Extracellular vesicles (EVs) were isolated from the pretreatment serum of 73 patients treated with consolidation durvalumab. Isolation was performed using CD9/CD63 antibodies, and EV proteins were identified using liquid chromatography-tandem mass spectrometry (LC-MS).