A hollow-tube-like hydrospongel for multimodal therapy of advanced colorectal cancer.

Preserving anal function in advanced-stage colorectal cancer (CRC) treatment remains a significant challenge. Here we introduce a hollow-tube-like hydrospongel (HTHSG) as an advanced neoadjuvant therapy. Constructed from cellulose nanofibers crosslinked with FeO@PDA (polydopamine) nanoparticles, the HTHSG combines quick swelling (~10 seconds) with high fracture strength (>250 kPa) for enhanced mechanical stability.

A First-in-Human Study of Givastomig, a CLDN18.2 and 4-1BB Bispecific Antibody, as Monotherapy in Patients with CLDN18.2-Positive Advanced or Metastatic Solid Tumors.

Purpose: Givastomig is a bispecific antibody that targets CLDN18.2 and conditionally activates local 4-1BB-expressing T cells. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of givastomig in advanced solid tumors.

LIMK1 as a Novel Kinase of β-Catenin Promotes Esophageal Cancer Metastasis by Cooperating With CDK5.

Metastasis is a major cause of cancer deaths, but the underlying molecular mechanisms remain largely unknown. Esophageal squamous cell carcinoma (ESCC) is a highly aggressive cancer with poor survival, yet the key kinases driving ESCC metastasis and their biological function have not been fully discovered. Here, a kinase-substrate map of metastatic ESCC is presented for the first time by conducting a phosphoproteomics analysis of 60 clinical specimens.

Comprehensive analysis of multi-omics single-cell data using the single-cell analyst.

The rapid advancement of multi-omics single-cell technologies has significantly enhanced our ability to investigate complex biological systems at unprecedented resolution. However, many existing analysis tools are complex, requiring substantial coding expertize, which can be a barrier for computationally less competent researchers. To address this challenge, we present single-cell analyst, a user-friendly, web-based platform to facilitate comprehensive multi-omics analysis.

Cleavage of CAD by caspase-3 determines the cancer cell fate during chemotherapy.

Metabolic heterogeneity resulting from the intra-tumoral heterogeneity mediates massive adverse outcomes of tumor therapy, including chemotherapeutic resistance, but the mechanisms inside remain largely unknown. Here, we find that the de novo pyrimidine synthesis pathway determines the chemosensitivity. Chemotherapeutic drugs promote the degradation of cytosolic Carbamoyl-phosphate synthetase II, Aspartate transcarbamylase, and Dihydroorotase (CAD), an enzyme that is rate-limiting for pyrimidine synthesis, leading to apoptosis.

Examining more than 35 lymph nodes improves the staging and survival in resectable advanced gastric cancer: a multi-institutional study in China.

Purpose: More examined lymph nodes (ELN) are correlated with better staging and a better prognosis of gastric cancer, although the optimal number of ELNs remains under dispute. This study explored the optimal number of ELNs for resectable advanced gastric cancer (AGC).

Methods: Clinicopathological characteristics and survival data of 4739 AGC patients were collected from 3 GC centers in China.

polysaccharides alleviate neuronal apoptosis induced by endoplasmic reticulum stress-activated PERK-ATF4-CHOP signaling in APP/PS1 mice.

Background (CPPs) shows neuroprotective potential in Alzheimer's disease (AD) and may reduce neuronal apoptosis by modulating endoplasmic reticulum stress (ERS).ObjectiveTo investigate the protective mechanisms of CPPs against neuronal apoptosis in APP/PS1 mice, focusing on the ERS response and the PERK-ATF4-CHOP signaling pathway.MethodsAPP/PS1 mice were orally administered CPPs at different doses.

The deubiquitination-PARylation positive feedback loop of the USP10-PARP1 axis promotes DNA damage repair and affects therapeutic efficacy of PARP1 inhibitor.

PARP1 initiates DNA repair pathways including single-strand break repair (SSBR) by recruiting multiple DNA repair factors via poly ADP-ribosylation (PARylation) of target proteins. However, how PARP1 is stabilized and activated to promote DNA damage repair remains unclear. Here we report that DNA damage generates a ROS signal, which triggers USP10 to interact with and stabilize PARP1 by deubiquitinating the K418 site in an ATM-dependent manner.

T-betCD8 T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers.

More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised learning to stratify potential ICI responders in MSS GCs, achieving high accuracy, quantified by an area under the curve of 0.

Atezolizumab and Trastuzumab Plus Chemotherapy for ERBB2-Positive Locally Advanced Resectable Gastric Cancer: A Randomized Clinical Trial.

Importance: Effective treatment of locally advanced gastric cancer (GC) or gastroesophageal junction (GEJ) cancer remains a challenge.

Objective: To compare the efficacy and safety of atezolizumab plus trastuzumab plus capecitabine and oxaliplatin chemotherapy (XELOX) vs trastuzumab plus XELOX in Chinese patients with locally advanced human epidermal growth factor receptor 2 (ERBB2; formerly HER2)-positive GC or adenocarcinoma of the GEJ.

Design, Setting, And Participants: This was an open-label phase 2 randomized clinical trial conducted at 8 study sites in China.

KAP1 promotes gastric adenocarcinoma progression by activating Hippo/YAP1 signaling via binding to HNRNPAB.

Gastric adenocarcinoma (GAC) remains a significant global health challenge, with over a million new cases annually. Peritoneal carcinomatosis (PC), detected in ∼20 % of cases at diagnosis and ∼45 % later, is uniformly fatal, with limited treatment options. This study investigated the role of KAP1 in GAC progression, focusing on its interaction with YAP1 and cancer stemness traits.

A novel optimized orthotopic mouse model for brain metastasis with sustained cerebral blood circulation and capability of multiple delivery.

Brain metastasis is thought to be related to the high mortality and poor prognosis of lung cancer. Despite significant advances in the treatment of primary lung cancer, the unique microenvironment of the brain renders current therapeutic strategies largely ineffective against brain metastasis. The lack of effective drugs for brain metastasis treatment is primarily due to the incomplete understanding of the mechanisms underlying its initiation and progression.

MXene-based nanosheet for enhanced glioma therapy via photonic hyperthermia to boost the abscopal effect of radioimmunotherapy.

Radiotherapy (RT) effectiveness is limited by low DNA damage in tumor cells, surrounding tissue harm, and tumor radioresistance with active DNA repair. Herein, we have engineered a two-dimensional nanomaterial consisting of MXene nanosheets at its core, coated with gold nanorods and a cisplatin shell, and further modified with polyvinyl alcohol, referred to as APMP. The APMP exploits its distinctive electronic properties and photothermal effects to augment radiosensitivity and impede DNA damage repair mechanisms.

CDK9 degradation Inhibits Gastroesophageal Cancer growth and Overcomes Radiation Resistance by Increasing Chromatin Accessibility and Downregulating YAP1/TEAD signaling.

Background: Gastroesophageal cancer (GEAC) remains a major health burden and urgently needs novel therapeutic targets. The inhibition of CDK9's activity holds the potential to be a highly effective anti-cancer therapeutic. However, the functional role of CDK9, and its potential targeting in GEAC, remain largely unknown.

Deciphering immune predictors of immunotherapy response: A multiomics approach at the pan-cancer level.

Immune checkpoint blockade (ICB) therapy has transformed cancer treatment, yet many patients fail to respond. Employing single-cell multiomics, we unveil T cell dynamics influencing ICB response across 480 pan-cancer and 27 normal tissue samples. We identify four immunotherapy response-associated T cells (IRATs) linked to responsiveness or resistance and analyze their pseudotemporal patterns, regulatory mechanisms, and T cell receptor clonal expansion profiles specific to each response.

Pathogen-derived glyoxylate inhibits Tet2 DNA dioxygenase to facilitate bacterial persister formation.

Pathogenic bacterial persistence enables survival during antibiotic treatment, leading to treatment failure and recurrent infections, yet its underlying mechanisms remain unclear. Here, we reveal that glyoxylate, a metabolite originally evolved for alternative carbon utilization, functions as a signaling molecule to reprogram the host transcriptome and promote persister formation. Glyoxylate inhibits the DNA dioxygenase TET2, suppressing pro-inflammatory gene expression and attenuating host immune defense.

Pcf11/Spt5 condensates stall RNA polymerase II to facilitate termination and piRNA-guided heterochromatin formation.

The PIWI-interacting RNA (piRNA) pathway plays a crucial role in protecting animal germ cells by repressing transposons. However, the mechanism of piRNA-guided heterochromatin formation and its relationship to transcriptional termination remains elusive. Through RNA interference screening, we discovered Pcf11 and PNUTS as essential for piRNA-guided silencing in Drosophila germ line.

An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling.

Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progression, particularly through gene expression and proteostasis control, remain unclear. By analyzing genomic data from a gastric cancer (GC) case-control study (2,117 individuals), focusing on the ubiquitin-specific protease (USP) family, we identify the SNP rs72856331 (G>A) in the promoter region of the proto-oncogene USP47 as a putative susceptibility allele for GC.

Catalytic-independent functions of the Integrator-PP2A complex (INTAC) confer sensitivity to BET inhibition.

Chromatin and transcription regulators are critical to defining cell identity through shaping epigenetic and transcriptional landscapes, with their misregulation being closely linked to oncogenesis. Pharmacologically targeting these regulators, particularly the transcription-activating BET proteins, has emerged as a promising approach in cancer therapy, yet intrinsic or acquired resistance frequently occurs, with poorly understood mechanisms. Here, using genome-wide CRISPR screens, we find that BET inhibitor efficacy in mediating transcriptional silencing and growth inhibition depends on the auxiliary/arm/tail module of the Integrator-PP2A complex (INTAC), a global regulator of RNA polymerase II pause-release dynamics.

Claudin 18.2-targeting antibody-drug conjugate CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer (KYM901): a multicentre, open-label, single-arm, phase 1 trial.

Background: CMG901 is a novel first-in-class antibody-drug conjugate with a humanised anticlaudin 18.2 antibody linked to microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the antitumour activity and safety of CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer and other solid tumours.

Interpretable multi-modal artificial intelligence model for predicting gastric cancer response to neoadjuvant chemotherapy.

Neoadjuvant chemotherapy assessment is imperative for prognostication and clinical management of locally advanced gastric cancer. We propose an incremental supervised contrastive learning model (iSCLM), an interpretable artificial intelligence framework integrating pretreatment CT scans and H&E-stained biopsy images, for improved decision-making regarding neoadjuvant chemotherapy. We have constructed and tested iSCLM using retrospective data from 2,387 patients across 10 medical centers and evaluated its discriminative ability in a prospective cohort (132 patients; ChiCTR2300068917).

The phosphatase PP1 sustains global transcription by promoting RNA polymerase II pause release.

RNA polymerase II progression from initiation to elongation is driven in part by a cascade of protein kinases acting on the core transcription machinery. Conversely, the corresponding phosphatases, notably PP2A and PP1-the most abundant serine-threonine phosphatases in cells-are thought to mainly impede polymerase progression, respectively restraining pause release at promoters and elongation at terminators. Here, we reveal an unexpected role of PP1, within the phosphatase 1 nuclear targeting subunit (PNUTS)-PP1 complex, in sustaining global transcriptional activation in human cells.

Integrated analyses of multi-omic data derived from paired primary lung cancer and brain metastasis reveal the metabolic vulnerability as a novel therapeutic target.

Background: Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs.

Methods: Here, we performed integrated analyses of genomic, transcriptomic, proteomic, metabolomic, and single-cell RNA sequencing data which were derived from a total number of 154 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels.