Xiaoning Zhang

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.

INTRODUCTION: Frailty has become a worldwide health burden that has a large influence on public health and clinical practice. The incidence of frailty is anticipated to increase as the ageing population increases. Myocardial injury after noncardiac surgery (MINS) is associated with short-term and long-term mortality. However, the incidence of MINS in frail geriatric patients is unknown. METHODS AND ANALYSIS: This prospective, multicentre, real-world observational cohort study will be conducted at 18 designated centres in China from January 2023 to December 2024, with an anticipated sample size of 856 patients aged 65 years and older who are scheduled to undergo noncardiac surgery. The primary outcome will be the incidence of MINS. MINS is defined as a fourth-generation plasma cardiac troponin T (cTnT) concentration ≥ 0.03 ng/mL exhibited at least once within 30 days after surgery, with or without symptoms of myocardial ischaemia. All data will be collected via electronic data acquisition. DISCUSSION: This study will explore the incidence of MINS in frail patients. The characteristics, predictive factors and 30-day outcomes of MINS in frail patients will be further investigated to lay the foundation for identifying clinical interventions. CLINICAL TRIAL REGISTRATION: https://beta. CLINICALTRIALS: gov/study/NCT05635877 , NCT05635877.

Both primary and metastatic brain malignancies are fatal and highly infiltrated with tumor-associated macrophages (TAMs). Enhancing the phagocytosis of neoplastic cells by TAMs is pivotal for slowing tumor growth. Great endeavors have been made to develop tyrosine kinase inhibitors (TKIs) for brain malignancies, yet whether tumor-targeting TKIs affect the phagocytic capacity of TAMs remains largely unknown. In this preclinical study, we report that repurposing ibrutinib, a blood-brain barrier-penetrable TKI, effectively suppresses the growth of several primary and metastatic brain tumors highly expressing Bruton's tyrosine kinase (BTK) or bone marrow X-linked nonreceptor tyrosine kinase (BMX) but concurrently dampens the TAM phagocytic function. Mechanistically, BTK, which is activated in TAMs, interacts with and phosphorylates Wiskott-Aldrich syndrome protein (WASp) to organize the actin cytoskeleton, which is imperative for phagocytosis. Ibrutinib treatment disrupts BTK-mediated WASp activation, thereby compromising TAM phagocytic efficacy. Pharmacological activation of WASp by its selective small-molecular activator EG-011 restores the ibrutinib-impaired TAM engulfment of tumor cells and effectively improves ibrutinib efficacy in mice bearing glioblastomas, primary central nervous system lymphomas, and lung carcinoma brain metastases. Furthermore, elevated expression of phosphorylated BTK or phosphorylated WASp in TAMs correlates with an increased phagocytic TAM subset identified by single-cell RNA sequencing and correlates with prolonged patient survival in a cohort with glioblastoma. Our preclinical study highlights the necessity of evaluating the on-target, off-tumor attack of TAMs during TKI administration and provides a proof of concept for reinvigorating the TAM phagocytic function to achieve additional clinical benefit.

Abstract Introduction: Frailty has become a worldwide health burden that has a large influence on public health and clinical practice. The incidence of frailty is anticipated to increase as the aging population increases. Myocardial injury after noncardiac surgery (MINS) is associated with short-term and long-term mortality. The incidence of MINS in geriatric frail patients is unknown. Methods and analysis: This prospective, multicentre, real-world observational cohort study will be conducted at 18 designated centres in China from January 2023 to December 2024, with an anticipated sample size of 856 patients aged 65 and older who are scheduled to undergo noncardiac surgery. The primary outcome measure will be the incidence of MINS. MINS is defined as a fourth-generation plasma cardiac troponin T (cTnT) concentration ≥ 0.03 ng/mL at least once within 30 days after surgery, with or without symptoms of myocardial ischaemia. All data will be collected using research electronic data acquisition. Discussion This study will explore the incidence of MINS in frail patients. The characteristics, predictive factors and 30-day outcomes of MINS in frail patients will be further investigated to lay the foundation for finding clinical interventions. Clinical trial registration: https://beta.clinicaltrials.gov/study/NCT05635877 , NCT05635877

Background: Chronic obstructive pulmonary disease (COPD), a prevalent chronic respiratory disorder with high morbidity and mortality, is closely associated with mitochondrial dysfunction and immune dysregulation; however, the underlying mechanisms remain unclear. Aims: The aim of this study is to identify mitochondrial hub genes and evaluate their diagnostic potential in COPD. Methods: This study combined bioinformatics and experimental methods to investigate mitochondria-related differentially expressed genes (MitoDEGs) in COPD pathogenesis. Two GEO datasets (GSE38974/GSE8545) were analyzed to identify MitoDEGs, which were functionally characterized and refined via machine learning (LASSO/SVM-RFE). Key genes were further validated using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot in bronchial epithelial cells and COPD mouse model lung tissues. Immune infiltration analysis revealed connections between MitoDEGs and immune dysregulation in COPD that were experimentally confirmed using immunohistochemistry (IHC) and immunofluorescence (IF). Results: as core hub genes. Immune profiling revealed significantly increased M0 macrophage infiltration and reduced activated NK cells in COPD. BAX and DLST expression was positively correlated with M0 macrophages but negatively with activated NK cells, a finding corroborated by IHC and IF assays. Conclusions: as potential mitochondrial dysfunction biomarkers in COPD, linking their roles to immune cell infiltration. This study provides novel insights into cigarette smoke-induced COPD pathogenesis and underscores the diagnostic utility of targeting mitochondrial-immune interactions.