Coronary atherosclerosis underlies life-threatening conditions such as myocardial infarction and stroke, yet its cellular dynamics remain incompletely understood. Here, through single-cell RNA sequencing of 27,941 cells from 56 human coronary segments, we constructed a disease-stage-resolved cellular atlas, revealing pathological remodelling of endothelial cells (ECs) into a progenitor-like state (EC5SLCO4A1+) with low expression of canonical EC dysfunction signatures. EC5SLCO4A1+ abundance increased with atherosclerotic stage, and its emergence is driven by PRDM15 through direct transcriptional activation. Analysis of the EC5SLCO4A1+ interaction network revealed extensive crosstalk with immune cell types, the interaction between which contributed to atherosclerotic progression. Endothelial overexpression of Prdm15 in vivo exacerbated atherosclerosis, while its suppression ameliorated the disease phenotype, with diminished EC5SLCO4A1+-like cells and immune infiltration. Our findings underscore the central role of EC subtype remodelling in the progression of human coronary atherosclerosis and reveal tractable targets for therapeutic intervention.

Cardiovascular diseases (CVDs) remain the leading cause of global mortality, perpetuated by pathological remodeling refractory to current pharmacotherapy. Recent single-cell atlasing has identified fibroblast activation protein (FAP) as a convergent marker of pathogenic stromal cells across disparate cardiovascular pathologies. In cardiac fibrosis, FAP demarcates myofibroblasts driving extracellular matrix (ECM) deposition, whereas in atherosclerosis, it marks modulated smooth muscle cells (modSMCs) mediating plaque instability. This review synthesizes emerging evidence to establish a precision cardio-immunology framework. We first characterize FAP not merely as a serine protease, but as a multifaceted integrative node aligned with TGF-β and PI3K/AKT pathways. We then systematically compare the expanding repertoire of FAP-targeted modalities, ranging from cytotoxic CAR T cells and transient bispecific engagers (BiTEs) to tolerogenic dendritic cells, and propose that therapeutic persistence must align with disease kinetics. Specifically, we suggest the use of durable CAR T cells in chronic fibrosis and transient BiTEs for acute plaque stabilization.​ Finally, we address translational challenges, including FAP’s context-dependent effects, and discuss logic-gated switches to improve the therapeutic index. This review offers a kinetic-matching roadmap for cardiovascular remodeling beyond conventional symptomatic relief.

As a hallmark of chronic kidney disease (CKD), arterial stiffening is related to increased vascular inflammation and cardiovascular morbidity, whereas the underlying mechanism is unclear. The study demonstrates that increased arterial stiffness precedes the onset of vascular inflammation, and matrix stiffness stimulates the transdifferentiation of vascular smooth muscle cells (VSMCs) to an inflammatory phenotype via activating Runx2-NLRP3 signaling, which provides novel insights into CKD-related cardiovascular disorder treatment.

Lactate produced during ischemia-reperfusion injury is known to promote lactylation of proteins, which play controversial roles. By analyzing the lactylomes and proteomes of mouse myocardium during ischemia-reperfusion injury using mass spectrometry, we show that both Serpina3k protein expression and its lactylation at lysine 351 are increased upon reperfusion. Both Serpina3k and its human homolog, SERPINA3, are abundantly expressed in cardiac fibroblasts, but not in cardiomyocytes. Biochemically, lactylation of Serpina3k enhances protein stability. Using Serpina3k knockout mice and mice overexpressing its lactylation-deficient mutant, we find that Serpina3k protects from cardiac injury in a lysine 351 lactylation-dependent manner. Mechanistically, ischemia-reperfusion-stimulated fibroblasts secrete Serpina3k/SERPINA3, and protect cardiomyocytes from reperfusion-induced apoptosis in a paracrine fashion, partially through the activation of cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways. Our results demonstrate the pivotal role of protein lactylation in cardiac ischemia-reperfusion injury, which may hold therapeutic value. Lactylation of proteins has been shown to carry diverse roles during cardiac reperfusion injury. Here, the authors show that lactylated Serpina3k/SERPINA3 secreted from fibroblasts during reperfusion protects cardiomyocytes from apoptosis in a paracrine fashion.

Thoracic aortic aneurysms (TAAs) develop asymptomatically and are characterized by dilatation of the aorta. This is considered a life-threating vascular disease due to the risk of aortic rupture and without effective treatments. The current understanding of the pathogenesis of TAA is still limited, especially for sporadic TAAs without known genetic mutation. Sirtuin 6 (SIRT6) expression was significantly decreased in the tunica media of sporadic human TAA tissues. Genetic knockout of Sirt6 in mouse vascular smooth muscle cells accelerated TAA formation and rupture, reduced survival, and increased vascular inflammation and senescence after angiotensin II infusion. Transcriptome analysis identified interleukin (IL)-1β as a pivotal target of SIRT6, and increased IL-1β levels correlated with vascular inflammation and senescence in human and mouse TAA samples. Chromatin immunoprecipitation revealed that SIRT6 bound to the Il1b promoter to repress expression partly by reducing the H3K9 and H3K56 acetylation. Genetic knockout of Il1b or pharmacological inhibition of IL-1β signaling with the receptor antagonist anakinra rescued Sirt6 deficiency mediated aggravation of vascular inflammation, senescence, TAA formation and survival in mice. The findings reveal that SIRT6 protects against TAA by epigenetically inhibiting vascular inflammation and senescence, providing insight into potential epigenetic strategies for TAA treatment.

Metastatic spread of lung adenocarcinoma to the stomach is rare and most gastric metastases are discovered at the advanced stage due to certain symptoms. The present study reported two cases of asymptomatic gastric metastases from lung adenocarcinoma presenting as diminutive nodules or erosion endoscopically. The manifestations were also visualized under magnifying endoscopy with blue laser imaging (BLI-ME), the two cases share certain common characteristics under BLI-ME, such as an obviously widened intervening part and extended subepithelial capillary network, which indicated that lesions developed beneath the superficial epithelium. Target biopsy and further immunohistochemical staining confirmed that the gastric lesions were metastatic from primary lung cancer. None of the two patients were candidates for surgery due to multiple distant metastases, but the gastric metastases regressed to scars after systemic anticancer therapy. These two cases were presented in order to improve the current understanding of the endoscopic manifestations of early gastric metastases from lung cancer, and the outcomes may demonstrate that systemic treatment is effective for eliminating early gastric metastatic lesions.

Aims Whether changes in endothelial tight junctions (TJs) lead to the formation of thoracic aortic aneurysm and dissection (TAAD) and serve as an early indicator and therapeutic target remains elusive. Methods and results Single-cell RNA sequencing analysis showed aberrant endothelial TJ expressions in the thoracic aortas of patients with TAAD. In a beta-aminopropionitrile (BAPN)-induced TAAD mouse model, endothelial TJ function was disrupted in the thoracic aortas at an early stage (5 and 10 days) as observed by a vascular permeability assay, while the intercellular distribution of crucial TJ components was significantly decreased by en face staining. For the non-invasive detection of endothelial TJ function, two dextrans of molecular weights 4 and 70 kDa were conjugated with the magnetic resonance imaging (MRI) contrast agent Gd-DOTA to synthesize FITC-dextran-DOTA-Gd and rhodamine B-dextran-DOTA-Gd. MRI images showed that both probes accumulated in the thoracic aortas of the BAPN-fed mice. Particularly, the mice with increased accumulated signals from 5 to 10 days developed TAAD at 14 days, whereas the mice with similar signals between the two time points did not. Furthermore, the protease-activated receptor 2 inhibitor AT-1001, which seals TJs, alleviated the BAPN-induced impairment of endothelial TJ function and expression and subsequently reduced TAAD incidence. Notably, endothelial-targeted ZO-1 conditional knockout increased TAAD incidence. Mechanistically, vascular inflammation and edema were observed in the thoracic aortas of the BAPN-fed mice, whereas these phenomena were attenuated by AT-1001. Conclusion The disruption of endothelial TJ function is an early event prior to TAAD formation, herein serving as a potential indicator and a promising target for TAAD.

Pathological subtypes are prognostic indicators independent of TNM stage. Patients with high-grade patterns (solid, micropapillary, or complex gland) have poorer prognosis. Previous studies have found that adjuvant chemotherapy can bring benefit to micropapillary predominant patients even with stage IA. Third-generation Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) have recently shown striking benefit for postoperative adjuvant therapy in patients with EGFR-mutated non-small cell lung cancer (NSCLC).

Background RAP1 interacting factor 1 ( Rif1 ) is highly expressed in mice embryos and mouse embryonic stem cells (mESCs). It plays critical roles in telomere length homeostasis, DNA damage, DNA replication timing and ERV silencing. However, whether Rif1 regulates early differentiation of mESC is still unclear. Methods In this study, we generated a Rif1 conditional knockout mouse embryonic stem (ES) cell line based on Cre-loxP system. Western blot, flow cytometry, quantitative real-time polymerase chain reaction (qRT-PCR), RNA high-throughput sequencing (RNA-Seq), chromatin immunoprecipitation followed high-throughput sequencing (ChIP-Seq), chromatin immunoprecipitation quantitative PCR (ChIP-qPCR), immunofluorescence, and immunoprecipitation were employed for phenotype and molecular mechanism assessment. Results Rif1 plays important roles in self-renewal and pluripotency of mESCs and loss of Rif1 promotes mESC differentiation toward the mesendodermal germ layers. We further show that Rif1 interacts with histone H3K27 methyltransferase EZH2, a subunit of PRC2, and regulates the expression of developmental genes by directly binding to their promoters. Rif1 deficiency reduces the occupancy of EZH2 and H3K27me3 on mesendodermal gene promoters and activates ERK1/2 activities. Conclusion Rif1 is a key factor in regulating the pluripotency, self-renewal, and lineage specification of mESCs. Our research provides new insights into the key roles of Rif1 in connecting epigenetic regulations and signaling pathways for cell fate determination and lineage specification of mESCs. Graphical abstract

Tissue slicing-assisted digestion (TSAD) of adult cardiomyocytes has shown significant improvements over conventional chunk methods. However, it remains unclear how this method compares to Langendorff perfusion, the current standard of adult cardiomyocyte isolation. Using adult Bama minipigs, we performed cardiomyocyte isolation via these two distinct methods, and compared the resulting cellular quality, including viability, cellular structure, gene expression, and electrophysiological properties, of cardiomyocytes from 3 distinct anatomical regions, namely the left ventricle, right ventricle, and left atrial appendage. Our results revealed largely indistinguishable cell quality in all of the measured parameters. These findings suggest that that TSAD can be reliably used to isolate adult mammalian cardiomyocytes as a reliable alternative to perfusion in cardiomyocyte isolation from larger mammals, particularly when Langendorff perfusion is not feasible.

Rationale: While cell-cell interaction plays a critical role in physiology and disease, a comprehensive understanding of its dynamics in vascular homeostasis and diseases is yet absent. Methods: Here, by use of single-cell RNA-sequencing and multi-color staining, we delineate the cellular composition and spatial characterization of human aorta with or without aortic dissection (AD). Results: Scrutinization of cell subtype alterations revealed significantly changed fibroblast (FB)-smooth muscle cell (SMC) interactions in AD. Of these cellular interactions, LOXhigh fibroblast (fibroblast subtype 2, FB2) in diseased state exerted the most pronounced effects on pathological deterioration of SMCs in AD. In addition, pharmacologically targeting the BMP (bone morphogenetic protein) signaling pathway effectively suppressed FB2 state transition and reduced AD incidence in mice. Finally, COL5A1 (collagen type V alpha 1 chain), one of the secreted proteins released from FB2, was significantly higher in the plasma of AD patients than in control patients, suggesting its potential use as a biomarker for AD diagnosis. Conclusions: Our work not only identified a pivotal role of a specific FB subtype in AD progression, but also shed light on cell interaction dynamics in vascular diseases.

Pathological subtypes are prognostic indicators independent of TNM stage, and patients with micropapillary and solid components have poorer prognosis. Previous studies have found that the presence of a micropapillary component was significantly associated with worse recurrence-free survival in patients with stage I lung adenocarcinoma, even the components are less than 5%, and postoperative adjuvant chemotherapy can still bring benefit to those patients even with stage IA. Third-generation EGFR-TKI have recently shown striking benefit for postoperative adjuvant therapy in patients with EGFR-mutated NSCLC. At present, there is no systematic study on the efficacy and safety of third-generation EGFR-TKI in stage I NSCLC patients with high-risk recurrence factors, such as solid and micropapillarycomponents. The third-generation EGFR-TKI, aumolertinib(HS-10296), showed promising efficacy in advanced NSCLC patients with sensitive EGFR mutation. This is the first study to explore the efficacy and safety of aumolertinib as adjuvant therapy in patients with EGFR mutant stage I NSCLC with solid and/or micropapillary component. Approximately 52 stage I EGFR-mutated NSCLC patients with solid and/or micropapillary components ≥10% will be enrolled in this multicenter single-arm study. After radical lung cancer surgery, they will receive oral almonertinib 110 mg/d as adjuvant therapy for 3 years. The primary endpoint is 2-year disease free survival (DFS) rates, and secondary endpoints included the 3-, 4-, and 5-year DFS rates, 5-year overall survival rates, safety and quality of life, Circulating tumor DNA will also be monitored during the study. Recruitment of this study is ongoing, and the first patient had been enrolled in January 2022. The author. Jiangsu Hansoh Pharmaceutical Group Co., Ltd.

Cardiovascular diseases are the most common cause of death globally. Accurately modeling cardiac homeostasis, dysfunction, and drug response lies at the heart of cardiac research. Adult human primary cardiomyocytes (hPCMs) are a promising cellular model, but unstable isolation efficiency and quality, rapid cell death in culture, and unknown response to cryopreservation prevent them from becoming a reliable and flexible in vitro cardiac model. Combing the use of a reversible inhibitor of myosin II ATPase, (-)-blebbistatin (Bleb), and multiple optimization steps of the isolation procedure, we achieved a 2.74-fold increase in cell viability over traditional methods, accompanied by better cellular morphology, minimally perturbed gene expression, intact electrophysiology, and normal neurohormonal signaling. Further optimization of culture conditions established a method that was capable of maintaining optimal cell viability, morphology, and mitochondrial respiration for at least 7 days. Most importantly, we successfully cryopreserved hPCMs, which were structurally, molecularly, and functionally intact after undergoing the freeze-thaw cycle. hPCMs demonstrated greater sensitivity towards a set of cardiotoxic drugs, compared to human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Further dissection of cardiomyocyte drug response at both the population and single-cell transcriptomic level revealed that hPCM responses were more pronouncedly enriched in cardiac function, whereas hiPSC-CMs responses reflected cardiac development. Together, we established a full set of methodologies for the efficient isolation and prolonged maintenance of functional primary adult human cardiomyocytes in vitro, unlocking their potential as a cellular model for cardiovascular research, drug discovery, and safety pharmacology.

Postnatal heart maturation is the basis of normal cardiac function and provides critical insights into heart repair and regenerative medicine. While static snapshots of the maturing heart have provided much insight into its molecular signatures, few key events during postnatal cardiomyocyte maturation have been uncovered. Here, we report that cardiomyocytes (CMs) experience epigenetic and transcriptional decline of cardiac gene expression immediately after birth, leading to a transition state of CMs at postnatal day 7 (P7) that was essential for CM subtype specification during heart maturation. Large-scale single-cell analysis and genetic lineage tracing confirm the presence of transition state CMs at P7 bridging immature state and mature states. Silencing of key transcription factor JUN in P1-hearts significantly repressed CM transition, resulting in perturbed CM subtype proportions and reduced cardiac function in mature hearts. In addition, transplantation of P7-CMs into infarcted hearts exhibited cardiac repair potential superior to P1-CMs. Collectively, our data uncover CM state transition as a key event in postnatal heart maturation, which not only provides insights into molecular foundations of heart maturation, but also opens an avenue for manipulation of cardiomyocyte fate in disease and regenerative medicine.

胃癌是危害世界和我国人民健康的重要疾病，早期诊断和治疗能够有效改善预后，符合适应证的早期胃癌患者可以通过内镜下治疗获得与外科手术相当的疗效，而术前准确判断早期胃癌的浸润深度对于制定治疗策略非常重要。本文系统论述白光内镜、色素内镜、电子染色放大内镜、超声内镜在判断胃癌浸润深度方面的作用，并就人工智能在该领域的应用进行了总结和展望。

Abstract Background: There is no standardized operation procedure for white light gastroscopy (WLG）in China. We aimed to established a standardized procedure of white light gastroscopy for clinic patients screening, to verify its effect and its feasibility in clinical practice. Methods: We applied the standardized procedure for WLG to out-patients at 9 tertiary hospitals in Beijing. All of the clinical information and operation procedure were recorded.Results: We set a standardized operation procedure for WLG. 1051 patients were enrolled in the base-line survey stage between March 2014 and December 2015. 2156 patients were enrolled in the WLG standardized operation stage from January 2016 to June 2017. The median durations of standardized procedure group were significantly longer than that of the base-line group (prolonged 60.3 seconds averagely, P=0.003). The taken picture numbers in the standardized procedure group were significantly higher than that in the base-line group (17 pictures more averagely, P<0.001). The overall detection rate of gastric mucosal lesions in the standardized procedure group was significantly higher than that in the base-line group (52.5% vs. 38.4%, P<0.01). Both the patient and endoscopist satisfaction scores in the standardized procedure group were all significantly improved than those in the base-line group.Conclusions: The standardized procedure for WLG can improve the detection rate of gastric lesions significantly, and also improve the satisfaction of patients and endoscopists despite prolonged duration. The standardized procedure for white light gastroscopy is effective and feasible in clinical practice with the present endoscopy equipment in China.

Objective We aimed to establish a standardized procedure for white light gastroscopy (WLG) to screen gastric lesions including early gastric cancer (EGC) in China and to verify its efficacy and feasibility in clinical practice. Methods A standardized WLG procedure for outpatients at nine tertiary hospitals in Beijing was established. Clinical information of the participants and details of the endoscopic procedures were recorded. Results A total of 1051 participants were enrolled in a baseline conventional endoscopic survey between March 2014 and December 2015, while 2156 patients were enrolled in the standardized WLG operation from January 2016 to June 2017. The procedure time of the standardized procedure was significantly longer than that of the baseline conventional procedure (P = 0.003). More images were obtained during the standardized procedure compared with the baseline conventional procedure (P < 0.001). The overall detection rate of gastric lesions in the standardized procedure group was significantly higher than that in the baseline procedure group (52.5% vs 38.4%, P < 0.01). The satisfaction scores of both participants and endoscopists in the standardized procedure group were significantly higher than in the baseline procedure group. Conclusions Compared with the conventional procedure, standardized WLG procedure significantly improves the detection rate of gastric lesions as well as the satisfaction score of participants and endoscopists despite its longer procedure time. It is effective and feasible in clinical practice in China for the use of currently available endoscopic equipment.

We aimed to establish a standardized procedure for white light gastroscopy (WLG) to screen gastric lesions including early gastric cancer (EGC) in China and to verify its efficacy and feasibility in clinical practice. A standardized WLG procedure for outpatients at nine tertiary hospitals in Beijing was established. Clinical information of the participants and details of the endoscopic procedures were recorded. A total of 1051 participants were enrolled in a baseline conventional endoscopic survey between March 2014 and December 2015, while 2156 patients were enrolled in the standardized WLG operation from January 2016 to June 2017. The procedure time of the standardized procedure was significantly longer than that of the baseline conventional procedure ( P  = 0.003). More images were obtained during the standardized procedure compared with the baseline conventional procedure ( P  < 0.001). The overall detection rate of gastric lesions in the standardized procedure group was significantly higher than that in the baseline procedure group (52.5% vs 38.4%, P  < 0.01). The satisfaction scores of both participants and endoscopists in the standardized procedure group were significantly higher than in the baseline procedure group. Compared with the conventional procedure, standardized WLG procedure significantly improves the detection rate of gastric lesions as well as the satisfaction score of participants and endoscopists despite its longer procedure time. It is effective and feasible in clinical practice in China for the use of currently available endoscopic equipment.