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BACKGROUND: Clinical trials support the efficacy of immune checkpoint blockades (ICBs) plus chemotherapy in a subset of patients with metastatic gastric cancer (mGC). To identify the determinants of response, we developed a TMEscore model to assess tumor microenvironment (TME), which was previously proven to be a biomarker for ICBs. METHODS: A reference database of TMEscore assays was established using PCR assay kits containing 30 TME genes. This multi-center prospective clinical trial (NCT#04850716) included patients with mGC who were administered ICB combined with chemotherapy as a first-line regimen. Eighty-six tumor samples extracted from five medical centers before treatment were used to estimate the TMEscore, PD-L1 (CPS), and mismatch repair deficiency. FINDINGS: The objective response rate (ORR) and median PFS of the cohort were 31.4% and six months. Enhanced ORR was observed in TMEscore-high mGC patients (ORR = 59%). The survival analysis demonstrated that high TMEscore was significantly associated with a more favorable PFS and OS. Moreover, TMEscore was found to be a predictive biomarker that surpassed MSI and CPS (AUC = 0.873, 0.511, and 0.524, respectively). By integrating the TMEscore and clinical variables, the fused model further enhances the predictive efficiency and translational application in a clinical setting. CONCLUSIONS: This prospective clinical study indicates that the TMEscore assay is a robust biomarker for screening patients with mGC who may derive survival benefits from ICB plus chemotherapy. FUNDING: Guangdong Basic and Applied Basic Research Foundation (2023A1515011214), Science and Technology Program of Guangzhou (202206080011), and Guangzhou Science and Technology Project (2023A03J0722 and 2023A04J2357).
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CONTEXT: Both physical activity (PA) and sedentary behavior (SB) exert important impact on type 2 diabetes, but it remains unclear how maximum impact on improving the mortality and optimized proportion of the two lifestyles combination exists. OBJECTIVE: To explore the impacts of PA/SB combinations on mortality in patients with diabetes. METHODS: Patients with type 2 diabetes patients samplings were collected from the National Health and Nutrition Examination Survey (NHANES) dataset. Their lifestyles were categorized into eight groups based on combinations of the PA and SB levels. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals. RESULTS: During the follow-up period, 1,148 deaths (18.94%) were recorded. High SB (sedentary time ≥6 hours/day) was significantly associated with higher all-cause mortality (HR 1.65). In participants with low SB (<6 hours/day), low PA was associated with lower all-cause mortality (HR 0.43), while further increase of PA level did not show further reduction in either all-cause or cardiovascular mortality. In contrast, in participants with high SBï¼all levels of PA were associated with lower all-cause mortality (p<0.05), but only moderate PA was associated with lower cardiovascular mortality (HR 0.30). CONCLUSIONS: In patients with type 2 diabetes, different combinations of various levels of PA and SB are associated with different degree of risk for all-cause or cardiovascular mortality.
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Objective: α-Klotho is a potential biological marker of aging with satisfactory clinical applicability. However, its prognostic significance in age-related diseases has largely been undermined. Therefore, we aimed to report the prognostic value of serum α-klotho levels in age-related diseases. Methods: Participants with available serum α-klotho data from the National Health and Nutrition Examination Survey (2007-2016) were included. Their survival status was collected at 7.62 ± 2.99 years after serum α-klotho data was collected, and the endpoint was all-cause and cardiovascular mortality. A Cox regression model was established to examine the association between serum α-klotho levels and all-cause and cardiovascular mortality. Results: The present study included 13,746 U.S. adults with a survey-weighted mean age of 56.19 ± 10.42 years old. Of these, 52.2 % were female and 72.9 % were non-Hispanic whites. The optimal cutoff value of serum α-klotho for predicting all-cause mortality risk in the general population was 603.5 pg/ml. Individuals with low serum α-klotho (<603.5 pg/ml) had a significantly higher risk of all-cause (adjusted HR: 1.34(1.18-1.52), P < 0.001) and cardiovascular mortality (adjusted HR: 1.63(1.27-2.10), P < 0.001). Subgroup analysis showed that low serum α-klotho level was an independent risk factor for all-cause and cardiovascular mortality in people with hypertension, congestive heart failure, diabetes mellitus, and emphysema, while it was an independent risk factor for all-cause mortality in patients with renal insufficiency. Conclusion: A low serum α-klotho concentration (<603.5 pg/ml) could serve as a marker of all-cause and cardiovascular mortality in the general population and in people with age-related diseases, including hypertension, congestive heart failure, diabetes mellitus, and emphysema.
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INTRODUCTION: Sympathetic hyperinnervation plays an important role in modulating the vascular smooth muscle cell (VSMC) phenotype and vascular diseases, but its role in abdominal aortic aneurysm (AAA) is still unknown. OBJECTIVES: This study aimed to investigate the role of sympathetic hyperinnervation in promoting AAA development and the underlying mechanism involved. METHODS: Western blotting and immunochemical staining were used to detect sympathetic hyperinnervation. We performed sympathetic denervation through coeliac ganglionectomy (CGX) and 6-OHDA administration to understand the role of sympathetic hyperinnervation in AAA and investigated the underlying mechanisms through transcriptome and functional studies. Sema4D knockout (Sema4D-/-) mice were utilized to determine the involvement of Sema4D in inducing sympathetic hyperinnervation and AAA development. RESULTS: We observed sympathetic hyperinnervation, the most important form of sympathetic neural remodeling, in both mouse AAA models and AAA patients. Elimination of sympathetic hyperinnervation by CGX or 6-OHDA significantly inhibited AAA development and progression. We further revealed that sympathetic hyperinnervation promoted VSMC phenotypic switching in AAA by releasing extracellular ATP (eATP) and activating eATP-P2rx4-p38 signaling. Moreover, single-cell RNA sequencing revealed that Sema4D secreted by osteoclast-like cells induces sympathetic nerve diffusion and hyperinnervation through binding to Plxnb1. We consistently observed that AAA progression was significantly ameliorated in Sema4D-deficient mice. CONCLUSIONS: Sympathetic hyperinnervation driven by osteoclast-like cell-derived Sema4D promotes VSMC phenotypic switching and accelerates pathological aneurysm progression by activating the eATP/P2rx4/p38 pathway. Inhibition of sympathetic hyperinnervation emerges as a potential novel therapeutic strategy for preventing and treating AAA.
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Immune checkpoint inhibitors provide a definite survival benefit for patients with driver-negative advanced non-small cell lung cancer (NSCLC), but predictors of efficacy are still lacking. There may be a relationship between immune inflammatory state and tumor immune response. We explored the relationship of serum neutrophil extracellular traps (NETs) with infiltrating cells in the tumor tissues of patients with NSCLC as well as their relationship with the therapeutic efficacy of programmed cell death protein 1 (PD-1) inhibitors. Serum myeloperoxidase (MPO)-double-stranded DNA (dsDNA) was detected as a marker of NET serum concentration. T cells were detected by immunohistochemical staining, and neutrophils were counted by MPO immunofluorescence staining. Of the 31 patients with NSCLC, a longer progression-free survival after PD-1 inhibitor treatment was associated with higher levels of CD3+ T cells, a lower neutrophil : CD3+-T-cell ratio (NEU/CD3+) and lower neutrophil : CD8+-T-cell ratio (NEU/CD8+) in tumor tissues. Patients with higher serum NETs were more likely to develop progressive disease after treatment (P = 0.003) and to have immune-related adverse events (IrAEs) as well as higher NEU/CD3+ and NEU/CD8+. The combined model of serum NETs, CD8+ T cells, and tumor proportion score (TPS) significantly improved the prediction of PD-1 inhibitor efficacy [P = 0.033; area under the curve (AUC) = 0.881]. Our results indicate that serum NETs are effective predictors of PD-1 inhibitor response and reflect the tissue neutrophil-to-lymphocyte ratio and IrAE levels. The combined model of serum NETs, CD8+ T cells, and TPS is a powerful tool for predicting the efficacy of PD-1 inhibitor treatment in patients with NSCLC.
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Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Armadilhas Extracelulares , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Receptor de Morte Celular Programada 1 , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Masculino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/sangue , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Pessoa de Meia-Idade , Idoso , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , AdultoRESUMO
Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism. Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI. Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI. Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.
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Interleucina-10 , Infarto do Miocárdio , Adulto , Humanos , Interleucina-10/genética , Optogenética , Infarto do Miocárdio/terapia , Nervo Vago , Miócitos CardíacosRESUMO
INTRODUCTION: Surgical ventricular reconstruction (SVR) is an alternative therapeutic approach in patients with refractory heart failure (HF), but residual remodeling after SVR limits the improvement of HF. Recently, we reported that SVR may act as an environmental cue to reactivate endogenous proliferation of cardiomyocytes; however, it is unclear whether enhancing endogenous cardiomyocyte regeneration further improves HF after SVR. OBJECTIVES: We aimed to explore whether circular RNAs (circRNAs) would involved in SVR and their mechanisms. METHODS: Male C57BL/6 mice were subjected to myocardial infarction (MI) or sham surgery. Four weeks later, MI mice with a large ventricular aneurysm underwent SVR or a second open-chest operation only. Echocardiography and histological analysis were used to evaluate heart function, cardiac remodeling, and myocardial regeneration. Sequencing of circular RNAs, RNA immunoprecipitation, RNA pulldown, and luciferase reporter assay were used to explore the underlying mechanisms. RESULTS: SVR markedly attenuated cardiac remodeling and induced cardiomyocyte regeneration, as evidenced by positive staining of Ki-67, phospho-histone H3 (pH3), and Aurora B in the plication zone, but significant residual remodeling still existed in comparison with the sham group. Sequencing results showed that SVR altered the expression profile of cardiac circRNAs, and circMap4k2 was identified as the most upregulated one. After characterizing circMap4k2, we noted that overexpression of circMap4k2 significantly promoted proliferation of cardiomyocytes in cultured neonatal rat cardiomyocytes and silencing of circMap4k2 significantly inhibited it; similar results were obtained in SVR-treated MI mice but not in MI mice without SVR treatment. Residual cardiac remodeling after SVR was further attenuated by circMap4k2 overexpression. CircMap4k2 bound with miR-106a-3p and inhibited cardiomyocyte proliferation by targeting a downstream effector of the antizyme inhibitor 1 (Azin1) gene. CONCLUSIONS: CircMap4k2 acts as an environmental cue and targets the miR-106a-3p/Azin1 pathway to increase cardiac regeneration in the plication zone and attenuate residual remodeling after SVR.
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Cardiac repair after myocardial infarction (MI) is orchestrated by multiple intrinsic mechanisms in the heart. Identifying cardiac cell heterogeneity and its effect on processes that mediate the ischemic myocardium repair may be key to developing novel therapeutics for preventing heart failure. With the rapid advancement of single-cell transcriptomics, recent studies have uncovered novel cardiac cell populations, dynamics of cell type composition, and molecular signatures of MI-associated cells at the single-cell level. In this review, we summarized the main findings during cardiac repair by applying single-cell transcriptomics, including endogenous myocardial regeneration, myocardial fibrosis, angiogenesis, and the immune microenvironment. Finally, we also discussed the integrative analysis of spatial multi-omics transcriptomics and single-cell transcriptomics. This review provided a basis for future studies to further advance the mechanism and development of therapeutic approaches for cardiac repair.
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BACKGROUND: Studies exploring whether metastatic organotropism and risk in gastric cancer (GC) differ by primary anatomical site are scarce. METHODS: This study included 15,260 and 1623 patients diagnosed with GC from the Surveillance, Epidemiology, and End Results (SEER) registry database and the Nanfang Hospital in China, respectively. Patients were stratified according to primary site of GC, and the incidence of metastasis to different organs was used to determine the metastatic organotropism for each GC subsite. Finally, the metastatic organotropism and risk were compared among the different subsite groups. RESULTS: Liver metastasis was the most common metastasis site in cardia GC, whereas other-site metastases were more common in the body, antrum, overlapping lesions, and unspecified GCs. Liver and other-site metastases were also frequently observed in the fundus, pylorus, lesser curvature, and greater curvature GCs. Patients with GC with definite primary tumor sites in the SEER and validation Nanfang hospital cohorts were compared by grouping as proximal and distal GCs for further analysis. In the SEER cohort, the top three metastatic sites of proximal GC were liver (21.4%), distant lymph node (LN) (14.6%), and other-site (mainly peritoneum, 11.9%), whereas those of distal GC were other-site (mainly peritoneum, 19.5%), liver (11.8%), and distant LN (9.5%). The incidence of metastasis to the liver, distant LN, lung, and brain was significantly higher in patients with proximal GC than in those with distal GC in both the SEER and Nanfang cohorts (p < 0.05). However, metastasis to other-site/peritoneum was significantly lower in patients with proximal GC compared to those with distal GC in the Nanfang Hospital and SEER cohorts, respectively (p < 0.05). CONCLUSION: Liver and distant LN are the preferred metastatic sites for proximal GC, whereas peritoneal metastasis is more common in distal GC. Proximal GC has a higher risk of lymphatic and hematogenous metastases, and a lower risk of transcoelomic metastasis than distal GC. Our findings highlight the need to stratify GC by its primary subsite to aid in planning and decision-making related to metastatic management in clinical practice.
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Neoplasias Gástricas , Humanos , Estudos de Coortes , População do Leste Asiático , Prognóstico , Sistema de Registros/estatística & dados numéricos , Programa de SEER/estatística & dados numéricos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia , Estados Unidos/epidemiologia , ChinaRESUMO
AIMS: Remnant cholesterol (RC) reportedly mediates residual cardiovascular risk in atherosclerotic cardiovascular diseases (ASCVD). However, few studies have characterized long-term cumulative RC exposure among elderly people. The study aimed to evaluate the association between cumulative exposure to RC and incident major adverse cardiovascular events (MACE) by analysing a cohort of elderly patients with ASCVD. METHODS AND RESULTS: This retrospective multicentre cohort study enrolled ASCVD participants aged ≥75 years with baseline visits occurring from 2006 to 2012 followed by four in-person visits. Cumulative RC was estimated as the area under the curve using measurements from the first to fourth visits by using 9-year data. The time-weighted average (TWA) RC was expressed as cumulative exposure to RC averaged by years. All outcomes were follow-up from the fourth visit to the year 2021. Outcomes included a composite of MACE (stroke, unstable angina pectoris, myocardial infarction, and cardiac death). We included 4,680 participants (73.1% male, mean age 79.3 ± 2.5 years). The median follow-up duration was 6.1 years (interquartile range: 3.4-6.6 years). In the multivariable model adjusted for traditional cardiovascular risk factors, low-density lipoprotein cholesterol level, and most recent RC level, the hazard ratios for MACE that compared the high and low tertiles of the RC variables were 1.30 [95% confidence interval (CI), 1.16-1.44] for cumulative RC and 1.36 (95% CI, 1.23-1.52) for TWA RC. Consistent significant associations were observed among most propensity score analyses. CONCLUSIONS: Long-term cumulative RC was independently associated with incident MACE in elderly participants with ASCVD, suggesting that achieving and maintaining optimal RC levels later in life may still improve cardiovascular outcomes.
This retrospective multicentre cohort study, enrolling 4680 participants aged ≥75 years with pre-existing atherosclerotic cardiovascular diseases (ASCVD), found that greater cumulative exposure to remnant cholesterol (RC) across a 9-year span was independently associated with an increased incidence of cardiovascular events, suggesting that cumulative RC may be a powerful predictor of cardiovascular outcomes in patients with ASCVD.
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Aterosclerose , Doenças Cardiovasculares , Acidente Vascular Cerebral , Idoso , Humanos , Masculino , Idoso de 80 Anos ou mais , Feminino , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/complicações , Estudos de Coortes , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Aterosclerose/complicações , Colesterol , Fatores de RiscoRESUMO
CONTEXT: Conflicting predictions of malnutrition for the long-term prognosis of coronary artery disease (CAD) exist. OBJECTIVE: This study aimed to investigate the relationship between malnutrition and long-term prognosis of patients with CAD. DATA SOURCES: Four databases were searched for articles from February 11, 1936, to September 10, 2022. DATA EXTRACTION: Cohort studies adjusting for multiple cardiovascular risk factors with data on CAD and malnutrition were included. Malnutrition was measured and defined by different nutritional evaluation tools. The hazard ratios (HRs) and confidence intervals (CIs) for all-cause mortality and major adverse cardiovascular events (MACEs) were synthesized. Subgroup analyses were performed based on study design, assessment tools, ethnicity/race, follow-up, sample size, and types of CAD. Meta-regression was used to compare whether the effect sizes of the 2 subgroups were statistically significant. DATA ANALYSIS: A total of 30 cohort studies were included, totaling 81â 361 participants with CAD. Nutritional evaluation tools, including the Geriatric Nutritional Risk Index (GNRI), Controlling Nutritional Status (CONUT), Nutritional Risk Screening 2002, Mini-Nutritional Assessment, and Prognostic Nutritional Index, were used. Malnutrition increased all-cause mortality (HR = 1.72; 95% CI: 1.53, 1.93) and MACEs (HR = 1.47; 95% CI: 1.35, 1.60) in patients with CAD. Subgroup analysis revealed the results were consistent across study design, ethnicity/race, follow-up, sample size, and types of CAD. Subgroup analyses and meta-regression revealed that malnutrition was associated with a higher risk of all-cause mortality (HR = 2.26; 95% CI: 1.91, 2.68) and MACEs (HR = 2.28; 95% CI: 1.69, 3.08) in patients with stable CAD than those with other types of CAD. Meta-regression revealed that the GNRI (HR = 2.20; 95% CI: 1.65, 2.93) was more effective than CONUT (HR = 1.47; 95% CI: 1.21, 1.78) in predicting all-cause mortality. CONCLUSION: Malnutrition independently increased all-cause mortality by 72% and MACEs by 47% in patients with CAD, especially with stable CAD. The GNRI is a more effective nutritional evaluation tool than CONUT in predicting all-cause mortality.
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OBJECTIVE: To explore the optimal low-density lipoprotein cholesterol (LDL-C) level in patients aged 75 years and older with established atherosclerotic cardiovascular disease (ASCVD). PATIENTS AND METHODS: We conducted a retrospective multicenter cohort study of veterans aged 75 years and older with ASCVD who were regularly hospitalized or medically examined in 15 medical institutions in southern China from January 1, 2006, to December 31, 2013. Follow-up continued through October 1, 2021. The time-weighted average (TWA) LDL-C level represented the average LDL-C level during follow-up. Participants were divided into TWA LDL-C groups of 55.0 mg/dL or lower, 55.1 to 70.0 mg/dL, 70.1 to 85.0 mg/dL, 85.1 to 100.0 mg/dL, and greater than 100.0 mg/dL. The subgroup with LDL-C levels lower than 55.0 mg/dL was further subdivided into groups with LDL-C levels from 40.1 to 55.0 mg/dL and 40.0 mg/dL or less. The association of TWA LDL-C levels with outcomes was evaluated with Cox proportional hazards models. RESULTS: Overall, 6387 patients aged 75 years or older with ASCVD were included (mean age, 79.4 years). In total, 4267 major adverse cardiovascular events, 1518 stroke events, and 515 myocardial infarction events occurred during a mean follow-up of 12.7 years. Generally, lower TWA LDL-C level was associated with a lower risk of cardiovascular events but was not associated with a higher risk of adverse events in elderly individuals with ASCVD, with the lowest cardiovascular risk observed for LDL-C levels of less than 55.0 mg/dL. After multivariable adjustment, the risk of a major adverse cardiovascular event was 1.30 (95% CI, 1.26 to 1.34; P<.001) for a per SD increment in TWA LDL-C level. Compared with TWA LDL-C levels of 40.1 to 55.0 mg/dL, TWA LDL-C levels of 40.0 mg/dL or less were associated with an increased risk of hemorrhagic stroke (hazard ratio, 3.71; 95% CI, 1.89 to 7.26). CONCLUSION: Low-density lipoprotein cholesterol levels from 40.1 to 55.0 mg/dL exhibited the maximum cardiovascular benefit in patients aged 75 years and older who had ASCVD. Lowering LDL-C levels to 40.0 mg/dL or less might increase the risk of hemorrhagic stroke.
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Aterosclerose , Doenças Cardiovasculares , Acidente Vascular Cerebral Hemorrágico , Idoso , Humanos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol , Estudos de Coortes , População do Leste Asiático , Aterosclerose/epidemiologiaRESUMO
Bevacizumab is an anti-VEGF monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer. However, resistance remains a major hurdle limiting bevacizumab efficacy, highlighting the importance of identifying a mechanism of antiangiogenic therapy resistance. Here, we investigated biophysical properties of the extracellular matrix (ECM) related to metabolic processes and acquired resistance to bevacizumab. Evaluation of paired pre- and posttreatment samples of liver metastases from 20 colorectal cancer patients treated with combination bevacizumab therapy, including 10 responders and 10 nonresponders, indicated that ECM deposition in liver metastases and a highly activated fatty acid oxidation (FAO) pathway were elevated in nonresponders after antiangiogenic therapy compared with responders. In mouse models of liver metastatic colorectal cancer (mCRC), anti-VEGF increased ECM deposition and FAO in colorectal cancer cells, and treatment with the FAO inhibitor etomoxir enhanced the efficacy of antiangiogenic therapy. Hepatic stellate cells (HSC) were essential for matrix stiffness-mediated FAO in colon cancer cells. Matrix stiffness activated lipolysis in HSCs via the focal adhesion kinase (FAK)/yes-associated protein (YAP) pathway, and free fatty acids secreted by HSCs were absorbed as metabolic substrates and activated FAO in colon cancer cells. Suppressing HSC lipolysis using FAK and YAP inhibition enhanced the efficacy of anti-VEGF therapy. Together, these results indicate that bevacizumab-induced ECM remodeling triggers lipid metabolic cross-talk between colon cancer cells and HSCs. This metabolic mechanism of bevacizumab resistance mediated by the physical tumor microenvironment represents a potential therapeutic target for reversing drug resistance. SIGNIFICANCE: Extracellular matrix stiffening drives bevacizumab resistance by stimulating hepatic stellate cells to provide fuel for mCRC cells in the liver, indicating a potential metabolism-based therapeutic strategy for overcoming resistance.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neoplasias Hepáticas/patologia , Neoplasias Colorretais/patologia , Neoplasias do Colo/tratamento farmacológico , Células Estromais/metabolismo , Lipídeos , Microambiente TumoralRESUMO
Previous studies show a woman's pregnancy is correlated with post-reproductive longevity, and nulliparity is associated with higher risk of incident heart failure, suggesting pregnancy likely exerts a cardioprotection. We previously reported a cardioprotective phenomenon termed myocardial hypertrophic preconditioning, but it is unknown whether pregnancy-induced physiological hypertrophic preconditioning (PHP) can also protect the heart against subsequent pathological hypertrophic stress. We aimed to clarify the phenomenon of PHP and its mechanisms. The pluripara mice whose pregnancy-induced physiological hypertrophy regressed and the nulliparous mice underwent angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Echocardiography, invasive left ventricular hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. Silencing or overexpression of Foxo3 by adeno-associated virus was used to investigate the role of FoxO3a involved in the antihypertrophic effect. Compared with nulliparous mice, pathological cardiac hypertrophy induced by Ang II infusion, or TAC was significantly attenuated and heart failure induced by TAC was markedly improved in mice with PHP. Activation of FoxO3a was significantly enhanced in the hearts of postpartum mice. FoxO3a inhibited myocardial hypertrophy by suppressing signaling pathway of phosphorylated glycogen synthase kinase-3ß (p-GSK3ß)/ß-catenin/Cyclin D1. Silencing or overexpression of Foxo3 attenuated or enhanced the anti-hypertrophic effect of PHP in mice with pathological stimulation. Our findings demonstrate that PHP confers resistance to subsequent hypertrophic stress and slows progression to heart failure through activation of FoxO3a/GSK3ß pathway.
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Estenose da Valva Aórtica , Insuficiência Cardíaca , Hormônios Peptídicos , Animais , Feminino , Camundongos , Gravidez , Angiotensina II , Cardiomegalia/genética , Glicogênio Sintase Quinase 3 beta/genética , CoraçãoRESUMO
Objective: Single-pill amlodipine besylate (AML) plus losartan (LOS) has been used to treat inadequately controlled hypertension after antihypertensive monotherapy; however, relevant data in China are limited. This study aimed to compare the efficacy and safety of single-pill AML/LOS and LOS alone in Chinese patients with inadequately controlled hypertension after LOS treatment. Methods: In this multicenter, double-blind, randomized, controlled phase III clinical trial, patients with inadequately controlled hypertension after 4 weeks of LOS treatment were randomized to receive daily single-pill AML/LOS (5/100â mg, AML/LOS group, N = 154) or LOS (100â mg, LOS group, N = 153) tablets for 8 weeks. At weeks 4 and 8 of treatment, sitting diastolic and systolic blood pressure (sitDBP and sitSBP, respectively) and the BP target achievement rate were assessed. Results: At week 8, the sitDBP change from baseline was greater in the AML/LOS group than in the LOS group (-8.84 ± 6.86 vs. -2.65 ± 7.62â mmHg, P < 0.001). In addition, the AML/LOS group also showed greater sitDBP change from baseline to week 4 (-8.77 ± 6.60 vs. -2.99 ± 7.05â mmHg) and sitSBP change from baseline to week 4 (-12.54 ± 11.65 vs. -2.36 ± 10.33â mmHg) and 8 (-13.93 ± 10.90 vs. -2.38 ± 12.71â mmHg) (all P < 0.001). Moreover, the BP target achievement rates at weeks 4 (57.1% vs. 25.3%, P < 0.001) and 8 (58.4% vs. 28.1%, P < 0.001) were higher in the AML/LOS group than those in the LOS group. Both treatments were safe and tolerable. Conclusion: Single-pill AML/LOS is superior to LOS monotherapy for controlling BP and is safe and well tolerated in Chinese patients with inadequately controlled hypertension after LOS treatment.
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BACKGROUND: Preexisting impaired renal function (IRF) and contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) are important prognostic parameters, but it is unknown whether delayed PCI is still beneficial for STEMI patients with IRF. METHODS: A retrospective single-center cohort study was performed in 164 patients who presented at least 12 h after symptom onset, and were diagnosed with STEMI and IRF. They were assigned to two groups to receive PCI plus optimal medical therapy (OMT) and OMT alone respectively. Clinical outcomes at 30 days and 1 year were compared between two groups, and hazard ratio for survival was analyzed using Cox regression model. A power analysis demanded 34 patients in each group to produce a power of 90% and a P value of 0.05. RESULTS: The 30-day mortality was significantly lower in PCI group (n = 126) than in non-PCI group (n = 38) (11.1% versus 28.9%, P = 0.018), while there was no significant difference in the 1-year mortality and incidence of cardiovascular comorbidities between the two groups. Cox regression analysis showed that patients with IRF didn't benefit from receiving PCI on survival rate (P = 0.267). CONCLUSIONS: Delayed PCI is not beneficial on one-year clinical outcomes for STEMI patients with IRF.
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Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Estudos Retrospectivos , Estudos de Coortes , Intervenção Coronária Percutânea/efeitos adversos , Rim/fisiologia , Resultado do TratamentoRESUMO
Systemic and pulmonary arterial hypertension (PAH) can induce left and right ventricular hypertrophy, respectively, but common therapeutic targets for both left and right hypertrophy are limited. In this study, we attempt to explore potential common therapeutic targets and screen out potential target drugs for further study. Cardiac mRNA expression profiles in mice with transverse aortic constriction (TAC) and pulmonary arterial constriction (PAC) are obtained from online databases. After bioinformatics analyses, we generate TAC and PAC mouse models to validate the phenotypes of cardiac remodelling as well as the identified hub genes. Bioinformatics analyses show that there are 214 independent differentially expressed genes (DEGs) in GSE136308 (TAC related) and 2607 independent DEGs in GSE30922 (PAC related), while 547 shared DEGs are associated with the function of the extracellular matrix (ECM) or involved in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and ECM-receptor interactions. We identifyd Fn1, Il6, Col1a1, Igf1, Col1a2, Timp1, Col3a1, Cd44, Ctgf and Postn as hub genes of the shared DEGs, and most of them are associated with myocardial fibrosis. Those hub genes and phenotypes of cardiac remodelling are validated in our TAC and PAC mouse models. Furthermore, we identify dehydroisoandrosterone (DHEA), iloprost and 4,5-dianilinophthalimide (DAPH) as potential therapeutic drugs targeting both left and right ventricular hypertrophy and validate the effect of DHEA. These findings suggest that DHEA could be an effective drug for pressure overload-induced left or right ventricular hypertrophy by regulating the shared hub differentially expressed genes associated with fibrosis.
Assuntos
Hipertrofia Ventricular Esquerda , Hipertensão Arterial Pulmonar , Camundongos , Animais , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Direita/genética , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/genética , Remodelação Ventricular , Fosfatidilinositol 3-Quinases , Cardiomegalia , Biologia Computacional , Desidroepiandrosterona , Fibrose , Camundongos Endogâmicos C57BLRESUMO
[This corrects the article DOI: 10.7150/thno.39553.].
RESUMO
Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by various pathophysiological processes, including chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Stress-induced premature senescence (SIPS) has been implicated in regulating these pathophysiological processes, but whether SIPS contributes to AAA formation remains unknown. Here, we detected SIPS in AAA from patients and young mice. The senolytic agent ABT263 prevented AAA development by inhibiting SIPS. Additionally, SIPS promoted the transformation of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a synthetic phenotype, whereas inhibition of SIPS by the senolytic drug ABT263 suppressed VSMC phenotypic switching. RNA sequencing and single-cell RNA sequencing analysis revealed that fibroblast growth factor 9 (FGF9), secreted by stress-induced premature senescent VSMCs, was a key regulator of VSMC phenotypic switching and that FGF9 knockdown abolished this effect. We further showed that the FGF9 level was critical for the activation of PDGFRß/ERK1/2 signaling, facilitating VSMC phenotypic change. Taken together, our findings demonstrated that SIPS is critical for VSMC phenotypic switching through the activation of FGF9/PDGFRß/ERK1/2 signaling, promoting AAA development and progression. Thus, targeting SIPS with the senolytic agent ABT263 may be a valuable therapeutic strategy for the prevention or treatment of AAA.
RESUMO
Epigenetic modification is involved in tumorigenesis and cancer progression. We developed an epigenetic modification-associated molecular classification of gastric cancer (GC) to identify signature genes that accurately predict prognosis and the efficacy of immunotherapy. Least absolute shrinkage and selection operator and multivariate Cox regression analysis were conducted to develop an epigenetic modification-associated molecular classification. We investigated the significance of PIP4P2, an independent prognostic factor of the classification system, in predicting the prognosis and immunotherapy efficacy of patients with GC. The epigenetic modification-associated molecular classification was highly associated with the clinicopathological characteristics of patients and the existing classification of GC. PIP4P2 was highly expressed in GC tissue and tumor-associated macrophages. High PIP4P2 expression in GC tissue-induced tumor progression by activating PI3K/AKT signal transduction had a negative impact on immunotherapy efficacy. High expression of PIP4P2 in macrophages was correlated with poor prognosis in patients with GC. PIP4P2 is an independent unfavorable prognostic factor of epigenetic modification-associated molecular classification, is involved in tumorigenic progression, and is essential for assessing the prognosis and immunotherapy efficacy of GC.