Vascular smooth muscle cell senescence contributes critically to vascular remodeling and atherosclerosis, with mitochondrial dysfunction and impaired mitophagy recognized as major contributors. SRC, a stress-responsive tyrosine kinase, has been linked to aging, yet its role in vascular aging remains unclear. Here, we examined the role of SRC in regulating autophagy/mitophagy using in vitro and in vivo models. An accelerated vascular aging model was established using a high-fat diet and streptozotocin injection in ApoE-/- mice, while senescence in mouse aortic vascular smooth muscle cells (MOVASs) was induced by doxorubicin. Elevated expression of SRC and phosphorylated SRC (Tyr418) was confirmed in both models. Pharmacological inhibition of SRC with KX2-391 partially mitigated features of vascular aging, improved mitochondrial morphology, reduced plaque burden, and enhanced fibrous cap stability. In senescent MOVASs, SRC knockdown decreased FUNDC1 Tyr18 phosphorylation, enhanced mitophagic flux, and reduced senescence, whereas SRC overexpression produced opposite effects and impaired KX2-391-mediated protection. Moreover, FUNDC1 knockdown abolished the anti-senescence effects of KX2-391, confirming that FUNDC1 is essential for SRC-mediated regulation. Together, these findings establish the SRC-FUNDC1 axis as an important regulator of mitophagy and vascular aging, suggesting that SRC inhibition may offer therapeutic benefit against vascular senescence and atherosclerosis.

To establish morphological and radiomic models for early prediction of cognitive impairment associated with cerebrovascular disease (CI-CVD) in an elderly cohort based on cerebral magnetic resonance angiography (MRA). One-hundred four patients with CI-CVD and 107 control subjects were retrospectively recruited from the 14-year elderly MRA cohort, and 63 subjects were enrolled for external validation. Automated quantitative analysis was applied to analyse the morphological features, including the stenosis score, length, relative length, twisted angle, and maximum deviation of cerebral arteries. Clinical and morphological risk factors were screened using univariate logistic regression. Radiomic features were extracted via least absolute shrinkage and selection operator (LASSO) regression. The predictive models of CI-CVD were established in the training set and verified in the external testing set. A history of stroke was demonstrated to be a clinical risk factor (OR 2.796, 1.359–5.751). Stenosis ≥ 50

Hypoxia-induced apoptosis plays a critical role in the progression of various cardiac diseases, such as heart failure and acute myocardial infarction (AMI). Aldosterone reductase 1C3 (AKR1C3), a member of the aldo-keto reductase superfamily, participates in the metabolism of steroid hormones and redox reactions in vivo. Imbalances in prostaglandin levels have been linked to coronary events. However, the function and molecular mechanism by which AKR1C3 influences AMI are not yet fully understood. This study aims to investigate the role of AKR1C3 in hypoxia-induced myocardial cell damage and elucidate its mechanism. Our findings reveal that a hypoxic microenvironment triggers cardiomyocyte apoptosis and elevates AKR1C3 expression in H9C2 and AC16 cells, as well as in cardiac tissue from rats and mice with AMI. The overexpression of AKR1C3 promotes cardiomyocyte proliferation and cell vitality, whereas the silencing of AKR1C3 exerts the opposite effects in vitro. AKR1C3 protects cardiomyocytes against hypoxia-induced cell apoptosis by reducing ROS levels, preventing mitochondrial damage, and maintaining the oxygen consumption rate (OCR) and ATP production; conversely, AKR1C3 knockdown leads to adverse outcomes. Moreover, the application of a ROS inhibitor (MitoQ10) mitigates the increase in mitochondrial ROS in cardiomyocytes induced by AKR1C3 knockdown under hypoxic conditions. Mechanically, AKR1C3 increases Nrf-2 expression through the ubiquitin-proteasome pathway in cardiomyocytes and subsequently inhibits the NF-κB signaling pathway, thereby inhibiting Bax/caspase-3 signaling. Collectively, these results suggest that AKR1C3 prevents hypoxia-induced cardiomyocyte injury by modulating the Nrf-2/NF-κB axis, suggesting new insights into the mechanisms underlying myocardial protection.

Doxorubicin (DOX) is the most effective chemotherapeutic for breast cancer, but it is usually associated with severe cardiotoxicity. Further investigation to alleviate its side effects is essential. The present study investigated the mechanism of the cross-organ communication between tumors and the heart and potential intervention targets. Morphological bubble-like protrusions were observed in both adult murine ventricular cardiomyocytes (AMVCs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cocultured with breast cancer cells (BCCs), along with elevated expression of pyroptosis-related proteins. Exosomes (EXOs) from DOX-treated BCCs aggravated DOX-induced cardiotoxicity (DOXIC) in an orthotopic mouse model of breast cancer. Blocking miRNAs by knocking down Rab27a or inhibiting the release of EXOs in cancer tissue by Dicer enzyme knockout attenuated this additional injury effect. Exosomal miRNA sequencing revealed that miR-216a-5p is especially upregulated in EXOs from DOX-induced BCCs. Mechanistically, miR-216a-5p was upregulated by enhanced transcription mediated by DOX-induced AMP-dependent transcription factor 3 (ATF3) and packaged into EXOs by splicing factor 3b subunit 4 (SF3B4) in BCCs. Itchy E3 ubiquitin-protein ligase (ITCH) was identified as a novel downstream target mRNA of miR-216a-5p. ITCH negatively mediated thioredoxin-interacting protein (TXNIP) ubiquitination to activate the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway, ultimately leading to cardiomyocyte pyroptosis. Our findings revealed novel cross-organ pathogenic communication between breast cancer and the heart through the exosomal miR-216a-5p-mediated ITCH/TXNIP/NLRP3 pathway, which drives cardiomyocyte pyroptosis. These findings suggest that targeting myocardial miR-216a-5p or blocking harmful EXOs from breast cancer is a potential therapeutic strategy for alleviating DOXIC.

Sepsis is the body's response to infection, which can result in multiple organ failure. The immune imbalance in patients with sepsis leads to high mortality. Recent research has greatly advanced our understanding of sepsis pathophysiology, especially in the regulation of inflammatory pathways and immune suppression. S100A9, an alarmin, plays a critical role in modulating the immune response during sepsis and is associated with the potential for multiple organ dysfunction. In the early stage of sepsis, S100A9 can represent the occurrence of inflammation, while in the late stage of sepsis, S100A9 is related to immune suppression. This review summarizes the latest developments in S100A9 research, including its biological functions, role in immune responses, effects on organ damage across different systems during sepsis, and potential clinical applications. It provides insights into the interactions between S100A9 and the immune response and explores S100A9's involvement in sepsis-associated organ injuries. Additionally, this review outlines a framework for future applications of targeted S100A9 interventions and therapeutic strategies to reduce organ injury in sepsis.

Cardiomyocyte death is a major cytopathologic response in acute myocardial infarction (AMI) and involves complex inflammatory interactions. Although existing reports indicating that mixed lineage kinase domain-like protein (MLKL) is involved in macrophage necroptosis and inflammasome activation, the downstream mechanism of MLKL in necroptosis remain poorly characterized in AMI. MLKL knockout mice (MLKLKO), RIPK3 knockout mice (RIPK3KO), and macrophage-specific MLKL conditional knockout mice (MLKLM−KO) were established. AMI was induced by coronary artery ligation. The role of MLKL in regulating myocardial morphological necroptosis was evaluated using immunofluorescence staining, flow cytometry, qRT-PCR, Western blot, CCK-8 assay, and ELISA. Our findings revealed that myocardial segmental necroptosis (MSN), a unique morphological characteristics of cell death observed post-AMI, was promoted by intercellular inflammatory adhesion mediated by MLKL. The key features of MSN included localized cytomembrane perforation, segmental attenuation of myofilaments, MLKL-mediated filling, and macrophage inflammatory adhesion. In a mouse model of AMI, we observed MSN, which was absent in immunosuppressed mice. Pharmacological depletion of macrophages or genetic knockout of macrophage-specific MLKL (MLKLM−KO) reduced the occurrence of MSN. This reduction was reversed upon reinfusion of wild-type macrophages. Additionally, myocardial injury was significantly ameliorated in MLKLM−KO mice following AMI. In a macrophage-cardiomyocyte co-culture system, MLKLM−KO attenuated hypoxia-induced MSN and inhibited macrophage-mediated inflammatory adhesion. Furthermore, MLKL was found to trigger the formation of membrane pores and the polymerization of integrin αvβ1, thereby enhancing inflammatory adhesion in the co-culture system. Notably, MLKL-enhanced inflammatory adhesion was not entirely dependent on RIPK3. Our study demonstrates that MLKL is directly involved in myocardial segmental necroptosis by interacting with macrophages through inflammatory adhesion, and possibly independently of RIPK3.

Damage to glycocalyx and tight junction are key determinants of endothelial permeability, which is the main pathological feature of acute respiratory distress syndrome (ARDS). However, the effect of glycocalyx heparan sulfate (HS) on tight junction proteins occludin and ZO-1 has not been revealed. In this study, the mice exposed to LPS results showed that FITC-albumin infiltration, HS shedding, and tight junction protein impairment were most severe at 6 h of LPS treatment compared with those in other treatment times. The in vitro and vivo experiments revealed that tight junction damage, FITC-albumin infiltration, and pathological injury induced by LPS were significantly alleviated via protection of glycocalyx HS shedding. mRNA sequencing analysis demonstrated that the STAT signaling pathways played a crucial role in the inhibition of LPS-induced HS shedding in mice. Supplementation of exogenous HS in human umbilical vein endothelial cells (HUVECs) and mice ameliorated LPS-induced the tight junction barrier defect by inhibiting STAT3 phosphorylation. Further analysis uncovered that intervention of STAT3 signaling significantly alleviated LPS-induced tight junction proteins damage and vascular permeability in HUVECs and mice. Mechanistically, HS modulated tight junction proteins by STAT3 signaling, which might directly bind to the promoter regions of occludin and ZO-1. In conclusion, glycocalyx HS played an important role in protecting endothelial barrier function and preventing injury development, in synergy with tight junction through STAT3 signaling, which further alleviated pulmonary edema.

Background The number and proportion of the elderly population have been continuously increasing in China, leading to the elevated prevalence of chronic diseases and multimorbidity, which ultimately brings heavy burden to society and families. Meanwhile, the status of multimorbidity tends to be more complex in elderly inpatients than community population. In view of the above concerns, this study was designed to investigate the health status of elderly inpatients by analyzing clinical data in Chinese People's Liberation Army (PLA) General Hospital from 2008 to 2019, including the constitution of common diseases, comorbidities, the status of multimorbidity, in-hospital death and polypharmacy among elderly inpatients, so as to better understand the diseases spectrum and multimorbidity of elderly inpatients and also to provide supporting evidence for targeted management of chronic diseases in the elderly. Methods A clinical inpatients database was set up by collecting medical records of elderly inpatients from 2008 to 2019 in Chinese PLA General Hospital, focusing on diseases spectrum and characteristics of elderly inpatients. In this study, we collected data of inpatients aged ≥ 65 years old, and further analyzed the constitution of diseases, multimorbidity rates and mortality causes in the past decade. In addition, the prescriptions were also analyzed to investigate the status of polypharmacy in elderly inpatients. Results A total of 210,169 elderly patients were hospitalized from January 1st, 2008 to December 31st, 2019. The corresponding number of hospitalizations was 290,833. The average age of the study population was 72.67 years old. Of the total population, 73,493 elderly patients were re-admitted within one year, with the re-hospitalization rate of 25.27%. Malignant tumor, hypertension, ischemic heart disease, diabetes mellitus and cerebrovascular disease were the top 5 diseases. Among the study population, the number of patients with two or more long-term health conditions was 267,259, accounting for 91.89%, with an average of 4.68 diseases. In addition, the average number of medications taken by the study population was 5.4, among which, the proportion of patients taking more than 5 types of medications accounted for 55.42%. Conclusions By analyzing the constitution of diseases and multimorbidity, we found that multimorbidity has turned out to be a prominent problem in elderly inpatients, greatly affecting the process of healthy aging and increasing the burden on families and society. Therefore, multidisciplinary treatment should be strengthened to make reasonable preventive and therapeutic strategies to improve the life quality of the elderly. Meanwhile, more attention should be paid to reasonable medications for elderly patients with multimorbidity to avoid preventable side effects caused by irrational medication therapy.

Background: The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety. Methods: From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions. Results: Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13–1.18; p = 1.29 × 10-31), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13–1.20; p = 4.73 × 10-24), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90–0.96; p = 1.08 × 10-5), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90–0.94; p = 8.05 × 10-13), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03–1.07; p = 1.41 × 10-5). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects. Conclusions: Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.

目的 探讨不同术式对胰十二指肠切除患者术后早期症状性血栓发生的影响.方法 2016年9月—2018年6月,采用便利抽样法选取中国医学科学院北京协和医院的111例行胰十二指肠切除术的患者为研究对象,按照术式将其分为腹腔镜组(47例)及开腹组(64例).比较两组术毕即刻及术后第1、2、3、7天的D-二聚体值及术后早期症状性血栓的发生情况.结果 重复测量方差分析结果显示,两组术毕即刻及术后第1、2、3、7天D-二聚体值比较存在组间、时间效应,差异均有统计学意义(P＜0.05).两组症状性血栓发生情况比较差异无统计学意义(P=0.62).结论 胰十二指肠切除术后早期症状性血栓的发生风险持续增高,腹腔镜在改善胰十二指肠切除术后早期症状性血栓风险方面无明显优势.

目的 比较不同检测方法基于局部热充血的2型糖尿病周围神经病变预测模型性能,为临床早期筛查提供参考.方法 纳入174例2型糖尿病患者,在试验局部加热至44℃并使用激光多普勒血流仪测量血流变化率.同时进行临床5项筛查、震动感觉阈值测定和神经传导检查,根据各自的诊断标准,采用多因素logistic回归分析探讨糖尿病周围神经病变的影响因素.以神经传导检查为"金标准",筛选最优模型构建列线图预测模型.结果 3种检测方法均提示,血流变化率、糖尿病病程、糖尿病肾病、糖化血红蛋白是糖尿病周围神经病变的影响因素(均P＜0.05).根据临床5项筛查结果建立的logit模型性能最好,据此构建的列线图模型具有较好的准确度(Hosmer-Lemeshow检验x2=11.147,P＞0.05)和区分度(AUC=0.872).结论 血流变化率、糖尿病病程、糖尿病肾病和糖化血红蛋白是糖尿病周围神经病变的影响因素.以临床5项筛查结果构建的列线图模型具有良好的诊断效能,可为临床筛选、识别糖尿病周围神经病变患者提供参考.

ObjectiveThis study aims to investigate novel clinical risk factors for cognitive impairment (CI) in elderly.MethodsA total of 3221 patients (259 patients with CI and 2,962 subjects without CI) were recruited into this nested case-control study who underwent cerebral magnetic resonance angiography (MRA) from 2007 to 2021. All of the clinical data with MRA imaging were recorded followed by standardization processing blindly. The maximum stenosis score of the posterior circulatory artery, including the basilar artery, and bilateral posterior cerebral artery (PCA), was calculated by the cerebral MRA automatic quantitative analysis method. Logistic regression (LR) analysis was used to evaluate the relationship between risk factors and CI. Four machine learning approaches, including LR, decision tree (DT), random forest (RF), and support vector machine (SVM), employing 5-fold cross-validation were used to establish CI predictive models.ResultsAfter matching with age and gender, 208 CI patients and 208 control subjects were finalized the follow-up (3.46 ± 3.19 years) with mean age at 84.47 ± 6.50 years old. Pulse pressure (PP) in first tertile (<58 mmHg) (OR 0.588, 95% confidence interval (CI): 0.362–0.955) was associated with a decreased risk for CI, and ≥50% stenosis of the left PCA (OR 2.854, 95% CI: 1.387–5.872) was associated with an increased risk for CI after adjusting for body mass index, myocardial infarction, and stroke history. Based on the means of various blood pressure (BP) parameters, the performance of the LR, DT, RF and SVM models accurately predicted CI (AUC 0.740, 0.786, 0.762, and 0.753, respectively) after adding the stenosis score of posterior circulatory artery.ConclusionElderly with low pulse differential pressure may have lower risk for cognitive impairment. The hybrid model combined with the stenosis score of posterior circulatory artery, clinical indicators, and the means of various BP parameters can effectively predict the risk of CI in elderly individuals.

Deubiquitinases (DUBs) play important roles in various human cancers and targeting DUBs is considered as a novel anticancer therapeutic strategy. Overexpression of ubiquitin specific protease 7 and 22 (USP7 and USP22) are associated with malignancy, therapy resistance, and poor prognosis in many cancers. Although both DUBs are involved in the regulation of similar genes and signaling pathways, such as histone H2B monoubiquitination (H2Bub1), c-Myc, FOXP3, and P53, the interdependence of USP22 and USP7 expression has never been described. In the study, we found targeting USP7 via either siRNA-mediated knockdown or pharmaceutical inhibitors dramatically upregulates USP22 in cancer cells. Mechanistically, the elevated USP22 occurs through a transcriptional pathway, possibly due to desuppression of the transcriptional activity of SP1 via promoting its degradation upon USP7 inhibition. Importantly, the elevated USP22 leads to significant activation of downstream signal pathways including H2Bub1 and c-Myc, which may potentially enhance cancer malignancy and counteract the anticancer efficacy of USP7 inhibition. Importantly, targeting USP7 further suppresses the in vitro proliferation of USP22-knockout (USP22-Ko) A549 and H1299 lung cancer cells and induces a stronger activation of P53 tumor suppressor signaling pathway. In addition, USP22-Ko cancer cells are more sensitive to a combination of cisplatin and USP7. USP7 inhibitor treatment further suppresses the in vivo angiogenesis and growth and induced more apoptosis in USP22-Ko cancer xenografts. Taken together, our findings demonstrate that USP7 inhibition can dramatically upregulate USP22 in cancer cells; and targeting USP7 and USP22 may represent a more effective approach for targeted cancer therapy, which warrants further study. Citation Format: Keqiang Zhang, Ting Sun, Wendong Li, Jun Wu, Dan Raz. Inhibition of USP7 upregulates USP22 through desuppression of transcriptional activity of Sp1 in human cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3939.

Objective:A clinical diagnostic model of gastric low-grade intraepithelial neoplasia (LGIN) was developed and validated to improve the identification of precancerous lesions in gastric cancer.Methods:A retrospective analysis of 1211 patients with chronic atrophic gastritis (CAG) and 1089 patients with LGIN admitted to the Endoscopy Center of the First Affiliated Hospital of Bengbu Medical College from January 2016 to December 2021 was performed to record basic clinical and pathological information.A total of 1756 patients were included after screening and were divided unequally and randomly into 2 groups, one for establishing an LGIN predictive nomogram (70% of patients) and the other for external validation of the model (30% of patients). R software was used for statistical analysis.Methods:A retrospective analysis of 1211 patients with chronic atrophic gastritis (CAG) and 1089 patients with LGIN admitted to the Endoscopy Center of the First Affiliated Hospital of Bengbu Medical College from January 2016 to December 2021 was performed to record basic clinical and pathological information.A total of 1756 patients were included after screening and were divided unequally and randomly into 2 groups, one for establishing an LGIN predictive nomogram (70% of patients) and the other for external validation of the model (30% of patients). R software was used for statistical analysis.Results:The nomogram was built with 10 predictors: age, sex, lesion location, intestinal metaplasia, multiple location, lesion size, erosion, edema, surface white fur, and form. The calibration curves showed good agreement between the predicted and actual diagnoses. The C-indexes were 0.841 (95% CI: 0.820-0.863) in the training dataset, 0.833 in the internal validation dataset, and 0.842 in the external validation dataset (Hosmer-Lemeshow test, P = .612), showing satisfactory stableness.Conclusions:This study provides a visual mathematical model that can be used to diagnose high-risk LGIN, improve follow-up or endoscopic treatment and the detection rate of precancerous gastric cancer lesions, reduce the incidence of gastric cancer, and provide a reliable basis for the treatment of LGIN.

Objective:To analyze the mutation types and distribution characteristics of thalassemia gene among high-risk populations in Sanya City, and to evaluate the effectiveness of blood routine screening, in order to provide scientific basis for formulating measures for prevention and control of thalassemia in Sanya City.Methods:Retrospective analysis was used to collect detection results and clinical data from high-risk individuals who completed genetic screening for thalassemia at Sanya Materal and Child Health Hospital from January 2019 to August 2021. Mutation types and distribution characteristics of thalassemia gene were analyzed, and the missed detection rate and sensitivity of blood routine indicators [mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH)] were evaluated based on the results of genetic screening for thalassemia.Results:A total of 5 760 high-risk individuals were included in the screening results of thalassemia genes, and 3 868 samples of thalassemia gene mutations were detected, with a detection rate of 67.15%. Among them, there were 2 979 samples with α-thalassemia genetic mutations, with a detection rate of 51.72%; including 2 966 common genotype samples (99.56%), the main genotype was αα/-α 3.7 (20.14%, 600/2 979); 13 rare genotype samples (0.44%), 4 cases of αα/-- THAI, 3 cases of α CD40(AAG>AA-)α/αα, 2 cases of α PPα/αα, and 1 case of Fusion gene/αα, Fusion gene/α WSα, α WSα/α PPα, and α CD40(AAG>AA-)α/α WSα each. There were 340 samples with β-thalassemia gene mutations, with a detection rate of 5.90%; including 336 common genotype samples (98.82%). The β CD41/42/β N genotype was dominant (57.65%, 196/340); 4 rare genotype samples (1.18%), β CD5(-CT)/β N, β IVS-Ⅱ-2(-T)/β N, β IVS-Ⅱ-761(-T)/β N and β Initiation(ATG>AGG)/β N 1 case each. There were 549 samples of αβ-compound type thalassemia, with a detection rate of 9.53%. The α missing recombination β CD41/42 genotype was dominant (61.02%, 335/549). There were a total of 4 226 samples that could be traced back to MCV and MCH. Among them, 3 007 samples were found to have mutations in thalassemia genes through screening, 2 584 cases were found to have abnormalities in the combination of MCV and MCH indicators, and 423 samples were missed in blood routine screening, with a missed detection rate of 14.07% (423/3 007). The missed samples were mainly α static type, accounting for 89.13% (377/423) of the total missed samples. The screening sensitivity of MCV combined with MCH for α-, β- and αβ-compound type thalassemia was 82.65%, 98.07% and 98.15%, respectively. Conclusion:The types of genetic mutations in thalassemia in Sanya City are complex and diverse, and there are certain omissions in the blood routine screening of MCV combined with MCH.

Introduction: Aging is a complex phenomenon that involves multifaceted changes, including significant alterations in telomere length and epigenetic aging. When aging affects the hematopoietic system, it leads to a gradual increase in mutations in hematopoietic stem cells, making individuals more susceptible to the development of hematologic diseases. However, due to the limitations of observational studies, such as potential confounding factors and reverse causality, the precise causal direction and magnitude of the relationship between telomere length, epigenetic aging, and the incidence of hematologic diseases remain uncertain. Therefore, we conducted an investigation to determine the causal relevance of telomere length and epigenetic aging in relation to hematologic diseases using Mendelian randomization (MR). Methods: Firstly, we conducted a 2-sample single-variable Mendelian randomization (SVMR) study to examine the genetically predicted effects of telomere length and epigenetic age acceleration, as measured by HannumAge, Horvath Intrinsic Age, PhenoAge, GrimAge, and DNAm PAI-1 (DNA methylation-estimated plasminogen activator inhibitor-1) levels, on multiple hematologic diseases, including anemia, lymphoma, leukemia, myeloproliferative diseases, and hemostasis and coagulation diseases. Additionally, we used lasso regression to exclude multicollinearity in SNPs and subsequently performed multivariable MR using the screened SNPs to adjust for statistically significant risk factors, and MR Bayesian model averaging was performed to rank the significant risk factors based on their genetic evidence (Figure A). Results: Summary data were available for 19 malignant hematological neoplasms and 35 non-malignant hematological disorders, corresponding to 70,813 cases and 12,253,012 controls. Increased telomere length due to germline genetic variation was generally associated with increased risk for hematologic diseases. The strongest associations were observed for lymphoma, lymphoid leukaemia, Hodgkin lymphoma, chronic lymphocytic leukaemia, essential thrombocythaemia, unspecified types of non-Hodgkin lymphoma, multiple myeloma, Non-follicular lymphoma, unspecified iron deficiency, leukaemia, while higher levels of telomere length was associated with a reduced risk of pernicious anaemia (Figure B). Meta-analyzed IVW MR findings suggested that higher PhenoAge acceleration was associated with increased risks of myeloid leukemia, chronic lymphocytic leukemia, and lymphoid leukemia. Conversely, higher PhenoAge acceleration was linked to reduced risks of unspecified disorders of white blood cells and unspecified coagulation defects. Similarly, SVMR showed genetic predisposition for GrimAge acceleration to be associated with increased risks of amyloidosis, unspecified anemias, and myeloid leukemia. Conversely, genetically predicted GrimAge acceleration was associated with reduced risks of hemorrhagic anemia, hemolytic anemias, and idiopathic thrombocytopenic purpura. Furthermore, our findings suggested that elevated HannumAge acceleration increased the risks of lymphoma, leukemia, and lymphoid leukemia.Conversely, higher HannumAge acceleration was associated with a reduced risk of chronic myeloid leukemia. Additionally, higher levels of DNAm PAI-1 were found to be associated with an increased risk of chronic myeloid leukemia. However, there was no evidence of causality between genetically predicted Intrinsic epigenetic age acceleration and the 19 malignant hematological neoplasms and 35 non-malignant hematological disorders mentioned (Figure C). We utilized MVMR-LASSO to estimate the combined effects of telomere length and five epigenetic clocks on hematologic diseases. After adjusting for epigenetic aging, we observed a significant positive association between telomere length and various hematologic diseases, including leukemia, lymphoid leukemia, chronic lymphocytic leukemia, lymphomas, Hodgkin lymphoma, non-follicular lymphoma, unspecified types of non-Hodgkin lymphoma, essential thrombocythemia, and multiple myeloma (Figure D&E). Conclusion: Longer telomeres and epigenetic aging may increase the risk of developing most hematologic malignancies, while simultaneously raising or decreasing the risk of certain non-malignant hematologic diseases.

Objective The cancer patients with severe acute respiratory distress syndrome (ARDS) benefit from extracorporeal membrane oxygenation (ECMO) remains unanswered. We analyzed clinical characteristics and outcomes of pediatric patients with leukemia/lymphoma who developed ARDS and treated with ECMO. Methods Pediatric leukemia or lymphoma patients with ARDS who underwent ECMO between August 2017 and December 2021 were retrospectively analyzed in a tertiary pediatric intensive care unit (PICU). Results Seven patients with median age 53 (IQR 42–117) months and 4 males were included. Six cases of leukemia [5 of acute lymphocytic leukemia (ALL) and 1 of acute myelogenous leukemia (AML, M5)] and 1 of non-Hodgkin lymphoma with severe ARDS received ECMO on chemotherapy period. The etiology of ARDS is community or chemotherapy-associated bacterial or/and fungal or viral infection. All the patients received chemotherapy in the 2 weeks prior to ECMO and five were neutropenic at initial ECMO. Six cases underwent veno-arterial ECMO (VA ECMO) and 1 for veno-venous ECMO (VV-ECMO). The median duration of ECMO support was 122 (IQR 56–166) hours. Overall, 42.9% (three of seven) survived to hospital discharge and 6 months survival rate was 28.6% (two of seven). Bleeding was the main ECMO-associated complication occurring in 7 patients, followed by nosocomial infection in 4 cases. All the patients required vasopressor support, and 6 received continuous renal replacement therapy (CRRT). Conclusion Our experiences suggest that rescue ECMO provides a selective treatment strategy in childhood hematologic malignancies with severe ARDS.

Background: Extracorporeal therapy that included therapeutic plasma exchange (TPE) or continuous hemofiltration (CHF) for toxic epidermal necrolysis (TEN) syndrome was used in small number of patients. We aimed to describe the sequential mode of combined application of CHF and TPE in 3 TEN patients with multiple organ dysfunction (MODS) in pediatric intensive care unit. Methods: Three patients with fatal TEN received sequential CHF and TPE due to unsatisfactorily conventional treatments. CHF was initiated and performed on a daily basis with 35–50 mL/kg.h replacement fluid at the rate of 3–5 mL/kg.min blood flow. CHF was temporarily interrupted for TPE, which was performed with exchange 1–1.5-fold of one body calculated plasma volume in each section. Results: All 3 fatal TEN (with >30% involvement of body surface and MODS) following unsuccessful treatment with corticosteroids and intravenous immunoglobulin. Antibiotics were suspected in the TEN-triggered drugs. The range number of TPE sessions was 3–5 and the duration of CHF was from 120 h to 202 h. After initiation of TPE and CHF, blistering with extensive epidermal necrosis halted and the skin re-epithelialized within 2 weeks. Serum C-reactive protein, procalcitonin, tumor necrosis factor-α , and interlukin-6 decreased and percentage of natural killer cells increased in surviving children. Two patients survived to discharge and one case died due to nosocomial infection with multidrug-resistant Acinetobacter baumannii. Conclusion: After sequential TPE and CHF, skin lesions and inflammatory response improved in TEN. Our result indicates extracorporeal therapy could be used as an alternative modality for fatal pediatric TEN.

幽门螺杆菌(Hp)感染是导致胃癌发生的重要原因,但是Hp感染与异时性胃癌(MGC)之间的关系仍然存在争议.Hp感染被认为是早期胃癌(EGC)患者经内镜下切除治疗后MGC发病的重要危险因素,根除Hp是降低MGC发病率的有效方法,但是Hp根除后仍需要实施密切的内镜监测以预防MGC发生.该文就Hp感染相关MGC的发病机制和临床研究进展作一综述,以期为MGC的防治提供新的思路.