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Deamidation enables pathogenic SMAD6 variants to activate the BMP signaling pathway

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Science China Life Sciences 2024年第9期67卷 1915-1927页

作者： Ling Li Lei Lu Ziqi Xiao Jingyi Lv Hefeng Huang Bo Wu Tongjin Zhao Chengtao Li Weimin Wang Hongyan Wang Obstetrics and Gynecology Hospital State Key Laboratory of Genetic Engineering Institute of Reproduction and Development and Children's Hospital Fudan University Shanghai Key Laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative Biology Fudan University prenatal diagnosis center of Shenzhen Maternity & Child Healthcare Hospital Shanghai Medical College Fudan University department of Pharmacy College of Life Sciences China Jiliang University

The BMP signaling pathway plays a crucial role in regulating early embryonic development and tissue homeostasis. SMAD6 encodes a negative regulator of BMP, and rare variants of SMAD6 are recurrently found in individuals with birth defects. However, we observed that a subset of rare pathogenic variants of SMAD6 consistently exhibited positive regulatory effects instead of the initial negative effects on the BMP signaling pathway. We sought to determine whether these SMAD6 variants have common pathogenic mechanisms. Here, we showed that pathogenic SMAD6 variants accompanying this functional reversal exhibit similar increases in deamidation. Mechanistically, increased deamidation of SMAD6 variants promotes the accumulation of the BMP receptor BMPR1A and the formation of new complexes, both of which lead to BMP signaling pathway activation. Specifically, two residues, N262 and N404, in SMAD6 were identified as the crucial sites of deamidation, which was catalyzed primarily by glutamine-fructose-6-phosphate transaminase 2(GFPT2). Additionally, treatment of cells harboring SMAD6 variants with a deamidase inhibitor restored the inhibitory effect of SMAD6 on the BMP signaling pathway. Conversely,when wild-type SMAD6 was manually simulated to mimic the deamidated state, the reversed function of activating BMP signaling was reproduced. Taken together, these findings show that deamidation of SMAD6 plays a crucial role in the functional reversal of BMP signaling activity, which can be induced by a subset of various SMAD6 variants. Our study reveals a common pathogenic mechanism shared by these variants and provides a potential strategy for preventing birth defects through deamidation regulation, which might prevent the off-target effects of gene editing.

关键词： SMAD6 deamidation BMP signaling pathway GFPT2

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Gene expression profiles contribute to robustly predicting prognosis in hepatocellular carcinoma

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Genes & Diseases 2024年第2期11卷 593-596页

作者： Long Liu Yuhui Wang Yuyuan Zhang Siyuan Weng Hui Xu Zaoqu Liu Xinwei Han department of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China prenatal diagnosis center The Third Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China department of Interventional Radiology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Interventional Institute of Zhengzhou University ZhengzhouHenan 450052China Interventional Treatment and Clinical Research center of Henan Province ZhengzhouHenan 450052China

Hepatocellular carcinoma(HCC)is characterized by both inter-and intra-tumor heterogeneity and has distinct clinical outcomes.1 A promising clinical tool to perform patient stratification,prognosis evaluation,and treatment recommendations is ***,we enrolled a total of 1595 tumor patients from 13 independent cohorts,including seven cohorts with survival data,four cohorts with immunotherapy information,and two cohorts with transcatheter arterial chemoembolization(TACE)and Sorafenib information,respectively(Table S1).Using 96 algorithms combinations derived from 10 popular machinelearning approaches,a novel framework was constructed and described in Figure ***,a total of 26 stable consensus prognostic genes were screened in seven cohorts harboring complete survival information via univariate Cox regression analysis(Fig.S2A).

关键词： prognosis clinical arterial

Bimetallic nanoparticles as cascade sensitizing amplifiers for low-dose and robust cancer radio-immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1787-1800页

作者： Yupeng Wang Lina Wang Tao Li Min Ouyang Hejian Xiong Dongfang Zhou department of Ultrasonic diagnosis Zhujiang HospitalKey Laboratory of Mental Health of the Ministry of EducationNMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Testing and Analysis center Hebei Normal UniversityShijiazhuang 050024China department of Mechanical Engineering The University of Texas at DallasRichardsonTX 75080USA

Radiotherapy(RT)is one of the most feasible and routinely used therapeutic modalities for treating malignant *** particular,immune responses triggered by RT,known as radio-immunotherapy,can partially inhibit the growth of distantly spreading tumors and recurrent ***-ever,the safety and efficacy of radio-immunotherapy is impeded by the radio-resistance and poor immu-nogenicity of ***,we report oxaliplatin(IV)-iron bimetallic nanoparticles(OXA/Fe NPs)as cascade sensitizing amplifiers for low-dose and robust *** OXA/Fe NPs exhibit tumor-specific accumulation and activation of OXA(I)and Fe^(2+)in response to the reductive and acidic microenvironment within tumor *** cascade reactions of the released metallic drugs can sensitize RT by inducing DNA damage,increasing ROS and O_(2) levels,and amplifying the immunogenic cell death(ICD)effect after RT to facilitate potent immune *** a result,OXA/Fe NPs-based low-dose RT triggered a robust immune response and inhibited the distant and metastatic tumors effectively by a strong abscopal ***,a long-term immunological memory effect to protect mice from tumor rechal-lenging is ***,the bimetallic NPs-based cascade sensitizing amplifier system offers an effi-cient radio-immunotherapy regimen that addresses the key challenges.

关键词： Bimetallic nanoparticles Radio-immunotherapy Cascade sensitizing amplifier,Oxaliplatin Fenton-typeHaber-Weiss reaction Radiosensitization Immunogenic cell death Radio-resistance

Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4

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Genes & Diseases 2024年第4期11卷 411-425页

作者： Mengmeng Guo Pan Hu Jiayi Xie Kefu Tang Shixiu Hu Jialiang Sun Yundong He Jing Li Weiqiang Lu Huirong Liu Mingyao Liu Zhengfang Yi Shihong Peng Shanghai Key Laboratory of Regulatory Biology School of Life SciencesEast China Normal UniversityShanghai 200241China prenatal diagnosis center Department of Clinical LaboratoryChangning Maternity and Infant Health HospitalEast China Normal UniversityShanghai 200051China Key Laboratory of Acupuncture and Immunological Effects Shanghai University of Traditional Chinese MedicineShanghai 201203China Fengxian Hospital Affiliated to Southern Medical University Shanghai 201400China Shanghai Yuyao Biotech Co. Ltd.Shanghai 200241China

Gastric cancer is highly prevalent among digestive tract *** to the intri-cate nature of the gastric cancer immune microenvironment,there is currently no effective treatment available for advanced gastric ***,there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4(EP4)in gastric *** our previous study,we identified a novel small molecule EP4 receptor antagonist called *** with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse ***,adminis-tration of YYo01 stimulated a robust immune response within the tumor microenvironment,characterized by increased infiltration of antigen-presenting cells,T cells,and M1 ***,our research revealed that YYo01 exhibited remarkable synergistic ef-fects when combined with the PD-1 antibody and the clinically targeted drug apatinib,rather than *** findings suggest that YYo01 holds great promise as a potential therapeutic strategy for gastric cancer,whether used as a standalone treatment or in combination with other drugs.

关键词： EP4 Immunomodulation Synergy Tumor microenvironment YY001

SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation

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Cancer Communications 2024年第3期44卷 384-407页

作者： Shiyu Zhang Xing Jia Haojiang Dai Xingxin Zhu Wenfeng Song Suchen Bian Hao Wu Shinuo Chen Yangbo Tang Junran Chen Cheng Jin Mengqiao Zhou Haiyang Xie Shusen Zheng Penghong Song Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China National Health Commission Key Laboratory of Combined Multi-organ Transplantation HangzhouZhejiangP.R.China Key Laboratory of the diagnosis and Treatment of Organ Transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical SciencesHangzhouZhejiangP.R.China Key Laboratory of Organ Transplantation Research Center for Diagnosis and Treatment of Hepatobiliary DiseasesHangzhouZhejiangP.R.China State Key Laboratory for diagnosis and Treatment of Infectious Diseases First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP.R.China

Background:Liver cancer is a malignancy with high morbidity and mortality *** family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many *** this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer ***:The Cancer Genome Atlas database(TCGA),including DNA methy-lation and transcriptome sequencing data,was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver *** from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clin-ical parameters of *** methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and *** sequencing,cytokine assays,immunoprecipitation(IP)and mass spectrometry(MS)assays,protein stability assays,and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer ***-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using ***:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA ***2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver ***2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and ***/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with ***,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,***,EGFR was activated in liver cancer cells after sorafenib treatment,and SER

关键词： liver cancer metastasis DNA methylation SERPINE2 EGFR c-Cbl ubiquitination

Role of inflammatory markers in the evaluation of indeterminate pulmonary nodules:a review

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Clinical Research Communications 2024年第3期7卷 48-52页

作者： Qiao-Li Wang Xiao-Qin Liu Ting Wang department of Health screening center Deyang Peoples'HospitalDeyang 618000China.

The global mortality rate of lung cancer surpasses that of any other type of cancer,establishing it as the foremost cause of cancer-related deaths *** objectives of lung nodule assessment are to expedite the diagnosis and treatment of patients with malignant nodules while minimizing unnecessary diagnostic procedures for those with benign *** systemic inflammatory response is closely linked to *** levels of inflammatory markers and their derived parameters markers including neutrophil-to-lymphocyte ratio(NLR),lymphocyte-to-monocyte ratio(LMR),monocyte-to-albumin ratio(MAR),platelet-to-lymphocyte ratio(PLR)and systemic immune‐inflammation index(SII),closely associated with lung *** objective of this article is to comprehensively evaluate the differentiation between benign and malignant pulmonary nodules in terms of inflammatory response indicators,aim at provide practical recommendations for the clinical diagnosis,treatment,and management of pulmonary nodules.

关键词： lung nodules inflammatory makers lung cancer

Global, regional, and national burden of early-onset gastric cancer

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Cancer Biology & Medicine 2024年第8期 667-678页

作者： Nuopei Tan Hongliang Wu Maomao Cao Fan Yang Xinxin Yan Siyi He Mengdi Cao Shaoli Zhang Yi Teng Qianru Li Jiachen Wang Changfa Xia Wanqing Chen department of Cancer screening National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical College department of Anesthesiology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College

Objective: The burden of gastric cancer(GC) across different age groups needs updating. We determined the GC global, regional, and national burden profiles and changes in incidence for 3 sequential 5-year intervals from 2003 to ***: The latest incidence and mortality estimates of GC from 185 countries and regions were extracted from the GLOBOCAN 2022 database. The 5-year interval age-standardised incidence rates(ASIRs) were evaluated using cancer registry data from volumes X±XII of the Cancer Incidence in Five Continents(CI5). Correlation analysis was used to evaluate the relationship between ASIR or the age-standardised mortality rate(ASMR) and the Human Development Index(HDI).Results: There was an estimated global 968,000 new GC cases and 660,000 deaths in 2022, with male predominance. GC ASIRs and ASMRs were 9.2 and 6.1 per 100,000 persons, respectively. East Asia had the highest burden, with 53.8% of cases and 48.2% of deaths among all geographic regions. There was a significant correlation between ASIR and HDI. Over three 5-year intervals from 2003 to 2017, the incidence of GC notably decreased in most countries but peaked at 2008±2012 in New Zealand, Turkey, and South Africa. Several countries in Europe, Oceania, and America suggest an increasingly concerning trend among younger individuals, especially ***: GC is a significant health issue, especially among males and in geographic regions with an HDI, such as eastern Asia. While the incidence of GC is decreasing in many countries due to prevention efforts and improved treatments, a rising trend persists among younger individuals. Comprehensive prevention strategies tailored to different age patterns are clearly needed.

关键词： GLOBOCAN Gastric cancer cancer burden incidence mortality

Prognosis and outcome of intrauterine treatment of fetuses with critical congenital heart disease

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Chinese Medical Journal 2024年第12期137卷 1431-1436页

作者： Liqing Zhao Lei Wang Hongping Xia Yurong Wu Xianting Jiao Hong Zhu Sun Chen Kun Sun department of Pediatric Cardiology Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China department of diagnosis and Treatment center for in utero Pediatric Disease Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China department of Neonatology Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China

Background:Intrauterine valvuloplasty is an innovative therapy,which promotes ventricular growth and function in some congenital heart diseases(CHDs).The technique remains challenging and can only be performed in a few *** study aimed to assess the feasibility and mid-term outcomes of fetal cardiac intervention(FCI)in fetuses with critical CHD in an experienced tertiary ***:Five fetal aortic valvuloplasty(FAV)or fetal pulmonary valvuloplasty(FPV)procedures were performed in our fetal heart center between August 2018 and May *** success was defined as crossing the aortic or pulmonary valve and balloon inflation,followed by evidence of increased blood flow across the valve and/or new ***-up clinical records and echocardiography were obtained during the prenatal and postnatal ***:Five fetuses received FAV or FPV,including critical aortic stenosis(n=2)and pulmonary atresia with intact ventricular septum(n=3).The mean maternal age was 33.0±2.6 *** median gestational age(GA)at diagnosis was 24 weeks(range,22-26 weeks).The median GA at intervention was 29 weeks(range,28-32 weeks).All five cases underwent successful or partially successful *** patient had pulmonary valve perforation without balloon *** procedure-related deaths or significant complications ***,one neonatal death occurred due to heart and renal *** median follow-up period was 29.5 months(range,8.0-48.0 months).The four surviving patients had achieved biventricular circulation,exhibited improved valve,and ventricular development at the last follow-up ***:Intrauterine FCI could be performed safely with good prognosis in critical CHD.

关键词： Fetal cardiac intervention Valvuloplasty Pulmonary atresia Critical aortic stenosis Congenital heart disease

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Development and validation of a preoperative prediction model for all-cause mortality in patients following abdominal aortic aneurysm repair

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Chinese Medical Journal 2024年第10期137卷 1255-1257页

作者： Tan Li Guangxiao Li Yijun Wu Chao Yang Jun Yang Liping Sun Chunyan Ma department of Cardiovascular Ultrasound The First Hospital of China Medical UniversityShenyangLiaoning 110001China Clinical Medical Research center of Imaging in Liaoning Province The First Hospital of China Medical UniversityShenyangLiaoning 110001China department of Medical Record Management center The First Hospital of China Medical UniversityShenyangLiaoning 110001China Tumor Etiology and screening department of Cancer Institute and General Surgery The First Hospital of China Medical UniversityShenyangLiaoning 110001China Trauma center and department of Burns The First Hospital of China Medical UniversityShenyangLiaoning 110001China

To the Editor:Abdominal aortic aneurysm(AAA)is a life-threatening vascular *** intervention is typically recommended when the maximum AAA diameter reaches a threshold of 5.5cm for men and 5.0cm for women,or when an AAA experiences a rapid expansion of greater than 1.0cm/year.[1]Survival after AAA repair is inuenced by various factors,and the identication of independent prognostic factors and the development of accurate prediction models are crucial for optimal treatment planning,counseling,and postoperative *** several scoring systems with varying degrees of accuracy have been developed to predict the risk of mortality after intervention for patients with ruptured AAA.

关键词： patients mortality aneurysm

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