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DNA-delivered monoclonal antibodies targeting the p53 R175H mutant epitope inhibit tumor development in mice

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Genes & Diseases 2024年第4期11卷 368-380页

作者： Dafei Chai Xu Wang Praveen Neeli Shan Zhou Xingfang Yu Kanaga Sabapathy Yong Li Department of Medicine Section of Epidemiology and Population SciencesDan L Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTX 77030USA Division of Cellular&Molecular research Humphrey Oei Institute of Cancer ResearchNational Cancer Centre SingaporeSingapore 168583Singapore

tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense ***,there are currently no approved targeted therapies or immunotherapies against mutant ***,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in *** then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic *** results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type *** cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular *** made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 *** vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in *** administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 *** results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

关键词： BsAb Cytotoxicity mAb Mutant p53 PD-1 R175H

Small mammal community composition impacts bank vole (Clethrionomys glareolus) population dynamics and associated seroprevalence of Puumala orthohantavirus

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Integrative Zoology 2024年第1期19卷 52-65页

作者： Felicitas Maria BUJNOCH Daniela REIL Stephan DREWES Ulrike MROSENFELD Rainer G.ULRICH Jens JACOB Christian IMHOLT Julius Kühn-Institute Federal Research Centre for Cultivated PlantsInstitute for Epidemiology and Pathogen DiagnosticsRodent ResearchMünsterGermany University of Münster Institute for Evolution and BiodiversityMünsterGermany Friedrich-Loeffler-Institut Federal Research Institute for Animal HealthInstitute of Novel and Emerging Infectious DiseasesGreifswald-Insel RiemsGermany

Rodents are important reservoirs for zoonotic pathogens that cause diseases in *** is hypoth-esized to be closely related to pathogen prevalence through multiple direct and indirect *** example,the presence of non-host species can reduce contact rates of the main reservoir host and thus reduce the risk of transmission(“dilution effect”).In addition,an overlap in ecological niches between two species could lead to increased interspecific competition,potentially limiting host densities and reducing density-dependent pathogen transmission *** this study,we investigated the relative impact of population-level regulation of direct and indirect drivers of the prevalence of Puumala orthohantavirus(PUUV)in bank voles(Clethrionomys glareolus)during years with high *** compiled data on small mammal community composition from four regions in Germany between 2010 and *** equation modeling revealed a strong seasonality in PUUV control mechanisms in bank *** abundance of shrews tended to have a negative relationship with host abundance,and host abundance positively influenced PUUV seroprevalence,while at the same time increasing the abundance of competing non-hosts like the wood mouse(Apodemus sylvaticus)and the yellow-neckedfield mouse(Apodemusflavicollis)were associated with reduced PUUV seroprevalence in the *** results indicate that for PUUV in bank voles,dilution is associated with increased interspecific *** pressures leading to the decline of Apodemus *** a specific habitat could lead to the amplification of mechanisms promoting PUUV transmission within the host populations.

关键词： bank vole biodiversity Puumala orthohantavirus small mammals

Weight change and all-cause and cause-specific mortality:A 25-year follow-up study

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Chinese Medical Journal 2024年第10期137卷 1169-1178页

作者： Huan Yang Jianbing Wang Xiaokun Wang Wanyi Sun Chenyunhao Tong Jinhu Fan Youlin Qiao Christian *** Department of Cancer epidemiology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Public Health Zhejiang University School of MedicineNational Clinical Research Center for Children’s HealthHangzhouZhejiang 310058China Metabolic epidemiology Branch Division of Cancer Epidemiology and GeneticsNational Cancer InstituteRockvilleMD 20850USA

Background:Whether the dynamic weight change is an independent risk factor for mortality remains *** study aimed to examine the association between weight change and risk of all-cause and cause-specific mortality based on the Linxian Nutrition Intervention Trial(NIT)***:Body weight of 21,028 healthy residents of Linxian,Henan province,aged 40-69 years was measured two times from 1986 to *** events were prospectively collected up to *** maintenance group(weight change<2 kg)or stable normal weight group was treated as the *** proportional hazard model was performed to calculate hazard ratios(HRs)and 95%confidence intervals(95%CIs)to estimate the risk of ***:A total of 21,028 subjects were included in the final *** with the weight maintenance group,subjects with weight loss≥2 kg had an increased risk of death from all-cause(HR_(All-cause)=1.14,95%CI:1.09-1.19,P<0.001),cancer(HR_(Cancer)=1.12,95%CI:1.03-1.21,P=0.009),and heart disease(HR_(Heart diseases)=1.21,95%CI:1.11-1.31,P<0.001),whereas subjects with weight gain≥5 kg had 11%(HR_(Cancer)=0.89,95%CI:0.79-0.99,P=0.033)lower risk of cancer mortality and 23%higher risk of stroke mortality(HR_(Stroke)=1.23,95%CI:1.12-1.34,P<0.001).For the change of weight status,both going from overweight to normal weight and becoming underweight within 5 years could increase the risk of total death(HR_(Overweight to normal)=1.18,95%CI:1.09-1.27;HR_(Becoming underweight)=1.35,95%CI:1.25-1.46)and cancer death(HR_(Overweight to normal)=1.20,95%CI:1.04-1.39;HR_(Becoming underweight)=1.44,95%CI:1.24-1.67),while stable overweight could increase the risk of total death(HR_(Stable overweight)=1.11,95%CI:1.05-1.17)and death from stroke(HR_(Stable overweight)=1.44,95%CI:1.33-1.56).Interaction effects were observed between age and weight change on cancer mortality,as well as between baseline BMI and weight change on all-cause,heart disease,and stroke mortality(all P_(

关键词： Weight change All-cause mortality Cancer Stroke Heart diseases Body mass index

Effectiveness of colorectal cancer screening integrating non-genetic and genetic risk: a prospective study based on UK Biobank data

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Cancer Biology & Medicine 2024年第8期21卷 712-723页

作者： Yu Zhang Chao Sheng Zhangyan Lyu Hongji Dai Fangfang Song Fengju Song Yubei Huang Kexin Chen Department of epidemiology and Biostatistics Key Laboratory of Molecular Cancer Epidemiology Key Laboratory of Prevention and Control of Human Major Diseases Ministry of Education National Clinical Research Center for Cancer Tianjin Medical University Cancer Institute and Hospital Tianjin Medical University

Objective: Few studies have evaluated the benefits of colorectal cancer(CRC) screening integrating both non-genetic and genetic risk factors. Here, we aimed to integrate an existing non-genetic risk model(QCancer-10) and a 139-variant polygenic risk score to evaluate the effectiveness of screening on CRC incidence and ***: We applied the integrated model to calculate 10-year CRC risk for 430,908 participants in the UK Biobank, and divided the participants into low-, intermediate-, and high-risk groups. We calculated the screening-associated hazard ratios(HRs) and absolute risk reductions(ARRs) for CRC incidence and mortality according to risk ***: During a median follow-up of 11.03 years and 12.60 years, we observed 5,158 CRC cases and 1,487 CRC deaths, respectively. CRC incidence and mortality were significantly lower among screened than non-screened participants in both the intermediateand high-risk groups [incidence: HR: 0.87, 95% confidence interval(CI): 0.81±0.94; 0.81, 0.73±0.90; mortality: 0.75, 0.64±0.87; 0.70, 0.58±0.85], which composed approximately 60% of the study population. The ARRs(95% CI) were 0.17(0.11±0.24) and 0.43(0.24±0.61), respectively, for CRC incidence, and 0.08(0.05±0.11) and 0.24(0.15±0.33), respectively, for mortality. Screening did not significantly reduce the relative or absolute risk of CRC incidence and mortality in the low-risk group. Further analysis revealed that screening was most effective for men and individuals with distal CRC among the intermediate to high-risk ***: After integrating both genetic and non-genetic factors, our findings provided priority evidence of risk-stratified CRC screening and valuable insights for the rational allocation of health resources.

关键词： Colorectal cancer incidence mortality polygenic risk score screening

Prevalence of Anemia in Patients with Diabetes Mellitus:A Systematic Review and Meta-Analysis

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Biomedical and Environmental Sciences 2024年第1期37卷 96-107页

作者： Monireh Faghir-Ganji Narjes Abdolmohammadi Maryam Nikbina Alireza Amanollahi Alireza Ansari-Moghaddam Rozhan Khezri Hamidreza Baradaran Student research Committee Iran University of Medical SciencesTehranIran Department of epidemiology School of Public HealthIran University of Medical SciencesTehranIran Department of epidemiology School of Public HealthTehran University of Medical SciencesTehranIran Department of Midwifery Shoushtar Faculty of Medical SciencesShoushtarIran Department of epidemiology School of Public Health and SafetyShahid Beheshti University of Medical SciencesTehranIran Trauma and Injury research Center Iran University of Medical SciencesTehranIran Health Promotion research Center Zahedan University of Medical SciencesZahedanIran Endocrine research Center Institute of Endocrinology and MetabolismIran University of Medical SciencesTehranIran

Objective Anemia is a common public health concern in patients with type 2 diabetes *** study aimed to identify the prevalence of anemia among patients with *** Electronic databases,including PubMed,Scopus,Web of Sciences,and Google Scholar,were searched systematically for studies published between 2010 and *** removing duplicates and inappropriate reports,the remaining manuscripts were reviewed and appraised using theNewcastleOttawa Scale(NOS)tool.A random-effects model was used to calculate the pooled estimates of the extracted data using Stata version *** of the studies was assessed using the Q *** A total of 51 articles containing information on 26,485 patients with diabetes were included in this *** articles were mainly from Asia(58.82%)and Africa(35.29%).The overall prevalence of anemia was 35.45%(95%CI:30.30–40.76),with no evidence of heterogeneity by *** the two continents with the highest number of studies,the prevalence of anemia in patients with diabetes was significantly higher in Asia[40.02;95%CI:32.72–47.54]compared to Africa[28.46;95%CI:21.90–35.50](P for heterogeneity=0.029).Moreover,there has been an increasing trend in the prevalence of anemia in patients with diabetes over time,from[15.28;95%CI:9.83–22.21]in 2012 to[40.70;95%CI:10.21–75.93]in *** Globally,approximately 4 in 10 patients with diabetes suffer from ***,routine anemia screening and control programs every 3 months might be useful in improving the quality of life of these patients.

关键词： Prevalence Diabetic foot Anemia Diabetes mellitus

Psychiatric comorbidities in epilepsy:population co-occurrence,genetic correlations and causal effects

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General Psychiatry 2024年第1期37卷 103-111页

作者： Viktor H Ahlqvist Christina Dardani Paul Madley-Dowd Harriet Forbes Jessica Rast Caichen Zhong Renee M Gardner Christina Dalman Kristen Lyal cRAIG Newschaffer Torbjorn Tomson Michael Lundberg Daniel Berglind Neil M Davies Brian K Lee Cecilia Magnusson Dheeraj Rai Department of Global Public Health Karolinska InstitutetStockholmSweden Medical research Council Integrative epidemiology Unit Bristol Medical SchoolUniversity of BristolBristolUK centre for Academic Mental Health Population Health SciencesBristol Medical SchoolUniversity of BristolBristolUK Faculty of epidemiology and Population Health London School of Hygiene and Tropical MedicineLondonUK A.J.Drexel Autism Institute Drexel UniversityPhiladelphiaPAUSA Department of epidemiology and Biostatistics School of Public HealthDrexel UniversityPhiladelphiaPAUSA College of Health and Human Development Pennsylvania State UniversityState CollegePAUSA Department of Clinical Neuroscience Karolinska InstitutetStockholmSweden centre for epidemiology and Community Medicine Region StockholmStockholmSweden K.G Jebsen Center for Genetic epidemiology Department of Public Health and NursingNorwegian University of Science and TechnologyTrondheimNorway Division of Psychiatry University Collge LondonLondonUK Department of Statistical Sciences University Cllge LondonLondonK NIHR Biomedical research centre University of BristoBristolUK Avon and Wiltshire Partnership NHS Mental Health TrustBristolUK

Background Psychiatric comorbidities are common in patients with *** for the co-occurrence of psychiatric conditions and epilepsy remain poorly *** We aimed to triangulate the relationship between epilepsy and psychiatric conditions to determine the extent and possible origins of these *** Using nationwide Swedish health registries,we quantified the lifetime prevalence of psychiatric disorders in patients with *** then used summarydata from genome-wide association studies to investigate whether the identified observational associations could be attributed to a shared underlying genetic aetiology using cross-trait linkage disequilibrium score ***,we assessed the potential bidirectional relationships using two-sample Mendelian *** In a cohort of 7628495 individuals,we found that almost half of the 94435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetime(adjusted lifetime prevalence,44.09%;95%confidence interval(Cl)43.78%to 44.39%).We found evidence for a genetic correlation between epilepsy and some neurodevelopmental and psychiatric *** example,we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder(r,=0.18,95%Cl 0.09 to 0.27,p<0.001)—a correlation that was more pronounced in focal epilepsy(r=0.23,95%CI 0.09 to 0.36,p<0.001).Findings from Mendelian randomisation using common genetic variants did not support bidirectional effects between epilepsy and neurodevelopmental or psychiatric *** Psychiatric comorbidities are common in patients with *** correlations may partially explain some comorbidities;however,there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric *** findings highlight the need to understand the role of environmental factors or rare genetic variations in the origins of psy

关键词： epilepsy Psychiat lifetime

Association between body mass index and in vitro fertilization/intra-cytoplasmic sperm injection outcomes:An analysis of 15,124 normal ovarian responders in China

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Chinese Medical Journal 2024年第7期137卷 837-845页

作者： Danlei Zheng Yuanyuan Wang Lixue Chen Lin Zeng Rong Li Department of Obstetrics and Gynecology Center for Reproductive MedicinePeking University Third HospitalBeijing 100191China research Center of Clinical epidemiology Peking University Third HospitalBeijing 100191China

Background:High body mass index(BMI)results in decreased fecundity,and women with high BMI have reduced rates of clinical pregnancy and live birth in in vitro fertilization/intra-cytoplasmic sperm injection(IVF/ICSI).Meanwhile,ovarian responses show great heterogeneity in patients with a high *** study aimed to analyze the effects of a high BMI on IVF/ICSI outcomes in the Chinese female with normal ovarian ***:We performed a retrospective cohort study comprising 15,124 patients from the medical record system of the Reproductive Center of Peking University Third Hospital,with 3530(23.3%)in the overweight group and 1380(9.1%)in the obese group,who had a normal ovarian response(5-15 oocytes retrieved)and underwent fresh embryo transfer(ET)cycles from January 2017 to December 2018,followed by linked frozen-thawed embryo transfer(FET)cycles from January 2017 to December *** live birth rate(CLBR)was used as the primary ***,a generalized additive model was applied to visually illustrate the curvilinear relationship between BMI and the *** used a decision tree to identify the specific population where high BMI had the greatest effect on IVF/ICSI ***:High BMI was associated with poor IVF/ICSI outcomes,both in cumulative cycles and in separate fresh ET or FET *** cumulative cycles,compared with the normal weight group,obesity was correlated with a lower positive pregnancy test rate(adjusted odds ratio[aOR]:0.809,95%confidence interval[CI]:0.682-0.960),lower clinical pregnancy rate(aOR:0.766,95%CI:0.646-0.907),lower live birth rate(aOR:0.706,95%CI:0.595-0.838),higher cesarean section rate(aOR:2.066,95%CI:1.533-2.785),and higher rate of large for gestational age(aOR:2.273,95%CI:1.547-3.341).In the generalized additive model,we found that CLBR declined with increasing BMI,with 24 kg/m^(2)as an inflection *** the decision tree,BMI only made a difference in the population aged≤34.5 years,with anti-Muller

关键词： Obesity Body mass index fertilization Live birth Decision trees Normal ovarian response

Detection and evaluation of different morphological forms of Mycoplasma hominis in human semen

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Asian Journal of Andrology 2024年第1期26卷 71-76页

作者： Elizaveta Bragina Tatyana Sorokina Avtandil Chogovadze Yulia Shevchenko Vyacheslav Chernykh Olga Barkhatova Irina Rakovskaya research centre for Medical Genetics Moscow 115522Russia A.N.Belozersky Institute of Physico-Chemical Biology Lomonosov Moscow State University Moscow 119992Russia Reprolab Limited Liability Company Moscow 119333Russia N.I.Pirogov Russian National research Medical University Moscow 117997Russia Federal Government Budgetary Institution"National research Center for epidemiology and Microbiology Named after Honorary Academician N.F.Gamaleya of the Ministry of Health of the Russian Federation" Moscow 123098Russia

Recently discovered microcolonial forms of Mycoplasma hominis(***)and their impact on human spermatogenesis are *** spermatozoa of 125 fertile men(sperm donors;from Reprobank[Reproductive Tissue Bank,Moscow,Russial)and of 93 patients with fertility problems(from the Federal State Budgetary Institution"research centre for Medical Genetics[RCMG]",Moscow,Russia)were *** colonies of *** and microcolonies were detected by molecular biological methods,culture of bacteria,and transmission electron *** unique structure of microcolonial cells,in which the cytoplasmic cylinder is surrounded by concentric electron-dense and electron-light layers with a periodicity of 12-14 nm,and the ability of microcolonial cells to attach to spermatozoa are *** patients with lower sperm quality,microcolonies of *** were detected 2.5 times more frequently than classical *** detection of microcolonies in the ejaculate and the frequent isolation of microcolonies from sperm samples of patients with fertility problems suggest that microcolonial cells may be one cause of infertility.

关键词： ejaculate fertility Mycoplasma hominis spermatogenesis transmission electron microscopy

Association of cardiometabolic multimorbidity with all-cause and cardiovascular disease mortality among Chinese hypertensive patients

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Journal of Geriatric Cardiology 2024年第2期21卷 211-218页

作者： Luo-Xi XIAO Zi-Yu WANG Jiang-Tao LI Hai-Mei WANG Yi-Ming HAO Pan ZHOU Yu-Lin HUANG Qiu-Ju DENG Yong-Chen HAO Na YANG Li-Zhen HAN Zhao YANG Ping-Ping JIA Yue QI Jing LIU Center for Clinical and Epidemiologic research Beijing Anzhen HospitalCapital Medical UniversityBeijing Institute of HeartLung and Blood Vessel DiseasesBeijing Municipal Key Laboratory of Clinical EpidemiologyBeijingChina

BACKGROUND Hypertension usually clusters with multiple ***,the association between cardiometabolic multimorbidity(CMM)and mortality in hypertensive patients is *** study aimed to investigate the association between CMM and all-cause and cardiovascular disease(CVD)mortality in Chinese patients with *** The data used in this study were from the China National Survey for Determinants of Detection and Treatment Status of Hypertensive Patients with Multiple Risk Factors(CONSIDER),which comprised 5006 participants aged 19–91 *** was defined as the presence of one or more of the following morbidities:diabetes mellitus,dyslipidemia,chronic kidney disease,coronary heart disease,and *** proportional hazard models were used to calculate the hazard ratios(HR)with 95%CI to determine the association between the number of CMMs and both all-cause and CVD *** Among 5006 participants[mean age:58.6±10.4 years,50%women(2509 participants)],76.4%of participants had at least one *** mortality rate was 4.57,4.76,8.48,and 16.04 deaths per 1000 person-years in hypertensive patients without any comorbidity and with one,two,and three or more morbidities,*** the fully adjusted model,hypertensive participants with two cardiometabolic diseases(HR=1.52,95%CI:1.09–2.13)and those with three or more cardiometabolic diseases(HR=2.44,95%CI:1.71–3.48)had a significantly elevated risk of all-cause *** findings were similar for CVD mortality but with a greater increase in risk *** In this study,three-fourths of hypertensive patients had *** with two or more comorbidities was associated with a significant increase in the risk of all-cause and cardiovascular mortality among hypertensive patients,suggesting more intensive treatment and control in this high-risk patient group.

关键词： hypertensive patients morbidity