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

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 mutant.However,there are currently no approved targeted therapies or immunotherapies against mutant p53.Here,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 vitro.We then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic effects.Our 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 p53.In cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular cytotoxicity.We made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 alleles.In vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in mice.The 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 antibody.These 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

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Development and Evaluation of a Promising Biomarker for Diagnosis of Latent and Active Tuberculosis Infection

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Infectious Diseases & Immunity 2024年第1期4卷 10-24页

作者： Cong Peng Fan Jiang Yinping Liu Yong Xue Peng Cheng Jie Wang Liang Wang Wenping Gong Hebei North University Zhangjiakou 075000Hebei ProvinceChina Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment Senior Department of TuberculosisEighth Medical Center of PLA General HospitalBeijing 100091China Department of Geriatrics Eighth Medical Center of PLA General HospitalBeijing 100091China section of health No.94804 Unit of the Chinese People's Liberation ArmyShanghai 200434China

Background:Diagnosing latent tuberculosis(TB)infection(LTBI)and active TB(ATB)is crucial for preventing disease progression and transmission.However,current diagnostic tests have limitations in terms of accuracy and sensitivity,making it challenging to diagnose these different infection states.Therefore,this study intends to develop a promising biomarker for LTBI and ATB diagnosis to overcome the limitations of the current diagnostic tests.Methods:We developed a novelmultiepitope-based diagnostic biomarker(MEBDB)fromLTBI region of differentiation antigens using bioinformatics and immunoinformatics.Immune responses induced byMEBDM were detected using enzyme-linked immunosorbent spot and cytometric bead assays.This study was conducted from April 2022 to December 2022 in the SeniorDepartment of Tuberculosis at the 8thMedical Center of PLA General Hospital,China.Blood samples were collected from participants with ATB,individuals with LTBI,and healthy controls(HCs).The diagnostic efficacy of MEBDB was evaluated using receiver operating characteristic curves.Results:A novel MEBDB,designated as CP19128P,was generated.CP19128P comprises 19 helper T lymphocyte epitopes,12 cytotoxic T lymphocyte epitopes,and 8 B-cell epitopes.In silico simulations demonstrated that CP19128P possesses strong affinity for Toll-like receptors and elicits robust innate and adaptive immune responses.CP19128P generated significantly higher levels of tumor necrosis factor(TNF-α),interleukin 4(IL-4),and IL-10 in ATB patients(n=7)and LTBI(n=8)individuals compared with HCs(n=62)(Phealthy subjects with high sensitivity and specificity.Combining IL-2 with IL-4 or TNF-α could differentiate LTBI from HCs(the area under the receiver operating characteristic curve[AUC],0.976[95% confidence interval[CI],0.934-1.000]or 0.986[0.956-1.000]),whereas combining IL-4 with IL-17A or TNF-α could differentiate ATB from HCs(AUC,0.887[0.782-0.993]or 0.984[0.958-1.000])

关键词： Tuberculosis Latent tuberculosis infection Active tuberculosis Multiepitope-based diagnostic biomarker Bioinformatics:Immunoinformatics

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Anti-methanogenic potential of seaweeds and seaweed-derived compounds in ruminant feed:current perspectives,risks and future prospects

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Journal of Animal Science and Biotechnology 2024年第2期15卷 463-489页

作者： Ailbhe McGurrin Julie Maguire Brijesh K.Tiwari Marco Garcia-Vaquero section of Food and Nutrition School of Agriculture and Food ScienceUniversity College DublinDublin 4BelfieldIreland TEAGASC Food Research CentreDublin 15AshtownIreland Bantry Marine Research Station Ltd BantryCo.CorkP75 AX07GearhiesIreland

With methane emissions from ruminant agriculture contributing 17%of total methane emissions worldwide,there is increasing urgency to develop strategies to reduce greenhouse gas emissions in this sector.One of the proposed strategies is ruminant feed intervention studies focused on the inclusion of anti-methanogenic compounds which are those capable of interacting with the rumen microbiome,reducing the capacity of ruminal microorganisms to produce methane.Recently,seaweeds have been investigated for their ability to reduce methane in ruminants in vitro and in vivo,with the greatest methane abatement reported when using the red seaweed Asparagopsis taxiformis(attributed to the bromoform content of this species).From the literature analysis in this study,levels of up to 99%reduction in ruminant methane emissions have been reported from inclusion of this seaweed in animal feed,although further in vivo and microbiome studies are required to confirm these results as other reports showed no effect on methane emission resulting from the inclusion of seaweed to basal feed.This review explores the current state of research aiming to integrate seaweeds as anti-methanogenic feed additives,as well as examining the specific bioactive compounds within seaweeds that are likely to be related to these effects.The effects of the inclusion of seaweeds on the ruminal microbiome are also reviewed,as well as the future challenges when considering the largescale inclusion of seaweeds into ruminant diets as anti-methanogenic agents.

关键词： Asparagopsis Bromoform Methanogenesis Phlorotannin Saponin Tannin

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Chinese and Western Civilizations:Concentric Circles and Jigsaw

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China Book International 2024年第2期 10-13页

作者： Li Yonggang Traditional Chinese Culture Research section of the Academy of Chinese Culture

Focusing on factors contributing to the lasting unity of China,this book explores several important historical periods and transitions in past dynasties.It elaborates on the ways of Life,values,and thinking modes of the Chinese in preserving and passing along the civilization,with the conclusion that the long history and vitality of Chinese civilization relies on its superb resistance,exceptional tolerance,and flexibility,as well as the collective will,determination,and capacity in looking for solutions.These qualities are also reflected in China's code of conduct in contemporary society,including consolidating the community consciousness of the Chinese nation and building a community with a shared future for mankind.

关键词： looking collective exceptional

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A Physical Core-Loss Model for Laminated Magnetic Sheet Steels

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Journal of Power and Energy Engineering 2024年第3期12卷 115-123页

作者： Kuofeng Chen Metal Forming Technology section Metal Industries Research & Development Centre Kaohsiung

A full-frequency instant core-loss equation built from the induction physical model of magnetic materials, where the iron loss, eddy loss, and hysteresis loss no longer have an integral term, and this new equation provides high simulation accuracy and performs dynamic core loss analysis on non-sinusoidal or pulse magnetic fields. The simulation examples use a high-grade electrical steel sheet 65CS400 by Epstein experimental data covering magnetic field 0.1 - 1.8 T and frequency 50 - 5000 Hz, and the average error of the simulated core loss is less than 4%. Since the simulation is converged by magnetic physical parameters, so the physical relevance of the similar laminated materials can be compared with the coefficient results. .

关键词： Core Loss Hysteresis Loss Electrical Steel Sheet

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Clinical and socioeconomic determinants of survival in biliary tract adenocarcinomas

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1374-1383页

作者： Laura Sahyoun Kay Chen Cynthia Tsay George Chen Petr Protiva Department of Gastroenterology and Hepatology Weill Cornell MedicineNew YorkNY 10065United States Gastroenterology section Jennifer Moreno VA San Diego Healthcare SystemSan DiegoCA 92161United States Division of Gastroenterology Department of MedicineUniversity of California San DiegoLa JollaCA 92093United States Department of Gastroenterology and Hepatology John Hopkins HospitalBaltimoreMD 21287United States Department of Digestive Diseases Yale New Haven HospitalNew HavenCT 06520United States Department of Gastroenterology VA Connecticut Health Care SystemWest HavenCT 06516United States

BACKGROUND Despite advances in detection and treatments,biliary tract cancers continue to have poor survival outcomes.Currently,there is limited data investigating the significance of socioeconomic status,race/ethnicity,and environmental factors in biliary tract cancer survival.Data from the Surveillance,Epidemiology,and End Results database for biliary and gallbladder adenocarcinomas were extracted from 1975 to 2016.Socioe-conomic data included smoking,poverty level,education,adjusted household income,and percentage of foreign-born persons and urban population.Survival was calculated with Cox proportional hazards models for death in the 5-year period following diagnosis.RESULTS Our study included 15883 gallbladder,11466 intrahepatic biliary,12869 extrahepatic biliary and 7268 ampulla of Vater adenocarcinoma cases.When analyzing county-specific demographics,patients from counties with higher incomes were associated with higher survival rates[hazard ratio(HR)=0.97,P<0.05].Similarly,counties with a higher percentage of patients with a college level education and counties with a higher urban population had higher 5-year survival rates(HR=0.96,P=0.002 and HR=0.97,P=0.004,respectively).CONCLUSION Worse survival outcomes were observed in lower income counties while higher income and education level were associated with higher 5-year overall survival among gallbladder and biliary malignancies.

关键词： Biliary tract cancers Survival Outcomes research Socioeconomic factors healthcare disparities

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Anoctamin 4 defines glucose-inhibited neurons in the ventromedial hypothalamus

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Neural Regeneration Research 2024年第6期19卷 1177-1178页

作者： Longlong Tu Yanlin He Yong Xu Children's Nutrition Research Center Department of Pediatrics Baylor College of Medicine Department of Molecular and Cellular Biology Section of Endocrinology Diabetes and Metabolism Department of Medicine Baylor College of Medicine Brain Glycemic and Metabolism Control Department Pennington Biomedical Research Center Louisiana State University

Glucose is the primary fuel source of the brain,and therefore glucose levels need to be tightly regulated and maintained within a small physiological range.Certainly,the body necessitates a stable supply of energy mainly provided by glucose for various bodily functions.High or low blood glucose levels would impair the physiological functions of various organs of the body.Prolonged high blood glucose(i.e.,

关键词： HYPOGLYCEMIA

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Hepatic grooves:An observational study at laparoscopic surgery

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World Journal of Experimental Medicine 2024年第2期14卷 97-102页

作者： Shamir O Cawich Dexter A Thomas Fawwaz Mohammed Michael T Gardner Marlene Craigie Shaneeta Johnson Ramnanand S Kedambady Department of Surgery University of the West IndiesSt Augustine 000000Trinidad and Tobago Department of Surgery Port of Spain General HospitalPort of Spain 000000Trinidad and Tobago section of Anatomy Basic Medical SciencesUniversity of the West IndiesKingston 000000Jamaica Department of Radiology University of the West IndiesKingston 000000Jamaica Department of Surgery Morehouse School of MedicineAtlantaGA 30310United States section of Anatomy Department of Basic Medical SciencesUniversity of the West IndiesKingston KIN7Jamaica

BACKGROUND In traditional descriptions,the upper surface of the liver is smooth and convex,but deep depressions are variants that are present in 5%-40%of patients.We sought to determine the relationship between surface depressions and the diaphragm.AIM To use exploratory laparoscopy to determine the relationship between surface depressions and the diaphragm.METHODS An observational study was performed in all patients undergoing laparoscopic upper gastro-intestinal operations between January 1,2023 and January 20,2024.A thirty-degree laparoscope was used to inspect the liver and diaphragm.When surface depressions were present,we recorded patient demographics,presence of diaphragmatic bands,rib protrusions and/or any other source of compression during inspection.RESULTS Of 394 patients,343 had normal surface anatomy,and 51(12.9%)had prominent surface depressions on the liver.There was no significant relationship between the presence of surface depressions and gender nor the presence of rib projections.However,there was significant association between the presence of surface depressions and diaphragmatic muscular bands(Psectional imaging to confirm relationships with intersectional planes as well as beta-catenin assays in the affected liver parenchyma.

关键词： Liver Variant Vein Hepatic Surgery

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Insights from an academic endeavor into central nervous system drug discovery

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Neural Regeneration Research 2025年第6期 1717-1718页

作者： Lieve van Veggel An M.Voets Tim Vanmierlo Rudy Schreiber BIOMED Biomedical Research Institute Faculty of Medicine and Life Sciences Hasselt University Department of Psychiatry and Neuropsychology Division of Translational Neuroscience European Graduate School of Neuroscience School for Mental Health and Neuroscience Maastricht University University MS Center (UMSC) section of Psychopharmacology Neuropsychology and Psychopharmacology Faculty of Psychology and Neuroscience Maastricht University

Historically,"big pharma"did most central nervous system drug discovery R&D in-house.Yet,in modern times their"management reductionism"resulted in disappointing pipelines and pharma resided to (late) development,regulatory approval,and marketing (Thong,2015).This had significant consequences for financing and executing research,resulting in a larger role for funding by governments and patient-organizations and a shift of research to academia (Mazzucato,2013).

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Laboratory evaluation of toxicity of selected insecticides against egg and larval stages of cotton pink bollworm, Pectinophora gossypiella (Saunders) (Lepidoptera: Gelechiidae)

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Journal of Cotton Research 2024年第1期7卷 15-28页

作者： BUSNOOR Abhishek V. WADASKAR R.M. FAND Babasaheb B. TAMBE V.J. PILLAI T. MAHULE D.J. NAGRARE V.S. PRASAD Y.G. Entomology section College of Agriculture(Dr.Panjabrao Deshmukh Krishi Vidyapeeth)Nagpur 440001MaharashtraIndia Indian Council of Agricultural Research-Central Institute for Cotton Research Nagpur 441108MaharashtraIndia

Background The cryptic nature of pink bollworm Pectinophora gossypiella(Saunders)larvae enables its reduced vul-nerability to insecticidal control.Further,the development of resistance against Bacillus thuringiensis(Bt)toxins posed a serious threat to transgenic cotton cultivation.This necessitated determining the critical timing of spray applications on the control effectiveness.This study assessed the influence of egg age(freshly laid vs.three-day-old)and the loca-tion of larvae(directly exposed to the insecticide residues on the boll rind vs.burrowed inside the bolls)on insecticide control efficacy.Results The results revealed a significant decrease in the ovicidal activity of tested insecticides with an increase in the age of eggs from one day old to three days old(paired t-test,P80%mortality)than the larvae exposed after they had bur-rowed inside the bolls(<49%mortality).The inhibitory effects of tested insecticides on developmental biology were more pronounced in the experiment on pre-larval release insecticide treatment compared with insecticide treatment given post-larval release and entry inside the bolls.Conclusion Egg age influences the insecticide susceptibility,as does the larval location,directly exposed vs bur-rowed inside the bolls.Older eggs and the larvae that had burrowed inside the green bolls of cotton were relatively less susceptible to the insecticide treatments.The toxic effects of insecticides on egg and larval stages were primar-ily ephemeral.These findings are significant for devising a comprehensive strategy for pink bollworm management on a sustainable basis.

关键词： Bioefficacy Cotton Insecticides Pink bollworm Pectinophora gossypiella Timings of spray

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