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Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension

Chronic Diseases and Translational Medicine 2024年第2期10卷 102-117页

作者： Nicholas r.Powell Tyler Shugg Jacob Leighty Matthew Martin rolf P.Kreutz Michael T.Eadon Dongbing Lai Tao Lu Todd C.Skaar Division of Clinical Pharmacology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Pharmacology and Toxicology School of MedicineIndiana UniversityIndianapolisIndianaUSA Department of cardiology School of MedicineKrannert Institute of CardiologyIndiana UniversityIndianapolisIndianaUSA Division of Nephrology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Medical and Molecular Genetics School of MedicineIndiana UniversityIndianapolisIndianaUSA

Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive *** previously reported that angiotensinogen(AGT)messenger rNA(mrNA)is endogenously bound by mir-122-5p and rs699 A>G decreases reporter mrNA in the microrNA functional-assay *** AGT promoter variant rs5051 C>T is in linkage disequilibrium(LD)with rs699 A>G and increases AGT *** independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C>T counterbalances AGT decreased by rs699 A>G,and when these variants occur independently,it translates to HTN-related *** We used in silico,in vitro,in vivo,and retrospective models to test this *** In silico,rs699 A>G is predicted to increase mir-122-5p binding affinity by 3%.Mir-eCLIP results show rs699 is 40–45 nucleotides from the strongest microrNA-binding site in the AGT ***,rs699 A>G increases AGT mrNA in an AGT-plasmid-cDNA HepG2 expression ***-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>***,GTEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGT mrNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with *** We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White *** studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>*** like this will help clinicians move beyond the use of race as a surrogate for genotype.

关键词： angiotensinogen genetic and genomic medicine hypertension rs699

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Circulating microrNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity

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World Journal of Gastroenterology 2024年第4期30卷 332-345页

作者： Yi-Jie Li Brittney O Baumert Nikos Stratakis Jesse A Goodrich Hao-Tian Wu Jing-Xuan He Yin-Qi Zhao Max T Aung Hong-Xu Wang Sandrah P Eckel Douglas I Walker Damaskini Valvi Michele A La Merrill Justin r ryder Thomas H Inge Todd Jenkins Stephanie Sisley rohit Kohli Stavra A Xanthakos Andrea A Baccarelli rob McConnell David V Conti Lida Chatzi Department of Population and Public Health Sciences Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90032United States Barcelona Institute of Global Health Barcelona Institute of Global HealthBarcelona 08036Spain Department of Environmental Health Sciences Mailman School of Public HealthColumbia UniversityNew YorkNY 10032United States Gangarosa Department of Environmental Health Rollins School of Public HealthEmory UniversityAtlantaGA 30329United States Department of Environmental Medicine and Public Health Icahn School of Medicine at Mount SinaiNew YorkNY 10029United States Department of Environmental Toxicology University of CaliforniaDavisCA 95616United States Department of Surgery Lurie Children’s Hospital of ChicagoChicagoIL 60611United States Northwestern University Feinberg School of Medicine Northwestern UniversityChicagoIL 60611United States Division of Biostatistics and Epidemiology Cincinnati Children's Hospital Medical CenterCincinnatiOH 45229United States Department of Pediatrics University of Cincinnati College of MedicineCincinnatiOH 45229United States Department of Pediatrics Children’s Nutrition Research Center USDA/ARSBaylor College of MedicineHoustonTX 77030United States Department of Gastroenterology Children’s Hospital Los AngelesLos AngelesCA 90027United States Division of Gastroenterology Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOH 45229United States

BACKGrOUND Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases in children and *** ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis(NASH),wherein hepatocellular inflammation and/or fibrosis coexist with *** microrNA(mirNA)levels have been suggested to be altered in NAFLD,but the extent to which mirNA are related to NAFLD features remains *** analysis tested the hypothesis that plasma mirNAs are significantly associated with histological features of NAFLD in *** To investigate the relationship between plasma mirNA expression and NAFLD features among adolescents with *** This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery ***-operative core liver biopsies were collected from participants and used to characterize histological features of *** samples were collected during surgery for mirNA profiling.A total of 843 plasma mirNAs were profiled using the HTG EdgeSeq *** examined associations of plasma mirNAs and NAFLD features using logistic regression after adjusting for age,sex,race,and other key *** Pathways Analysis was used to identify biological functions of mirNAs that were associated with multiple histological features of *** We identified 16 upregulated plasma mirNAs,including mir-193a-5p and mir-193b-5p,and 22 downregulated plasma mirNAs,including mir-1282 and mir-6734-5p,in adolescents with ***,52,16,15,and 9 plasma mirNAs were associated with NASH,fibrosis,ballooning degeneration,and lobular inflammation,***,16 mirNAs were associated with two or more histological features of *** those mirNAs,mir-411-5p was downregulated in NASH,ballooning,and fibrosis,while mir-122-5p,mir-1343-5p,mir-193a-5p,mir-193b-5p,and mir-7845-5p were consistently and posi

关键词： MicrorNA Nonalcoholic fatty liver disease Non-alcoholic steatohepatitis Liver fibrosis Lobular inflammation Ballooning degeneration

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Integrative genomic and transcriptomic profiling of pulmonary sarcomatoid carcinoma identifies molecular subtypes associated with distinct immune features and clinical outcomes

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cancer Innovation 2024年第3期3卷 81-94页

作者： Sahil Seth runzhe Chen Yang Liu Junya Fujimoto Lingzhi Hong Alexandre reuben Susan Varghese carmen Behrens Tina McDowell Luisa Solis Soto cara Haymaker Annikka Weissferdt Neda Kalhor Jia Wu Xiuning Le Natalie I Vokes Chao Cheng John V.Heymach Don L.Gibbons P.Andrew Futreal Ignacio IWistuba Humam Kadara Jianhua Zhang Cesar Moran Jianjun Zhang Department of Genomic Medicine The University of Texas MD Anderson Cancer CenterHoustonTexasUSA TrACTION The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Graduate School of Biomedical Sciences The University of Texas MD Anderson and the University of Texas Health Science CenterHoustonTexasUSA Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Epidemiology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Pathology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Imaging Physics The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Medicine Baylor College of MedicineHoustonTexasUSA

Background:Pulmonary sarcomatoid carcinoma(PSC)is a rare and aggressive subtype of non-small cell lung cancer(NSCLC),characterized by the presence of epithelial and sarcoma-like *** molecular and immune landscape of PSC has not been well ***:Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel,whole-exome,and rNA *** describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical ***:In total,27 canonical cancer gene mutations were identified,with TP53 the most frequently mutated gene,followed by ***,most TP53 and KrAS mutations were earlier genomic events mapped to the trunks of the tumors,suggesting branching evolution in most PSC *** identified two distinct molecular subtypes of PSC,driven primarily by immune infiltration and *** Immune High(IM-H)subtype was associated with superior survival,highlighting the impact of immune infiltration on the biological and clinical features of localized ***:We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with ***-H tumors were associated with favorable recurrence-free survival and overall survival,highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.

关键词： genomic immune pulmonary sarcomatoid carcinoma survival

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A Therapeutic Sheep in Metastatic Wolf’s Clothing: Trojan Horse Approach for cancer Brain Metastases Treatment

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Nano-Micro Letters 2022年第7期14卷 140-156页

作者： Hai-jun Liu Mingming Wang Shanshan Shi Xiangxiang Hu Peisheng Xu Department of Drug Discovery and Biomedical Sciences College of PharmacyUniversity of South CarolinaColumbiaSC 29208USA

Early-stage brain metastasis of breast cancer(BMBC), due to the existence of an intact blood–brain barrier(BBB), is one of the deadliest neurologic complications. To improve the efficacy of chemotherapy for BMBC, a Trojan horse strategy-based nanocarrier has been developed by integrating the cell membrane of a brain-homing cancer cell and a polymeric drug depot. With the camouflage of a MDA-MB-231/Br cell membrane, doxorubicin-loaded poly(D, L-lactic-co-glycolic acid) nanoparticle(DOX-PLGA@CM) shows enhanced cellular uptake and boosted killing potency for MDA-MB-231/Br cells. Furthermore, DOX-PLGA@CM is equipped with naturally selected molecules for BBB penetration, as evidenced by its boosted capacity in entering the brain of both healthy and early-stage BMBC mouse models. Consequently, DOX-PLGA@CM effectively reaches the metastatic tumor lesions in the brain, slows down cancer progression, reduces tumor burden, and extends the survival time for the BMBC ***, the simplicity and easy scale-up of the design opens a new window for the treatment of BMBC and other brain metastatic cancers.

关键词： Trojan horse Brain metastasis Blood-brain barrier Cell membrane Nanomedicine

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Monoclonal antibody-based cancer therapies

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Chinese Journal of Chemical Engineering 2021年第2期34卷 301-307页

作者： Yingnan Si Arin L.Melkonian Keegan C.Curry Yuanxin Xu Maranda Tidwell Mingming Liu Ahmed F.Zaky Xiaoguang(Margaret)Liu Department of Biomedical Engineering University of Alabama at Birmingham(UAB)1825 University BlvdBirminghamAL 35294USA Department of Medicine UAB17202nd Ave S.BirminghamAL 35294USA Chinese Medicine Hospital 98 Shengcheng StreetShouguang 262700China Department of Anesthesiology and Perioperative Medicine UAB62519th Street SouthBirminghamAL 35294USA

Targeted therapy has been widely demonstrated as an effective strategy to treat cancers,the leading cause of death in the *** minireview summarizes the technical platforms and methodologies utilized to develop and engineer therapeutic monoclonal antibodies and antibody-drug ***,the USA FDA approved monoclonal antibody(mAb)-based targeted therapies are *** the representative innovative chimeric,humanized and fully human anti-cancer antibodies and antibody-drug conjugates are ***,the past and predictive market trend of therapeutic antibodies is discussed.

关键词： Monoclonal antibody Antibody-drug conjugate Anti-cancer therapy Market

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