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Targeting tumor microenvironment with antibody-guided IL-2 pro-cytokine promotes and rejuvenates dysfunctional cD8^(+) T cells

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Signal Transduction and Targeted Therapy 2023年第8期8卷 3573-3575页

作者： Xue Wang Longchao Liu Tao Yue Zhichen Sun Joonbeom Bae Kuo-Fu Tseng Anli Zhang Jian Qiao Yang-Xin Fu Department of Pathology University of Texas Southwestern Medical CenterDallasTX 75235USA cAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China Aetio Biotherapy DallasTX 75247USA Department of Pharmacology Harold C.Simmons Comprehensive Cancer CenterUniversity of Texas Southwestern Medical CenterDallasTX 75390USA Lyda Hill Department of Bioinformatics University of Texas Southwestern Medical CenterDallasTXUSA Department of Basic Medical Sciences School of MedicineTsinghua UniversityBeijing 100084China

Dear Editor,cLDN18.2(cLDN),a member of tight junction protein family,is strictly limited to express on differentiated epithelial cells of the gastric mucosa and abnormal overexpression has been found in many cancers,especially in digestive system malignancies.1 Those features make cLDN a potential therapeutic ***,monoclonal antibody targeting cLDN induce limited antitumor immune responses in clinical trials and fusion of strong immunomodulators might be needed to enhance its *** dose IL-2 activates tumor infiltrating lymphocytes(TILs),but the severe toxicity and poor tumor targeting limits its use.

关键词： cytokine lymphocytes clinical

comment on:“A review on radiofrequency,microwave and high-intensity focused ultrasound ablations for hepatocellular carcinoma with cirrhosis”

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Hepatobiliary Surgery and Nutrition 2022年第4期11卷 640-642页

作者： Michele Finotti Maurizio Romano Marco Brizzolari Michele Scopelliti Giacomo Zanus 4th Surgery Unit Regional Hospital TrevisoUniversity of PaduaDipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche(DISCOG)PaduaItaly Baylor Scott&White Annette c.and harold c.simmons Transplant Institute Baylor University MedicalDallasTXUSA

We read with great interest the published article of cheung et al.(1)on Hepatobiliary Surgery and *** authors provided a comprehensive review and critical evaluation of the three main locoregional ablation(LRA)techniques for liver cancer:radiofrequency(RFA),microwave(MWA),and high-intensity focused ultrasound ablations(HIFU).The focus of the paper is on their application to patients affected by hepatocellular carcinoma(Hcc)in the context of end-stage liver disease.

关键词： hepatocellular Surgery al.

Hepatic Encephalopathy: An Update on the Pathophysiology and Therapeutic Options

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Journal of clinical and Translational Hepatology 2017年第2期5卷 142-151页

作者： Saleh Elwir Robert S.Rahimi Annette c.and harold c.simmons Transplant Institute Baylor University Medical Center Dallas TX USA

Hepatic encephalopathy is a spectrum of reversible neuropsychiatric abnormalities,seen in patients with liver dysfunction and/or portosystemic *** of the most debilitating complications of cirrhosis,encephalopathy affects 30-45% of *** addition to significantly affecting the lives of patients and their caregivers,it is also associated with increased morbidity and mortality as well as significant utilization of health care *** this paper,we provide an overview on the pathophysiology,diagnosis,management and newer therapies of hepatic encephalopathy.

关键词： Hepatic encephalopathy cirrhosis Lactulose Rifaximin

cancer and neurodegenerative disorders:pathogenic convergence through microRNA regulation

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分子细胞生物学报:英文版 2011年第3期3卷 176-180页

作者： Liqin Du Alexander Pertsemlidis harold c.simmons comprehensive cancer center UT Southwestern Medical Center5323 Harry Hines BoulevardDallasTexas 75390USA Eugene McDermott center for Human Growth and Development UT Southwestern Medical Center5323 Harry Hines BoulevardDallasTexas 75390USA Department of Internal Medicine UT Southwestern Medical Center5323 Harry Hines BoulevardDallasTexas 75390USA

Although cancer and neurodegenerative disease are two distinct pathological disorders,emerging evidence indicates that these two types of disease share common mechanisms of genetic and molecular *** studies show that individual microRNAs(miRNAs)could be involved in the pathology of both diseases,indicating that the mechanisms of these two seemingly dichotomous diseases converge in the dysregulation of gene expression at the post-transcriptional *** the increasing evidence showing that miRNA-based therapeutic strategies that modulate the activity of one or more miRNAs are potentially effective for a wide range of pathological conditions,the involvement of miRNAs in the common pathways of leading both diseases suggests a bright future for developing common therapeutic approaches for both ***,the miRNAs that are dysregulated in both diseases may hold promise as uniquely informative diagnostic ***,we review recent studies on the miRNAs that have been implicated in both cancer and neurodegenerative diseases.

关键词： microRNA cancer neurodegenerative disease

Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles

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Nano Research 2017年第4期10卷 1366-1376页

作者： chuanqi Peng Xiaofei Gao Jing Xu Bujie Du Xuhui Ning Shaoheng Tang Robert M. Bachoo Mengxiao Yu Woo-Ping Ge Jie Zheng Department of chemistry and Biochemistry The University of Texas at Dallas Richardson TX 75080 USA children's Research Institute Department of Pediatrics Department of Neuroscience Harold C. Simmons Comprehensive Cancer Center UT Southwestem Medical Center Dallas TX 75390 USA simmons cancer center Annette G. Strauss Center for Neuro-Oncology Department of Internal Medicine Department of Neurology and Neurotherapeutics UT Southwestern Medical Center Dallas TX 75390 USA

A major clinical translational challenge in nanomedicine is the potential of toxicity associated with the uptake and long-term retention of non-degradable nanoparticles （NPs） in major organs. The development of inorganic NPs that undergo renal clearance could potentially resolve this significant biosafety concern. However, it remains unclear whether inorganic NPs that can be excreted by the kidneys remain capable of targeting tumors with poor permeability. Glioblastoma multiforme, the most malignant orthotopic brain tumor, presents a unique challenge for NP delivery because of the blood-brain barrier and robust blood-tumor barrier of reactive microglia and macroglia in the tumor microenvironment. Herein, we used an orthotopic murine glioma model to investigate the passive targeting of glutathione-coated gold nanoparticles （AuNPs） of 3 nm in diameter that undergo renal clearance and 18-nm AuNPs that fail to undergo renal clearance. Remarkably, we report that 3-nm AuNPs were able to target intracranial tumor tissues with higher efficiency （2.3× relative to surrounding non-tumor normal brain tissues） and greater specificity （3.0×） than did the larger AuNPs. Pharmacokinetics studies suggested that the higher glioma targeting ability of the 3-nm AuNPs may be attributed to the longer retention time in circulation. The total accumulation of the 3-nm AuNPs in major organs was significantly less （8.4×） than that of the 18-nm AuNPs. Microscopic imaging of blood vessels and renal-clearable AuNPs showed extravasation of NPs from the leaky blood-tumor barrier into the tumor interstitium. Taken together, our results suggest that the 3-nm AuNPs, characterized by enhanced permeability and retention, are able to target brain tumors and undergo renal clearance.

关键词： enhanced permeability and retention brain tumor passive targeting gold nanoparticles renal clearance

Use of robotics in liver donor right hepatectomy

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Hepatobiliary Surgery and Nutrition 2018年第2期7卷 154-155页

作者： Fabrizio Panaro Giuliano Testa Division of Transplantation Department of SurgeryMontpellier University Hospital-School of MedicineMontpellierFrance Annette c.and harold c.simmons Transplant Institute Baylor University Medical CenterDallasTXUSA

Thank you for inviting us to comment the review article entitled"Use of robotics in liver donor right hepatectomy"by chen PD et al.(1),published on HBSN *** their interesting paper,the authors stated that despite the fact that minimally invasive surgery(MIS)has been documented with safety and feasibility in complex liver surgery the progress has been slow in regard to the application of MIS in donor graft *** surgeons have devoted themselves to develop pure MIS approach for donor hepatectomy,but the steep learning curve remains barrier for its wide *** authors suggest that the introduction or robotic assisted surgery may contribute to a wider acceptance of MIS as the technique of choice for live donor *** a great attention to donor selection and continuous improvement in donor care the risks of donor hepatectomy remain real and the complication rate not insignificant(2).Traditional open liver resection results in post-operative pain and in at least 30%of the cases these pains were attributed to abdominal wall trauma(1,2).For these reasons and with the aim of facilitating donor recovery,transplant surgeons have been exploring the possibility of routinely applying MIS to live donor *** bridge the gap between open and pure MIS donor procurement,hand-assisted laparoscopic surgery was initially introduced in the 90'.It was not until 2002 that Soubrane O presented the first two cases of pure laparoscopic left lateral living donor hepatectomy,followed in the years to come by several successful attempts to extend the procedure to the procurements of full left and right hepatic lobes(1-6).

关键词： routine donor stated

Efficacy of sequential treatment of HcT116 colon cancer monolayers and xenografts with docetaxel,flavopiridol,and 5-fluorouracil

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Acta Pharmacologica Sinica 2006年第10期27卷 1375-1381页

作者： Jun GUO~2 an-wu ZHOU~2 Yu-cai FU~3 Udit N VERMA~2 Debu TRIPATHY~2 Eugene P FRENKEL~(2,5) carlos R BEcERRA~4 ~2harold c.simmons cancer center,Division of Hematology-Oncology,Department of Medicine,University of Texas Southwestern Medical centel.Dallas,Texas 75390,USA ~3Laboratory of cell Senescence,Shantou University Medical college,Shantou 515041,china ~4Sammons cancer center,Baylor University Medical center,TOPA-US Oncology,Dallas,Texas 75246,USA Division of Hematology-Oncology Department of Medicine Harold C. Simmons Cancer Center University of Texas Southwestern Medical Center Dallas USA Laboratory of cell Senescence Shantou University Medical College Shantou China Sammons cancer center Baylor University Medical Center TOPA-US Oncology Dallas USA

Aim:clinical treatment of solid tumors with docetaxel,flavopiridol,or 5-fluorou-racil(5-FU)often encounters undesirable side effects and drug *** aims to evaluate the potential role of combination therapy with docetaxel,flavopiridol,or 5-FU in modulating chemosensitivity and better understand howthey might be used ***:HcT116 colon cancer cells were treatedwith docetaxel,flavopiridol,and 5-FU in several different administrative sche-dules in vitro,either sequentially or *** survival was measuredby MTT *** activity of caspase-3 was determined by caspase-3 assaysand the soft agar colony assay was used to test the colony formation of HcT116cells in soft *** also established xenograft models to extend in vitro obser-vations to an in vivo ***:The maximum cytotoxicity was found whenhuman colon cancer HcT116 cells were treated with docetaxel for 1 h followed byflavopiridol for 24 h and 5-FU for another 24 *** sequential combinationtherapy not only inhibits tumor cell growth more strongly compared to othercombination therapies but also significantly reduces colony formation in soft agarand augments apoptosis of HcT116 *** of docetaxel followed 1 hlater by flavopiridol,followed 24 h later by 5-FU in xenograft models,also resultedin delayed tumor growth and higher survival ***:These resultshighlight the importance of an administrative schedule when combining docetaxelwith flavopiridol and 5-FU,providing a rationale explanation for its developmentin clinical trials.

关键词： combination drug therapy docetaxel flavopiridol fluorouracil colonic neoplasms

Women on the liver transplantation waitlist are at increased risk of hospitalization compared to men

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World Journal of Gastroenterology 2019年第8期25卷 980-988页

作者： Jessica B Rubin Marie Sinclair Robert S Rahimi Elliot B Tapper Jennifer c Lai Division of Gastroenterology and Hepatology Department of MedicineUniversity of California-San FranciscoSan FranciscoCA 94143 United States Department of Gastroenterology and Hepatology Austin HealthHeidelberg 3084VictoriaAustralia Department of Medicine the University of MelbourneMelbourne 3010VictoriaAustralia Division of Hepatology Annette C.and Harold C.Simmons Transplant InstituteBaylor University Medical CenterDallasTX 75346United States Division of Gastroenterology and Hepatology University of MichiganAnn ArborMI 48109United States

BAcKGROUND Hospital admissions are common among patients with cirrhosis,but patient factors associated with hospitalization have not been well *** recent data suggesting increased liver transplant waitlist dropout among women,we hypothesized that women on the liver transplant waitlist would have increased rates of hospitalization compared with *** To evaluate the role of gender on risk of hospitalization for patients on the liver transplant waitlist,in order to help explain gender disparities in waitlist *** Patients listed for liver transplant at a single center in the United States were prospectively enrolled in the Functional Assessment in Liver Transplantation *** included in this retrospective analysis included those enrolled between March 2012 and December 2014 with at least 12 mo of follow up and without hepatocellular *** primary and secondary outcomes were hospitalization and total inpatient days within 12 mo,*** and negative binomial regression associated baseline factors with *** Of the 392 patients,41%were female,with median(interquartile range)age 58 years(52-63)and model for end-stage liver disease 18(15-22).Within 12 mo,186(47%)patients were hospitalized≥1 time;48%were readmitted,with a median of 8(4-15)inpatient *** women than men were hospitalized(54%vs 43%;P=0.03).In univariable analysis,female sex was associated with an increased risk of hospitalization[odds ratios(OR)1.6,95%confidence interval(cI)1.0-2.4;P=0.03],which remained significant on adjusted multivariable analysis(OR 1.6,95%cI:1.1-2.6;P=0.03).Female gender was also associated with an increased number of inpatient days within 12 mo in both univariable and multivariable *** Women with cirrhosis on the liver transplant waitlist have more hospitalizations and inpatient days in one year compared with men,suggesting that the experience of cirrhosis differs between men and women,despite

关键词： Gender cirrhosis Liver transplantation waitlist Hospitalization Readmission Women

A Bayesian hierarchical model for analyzing methylated RNA immunoprecipitation sequencing data

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Frontiers of Electrical and Electronic Engineering in china 2018年第3期6卷 275-286页

作者： Minzhe Zhangl Qiwei Lil Yang Xie Quantitative Biomedical Research center Department of Clinical Sciences U.T. Southwestern Medical Center Dallas USA Department of Bioinformatics U.T. Southwestern Medical Center Dallas USA simmons comprehensive cancer center U.T. Southwestern Medical Center Dallas USA

Background： The recently emerged technology of methylated RNA immunoprecipitation sequencing （MeRIP-seq） sheds light on the study of RNA epigenetics. This new bioinformatics question calls for effective and robust peaking calling algorithms to detect mRNA methylation sites from MeRIP-seq data. Methods： We propose a Bayesian hierarchical model to detect methylation sites from MeRIP-seq data. Our modeling approach includes several important characteristics. First, it models the zero-inflated and over-dispersed counts by deploying a zero-inflated negative binomial model. Second, it incorporates a hidden Markov model （HMM） to account for the spatial dependency of neighboring read enrichment. Third, our Bayesian inference allows the proposed model to borrow strength in parameter estimation, which greatly improves the model stability when dealing with MeRIP-seq data with a small number of replicates. We use Markov chain Monte carlo （McMc） algorithms to simultaneously infer the model parameters in a de novo fashion. The R Shiny demo is available at https：//qiwei. ***/BaySeqPeak and the R/c ＋＋ code is available at https：//***/liqiwei2000/BaySeqPeak. Results： In simulation studies, the proposed method outperformed the competing methods exomePeak and MeTPeak, especially when an excess of zeros were present in the data. In real MeRIP-seq data analysis, the proposed method identified methylation sites that were more consistent with biological knowledge, and had better spatial resolution compared to the other methods. conclusions： In this study, we develop a Bayesian hierarchical model to identify methylation peaks in MeRIP-seq data. The proposed method has a competitive edge over existing methods in terms of accuracy, robustness and spatial resolution.

关键词： MeRIP-seq data RNA epigenomics Bayesian inference hidden Markov model zero-inflated negativebinomial