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Exploiting fly models to investigate rare human neurological disorders

Neural Regeneration research 2025年第1期20卷 21-28页

作者： Tomomi Tanaka Hyung-Lok Chung Department of Neurology Houston Methodist Research InstituteHoustonTXUSA Department of Neurology Weill Cornell Medical CollegeNew YorkNYUSA

Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological *** attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted *** investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary *** tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological *** boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug *** can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical *** this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic *** discuss rare diseases associated with both neuron-expressed and glial-expressed *** cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal *** we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell ***-of-fun

关键词： ACOX1 Drosophila melanogaster glia lipid metabolism model organisms neuroinflammation neurologic disorders neuron rare disease VLCFA

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Pancreatic head vs pancreatic body/tail cancer:Are they different?

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World Journal of Gastrointestinal Oncology 2022年第3期14卷 716-723页

作者： Kai Sun Charisma Mylavarapu Aubrey Crenshaw Yuqi Zhang Enshuo Hsu Jiaqiong Xu Marilyn Niravath Stephen L Jones Adriana Ordonez Maen Abdelrahim houston methodist Cancer Center Houston Methodist HospitalHoustonTX 77030United States Department of Internal Medicine Houston Methodist HospitalHoustonTX 77030United States Center for Outcomes research Houston Methodist Research InstituteHoustonTX 77030United States

BACKGROUND The impact of pancreatic tumor location on patient survival has been studied in large national data-based analyses which yielded controversial *** To explore if pancreatic head cancer(PHC)and pancreatic body/tail cancer(PBTC)have different overall survival(OS),molecular signature and response to *** We retrospectively queried patient records from July 2016 to June 2020 in our *** demographics,cancer stage on diagnosis,tumor location,somatic mutations,treatment,and survival are recorded and analyzed.A test is considered statistically significant if the P value was<*** We reviewed 101 patients with complete records,among which 67(66.34%)were PHC and 34(33.66%)were *** PHC were diagnosed at younger age[61.49 vs 68.97,P=0.010],earlier stages(P=0.006)and underwent surgical resection(P=0.025).There were no significant differences among all mutations and pathways studied except for TP53 mutations(37.0%in PHC vs 70.0%in PBTC,P=0.03).OS was not statistically different between PHC and PBTC(P=0.636)in the overall population and in subgroups according to surgical resection status or *** terms of response to chemotherapy,chemotherapy regimens(FOLFIRINOX-based vs gemcitabine-based)didn’t impact disease free interval in those who had surgical resection in either PHC(P=0.546)or PBTC(P=0.654),or the duration of response to first line palliative treatment in those with advanced disease in PHC(P=0.915)or PBTC(P=0.524).CONCLUSION Even though PHC and PBTC have similar poor OS and response to chemotherapy,the different presentations and molecular profiles indicate they are different *** of molecular profiling to develop targeted therapy for individualization of treatment is needed.

关键词： Pancreatic cancer Tumor location Molecular profiling Survival Response to chemotherapy

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Chronic allograft rejection:A significant hurdle to transplant success

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Burns & Trauma 2014年第1期2卷 3-10页

作者： Malgorzata Kloc Rafik M.Ghobrial Department of Surgery Houston Methodist HospitalHouston houston methodist hospital research institute HoustonTXUSA

The state-of-the-art immunosuppression drugs do not ensure indefi nite transplant survival,and most transplants are continuously lost to chronic rejection even years *** form of rejection is responsible for long-term failure of transplanted *** mechanisms involved in development of chronic rejection are not *** of the main features of chronic rejection is progressive luminal narrowing of graft vessels,which results in compromised blood flow,ischemia,cell death,and finally graft *** the existing immunosuppressive regimens are targeting acute rejection,and at present there is no available therapy for prevention of chronic *** rejection involves two major,but interrelated responses:The first is the host immune response against the transplant mediated primarily by alloreactive T and B cells,and the second is injury and repair of the graft(vasculopathy of graft vessels).Here we focus on recent advances in understanding the cellular and molecular aspects of chronic transplant vasculopathy and function of macrophages,topics pivotal for development of novel antichronic rejection therapies.

关键词： Chronic rejection macrophage neointima consists of smooth muscle cells vasculopathy

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Adenosine to facilitate the clipping of cerebral aneurysms:literature review

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Stroke & Vascular Neurology 2017年第4期2卷 205-210页

作者： Virendra R Desai Alejandro L Rosas Gavin W Britz Department of Neurosurgery Houston Methodist Neurological InstituteHouston Methodist HospitalHoustonTexasUSA Department of Anesthesiology and Critical Care Houston Methodist HospitalHoustonTexasUSA

Cerebral aneurysms have a high mortality rate when *** techniques have improved substantially in treating this ***,surgical clip ligation remains the preferred option for some *** techniques are used intraoperatively to assist the surgeon in dissecting the aneurysmal dome free of surrounding tissue and placing a clip around the neck safely and effectively so that no nearby perforating vessels are affected and no residual *** techniques include temporary clip ligation,endovascular balloon occlusion and cardiac *** use is one viable option for induced cardiac arrest leading to a short period of controlled *** predictable course of action,rapid onset and offset and rare incidence of adverse side effects make it an attractive agent in this ***,we provide an introduction to adenosine use,describing its pharmacokinetic properties,indications,contraindications,complications and future directions.

关键词： aneurysm balloon viable

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Cytokine regulation of immune tolerance

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Burns & Trauma 2014年第1期2卷 11-17页

作者： Jie Wu Aini Xie Wenhao Chen Department of Surgery Center for Immunobiology and Transplantation ResearchHouston Methodist Research InstituteHouston Methodist HospitalHoustonTexasUnited States

The immune system provides defenses against invading pathogens while maintaining immune tolerance to *** immune homeostasis is harmonized by the direct interactions between immune cells and the cytokine environment in which immune cells develop and ***,we discuss three non-redundant paradigms by which cytokines maintain or break immune *** firstly describe how anti-inflammatory cytokines exert direct inhibitory effects on immune cells to enforce immune tolerance,followed by discussing other cytokines that maintain immune tolerance through inducing CD_(4)^(+) Foxp_(3)^(+) regulatory T cells(Tregs),which negatively control immune ***(IL)-2 is the most potent cytokine in promoting the development and survival of Tregs,thereby mediating immune ***-35 is mainly produced by Tregs,but its biology function remains to be defi ***,we discuss the actions of proinflammatory cytokines that breach immune tolerance and induce autoimmunity,which include IL-7,IL-12,IL-21,and *** genetic studies have revealed the role of these cytokines(or their cognate receptors)in susceptibility to autoimmune *** together,we highlight in this review the cytokine regulation of immune tolerance,which will help in further understanding of human diseases that are caused by dysregulated immune system.

关键词： Cytokine immune tolerance T cell differentiation regulatory T cell

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DNAzyme as a rising gene-silencing agent in theranostic settings

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Neural Regeneration research 2022年第9期17卷 1989-1990页

作者： Nan Zhang Neuroscience Program Department of NeurologyHouston Methodist Research InstituteHoustonTXUSA

Decades of biochemical studies have advanced DNA beyond its primary role as genetic *** are single-stranded enzymatic DNA molecules that do not exist in *** are ideal candidates for gene silencing owing to their scalability by solid-phase synthesis(without batch variations),reprogrammability by directed evolution and local sequence alterations,compatibility with diverse delivery methods,and capability of achieving high catalytic turnover independent of any auxiliary *** these unique features,various artificially evolved DNAzymes have been employed as theranostic tools in designing biosensors and logic gates,RNA/DNA cleavage and ligation,phosphorylation and dephosphorylation,DNA photorepair,and peptide side-chain modifications,to name but a few(Ponce-Salvatierra et al.,2021).This perspective will focus on the functional aspects and therapeutic potentials of RNA-cleaving DNAzymes.

关键词： compatibility auxiliary batch

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Multifunctional to multistage delivery systems: The evolution of nanoparticles for biomedical applications

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Chinese Science Bulletin 2012年第31期57卷 3961-3971页

作者： MARTINEZ Jonathan O BROWN Brandon S QUATTROCCHI Nicoletta EVANGELOPOULOS Michael FERRARI Mauro TASCIOTTI Ennio Department of Nanomedicine The Methodist Hospital Research Institute Graduate School of Biomedical Sciences The University of Texas at Houston

Nanomaterials are advancing in several directions with significant progress being achieved with respect to their synthesis, functionalization and biomedical application. In this review, we will describe several classes of prototypical nanocarriers, such as liposomes, silicon particles, and gold nanoshells, in terms of their individual function as well as their synergistic use. Active and passive targeting, photothermal ablation, and drug controlled release constitute some of the crucial functions identified to achieve a medical purpose. Current limitations in targeting, slow clearance, and systemic as well as local toxicity are addressed in reference to the recent studies that attempted to comprehend and solve these issues. The demand for a more sophisticated understanding of the impact of nanomaterials on the body and of their potential immune response underlies this discussion. Combined components are then discussed in the setting of multifunctional nanocarriers, a class of drug delivery systems we envisioned, proposed, and evolved in the last 5 years. In particular, our third generation of nanocarriers, the multistage vectors, usher in the new field of nanomedicine by combining several components onto multifunctional nanocarriers characterized by emerging properties and able to achieve synergistic effects.

关键词：生物医学应用纳米粒子多功能传递系统演变多级药物控制释放纳米载体

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Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8^(+)T Cell Immunity against Tumor

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research 2024年第3期2023卷 433-444页

作者： Anze Yu Jinfei Fu Zheng Yin Hui Yan Xiang Xiao Dawei Zou Xiaolong Zhang Xiongbing Zu Xian C.Li Wenhao Chen Immunobiology and Transplant Science Center Department of SurgeryHouston Methodist Research Institute and Institute for Academic MedicineHouston Methodist HospitalHoustonTXUSA Department of Urology First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdongChina Systems Medicine and Bioengineering Department Houston Methodist Neal Cancer CenterHoustonTXUSA Department of Radiology Houston Methodist HospitalWeill Cornell MedicineHoustonTXUSA Department of Urology Xiangya HospitalCentral South UniversityChangshaHunanChina Department of Surgery Weill Cornell MedicineCornell UniversityNew YorkNYUSA.

T-cell-based immunotherapy is gaining momentum in cancer treatment;however,our comprehension of the transcriptional regulation governing T cell antitumor activity remains *** objective of this study was to explore the function of interferon regulatory factor 4(IRF4)in antitumor CD8^(+)T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma *** achieve this,we generated an Irf4^(GFP-DTR) mouse strain and discovered that CD8^(+)tumor-infiltrating lymphocytes(TILs)expressing high levels of *** exhibited a more differentiated PD-1high cell *** administering diphtheria toxin to tumor-bearing Irf4^(GFP-DTR) mice,we partially depleted ***^(+)TILs and observed an accelerated tumor *** specifically explore the function of IRF4 in antitumor CD8^(+)T cells,we conducted 3 adoptive cell therapy(ACT)***,depleting ***^(+)CD8^(+)TILs derived from ACT significantly accelerated tumor growth,emphasizing their crucial role in controlling tumor ***,deleting the Irf4 gene in antitumor CD8^(+)T cells used for ACT led to a reduction in the frequency and effector differentiation of CD8^(+)TILs,completely abolishing the antitumor effects of ***,we performed a temporal deletion of the Irf4 gene in antitumor CD8^(+)T cells during ACT,starting from 20 days after tumor implantation,which significantly compromised tumor ***,sustained expression of IRF4 is essential for maintaining CD8^(+)T cell immunity in the melanoma model,and these findings carry noteworthy implications for the advancement of more potent immunotherapies for solid tumors.

关键词： sustained immunity implantation

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Aerobic glycolysis enables the effector differentiation potential of stem-like CD4^(+)T cells to combat cancer

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Cellular & Molecular Immunology 2024年第5期21卷 527-529页

作者： Dawei Zou Xiaolong Zhang Shuang Li Xiang Xiao Nancy M.Gonzalez Laurie J.Minze Xian C.Li Wenhao Chen Immunobiology&Transplant Science Center Department of SurgeryHouston Methodist Research InstituteHouston Methodist HospitalHoustonTXUSA Department of Cardiovascular Science Houston Methodist Research InstituteHoustonTXUSA Department of Surgery Weill Cornell MedicineCornell UniversityNew YorkNYUSA

In 1957,Macfarlane Burnet proposed the theory that harnessing the body’s immune system could be an effective method for cancer treatment[1].Today,T-cell-based immunotherapies have indeed become a vital part of cancer treatment[2].However,a deeper understanding of antitumor immunity is still necessary to further support these ***,CD4^(+)T cells are central to mediating antitumor immune responses[3,4,5,6],yet the cellular and molecular programs governing CD4^(+)T-cell antitumor immunity remain *** recent research revealed that CD4^(+)T-cell immunity is critically dependent on an intrinsic stem-like program[7].

关键词： immunity cancer enable

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NF-κB and STAT3 signaling pathways collaboratively link infl ammation to cancer

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Protein & Cell 2013年第3期4卷 176-185页

作者： Yihui Fan Renfang Mao Jianhua Yang Texas Children's Cancer Center Department of PediatricsDan L.Duncan Cancer CenterBaylor College of MedicineHoustonTX 77030USA The methodist hospital research institute and the Departments of Radiology the Methodist HospitalHoustonTX 77030USA

Although links between cancer and inflammation were fi rstly proposed in the nineteenth century,the molecular mechanism has not yet been clearly *** studies have identified chronic infections and infl ammation as major risk factors for various types of ***-κB transcription factors and the signaling pathways are central coordinators in innate and adaptive immune ***3 regulates the expression of a variety of genes in response to cellular stimuli,and thus plays a key role in cell growth and ***,roles of NF-κB and STAT3 in colon,gastric and liver cancers have been extensively *** activation and interaction between STAT3 and NF-κB play vital roles in control of the communication between cancer cells and infl ammatory ***-κB and STAT3 are two major factors controlling the ability of pre-neoplastic and malignant cells to resist apoptosis-based tumor-surveillance and regulating tumor angiogenesis and *** the molecular mechanisms of NF-κB and STAT3 cooperation in cancer will offer opportunities for the design of new chemo-preventive and chemotherapeutic approaches.

关键词： infl ammation tumorigenesis NF-κB STAT3

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