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Structural basis for polyuridine tract recognition by SARS-CoV-2 Nsp15

Protein & Cell 2024年第7期15卷 547-552页

作者： Fumiaki Ito Hanjing Yang Z.Hong Zhou Xiaojiang S.Chen Molecular and Computational Biology Department of Biological SciencesUniversity of Southern CaliforniaLos AngelesCA 90089United States Department of Microbiology Immunology and Molecular GeneticsUniversity of CaliforniaLos AngelesCA 90095United States California NanoSystems Institute University of CaliforniaLos AngelesCA90095United States Genetic Molecular and Cellular Biology ProgramKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90089United States norris comprehensive cancer center University of Southern CaliforniaLos AngelesCA 90089United States center of Excellence in NanoBiophysics University of Southern CaliforniaLos AngelesCA 90089United States

Dear Editor,Coronaviruses have evolved a wide array of tactics to evade host antiviral *** host cells detect invading foreign nucleic acids including viral genome and viral replication intermediates,they activate interferon(IFN)signaling via cytoplasmic pattern recognition receptors(Kang et al.,2002;Kato et al.,2006).Remarkable stealth activities exhibited by coronaviruses are facilitated by a series of non-structural proteins(Nsps),such as Nsp15(Deng and Baker,2018;Deng et al.,2019;Hackbart et al.,2020),which is a uridine-specific endoribonuclease that mediates evasion of host detection of viral double-stranded RNA(dsRNA)(Bhardwaj et al.,2004;Deng et al.,2017;Frazier et al.,2021;Ivanov et al.,2004).Nsp15 targets a polyuridine[poly(U)]tract on the coronavirus negative strand RNA(Hackbart et al.,2020).Nsp15 limits the abundance and length of poly(U)within the negative strand RNA 5ʹ-extension by trimming down the initially synthesized poly(U)lead sequence to the optimal length that can suppress dsRNA formation but still serves as a template for poly(A)tail of the positive strand genome of the coronaviruses(Hofmann and Brian,1991).

关键词： p15 interferon template

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Bone-targeted therapies to reduce skeletal morbidity in prostate cancer

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Asian Journal of Andrology 2018年第3期20卷 215-220页

作者： Tanya B Dorff Neeraj Agarwal usc Keck School of Medicine USC Norris Comprehensive Cancer Center Genitourinary Oncology Los Angeles CA 90033 USA Hunts Man cancer Institute Universityof Utah 2000 Circle of Hope Salt Lake City UT 84112 USA

Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including （1） bisphosphonates such as zoledronic acid, which directly target osteoclasts, （2） denosumab, a receptor activator of nuclear factor-kappa B （RANK） ligand inhibitor, which targets a key component of bone stromal interaction, and （3） radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer （mCRPC）. Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents.

关键词： bisphosphonate bone metastases prostate cancer radiopharmaceutical receptor activator of nuclear factor-kappa B-ligand

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Celebrating the work of Nobel Laureate Paul Modrich

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Science China(Life Sciences) 2016年第1期59卷 93-96页

作者： Guo-Min Li Department of Biochemistry and Molecular Biology Norris Comprehensive Cancer Center University of Southern California Keck School of Medicine University of Southern California

On October 7, 2015, the Nobel Prize Committee announced that the 2015 Nobel Prize in Chemistry had been awarded jointly to Professors Paul Modrich, Tomas Lindahl and Aziz Sancar （Figure 1）, each of whom made ground-breaking discoveries about the molecular mechanisms of DNA Re- pair. In one of life＇s unpredictable turns, Paul was among the last individuals in his entire personal, professional and social network to learn of the Committee＇s decision, be- cause Paul was very far ＂off-the-grid＂ at the time of the announcement. The news that he had been selected as a 2015 Nobel Laureate may have taken Paul by surprise, but it certainly was not a surprise to most, if not all, of Paul＇s colleagues, students, family and friends.

关键词：诺贝尔奖获得者诺贝尔化学奖诺贝尔奖得主分子机制委员会托马斯 DNA 突破性

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The potential for liquid biopsies in the precision medical treatment of breast cancer

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cancer Biology & Medicine 2016年第1期13卷 19-40页

作者： Victoria A.Forte Dany K.Barrak Mostafa Elhodaky Lily Tung Anson Snow Julie E.Lang Department of Medicine Division of Medical Oncology University of Southern California (USC) Los Angeles CA 90033USA usc norris comprehensive cancer center Los Angeles CA 90033 USA Department of Surgery Division of BreastEndocrine and Soft Tissue Surgery USC Los Angeles CA 90033 USA Department of Stem Cell and Regenerative Medicine USC Los Angeles CA 90033 USA

Currently the clinical management of breast cancer relies on relatively few prognostic/predictive clinical markers(estrogen receptor, progesterone receptor, HER2), based on primary tumor biology. Circulating biomarkers, such as circulating tumor DNA(ctDNA) or circulating tumor cells(CTCs) may enhance our treatment options by focusing on the very cells that are the direct precursors of distant metastatic disease, and probably inherently different than the primary tumor's biology. To shift the current clinical paradigm, assessing tumor biology in real time by molecularly profiling CTCs or ctDNA may serve to discover therapeutic targets, detect minimal residual disease and predict response to treatment. This review serves to elucidate the detection,characterization, and clinical application of CTCs and ctDNA with the goal of precision treatment of breast cancer.

关键词： Circulating tumor cells(CTCs) circulating tumor DNA(ctDNA) cell free DNA(cfDNA) biomarker cancer

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DNA mismatch repair in trinucleotide repeat instability

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Science China(Life Sciences) 2017年第10期60卷 1087-1092页

作者： Jinzhen Guo Luping Chen Guo-Min Li Department of Radiation Oncology University of Texas Southwestern Medical Center Department of Biochemistry and Molecular Medicine Norris Comprehensive Cancer Center University of Southern California Keck School of Medicine

Trinucleotide repeat expansions cause over 30 severe neuromuscular and neurodegenerative disorders, including Huntington's disease, myotonic dystrophy type 1, and fragile X syndrome. Although previous studies have substantially advanced the understanding of the disease biology, many key features remain unknown. DNA mismatch repair(MMR) plays a critical role in genome maintenance by removing DNA mismatches generated during DNA replication. However, MMR components,particularly mismatch recognition protein MutSβ and its interacting factors MutLα and MutLγ, have been implicated in trinucleotide repeat instability. In this review, we will discuss the roles of these key MMR proteins in promoting trinucleotide repeat instability.

关键词： DNA mismatch repair trinucleotide repeat instability neurodegenerative diseases MutSβ

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MicroRNA-371a-3p as a blood-based biomarker in testis cancer

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Asian Journal of Urology 2021年第4期8卷 400-406页

作者： Hamed Ahmadi Thomas L.Jang Siamak Daneshmand Saum Ghodoussipour Department of Urology University of Southern California/Norris Comprehensive Cancer CenterLos AngelesCAUSA Section of Urologic Oncology Rutgers Cancer Institute of New JerseyNew BrunswickNJUSA

MicroRNAs(miRNAs)are small noncoding RNAs involved in the regulation of mRNA transcription and translation,and possess all desirable features of an ideal tumor *** almost 31 different miRNA clusters identified in germ cell tumors(GCTs),miR-371a-3p has shown exceptionally high sensitivity and specificity for both seminomatous and nonseminomatous *** is easily obtainable and correlates well with tumor *** multiinstitutional prospective studies have shown promising test characteristics for miR-371a-3p as a diagnostic blood-based biomarker for GCT prior to orchiectomy including 80%e100%sensitivity and 90%e100%*** accuracy may address other unmet needs in the management of patients with *** studies have suggested the utility of miR-371a-3p in detecting occult nodal metastasis in high-risk clinical stage I and early stage II *** clinical trials including SWOG 1823 and AGCT1531 are specifically designed to confirm the utility of miR-371a-3p in clinical stage I *** its strong association with viable GCT after treatment with chemotherapy,miR-371a-3p does not seem to accurately predict the presence of teratoma in residual ***,standardization of extraction and interpretation methods is a necessary step to assure uniform results across different institutions.

关键词： Biomarker MicroRNA Non Seminoma Seminoma Testis cancer Tumor marker

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Identification and targeting of CD22ΔE12 as a molecular RNAi target to overcome drug resistance in high-risk B-lineage leukemias and lymphomas

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cancer Drug Resistance 2018年第1期1卷 30-47页

作者： Fatih M.Uckun Sanjive Qazi AresMIT Biomedical Computational Strategies(ABCS) MinneapolisMN 55402USA Ares Pharmaceuticals LLCSt.PaulMN 55110USA Division of Hematology-Oncology Department of PediatricsUniversity of Southern California Keck School of Medicine(USC KSOM)Los AngelesCA 90027USA norris comprehensive cancer center University of Southern California Keck School of Medicine(USC KSOM)Los AngelesCA 90027USA Bioinformatics Program Gustavus Adolphus CollegeSt.PeterMN 56082USA.

Aim:CD22ΔE12 as an oncogenic driver lesion in aggressive and drug-resistant B-precursor acute lymphoblastic leukemia(BPL)*** purpose of the present study was to identify the CD22ΔE12-specific signature transcriptome in human BPL cells and evaluate the clinical potential of a nanoscale formulation of CD22ΔE12-siRNA as an RNAi therapeutic against drug-resistant ***22ΔE12-siRNA nanoparticles significantly improved the event-free survival(EFS)outcome of NOD/SCID(NS)mice challenged with human BPL xenograft ***:Gene expression and translational bioinformatics methods were applied to examine the expression of the CD22ΔE12-specific signature transcriptome in human BPL cells in subsets of BPL *** analysis for mice challenged with BPL cells and treated with CD22ΔE12 siRNA was performed using standard ***:Leukemia cells from CD22ΔE12-Tg mice exhibit gene and protein expression profiles consistent with constitutive activation of multiple signaling networks,mimicking the profiles of relapsed BPL patients as well as newly diagnosed high-risk patients with BCR-ABL+/Philadelphia chromosome(Ph)+BPL as well as Ph-like BPL.A nanoscale formulation of CD22ΔE12-siRNA abrogated the in vivo clonogenicity of the leukemia-initiating leukemic cell fraction in xenograft specimens derived from patients with relapsed BPL and significantly improved the EFS outcome of NS mice challenged with drug-resistant human BPL xenograft ***:The CD22-RNAi technology is applicable to all BPL patients both high risk and standard *** is because CD22ΔE12 is a characteristic feature of drug-resistant leukemic clones that escape chemotherapy and cause relapse in both high risk and low risk subgroups of *** technology therefore has the potential(1)for prevention of relapses by selectively killing the clones that are most likely to escape chemotherapy and cause relapse as well(2)for treatment of relapses in *** research project may also lea

关键词： cancer leukemia RNA interference nanomedicine personalized medicine driver lesion

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Design and in vivo characterization of kidney-targeting multimodal micelles for renal drug delivery

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Nano Research 2018年第10期11卷 5584-5595页

作者： Jonathan Wang Christopher Poon Deborah Chin Sarah Milkowski Vivian Lu Kenneth R. Hallows Eun Ji Chung Department of Biomedical Engineering University of Southern California Los Angeles CA 90089 USA Division of Nephrology and Hypertension Department of Medicine Keck School of Medicine University of Southern California Los Angeles CA 90033 USA usc/UKRO Kidney Research center Keck School of Medicine University of Southern California Los Angeles CA 90033 USA norris comprehensive cancer center University of Southern California Los Angeles CA 90033 USA Department of Stem Cell Biology and Regenerative Medicine University of Southern California Los Angeles CA 90033 USA Mork Family Department of Chemical Engineering and Materials Science University of Southern California Los Angeles CA 90089 USA

One in three Americans is at risk for developing chronic kidney disease （CKD） and end-stage renal disease （ESRD）, leading to the need for dialysis or a kidney transplant. Small-molecule drugs have been proposed as therapies to manage kidney diseases, but high dosages are often required to achieve therapeutic efficacy, generating off-target side effects, some of which are lethal. To address these limitations, we developed a novel kidney-targeting multimodal micelle （KM） system for drug delivery applications. SpecificaU~ we incorporated the kidney-targeting peptide （Lysine-Lysine-Glutamic acid-Glutamic acid-Glutamic acid）3-Lysine）（（KKEEE）3K） into micelles. This peptide binds to megalin, a multi-ligand cell surface receptor present on renal tubule cells. When incubated with human kidney proximal tubule cells, KMs were found to be biocompatible in vitro. In vivo, KMs showed higher accumulation in the kidneys as compared to a non-targeted （NT） control upon intravenous injection in wild-type C57BL/6J mice. Histological evaluation showed no signs of tissue damage, while blood urea nitrogen （BUN） and creatinine levels were within normal ranges, validating the preservation of kidney health upon micelle administration. To our knowledge, this is the first utilization of （KKEEE）BK in a nanoparticle formulation, and our study offers strong evidence that this novel nanoparticle platform can be used as a candidate drug delivery carrier to direct therapeutics to diseased tissue in CKD.

关键词： micelle kidney disease renal targeting biodistribution nanoparticle

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Novel strategy for disease risk prediction incorporating predicted gene expression and DNA methylation data:a multi-phased study of prostate cancer

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cancer Communications 2021年第12期41卷 1387-1397页

作者： Chong Wu Jingjing Zhu Austin King Xiaoran Tong Qing Lu Jong Y.Park Liang Wang Guimin Gao Hong-Wen Deng Yaohua Yang Karen E.Knudsen Timothy R.Rebbeck Jirong Long Wei Zheng Wei Pan David V.Conti Christopher A Haiman Lang Wu Department of Statistics Florida State UniversityTallahasseeFL 32304USA cancer Epidemiology Division Population Sciences in the Pacific ProgramUniversity of Hawaii Cancer CenterUniversity of Hawaii at ManoaHonoluluHI 96813USA Department of Epidemiology and Biostatistics Michigan State UniversityEast LansingMI 48824USA Department of Biostatistics University of FloridaGainesvilleFL 32603USA Department of cancer Epidemiology H.Lee Moffitt Cancer Center and Research InstituteTampaFL 33612USA Department of Tumor Biology H.Lee Moffitt Cancer Center and Research InstituteTampaFL 33612USA Department of Public Health Sciences University of ChicagoChicagoIL 60637USA center of Bioinformatics and Genomics Department of Global Biostatistics and Data ScienceTulane UniversityNew OrleansLA 70112USA Division of Epidemiology Department of MedicineVanderbilt Epidemiology CenterVanderbilt-Ingram Cancer CenterVanderbilt University Medical CenterNashvilleTN 37203USA Department of cancer Biology Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaPA 19107USA Department of Medical Oncology Dana-Farber Cancer InstituteBostonMA 02215USA Department of Epidemiology Harvard TH Chan School of Public HealthBostonMA 02115USA Division of Biostatistics University of MinnesotaMinneapolisMN 55455USA Department of Preventive Medicine Keck School of MedicineUniversity of Southern California/Norris Comprehensive Cancer CenterLos AngelesCA 90033USA

Background:DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer(PCa).However,it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores(PRSs).Here,we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation,and other genomic information using an integrative ***:Using data from the PRACTICAL consortium,we derived multiple sets of genetic scores,including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding,LDpred,LDpred-funt,AnnoPred,and EBPRS,as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding *** the tuning step,using the UK Biobank data(1458 prevalent cases and 1467 controls),we selected PRSs with the best *** an independent set of data from the UK Biobank,we developed an integrative PRS combining information from individual ***,in the testing step,we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and ***:Our constructed PRS had improved performance(C statistics:76.1%)over PRSs constructed by individual benchmark methods(from 69.6%to 74.7%).Furthermore,our new PRS had much higher risk assessment power than family *** overall net reclassification improvement was 69.0%by adding PRS to the baseline model compared with 12.5%by adding family ***:We developed and validated a new PRS which may improve the utility in predicting the risk of developing *** innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.

关键词： risk prediction polygenic risk scores predicted gene expression predicted DNA methylation integrative models prostate cancer

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Design and realization of lung organoid cultures for COVID-19 applications

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Bio-Design and Manufacturing 2023年第6期6卷 646-660页

作者： Bing Ren Tryanni R.Chiaravalloti Nadine L.Belony Diana I.Romero Wenxuan Chai Christopher Leon Lizi Wu Nazarius S.Lamango Ite A.Offringa Yong Huang Department of Mechanical and Aerospace Engineering University of FloridaGainesvilleFL 32611USA Department of Biomedical Engineering University of FloridaGainesvilleFL 32611USA College of Pharmacy University of FloridaGainesvilleFL 32611USA norris comprehensive cancer center Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90089USA Department of Molecular Genetics and Microbiology University of FloridaGainesvilleFL 32611USA College of Pharmacy and Pharmaceutical Sciences Florida A&M UniversityTallahasseeFL 32307USA

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2,has spread globally and threatens public *** in vitro models that recapitulate the architecture and functioning of specific tissues and organs are in high demand for COVID-19-related pathology studies and drug *** three-dimensional in vitro cultures,such as self-assembled and engineered organoid cultures,surpass conventional two-dimensional cultures and animal models with respect to increased cellular complexity,an environment more relevant to humans,and reduced cost,they are promising platforms for understanding viral pathogenesis and developing new *** review highlights the recent advances in self-assembled and engineered organoid technologies that are used for COVID-19 *** challenges and future perspectives are also discussed.

关键词： Lung organoid COVID-19 Self-assembled organoid Engineered organoid

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