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ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers

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Cancer Innovation 2022年第1期1卷 55-69页

作者： Zhikang Chen Xiaobo Lai Hui Ding Aijun Zhang Yufei Sun jianhua Ling Paul J.Chiao Zihua Chen Xuefeng Xia The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor ChangshaHunanChina Department of General Surgery Xiangya HospitalCentral South UniversityChangshaHunanChina International joint Research Center of Minimally Invasive Endoscopic Technology Equipment&Standardization ChangshaHunanChina National Clinical Research Center for Geriatric Disorders Xiangya HospitalChangshaHunanChina Guangzhou First People's Hospital The Second Affiliated Hospital of South China University of TechnologyGuangzhouGuangdongChina Hainan Eye Hospital and Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-Sen UniversityHaikouHainanChina Houston Methodist Research Institute HoustonTexasUSA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA GenePlus‐Beijing Institute BeijingChina

Background:Limited by difficulties in early detection and availabilities of effective treatments,pancreatic cancer is a highly malignant disease with poor prognosis.Nuclear receptors are a family of ligand‐dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development,including cancer.In this study,we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor(LXR)agonist GW3965 in pancreatic cancer.Methods:Soft‐agar colony formation assay,xenograft tumors,Oligonucleotide microarray,Reverse transcription real‐time polymerase chain reaction,Western immunoblotting and Immunohistochemistry were used in this study.Results:We demonstrated pleotropic in vitro activities of GW3965 in pancreatic cell lines MIA PaCa‐2 and BXPC3 including reduction of cell viability,inhibition of cell proliferation,stimulation of cell death,and suppression of colony formation,which translated to significant inhibition of xenograft tumor growth in vitro.By mapping the gene expression profiles,we identified the up‐regulations of 188 and the down‐regulations of 92 genes common to both cell lines following GW3965 treatment.Genes responsive to GW3965 represent a variety of biological pathways vital for multiple cellular functions.Specifically,we identified that the activating transcription factor 4/thioredoxin‐interacting protein/regulated in development and DNA damage responses 1/mechanistic target of rapamycin(ATF4/TXNIP/REDD1/mTOR)signaling critically controls GW3965‐mediated regulation of cell proliferation/death.The significance of the ATF4/TXNIP/REDD1/mTOR pathway was further supported by associated expressions in xenograft tumors as well as human pancreatic cancer samples.Conclusions:This study provides the pre‐clinical evidence that LXR agonist is a promising therapy for pancreatic cancer.

关键词： GW3965 liver X receptor nuclear receptors pancreatic cancer signaling pathways

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血液中羟基化缓激肽作为肿瘤厌氧指标的研究

Science Bulletin 2020年第18期65卷 1570-1579,M0004页

作者：刘洋谷雅君 Serina Ng 邓载安 Christopher j.Lyon Eugene j.Koay 宁波 Matthew H.Katz Paul J.Chiao 范佳韩海勇 Daniel Von Hoff 胡晔 Department of Biochemistry and Molecular Biology Tulane University School of MedicineNew Orleans.LA 70112USA Department of Nanomedicine Houston Methodist Research InstituteHoustonTX 77030USA Molecular Medicine Division Translational Genomics Research InstitutePhoenixAZ 85004USA Department of Radiation Oncology Division of Radiation OncologyThe University of Texas M.D.Anderson Cancer CenterHoustonTX 77030USA Department of Surgical Oncology Division of SurgeryThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Molecular and Cellular Oncology Division of Basic SciencesThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

组织缺氧在消化系统、呼吸系统、肾脏疾病和癌症等多种疾病的发生发展中起到关键作用.然而,由于缺乏快速、准确和非侵入性的检测方法,评估组织缺氧情况和预测患者的预后结果仍然具有非常大的挑战性.本文假设血液中Hyp-BK/BK比率可以作... 详细信息

组织缺氧在消化系统、呼吸系统、肾脏疾病和癌症等多种疾病的发生发展中起到关键作用.然而,由于缺乏快速、准确和非侵入性的检测方法,评估组织缺氧情况和预测患者的预后结果仍然具有非常大的挑战性.本文假设血液中Hyp-BK/BK比率可以作为缺氧检测的标志物,以胰腺癌作为研究模型,通过监测Hyp-BK/BK比率可以预测组织缺氧水平以及抗肿瘤治疗的预后情况.研究表明,缺氧条件下肿瘤组织中高表达的P4HA1和治疗前患者血液样本中Hyp-BK/BK比率升高有关,并且两者都与患者预后不良相关.这些结果有力地表明血液中Hyp-BK/BK比率可以作为非侵入性的组织缺氧标志物,对胰腺癌的预后和治疗效果进行预测.

关键词： HIF-1α Hypoxia Circulating indicator Hydroxyprolyl bradykinin P4HA1

Constitutive Activation of NF-κB in Pancreatic Cancer:The Mechanism, Function, and Therapeutic Target

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Constitutive Activation of NF-κB in Pancreatic Cancer:The M...

Malignant transformation by oncogenic K-ras requires IDH2-mediated reductive carboxylation to promote glutamine utilization

第四届中国肿瘤学术大会暨第五届海峡两岸肿瘤学术会议

作者： paul j. chiao The University of Texas M. D. Anderson Cancer Center

＜正＞Pancreatic adenocarcinoma is the fourth leading cause of adult cancer mortality in the United States. The five -year survival rate continues at 1-3% and the median survival after diagnosis is often less than 6 months. Pancreatic-cancer is characterized by poor prognosis and lack of response to conventional therapy. Hence, pancreatic cancer poses one of the greatest challenges incancer research. Only through basic and translational research aimed at understanding

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Cancer Communications 2023年第2期43卷 285-289页

作者： Rui Liu Panpan Liu Huichang Bi jianhua Ling Huiqin Zhang Mingquan Zhang Yumin Hu Paul J.Chiao Peng Huang jinyun Liu Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060P.R.China School of Materials Science and Engineering Sun Yat-sen UniversityGuangzhouGuangdong 510275P.R.China School of Pharmaceutical Sciences Southern Medical UniversityGuangzhouGuangdong 510515P.R.China Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTexas 77030USA Metabolic Research Platform Center for Precision MedicineZhongshan School of MedicineSun Yat-sen UniversityGuangzhouGuangdong 510080P.R.China

Dear Editor,Oncogenic K-ras mutation plays a major role in malignant transformation and induces significant alterations in cancer cell metabolism[1–4].However,the major molecular players mediating metabolic alterations during K-ras-driven cancer development remain elusive.The observations that tumorigenesis often requires multiple hits suggest that K-ras mutation likely needs the coordination of other molecular events that enable adaptive cellular metabolism for a full malignant transformation.Based on our previous study on the impact of K-ras onmitochondrial metabolism[1,5]and our recent findings that mitochondrial isocitrate dehydrogenase 2(IDH2)could promote the“reverse”flow of the tricarboxylic acid(TCA)cycle fromα-KG to isocitrate and enhance the survival and proliferation of acute myeloid leukemia cells[6],we investigated the potential role of IDH2 in metabolic adaptation during K-ras-driven tumorigenesis.

关键词： metabolism alterations cancer

Hyperbolic Divergence Cleaning in Lattice Boltzmann Magnetohydrodynamics

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Communications in Computational Physics 2023年第1期33卷 245-272页

作者： paul j.Dellar OCIAM Mathematical InstituteUniversity of OxfordRadcliffe Observatory QuarterOxford OX26GGUK

Magnetohydrodynamics couples the Navier-Stokes and Maxwell’s equations to describe the flow of electrically conducting fluids in magnetic fields.Maxwell’s equations require the divergence of the magnetic field to vanish,but this condition is typically not preserved exactly by numerical algorithms.Solutions can develop artifacts because structural properties of the magnetohydrodynamic equations then fail to hold.Magnetohydrodynamics with hyperbolic divergence cleaning permits a nonzero divergence that evolves under a telegraph equation,designed to both damp the divergence,and propagate it away from any sources,such as poorly resolved regions with large spatial gradients,without significantly increasing the computational cost.We show that existing lattice Boltzmann algorithms for magnetohydrodynamics already incorporate hyperbolic divergence cleaning,though they typically use parameter values for which it reduces to parabolic divergence cleaning under a slowly-varying approximation.We recover hyperbolic divergence cleaning by adjusting the relaxation rate for the trace of the tensor that represents the electric field,and absorb the contribution from the symmetric-traceless part of this tensor using a change of variables.Numerical experiments confirm that the qualitative behaviour changes from parabolic to hyperbolic when the relaxation time for the trace of the electric field tensor is increased.

关键词： Magnetohydrodynamics divergence cleaning telegraph equations matrix collision operators linear viscoelasticity

Utility of droplet digital polymerase chain reaction for studying somatic mosaicism:brain malformations and beyond

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Neural Regeneration Research 2023年第11期18卷 2389-2390页

作者： Wei Shern Lee paul j.Lockhart Bruce Lefroy Centre Murdoch Children’s Research InstituteParkvilleVICAustralia Department of Paediatrics The University of MelbourneParkvilleVICAustralia

Somatic variants and how to find them:One major challenge in studying somatic mosaicism is the low abundance of potentially pathogenic somatic variant(s).Unlike inherited germline variants,which are essentially present in all cells,pathogenic somatic variants only exist in a subset of cells and may be present at very low (<1%)variant allele frequency (VAF).Despite the low VAF,these somatic variants are disease-relevant and considered pathogenic.In the context of focal brain malformations,which constitute a frequent cause of drug-resistant focal epilepsy,a pathogenic somatic mammalian ta rget of rapamycin (MTOR)variant with a VAF of 0.3%has been described(Baldassari et al.,2019).The identification of pathogenic somatic variants has importa nt implications both clinically and biologically.

关键词： epilepsy beyond

Preserving the past or past preserving: sustaining the legacy of postmodern museum architecture

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Built Heritage 2022年第2期6卷 24-42页

作者： paul j.Armstrong paul H.Kapp Illinois School of Architecture University of Illinois at Urbana-Champaign117 Buell Hall611 Taft DriveChampaignIL 61820USA

The publication of Complexity and Contradiction in Architecture in 1964 signaled the end of Modernism.The reality was that the modern movement had already jettisoned its ideological underpinnings and had become merely another‘style.’The avant garde architects in Europe and in North America were ready to move on and saw Postmodernism as a liberating antidote to the strictures of high Modernism.Historic architectural styles,which had been vilified as antiquated and out of step with modern culture,were revived,reinterpreted,and manipulated.However,Postmodernism,which had burned brightly during the 1970s and 1980s,was superseded by other architectural movements,namely,Deconstructivism,Pluralism,during the waning years of the 12th century.Even though new building forms and design theory changed during Postmodernism,building technology remained the same.Exterior walls continued to be built as skins,comprised of either glass,masonry,metal,or synthetic cladding,which were hung of steel or concrete framing.Rubberised membranes covered essentially flat roofs.Moisture infiltration was managed in ever complex composite wall assemblies.More important,environmental systems decoupled nature from interiors and were designed to manage ever demanding humidity control requirements.Through the development of new building technology,Modernism severed design style from traditional construction.In re-introducing historical forms back into architecture,Postmodernism complicated constructability.Moreover,Postmodernism and its successors rarely developed new technological ideas by introducing more intricate building forms,which were based on theoretical ideas rather than technical ones,while continuing to employ Modernism building technology into their buildings.This inherent paradox is the most consequential challenge in preserving Postmodernism.Today,approximately 40 years after its inception,we must consider if,in some cases.is it tenable to preserve Postmodern buildings?This paper reassesses three museums of the Postmodern era through

关键词： Postmodernism Modern movement Preservation Museums Materials Technology Moisture Memory Adaptation

New and emerging therapies in gout

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Rheumatology & Autoimmunity 2023年第2期3卷 70-77页

作者： Reeta james Binoy j.paul Department of General Medicine KMCT Medical CollegeCalicutIndia Department of Rheumatology KMCT Medical CollegeCalicutIndia

Gout is a disease that has been pestering humankind for centuries.Hence,gout therapeutics has always been a field of ongoing research.Beginning from colchicine,which was the first drug to come into use,to the latest inflammasome inhibitors and monoclonal antibodies,therapies for gout have evolved remarkably over the years.Although gout-related research came to a standstill in the late 20th century,the 21st century witnessed a renaissance in gout therapeutics with the advent of new xanthine oxidase inhibitors.Our present armamentarium against gout includes drugs that exploit the newfound knowledge about the various mechanisms involved in the pathogenesis of gout as well as drugs used in other conditions,which are effective in gout as well.Many more drugs that promise better management of gout in the future are in the pipeline.

关键词： caspase inhibitor gout inflammasome inhibitor urate transporter-1 inhibition

Nanotrap-enabled quantification of KRAS-induced peptide hydroxylation in blood for cancer early detection

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Nano Research 2019年第6期12卷 1445-1452页

作者： Zaian Deng Zhen Zhao Bo Ning jeffery Basilio Karen Mann jie Fu Yajun Gu Yuanqing Ye Xifeng Wu jia Fan paul chiao Tony Hu College of Health Science and Environmental Engineering Shenzhen Technology UniversityShenzhen 518118 China School of Biological and Health Systems Engineering Virginia G. Piper Biodesign Center for Personalized DiagnosticsThe Biodesign InstituteArizona State UniversityTempeArizona 85287USA Department of Nanomedicine Houston Methodist Research InstituteHoustonTexas 77030USA Pathology and Laboratory Medicine Weill Cornell Medical CollegeNew York New York 10065USA Center for Molecular Design and Biomimetics The Biodesign InstituteArizona State UniversityTempeArizona 85287USA Department of Laboratory Medicine Clinical CenterNational Institutes of HealthBethesdaMaryland 20892USA Department of Molecular Oncology H. Lee Moffitt Cancer CenterTampaFlorida 33612USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTexas 77030USA School of Medical Laboratory Tianjin Medical UniversityTianjin 300203China Department of Epidemiology The University of Texas MD Anderson Cancer CenterHoustonTexas 77030USA

Circulating peptide is a potential source of biomarkers for cancer detection.However,the existence of large molecular weight proteins in plasma have a disastrous effect on circulating peptides isolating and detecting.Herein,nanotrap fractionation following by mass spectrometry have been applied to quantify the levels of bradykinin (BK) and hydroxylated bradykinin (Hyp-BK) as a relative measure of KRAS-regulated prolyl-4-hydroxylase alpha-1 (P4HA1) which may serve as early diagnosis marker for pancreatic ductal adenocarcinoma (PDAC).We found that P4HA1 can be upregulated by KRASG12v,which is a PDAC driver mutation,using HPNE/KRAS and HPNE cells.And we revealed that P4HA1 is overexpressed in PDAC tumors,compared to normal and inflamed pancreatic tissues.RNA interference revealed that P4HA1 activity was primarily responsible for Hyp-BK production.Mass spectrometry analysis revealed that plasma Hyp-BK/BK ratio was higher in PDAC than pancreatitis patients and healthy controls,while the area under the receiver operating characteristic (ROC) curve (AUC) is 0.8209 (95%Cl,0.7269-0.9149).The Hyp-BK/BK association with PDAC was reproduced in another cohort,where this ratio was found to increase with advancing tumor stage.These novel findings paved the way for wider applications of Nanotrap coupled mass spectrometry as a powerful tool for revealing biosignatures from plasma.

关键词： nanotrap hydroxylation level bradykinin pancreatic ductal adenocarcinoma