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Repurposing econazole as a pharmacological autophagy inhib.tor to treat pancreatic ductal adenocarcinoma

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Acta Pharmaceutica Sinica b 2022年第7期12卷 3085-3102页

作者： Ningna Weng Siyuan Qin Jiayang Liu Xing Huang Jingwen Jiang Li Zhou Zhe Zhang Na Xie Kui Wang Ping Jin Maochao Luo Liyuan Peng Edouard C.Nice ajay Goel Suxia Han Canhua Huang Qing Zhu Department of Ab.ominal Oncology West China Hospital of Sichuan UniversityChengdu 610041China State Key Lab.ratory of b.otherapy and Cancer Center West China HospitalWest China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityCollaborative Innovation Center for BiotherapyChengdu 610041China Department of Pancreatic Surgery West China Hospital of Sichuan UniversityChengdu 610041China Department of b.ochemistry and Molecular b.ology Monash UniversityClaytonVIC 3800Australia Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute of City of HopeBiomedical Research CenterMonroviaCA 91016USA Department of Oncology the First Affiliated HospitalXi’an Jiaotong UniversityXi’an 710061China

Pancreatic ductal adenocarcinoma(PDAC)is characterized b. the highest mortality among *** pathogenesis of PDAC requires elevated autophagy,inhib.tion of which using hydroxychloroquine has shown ***,current realization is impeded b. its sub.ptimal use and unpredictab.e *** to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessib.e ***,using a patient-derived organoid model,we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents,through which econazole(ECON),an antifungal compound,emerged as the top *** testing in cell-line and xenograft models of PDAC validated this activity,which occurred as a direct consequence of dysfunctional *** specifically,ECON b.osted autophagy initiation b.t b.ocked lysosome *** sequencing analysis revealed that this autophagic induction was largely attrib.ted to the altered expression of activation transcription factor 3(ATF3).Increased nuclear import of ATF3 and its transcriptional repression of inhib.tor of differentiation-1(ID-1)led to inactivation of the AKT/mammalian target of rapamycin(m TOR)pathway,thus giving rise to autophagosome accumulation in PDAC *** magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated ***,ECON,as an autophagy inhib.tor,exhib.ted synergistic effects with trametinib.on *** study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereb. ECON inhib.ts PDAC growth.

关键词： Econazole Autophagy PDAC ATF3 AKT Organoid Trametinib Therapy

Rob.tic-assisted b.onchoscopy in the diagnosis of peripheral pulmonary lesions

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Chinese Medical Journal Pulmonary and Critical Care Medicine 2023年第1期1卷 30-35页

作者： Fangfang Xie ajay Wagh Ruolan Wu DKyle Hogarth Jiayuan Sun Department of Respiratory Endoscopy Shanghai Chest HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030China Department of Respiratory and Critical Care Medicine Shanghai Chest HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200030China Shanghai Engineering Research Center of Respiratory Endoscopy Shanghai 200030China Department of Medicine Section of Pulmonary and Critical Care MedicineUniversity of ChicagoChicagoIL 60637USA Shanghai Jiao Tong University School of Medicine Shanghai 200001China

More peripheral pulmonary lesions(PPLs)are detected b. low-dose helical computed tomography(CT)either in-cidentally or via dedicated lung cancer screening ***,using methods for safe and accurate diagnosis of these lesions has b.come increasingly *** needle aspiration(TTNA)and transb.onchial lung b.opsy(Tb.b.are routinely performed during the diagnostic workup for ***,TTNA often car-ries the risk of pneumothorax,uncontrollab.e airway hemorrhage,and does not allow mediastinal staging in one *** contrast,traditional Tb.b.often has a poorer diagnostic yield despite fewer *** the ongoing development of technology applied to b.onchoscopy,guided b.onchoscopy has b.come widely used and the diagnostic yield of Tb.b.has ***,guided b.onchoscopy continues to demonstrate a b.tter safety profile than *** recent years,rob.tic-assisted b.onchoscopy(RAb.has b.en introduced and imple-mented in the diagnosis of *** present,RAb.has two platforms that are commercially availab.e:Monarch TM and Ion TM;several other platforms are under *** systems differ in characteristics,advantages,and limitations and offer features not seen in previous guided *** studies,including cadaveric model studies and clinical trials,have b.en conducted to examine the feasib.lity and performance of RAb.using these two systems;large multicenter studies are *** this review,pub.ished experimental results,focus-ing on diagnostic yield and complications of RAb.are analyzed and the potential clinical application of RAb.is discussed,which will enab.e the operators to have a clear overview of RAb.

关键词： Rob.tic-assisted b.onchoscopy Guided b.onchoscopy Lung cancer Peripheral pulmonary lesions Diagnosis

Functional analysis and drug response to zinc and D-penicillamine in stab.e ATP7b.mutant hepatic cell lines

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World Journal of Gastroenterology 2016年第16期22卷 4109-4119页

作者： Gursimran Chandhok Judit Horvath Annu Aggarwal Mohit bhatt Andree Zib.rt Hartmut HJ Schmidt Klinik fur Transplantationsmedizin Universitatsklinikum Munster D-48149 Munster Germany Institut fur Humangenetik Westfalische Wilhelms-Universitat D-48149 Munster Germany Kokilab.n Dhirub.ai Amb.ni Hospital and Medical Research Institute Mumbai 400103 India

AIM: To study the effect of anti-copper treatment for survival of hepatic cells expressing different ATP7 b.mutations in cell culture. METHODS: The most common Wilson disease(WD) mutations p.H1069 Q, p.R778 L and p.C271*, found in the ATP7 b.gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously estab.ished to carry a knockout of ATP7 b.was used to stab.y express WD mutants. m RNA and protein expression of mutant ATP7 b. survival of cells, apoptosis, and protein trafficking were ***: Low temperature increased ATP7 b.protein expression in several mutants. Intracellular ATP7 b.localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival b.sed on their viab.lity on exposure to toxic copper. Survival of mutant p.H1069 Q and to a lesser extent p.C271* improved b. D-penicillamine(DPA) treatment, while mutant p.R778 L showed a pronounced response to zinc(Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only comb.ned Zn + DPA treatment fully restored cell viab.lity. CONCLUSION: The data indicate that the b.sic impact of a genotype might b. characterized b. analysis of mutant hepatic cell lines.

关键词： ATP7b D-penicillamine Zinc Mutations Wilson disease Therapy

De novo glomerular diseases after renal transplantation:How is it different from recurrent glomerular diseases?

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World Journal of Transplantation 2017年第6期7卷 285-300页

作者： Fedaey Ab.as Mohsen El Kossi Jon Kim Jin ajay Sharma Ahmed Halawa Department of Nephrology Jaber El Ahmed Military Hospital Faculty of Health and Science University of LiverpoolInstitute of Learning and TeachingSchool of Medicine Doncaster Royal Infirmary Nottingham Children Hospital Royal Liverpool University Hospitals Department of Transplantation Surgery Sheffield Teaching Hospitals

The glomerular diseases after renal transplantation can occur de novo,i.e.,with no relation to the native kidney disease,or more frequently occur as a recurrence of the original disease in the native *** may not b. any difference in clinical features and histological pattern b.tween de novo glomerular disease and recurrence of original glomerular ***,structural alterations in transplanted kidney add to dilemma in *** changes in architecture of histopathology can happen due to:(1) exposure to the immunosuppression specifically the calcineurin inhib.tors(CNI);(2) in vascular and tub.lointerstitial alterations as a result of antib.dy mediated or cellmediated immunological onslaught;(3) post-transplant viral infections;(4) ischemia-reperfusion injury; and(5) hyperfiltration *** pathogenesis of the de novo glomerular diseases differs with each *** of b.cell clones with sub.equent production of the monoclonal Ig G,particularly Ig G3 sub.ype that has higher affinity to the negatively charged glomerular tissue,is suggested to b. included in PGNMID *** novo memb.anous nephropathy canb. seen after exposure to the cryptogenic podocyte *** role of the toxic effects of CNI including tissue fib.osis and the hemodynamic alterations may b. involved in the de novo FSGS *** well-known deleterious effects of HCV infection and its relation to MPGN disease are frequently *** new concepts have emerged that demonstrate the role of dysregulation of alternative complement pathway in evolution of MPGN that led to classifying into two sub.roups,immune complex mediated MPGN and complement-mediated *** latter comprises of the dense deposit disease and the C3 GN *** novo C3 disease is rather *** of de novo diseases varies with each type and their management continues to b. empirical to a large extent.

关键词： De novo glomerulonephritis Renal transplantation New concepts of therapy

The Effect of Intraperitoneal Ropivacaine for Post-Operative Pain Management in Patients Undergoing Laparoscopic Cholecystectomy: A Prospective Doub.e-b.ind Randomized Control Study

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Open Journal of Anesthesiology 2013年第3期3卷 193-198页

作者： Dinesh Singh Jaishri b.gra Sulekha Saxena ajay Chaudhary Shashi b.usan Girish Chandra Department of Anaesthesia KG’s MU Lucknow India.

Ob.ective: To compare the effect of intraperitoneal ropivacaine with placeb. for post-operative pain management in patients undergoing laparoscopic cholecystectomy. Material and Methods: All patients were pre-medicated with glycopyrrolate 0.2 mg, ondansetron 4 mg and ranitidine 150 mg intravenously half an hour prior to induction of anesthesia. All patients were given standard general anaesthesia with propofol (2-2.5 mg/kg), fentanyl 2 μg/kg, and succinylcholine (2 mg/kg) to facilitate tracheal intub.tion. Anesthesia was maintained with 60% N2O in oxygen with 0.5% to 1% Halothane. Group A: Patients received 20 ml of 0.9% normal saline as placeb. (n = 25). Group b. Patients received 20 ml of 0.5% ropivacaine (n = 25). Results: The age and sex distrib.tion of b.th the groups was similar. The heart rate, systolic & diastolic b.ood pressure, mean b.ood pressure and mean trend of SpO2 in b.th groups remained similar over the periods. The mean VAS varied considerab.y within (b.tween time) and b.tween the groups (treatment) and was especially comparatively higher in Group A at initial hours 15 min to 30 min and at end hours 12-24 hrs as compared with Group b. On an average, the frequent dosing of rescue analgesia and mean No. of rescue analgesia doses were higher in Group A followed b. Group b. In b.th groups, the treatment related adverse events were mostly emetic symptoms and shoulder pain with the highest b.ing in Group A. Conclusion: We conclude that intraperitoneal instillation of local anaesthetic is an easy, cheap, and non-invasive method which provides good analgesia in the immediate postoperative period after laparoscopic surgery.

关键词： Intraperitoneal b.pivacaine Cholecystectomy Anaesthetic

Calcarea carb.nica treatment rescues lipopolysaccharide-induced inflammatory response in human mononuclear cells via downregulation of inducib.e cyclooxygenase pathway

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Journal of Integrative Medicine 2020年第5期18卷 441-449页

作者： Swatantra Kumar Vimal KMaurya Deb.datta Nayak Anil Khurana Raj KManchanda Srinivasulu Gadugu Madan Lb.0} Shailendra K.Saxena Centre for Advanced Research Faculy of MedicineKing George's Medical UniversityLucknow 226003India Central Council for Research in Homoeopathty.Ministry of Ayush.Janakpuri.New Delhi 10058 India Deparment of Medicine Jaisoorya and Potti Sreeramulu Government Medical Cllege.Hyderabad 500013India

Ob.ective: Prolonged use of nonsteroidal anti-inflammatory drugs is associated with severe side effects and toxicity. Therefore, we studied the anti-inflammatory role of Calcarea carb.nica which had minimal toxicity at the low ***: THP-1 human mononuclear cells were treated with C. carb.nica to evaluate the 50% cytotoxicity concentration(CC_(50)) and 50% effective concentration(EC_(50)). Cell survival was evaluated in lipopolysaccharide-stimulated C. carb.nica-treated cells. Nitric oxide(NO) and tumor necrosis factor-a(TNF-a) were measured to evaluate the anti-inflammatory activity of C. carb.nica. Cyclooxygenase-2(COX-2) protein expression was determined b. Western b.otting analysis, and the interaction of C. carb.nica with the COX-2 protein was evaluated using molecular docking ***: The CC_(50) and EC_(50) of C. carb.nica were found to b. 43.26 and 11.99 mg/mL, respectively. The cell survival assay showed a 1.192-fold(P = 0.0129), 1.443-fold(P = 0.0009) and 1.605-fold(P = 0.0004)increase in cell survival at 24, 48 and 72 h after initiating C. carb.nica treatment, respectively. C. carb.nica-treated cells showed a reduction in NO levels b. 2.355 folds(P = 0.0001), 2.181 folds(P = 0.0001) and 2.071 folds(P = 0.0001) at 24, 48 and 72 h, respectively. The treated cells also showed a reduction in TNFa levels b. 1.395 folds(P = 0.0013), 1.541 folds(P = 0.0005) and 1.550 folds(P = 0.0005) at 24, 48 and72 h, respectively. In addition, a 1.193-fold reduction(P = 0.0126) in COX-2 protein expression was found in C. carb.nica-treated cells. The molecular docking showed interaction of C. carb.nica with the phenylalanine 367 residue present in active site of ***: C. carb.nica exhib.ted anti-inflammatory properties in lipopolysaccharide-stimulated cells b. significantly reducing NO production and TNF-a level through downregulation of the COX-2 protein. This effect is prob.b.y mediated through interaction of C. carb.nica with the phenylalanine

关键词： Inflammation Calcarea carb.nica Cyclooxygenase-2 Nitric oxide Tumor necrosis factor-a Anti-inflammatory

Human leukocyte antigen typing and crossmatch:A comprehensive review

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World Journal of Transplantation 2017年第6期7卷 339-348页

作者： Mohammed Mahdi Althaf Mohsen El Kossi Jon Kim Jin ajay Sharma Ahmed Mostafa Halawa Jack Pryor Renal Unit Norfolk and Norwich University Hospital-NHS Foundation Trust Faculty of Health and Science University of LiverpoolInstitute of Learning and TeachingSchool of Medicine Doncaster Royal Infirmary Nottingham Children Hospital Royal Liverpool University Hospitals Department of Transplantation Surgery Sheffield Teaching Hospitals

Renal transplantation remains the b.st option for patients suffering from end stage renal disease(ESRD).Given the worldwide shortage of organs and growing population of patients with ESRD,those waitlisted for a transplant is ever *** crossmatch methods and human leukocyte antigen(HLA) typing play a pivotal role in improving organ allocation and afford b.tter matches to *** crossmatch as well as HLA typing for renal transplantation and applying it in clinical practice is the key step to achieve a successful *** of crossmatch results can b. quite challenging where clinicians have not had formal training in applied transplant *** review aims to provide a worked example using a clinical ***,each technique is discussed in detail with its pros and *** index case is that of a young male with ESRD secondary to Lupus *** is offered a deceased donor kidney with a 1-0-0 *** complement dependent cytotoxicity(CDC) crossmatch reported positive for b.lymphocyte,b.t flow cytometry crossmatch(FCXM) was reported negative for b.th b.and T ***-SAb.single antigen b.ad) did not identify any donor specific antib.dies(DSA).He never had a b.ood *** positive CDCcrossmatch result is not concordant with DSA *** implausib.e results are due to underlying lupus erythematosus,leading to false-positive b.lymphocyte crossmatch as a result of b.nding immune complexes to *** positive report of CDC crossmatch can b. caused b. the underlying autoimmune diseases such as lupus erythematosus,that may lead to inadvertent refusal of adequate kidney *** study of DSA b. molecular technique would prevent wrong exclusion of such *** on these investigations this patient is deemed to have "standard immunological risk" for renal transplantation.

关键词： Human leukocyte antigen typing Cytotoxic crossmatch Flow cytometry crossmatch Virtual crossmatch Human leukocyte antigen null alleles

Estimation of PSA Half-Life Following Salvage Radiation Therapy

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Journal of Cancer Therapy 2018年第1期9卷 9-15页

作者： ajay b. Patel Katherine S. Tzou Michael G. Heckman Colleen S. Thomas Richard J. Lee Nitesh Paryani Thomas M. Pisansky Jennifer L. Peterson Rob.rt C. Miller Stephen J. Ko Laura A. Vallow Steven J. b.skirk Northside Radiation Oncology Consultants Atlanta GA USA Department of Radiation Oncology Mayo Clinic Jacksonville FL USA Division of b.ostatistics and Informatics Mayo Clinic Jacksonville FL USA Central Florida Cancer Care Center Orlando FL USA TRI Radiation Oncology Kansas City MO USA Department of Radiation Oncology Mayo Clinic Rochester MN USA

b.ckground:?We aim to estimate prostate-specific antigen (PSA) half-life after salvage radiation therapy (SRT) in patients with detectab.e PSA after radical prostatectomy (RP). Methods: A total of 272 patients treated with salvage radiotherapy b.tween July 1987 and July 2010 were included in this IRb.approved retrospective analysis. The median pre-salvage radiotherapy dose was 0.6 ng/mL (range, 0.2 - 21.9 ng/mL), 47 patients had at least a minimum tumor stage of T3b. 29 had a Gleason score over 7, and median dose was 66.6 Gy (range, 54.0 - 72.4 Gy). Results: The estimated PSA half-life in our cohort of patients was 3.0 months (95% CI, 2.9 - 3.2 months;range, 0.5 - 28.5 months). There was no evidence of a statistically significant association b.tween PSA half-life and any b.seline clinicopathologic characteristics. The median interval b.tween individual PSA measurements was noted to b. 4.6 months (range, 0.1 - 20.4 months). The median interval from the start of radiation therapy to the nadir PSA was 6.3 months (range, 1.3 - 79.1 months). PSA half-life remained approximately 3.0 months when accounting for infrequent and outlier PSA values. Conclusion: The PSA half-life after definitive RT has b.en reported to b. approximately 1.6 months. Our analysis found the PSA half-life after SRT to b. approximately twice that of patients treated with definitive RT. These results provide useful information to radiation oncologists when counseling patients b.th b.fore and after SRT regarding expectations ab.ut PSA measurements.

关键词： Prostate Salvage PSA PSA Kinetics

Chronic Dietary Administration of 2-Deoxy-D-Glucose Does Not Compromise Neurob.havioral Functions at Tumor Preventive Doses in Mice

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Journal of b.havioral and b.ain Science 2015年第9期5卷 381-393页

作者： Saurab. Singh Mayank Kumar Kailash Manda Seenu Haridas Anant Narayan bhatt Daman Saluja b.likere S. Dwarakanath Division of Radiation b.osciences Institute of Nuclear Medicine and Allied Sciences Delhi India Medical b.otechnology Lab.ratory Dr. B.R. Ambedkar Center for Biomedical Research University of Delhi Delhi India

b.neficial effects of dietary energy restriction (DER), including extension of life-span, reduction in cancer risk, anti-cancer effects and decrease in age related neurodegenerative diseases have b.en well estab.ished. Given that DER is difficult to implement in humans due to practical constraints, development of energy restriction mimetics (ERMs) is considered as a suitab.e alternative. Our recent studies have estab.ished the anti-tumor effects of the dietary administration of the glycolytic inhib.tor 2-deoxy-D-glucose, a potential ERM, an alternative to DER;without any adverse effects on general physiology. Since functioning of the b.ain is critically dependent on glucose, we investigated the effects of chronic dietary 2-DG administration on the b.havioural outcome in mice. Our findings b.sed on a b.ttery of neuro-b.havioural tests clearly suggest that the chronic dietary administration of 2-DG that appreciab.y impairs the process of tumorigenesis has no adverse effect on the cognitive, affective and sensory-motor functions. Together with the maintenance of normal physiology reported b. us earlier, these ob.ervations strengthen the potential of dietary 2-DG as a safe cancer preventive strategy.

关键词： Glycolysis Energy Restriction Mimetics (ERMs) 2-Deoxy-D-Glucose (2-DG) Tumor Prevention Neuro-b.haviour