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World Journal of Gastroenterology 2014年第47期20卷 17830-17838页

作者： Kate S O'Connor Jacob George David Booth Golo Ahlenstiel Institute for Immunology and Allergy research Westmead Millennium InstituteUniversity of SydneySydneyNSW 2145Australia Storr Liver Unit Westmead Millennium Institute and Westmead HospitalUniversity of SydneySydneyNSW 2145Australia

Recently,single nucleotide polymorphisms,in the vicinity of the interferon lambda 3(IFNL3)gene have been identified as the strongest predictor of spontaneous and treatment induced clearance of hepatitis C virus(HCV)*** then,increasing evidence has implicated the innate immune response in mediating the IFNL3 genotype *** cells(DCs)are key to the host immune response in HCV infection and their vital role in the IFNL3 genotype effect is *** have identified subclasses of DCs,particularly myeloid DC2s and potentially plasmacytoid DCs as the major producers of IFNL3 in the setting of HCV *** the complexities of dendritic cell biology and the conflicting current available data,this review aims to summarize what is currently known regarding the role of dendritic cells in HCV infection and to placeit into context of what is know about lambda interferons and dendritic cells in general.

关键词： Hepatitis C virus Interferon lambda 3 Dendritic ce

通过核心蛋白簇分析鉴定导致甲硝唑耐药的幽门螺杆菌变异位点

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Gastroenterology Report 2019年第1期7卷 42-49,I0002页

作者： Eng-Guan Chua Aleksandra W.Debowski KMary Webberley Fanny Peters Binit Lamichhane Mun-Fai Loke Jamuna Vadivelu Chin-Yen Tay Barry J.Marshall Michael J.Wise The Marshall Centre for Infectious Diseases research and Training University of Western AustraliaPerthWestern AustraliaAustralia School of Biomedical Sciences Faculty of Health and Medical SciencesUniversity of Western AustraliaPerthWestern AustraliaAustralia Department of medical Microbiology University of MalayaKuala LumpurWilayah PersekutuanMalaysia Shenzhen Dapeng New District Kuichong People Hospital ShenzhenGuangdongChina UM Marshall Centre University of MalayaKuala LumpurWilayah PersekutuanMalaysia School of Computer Science and Software Engineering University of Western AustraliaPerthWestern AustraliaAustralia

背景:在根治幽门螺杆菌(Hp)的标准三联治疗中,甲硝唑是其中的一种一线药物。因此,甲硝唑耐药是一个重大健康问题。RdxA失活被认为是甲硝唑耐药的主要机制。然而,表达功能性RdxA蛋白的Hp菌珠更容易对甲硝唑耐药,提示还存在其他一些导致... 详细信息

背景:在根治幽门螺杆菌(Hp)的标准三联治疗中,甲硝唑是其中的一种一线药物。因此,甲硝唑耐药是一个重大健康问题。RdxA失活被认为是甲硝唑耐药的主要机制。然而,表达功能性RdxA蛋白的Hp菌珠更容易对甲硝唑耐药,提示还存在其他一些导致甲硝唑耐药的机制。方法:我们对121份Hp菌珠进行了全基因组测序,其中73份是甲哨唑耐药菌珠。对包含全长RdxA基因的Hp临床菌珠的核心蛋白簇进行序列比对分析。对耐药菌珠与敏感菌珠的差异位点进行分析,以鉴定出差异基因及其导致甲硝唑耐药的氨基酸改变。结果:在73份甲硝唑耐药菌珠中,25份(34%)是由于RdxA无义突变所导致。对来自剩余48份甲硝唑耐药菌珠和48份甲硝唑敏感菌株的核心蛋白簇进行分析发现,有4个差异位点与甲硝唑耐药显著相关。这4个位点包括RdxA的R16H/C位点、内膜蛋白RclC(HP0565)的D85N位点、biotin carboxylase蛋白(HP0370)的V265I位点和putative threonylcarbamoyl-AMP合酶(HP0918)的A51V/T位点。结论:我们发现了Hp对甲硝唑耐药的一些新的潜在机制,值得进一步研究。

关键词： Helicobacter pylori metronidazole antibiotic resistance whole-genome sequencing core protein clusters sequence alignment

Aurone derivatives as Vps34 inhibitors that modulate autophagy

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Acta Pharmaceutica Sinica B 2019年第3期9卷 537-544页

作者： Guodong Li Joshua William Boyle Chung-Nga Ko Wu Zeng Vincent Kam Wai Wong Jian-Bo Wan Philip Wai Hong Chan Dik-Lung Ma Chung-Hang Leung State Key Laboratory of Quality research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao999078China School of Chemistry Monash UniversityClayton3800Australia Department of Chemistry Hong Kong Baptist UniversityHong Kong999077China State Key Laboratory of Quality research in Chinese Medicine Macao University of Science and TechnologyMacao999078China Department of Chemistry University of WarwickCoventry CV47ALUK

We report in this study the identification of a natural product-like antagonist(1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mT OR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.

关键词： Autophagy Natural products Vps34 Inhibitor Structure-based virtual screening Vesicle trafficking Heart or liver damage Aurone derivative

Engineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment

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Bone research 2019年第2期7卷 157-170页

作者： Nathalie Bock Ali Shokoohmand Thomas Kryza Joan Rohl Jonelle Meijer Phong A. Tran Colleen C. Nelson Judith A. Clements Dietmar W. Hutmacher School of Biomedical Sciences Faculty of Health and Australian Prostate Cancer Research Centre (APCRC-Q)Institute of Health and Biomedical Innovation (IHBI)Queensland University of Technology (QUT)BrisbaneQLD 4000Australia Translational research Institute (TRI) WoolloongabbaQLD 4102Australia Centre in Regenerative Medicine QUTKelvin GroveQLD 4059Australia Bone and Joint Disorders Program School of ChemistryPhysics and Mechanical EngineeringScience and Engineering Faculty (SEF)QUTBrisbaneQLD 4000Australia australian research council (ARC) Training Centre in Additive Biomanufacturing QUTKelvin GroveQLD 4059Australia

While stromal interactions are essential in cancer adaptation to hormonal therapies,the effects of bone stroma and androgen deprivation on cancer progression in bone are poorly ***,we tissue-engineered and validated an in vitro microtissue model of osteoblastic bone metastases,and used it to study the effects of androgen deprivation in this *** model was established by culturing primary human osteoprogenitor cells on melt electrowritten polymer scaffolds,leading to a mineralized osteoblast-derived microtissue containing,in a 3D setting,viable osteoblastic cells,osteocytic cells,and appropriate expression of osteoblast/osteocyte-derived mRNA and proteins,and mineral *** co-culture of androgen receptordependent/ independent cell lines (LNCaP,C4-2B,and PC3) led cancer cells to display functional and molecular features as observed in ***-cultured cancer cells showed increased affinity to the microtissues,as a function of their bone metastatic *** led to alkaline phosphatase and collagen-I upregulation and sclerostin downregulation,consistent with the clinical marker profile of osteoblastic bone *** showed a significant adaptive response under androgen deprivation in the microtissues,with the notable appearance of neuroendocrine transdifferentiation features and increased expression of related markers (dopa decarboxylase,enolase 2).Androgen deprivation affected the biology of the metastatic microenvironment with stronger upregulation of androgen receptor,alkaline phosphatase,and dopa decarboxylase,as seen in the transition towards *** unique microtissues engineered here represent a substantial asset to determine the involvement of the human bone microenvironment in prostate cancer progression and response to a therapeutic context in this microenvironment.

关键词： Engineering osteoblastic metastases the adaptive response metastatic microenvironment

Histamine 3 receptor activation mediates inhibition of acid secretion during Helicobacter-induced gastritis

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World Journal of Gastrointestinal Pathophysiology 2010年第5期1卷 154-165页

作者： Yana Zavros Nisreen Mesiwala Meghna Waghray Andrea Todisco Arthur Shulkes Juanita L Merchant Departments of Internal Medicine-Gastroenterology University of Michigan Department of Molecular and Cellular Physiology University of Cincinnati Department of Surgery Austin and Repatriation Medical CenterUniversity of Melbourne Departments of Internal Medicine and Molecular and Integrative Physiology University of Michigan

AIM:To test the hypothesis that histamine 3 receptor (H3R)activation during Helicobacter infection inhibits gastric acid secretion in vivo and in ***:Helicobacter felis(***)infected and uninfected C57Bl/6 mice were infused with either PBS or the H3 receptor antagonist thioperamide(THIO)for 12 *** treatment,mice were analyzed for morphological changes and gastric acid *** RNA was prepared from the stomachs of each group and analyzed for changes in somatostatin and gastrin mRNA abundance by real time-polymerase chain reaction(RTPCR).Location of H3 receptors in the stomach was analyzed by co-localization using antibodies specific for the H3 receptor and parietal cell marker H + ,K + -ATPase βsubunit. RESULTS:Inflammation and parietal cell atrophy was observed after 12 wk of *** ***, treatment with the H3R antagonist thioperamide(THIO) prior to and during infection prevented ***-induced inflammation and *** to the uninfected controls,infected mice also had significantly decreased gastric *** eradication of *** with THIO treatment,gastric acidity was *** to the control mice,somatostatin mRNA abundance was decreased while gastrin gene expression was elevated during *** elevated gastric acid levels, after eradication of *** with THIO,somatostatin mRNA was elevated whereas gastrin mRNA was *** revealed the presence of H3 receptors on the parietal cells,somatostatin-secreting D-cells as well as the inflammatory cells. CONCLUSION:This study shows that during *** infection,gastric acidity is suppressed as a consequence of an inhibitory effect on the parietal cell by H3R *** stimulation of gastric mucosal H3Rs increases gastrin expression and release by inhibiting release of somatostatin.

关键词： Gastrin Somatostatin Histamine Parietal

Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease

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World Journal of Hepatology 2014年第4期6卷 188-198页

作者： Sara Heebll Karen Louise Thomsen Steen B Pedersen Hendrik Vilstrup Jacob George Henning Grnbk Department of Hepatology and Gastroenterology Aarhus University Hospital Department of Endocrinology Aarhus University Hospital Storr Liver Unit Westmead Millennium InstituteWestmead Hospital and University of Sydney

The prevalence of obesity and related conditions like non-alcoholic fatty liver disease(NAFLD) is increasing worldwide and therapeutic options are *** treatment options are therefore intensively sought *** interesting candidate is the natural polyphenol resveratrol(RSV) that activates adenosinmonophosphate-activated protein kinase(AMPK) and silent information regulation-2 homolog 1(SIRT1).In addition,RSV has known anti-oxidant and anti-inflammatory ***,we review the current evidence for RSVmediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis(NASH) pathogenesis with respect to free fatty acid(FFA) flux from adipose tissue,hepatic de novo lipogenesis,inadequate FFA β-oxidation and additional intra- and extrahepatic inflammatory and oxidant *** review the in vivo evidence from animal studies and clinical *** abundance of animal studies reports a decrease in hepatic triglyceride accumulation,liver weight and a general improvement in histological fatty liver changes,along with a reduction in circulating insulin,glucose and lipid *** studies document AMPK or SIRT1 activation,and modulation of relevant markers of hepatic lipogenesis,inflammation and oxidation ***,AMPK/SIRT1-independent actions are also *** trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver *** clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients.

关键词： Non-alcoholic fatty liver disease Nonalcoholic steatohepatitis Steatosis Resveratrol AMPactivated protein kinase Silent information regulation-2 homolog 1 Anti-oxidants Anti-inflammatory agents Animal studies Clinical trial

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个体化癫痫治疗管理的新时代

英国医学杂志中文版 2021年第1期24卷 17-22页

作者： Zhibin Chen Ben Rollo Ana Antonic-Baker Alison Anderson 马远林 Terence J O′Brien Zongyuan Ge 王学峰关国良重庆医科大学附属第一医院重庆市神经病学重点实验室 Department of Neuroscience Central Clinical SchoolMonash UniversityMelbourneAustralia School of Public health and Preventive Medicine Monash UniversityMelbourneAustralia Department of Neurology Alfred HospitalMelbourneAustralia Faculty of Engineering Monash UniversityMelbourneAustralia eresearch Centre Monash UniversityMelbourneAustralia Airdoc research australia MelbourneAustralia

关国良及同事探讨认为,癫痫治疗的试错法已有一个多世纪没有改变,但机器学习和患者衍生的干细胞有望提供一种个体化且更有效的治疗策略。癫痫影响了全世界5000万人,没有年龄、种族或地域上的界限1。患者反复癫痫发作,可导致损伤、认知... 详细信息

关国良及同事探讨认为,癫痫治疗的试错法已有一个多世纪没有改变,但机器学习和患者衍生的干细胞有望提供一种个体化且更有效的治疗策略。癫痫影响了全世界5000万人,没有年龄、种族或地域上的界限1。患者反复癫痫发作,可导致损伤、认知能力下降、社会心理功能障碍,甚至死亡。癫痫是由脑损伤,如创伤、卒中、肿瘤、炎症和感染,以及基因组变异导致的系统性变化而引起的。癫痫患者会有更多的合并症,包括脑血管疾病、神经认知疾病和精神疾病2。因此更好的控制癫痫将改善整体脑健康。

关键词：癫痫治疗精神疾病神经认知脑损伤治疗策略脑血管疾病机器学习个体化

澳大利亚初级保健诊所新发腰背痛患者的预后：起始队列研究

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英国医学杂志中文版 2008年第6期11卷 339-342页

作者： Nicholas Henschke Christopher G Maher Kathryn M Refshauge Robert D Herbert Robert G Cumming Jane Bleasel John York Anurina Das James H McAuley 蓝恭涛(译) Musculoskeletal Division The George Institute for International Health Sydney Australia Back Pain research Group Faculty of Health Sciences University of Sydney School of Public health University of Sydney Department of Rheumatology Royal Prince Alfred Hospital Sydney 不详

目的估计初级保健诊所内新发腰背痛患者的1年预后，并确定其预后因素。设计1年随访队列研究。地点澳大利亚悉尼的初级保健诊所。参试者初级保健诊所接诊的973例非特异性腰背痛连续患者（平均年龄43.3岁，男性54.8％）。该起始队列患者... 详细信息

目的估计初级保健诊所内新发腰背痛患者的1年预后，并确定其预后因素。设计1年随访队列研究。地点澳大利亚悉尼的初级保健诊所。参试者初级保健诊所接诊的973例非特异性腰背痛连续患者（平均年龄43.3岁，男性54.8％）。该起始队列患者腰背痛时间不足两周，征集自170名全科医生、理疗师或按摩师诊所。主要评估指标参试者完成基线调查问卷后，分别于初次就诊后6周、3个月和21个月时复查评估。评估内容包括：工作恢复情况、功能恢复情况和疼痛消失情况。潜在预后因素与恢复所需时间的关联性用Cox回归建模分析。结果12个月随访率〉97％。基线时工作能力下降的患者半数在14天内恢复了以前的工作状态（95％可信区间11-17天），83％在3个月内恢复。残疾（中位恢复时间31天，25-37天）和疼痛（中位58天，52-63天）则需要较长的时间才能恢复。只有72％的受试者于基线访问后12个月获得完全康复。高龄、赔偿诉讼、疼痛较重、就诊前腰背痛时间较长、就诊前因疼痛活动减少天数较多、抑郁情绪以及预期危险持续与所需恢复时问较长相关。结论在这个急性腰背痛初级保健患者队列，患者的预后并不像临床指南声称的那样乐观。多数患者的恢复缓慢。近三分之一的患者在腰背痛发作后1年尚未恢复。

关键词：腰背痛患者初级保健预后因素队列研究澳大利亚诊所新发评估指标