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Hepatocellular carcinoma xenograft supports HCV replication:A mouse model for evaluating antivirals

World journal of Gastroenterology 2011年第3期17卷 300-312页

作者： Sidhartha Hazari henry j hefler Partha K Chandra Bret Poat Feyza Gunduz Tara Ooms Tong Wu Luis A Balart Srikanta Dash Department of Pathology and Laboratory Medicine Tulane University Health Sciences Center New Orleans LA 70112 United States Department of Gastroenterology and Hepatology Tulane University Health Sciences Center New Orleans LA 70112 United States Department of Comparative Medicine Tulane University Health Sciences Center New Orleans LA 70112 United States

AIM: To develop a hepatocellular carcinoma (HCC) xenograft model for studying hepatitis C virus (HCV) replication in a mice, and antiviral ***: We developed a stable S3-green fluorescence protein (GFP) cell line that replicated the GFP-tagged HCV sub-genomic RNA derived from a highly efficient jFH1 virus. S3-GFP replicon cell line was injected subcutaneously into γ-irradiated SCID mice. We showed that the S3-GFP replicon cell line formed human HCC xenografts in SCID mice. Cells were isolated from subcutaneous tumors and then serially passaged multiple times in SCID mice by culturing in growth medium supplemented with G-418. The mouse-adapted S3-GFP replicon cells were implanted subcutaneously and also into the liver of SCID mice via intrasplenic infusion to study the replication of HCV in the HCC xenografts. The tumor model was validated for antiviral testing after intraperitoneal injection of interferon-α (IFN-α). RESULTS: A highly tumorigenic S3-GFP replicon cell line was developed that formed subcutaneous tumors within 2 wk and diffuse liver metastasis within 4 wk in SCID mice. Replication of HCV in the subcutaneous and liver tumors was confirmed by cell colony assay, detection of the viral RNA by ribonuclease protection assay and real-time quantitative reverse transcription polymerase chain reaction. High-level replication of HCV sub-genomic RNA in the tumor could be visualized by GFP expression using fluorescence microscopy. IFN-α cleared HCV RNA replication in the subcutaneous tumors within 2 wk and 4 wk in the liver tumor model. CONCLUSION: A non-infectious mouse model allows us to study replication of HCV in subcutaneous and metastatic liver tumors. Clearance of HCV by IFN-α supports use of this model to test other anti-HCV drugs.

关键词： Hepatitis C virus Hepatocellular carcinoma Tumor xenograft SCID mouse Interferon-α Antiviral agent Virus replication

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The Importance of Flapping Kinematic Parameters in the Facilitation of the Different Flight Modes of Dragonflies

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journal of Bionic Engineering 2021年第2期18卷 419-427页

作者： Xiaohui Liu Csaba hefler Wei Shyy Huihe Qiu Department of Mechanical and Aerospace Engineering The Hong Kong University of Science and TechnologyHong Kong SARChina

To better understand dragonflies’remarkable flapping wing aerodynamic performance,we measured the kinematic parameters of the wings in two different flight modes(Normal Flight Mode(NFM)and Escape Flight Mode(EFM)).When the specimens switched from normal to escape mode the flapping frequency was invariant,but the stroke plane of the wings was more horizontally *** flapping of both wings was adjusted to be more ventral with a change of the pitching angle that resulted in a larger angle of attack during downstroke and smaller during upstroke to affect the flow directions and the added mass ***,the phasing between the fore and hind pair of wings varies between two flight modes,which affects the wing-wing interaction as well as body *** is found that the momentum stream in the wake of EFM is qualitatively different from that in *** change of the stroke plane angle and the varied pitching angle of the wings diverts the momentum downwards,while the smaller flapping amplitude and less phase difference between the wings compresses the momentum *** seems that in order to achieve greater flight maneuverability a flight vehicle needs to actively control positional angle as well as the pitching angle of the flapping wings.

关键词： wing kinematics flight mode dragonfly flight aerodynamics

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Effects of aspect ratio on flapping wing aerodynamics in animal flight

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Acta Mechanica Sinica 2014年第6期30卷 776-786页

作者： jun-jiang Fu Csaba hefler Hui-He Qiu Wei Shyy Department of Mechanical and Aerospace Engineering The Hong Kong University of Science & Technology

Morphology as well as kinematics is a critical determinant of performance in flapping *** understand the effects of the structural traits on aerodynamics of bioflyers,three rectangular wings with aspect ratios（AR）of1,2,and 4 performing hovering-like sinusoidal kinematics at wingtip based Reynolds number of 5 300 are experimentally *** structures on sectional cuts along the wing span are *** K-H instability is found on the leading edge vortex of wings with higher aspect *** bursting only appears on the outer spanwise locations of high-aspect-ratio *** vortex bursting on high-aspect-ratio wings is perhaps one of the reasons why bio-flyers normally have low-aspect-ratio *** analysis exhibits larger dimensionless circulation of the leading edge vortex（LEV）over higher aspect ratio wings except when vortex bursting *** average dimensionless circulation of AR1 and AR2 along the span almost equals the dimensionless circulation at the 50%*** flow structure and the circulation analysis show that the sinusoidal kinematics suppresses breakdown of the LEV compared with simplified flapping kinematics used in similar *** Reynolds number effect results on AR4 show that in the current Re range,the overall flow structure is not sensitive to Reynolds number.

关键词： Aspect ratio Aerodynamics Leading edge vortex Flapping wing

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Decline of semen quality during IVF is not associated with subjective male stress

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Asian journal of Andrology 2014年第4期16卷 597-601页

作者： Kazem Nouri Brigitte Litschauer Michael Sator Denise Tiringer johannes Ott Katherina Walch Lukas A hefler Clemens B Tempfer Department of Obstetrics and Gynecolog Department of Clinical Pharmacology Medical University of Vienna Vienna Department of Obstetrics and Gynecology Krankenhaus Barmherzige Schwestern Linz Austria Department of Obstetrics and Gynecology Ruhr University Bochum Bochum Germany.

The aim of the present study was to assess if semen quality declines during in vitro fertilization （IVF） and whether or not this phenomenon is triggered by chronic male stress. In order to test this hypothesis, we first investigated a retrospective cohort of 155 male IVF patients （testing cohort）. Subsequently, we started a prospective cohort study in men undergoing their first IVF and assessed semen quality and subjective male chronic stress using a validated tool, i.e. the Fertility Problem Inventory （FPI） questionnaire. The association between stress and sperm quality decline measured 4-6weeks before the start of IVF （T1） and at the day of oocyte retrieval （T2） was the primary outcome. Live birth rate, first trimester abortion and rate of poor responders were secondary outcomes. In the testing cohort, mean progressive motility, but not mean sperm density significantly declined. There were 78/154 （51%） men who showed a decline in semen density and 50/154 （32%） men who showed a decline in progressive motility. In the validation cohort, progressive motility declined, whereas, sperm density increased from T1 to T2. Of 78 men, 27 men had increased stress （FPI-score 〉 146）. Sperm density and progressive motility were not significantly different in men with and without stress. However, in the presence of male stress, couples had a higher rate of poor responders, miscarriages and a lower rate of live births. Subjective stress is not associated with a decline in semen quality observed during IVF but may be associated with adverse ore^nancv outcome.

关键词： in vitro fertilization questionnaire semen quality stress

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Protective effects of cyclosporine and its analog NIM-811 in a murine model of hepatic ischemia-reperfusion injury

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Liver Research 2024年第1期8卷 46-53页

作者： joshua hefler Rena Pawlick Braulio A.Marfil-Garza Aducio Thiesen Nerea Cuesta-Gomez Sanaz Hatami Darren H.Freed Constantine Karvellas David L.Bigam A.M.james Shapiro Department of Surgery Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada Department of Medicine Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada CHRISTUS-LatAm Hub Excellence&Innovation Center MonterreyMexico Alberta Diabetes Institute University of AlbertaEdmontonABCanada Clinical Islet Transplant Program University of AlbertaEdmontonABCanada Department of Laboratory Medicine&Pathology Faculty of Medicine&DentistryUniversity of AlbertaEdmontonABCanada

Background and aim:The liver is susceptible to ischemia-reperfusion injury(IRI)during hepatic surgery,when the vessels are compressed to control bleeding,or liver transplantation,when there is an obligate period of *** hallmark of IRI comprises mitochondrial dysfunction,which generates reactive oxygen species,and cell death through necrosis or ***(CsA),which is a well-known immunosuppressive agent that inhibits calcineurin,has the additional effect of inhibiting the mito-chondrial permeability transition pore(mPTP),thereby,preventing mitochondrial swelling and ***-811,which is the nonimmunosuppressive analog of CsA,has a similar effect on the *** this study,we tested the effect of both agents on mitigating warm hepatic IRI in a murine *** and methods:Before ischemic insult,the mice were administered with intraperitoneal normal saline(control);CsA at 2.5,10,or 25 mg/kg;or NIM-811 at 10 mg/***,the mice were subjected to partial warm hepatic ischemia by selective pedicle clamping for 60 min,followed by 6 h of recovery after *** alanine transaminase(ALT)was measured,and the liver tissue was examined histologically for the presence of apoptosis and the levels of inflammatory ***:Compared with the control mice,the mice treated with 10 and 25 mg/kg of CsA and NIM-811 had significantly lower ALT levels(Pjury scores after treatment with CsA at 2.5,10,and 25 mg/kg and NIM-811(P=0.041,<0.001,0.003,and 0.043,respectively)and significant decrease in apoptosis after treatment with CsA at all doses(P=0.012,0.007,and<0.001,respectively).Levels of the pro-inflammatory cyto-kines,particularly interleukin(IL)-1β,IL-2,IL-4,IL-10,and keratinocyte chemoattractant/human growth-regulated oncogene significantly decreased in the mice treated with the highest dose of CsA(25 mg/kg)than those in the control ***

关键词： Cyclosporine(CsA) Cyclosporine analogue Liver surgery Ischemia-reperfusion injury(IRI) Animal model NIM-811

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Re： Commentary on ＇Decline of semen quality during IVF is not associated with subjective male stress＇

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Asian journal of Andrology 2014年第4期16卷 640-640页

作者： Kazem Nouri Brigitte Litschauer Michael Sator Denise Tiringer johannes Ott Katherina Walch Lukas A hefler Clemens B Tempfer Departments of Obstetrics and Gynecology Clinical Pharmacology Medical University of Vienna Vienna Department of Obstetrics and Gynecology Krankenhaus Barmherzige Schwestern Linz Austria Obstetrics and Gynecology Ruhr University Bochum Bochum Germany.

We thank the commentator for his valuable insights as expressed in the above commentary. We fully agree that numerous lines of evidence support the assumption that male as well as female stress and the interaction of the stressed couple plays a role in the success of assisted reproduction. Furthermore, it is common ground that in vitro fertilization （IVF）/intracytoplasmic sperm injection （ICSI） couples are an especially vulnerable patient collective in this respect. We have, however, not yet identified the optimal means of measuring stress or the relevant aspects of it during the management of couples undergoing IVF/ICSI. This fact is also highlighted by our findings,t Further work is necessary to identify efficient and reliable tools to measure and treat stress in males and females undergoing IVF/ICSI with the goal of further improving reproductive outcomes.

关键词： @@

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一种预测白种女性绝经期年龄的模型

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世界核心医学期刊文摘（妇产科学分册） 2006年第6期2卷 21-22页

作者： hefler L.A. Grimm C. Bentz E.-K. 马超 Department of Obstetrics and Gynecology Medical University of Vienna Waehringer Guertel 18- 20 A- 1090 Vienna AustriaDr.

Objective: To develop a model to predict the age at natural menopause and the risk for premenopausal hysterectomy. Design: Cross- sectional study. Setting: Multicenter study. Patient(s): A total of 1,345 white women. Intervention(s): Ten single nucleotide polymorphisms (SNPs) of seven estrogen (E)- metabolizing genes (i.e., catechol- O- methylt- cytochrome P- 450 [CYP] 17, CYP1A1, CYP1B1, CYP19, and E receptor [ER]- α ) were analyzed by sequencing- on- chip- technology. Main Outcome Measure(s): Patients’ reproductive and medical histories were ascertained and correlated to genotypes. Result(s): The model incorporates the number of full term pregnancies, the body mass index (BMI), a history of breast surgery, and the presence of CYP17 and CYP1B1- 4 polymorphisms as well as the BMI to predict age at natural menopause and the risk for undergoing premenopausal hysterectomy. Conclusion(s): We present the first model to date, which can predict age at natural menopause and the risk for undergoing premenopausal hysterectomy based on genotype information and personal history.

关键词：绝经年龄模型预测儿茶酚-O-甲基转移酶女性单核苷酸多态性绝经期羟类固醇脱氢酶代谢相关基因

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单核苷酸多态性DNA微矩阵分析有利于评估激素治疗的利弊

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世界核心医学期刊文摘（妇产科学分册） 2005年第1期1卷 30-31页

作者： Tempfer C.B. Riener E.-K. hefler L.A. 闫坤 Dept. of Obste trics and Gynecology Univ. of Freiburg Medical School Freiburg Germany Dr.

Objective To determine what percentage of women can be given individu alized co unseling based on genetic information, as single nucleotide polymorphisms (SNPs) are associated with risks and benefits of estrogen therapy and hormone therapy such as thrombosis, myocardial infarction, breast cancer, and bone protection. D esign Cross-sectional study. Setting Academic research institution. Patient(s) A consecutive series of 2,507 perimenopausal and postmenopausal women. Intervent ion(s) Peripheral venous puncture and multiplex polymerase chain reaction on a m icroarray system. Main outcome measure(s) Analysis of 22 SNPs of 17 genes: AGTMe t235Thr, APOECys112Arg, APOEArg158-Cys, COMTVal158Met, CYP17-34T >C, CYP191558 C >T, CYP19Arg264Cys, CYP1A16235T >C, CYP1A1Ile462Val, CYP1B1Leu432Val, CYP1B1A -sn453Ser, HSD17B1-27A >C, ER-αIVS-401T >C, prothrombin20210G >A, factor V Leiden, eNOS-786T >C, eNOSGlu298Asp, MRSer810L eu, MTHFR677C >T, PAI 15G >4G, SRD5A2Val89Leu, and VDRb >B. Result(s) Among the women in the study, 66%had at least two homozygous mutant SNPs of interest. A t hrombophilic disposition was found in 9.9%of women, and 23%of women had at lea st two SNPs associated with an increased risk of breast cancer (COMT, CYP17, CYP 19, CYP1A1, and CYP1B1). The SNPs predisposing women to cardiovascular pathologi es (e.g., APOE, AGT, eNOS, and PAI 1) were found in 12.3%of women. Carriage of SNPs predisposing to early postmenopausal bone loss and osteoporosis (ER-αand VDR) were found in 26.7%of women. Conclusion( s) These data suggest that the as sessment of SNPs associated with risks and benefits of estrogen/hormone therapy may be a new means to individualize counseling about and prescription of estroge n/hormone therapy in up to 66%of women.

关键词：激素替代治疗 DNA微矩阵单核苷酸多态性矩阵分析围绝经期患病风险 prothrombin 外周静脉穿刺骨质疏松突变纯合子

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文献快报(11)：如何降低中低等收入国家青少年烟草使用

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中国学校卫生 2016年第11期37卷 1687-1687页

作者： THOMAS DP hefler M 苏普玉（编译）不详安徽医科大学公共卫生学院儿少卫生与妇幼保健学系合肥230032

当前烟草的流行已从高收入国家蔓延至中等及低收入国家,为了达成全球烟草使用率低于5%的目标,对中低收入国家的持续关注是很有必要的。高收入国家因烟草而死亡的病例在持续下降,到2030年,预计全球8 300万因烟草而死亡的病例中将会有6 80... 详细信息

当前烟草的流行已从高收入国家蔓延至中等及低收入国家,为了达成全球烟草使用率低于5%的目标,对中低收入国家的持续关注是很有必要的。高收入国家因烟草而死亡的病例在持续下降,到2030年,预计全球8 300万因烟草而死亡的病例中将会有6 800万发生在中低等收入国家,而且预计这些中低等收入国家2002至2030年因烟草而死亡的病例将会翻倍。

关键词：干预政策调查数据暴露情况

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基质金属蛋白酶-1启动子基因多态性与卵巢癌患者的预后相关

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世界核心医学期刊文摘（妇产科学分册） 2006年第8期2卷 46-47页

作者： Six L. Grimm C. Leodolter S. L.A. hefler 李奎 Department of Obstetrics and Gynecology Medical University of Vienna Waehringer Guertel 18- 20 A- 1090 Vienna Austria

Objective. The enzyme matrix metalloproteinase (MMP)- 1 is involved in ovarian carcinogenesis. A common guanine insertion-deletion promoter polymorphism within the gene encoding MMP- 1 (MMP1) has been suggested to be a candidate gene for ovarian cancer. We investigated whether this common polymorphism can also serve as independent prognostic parameter in a large series of affected women. Methods. The MMP1 promoter polymorphism was examined in 151 Caucasian patients with epithelial ovarian cancer using polymerase chain reaction. Results were correlated with clinical data. Results. No associations were ascertained between the MMP1 polymorphism and tumor stage (P = 1.0, odds ratio [OR] 1.08), lymph node involve-ment (P = 1.0, OR 0.8), tumor grading (P = 0.2, OR 0.5), and patient’ s age at diagnosis (P = 1.0, OR 1.04). Besides the clinically established prognosticators, tumor stage and histological grade, presence of the MMP1 polymorphism was associated with a shortened disease-free and overall survival in a univariate Kaplan-Meier analysis (P = 0.01) and a multivariate Cox regression model (P = 0.04). Conclusion. Presence of the MMP1 gene promoter polymorphisms was found to be a negative prognostic parameter in patients with ovarian cancer.

关键词：基质金属蛋白酶上皮性卵巢癌启动子基因多态性肿瘤分期预后指标临床数据肿瘤分级生存时间

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