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The role of chemokines in acute and chronic hepatitis C infection

Cellular & Molecular Immunology 2014年第1期11卷 25-40页

作者： stephen fahey Eugene Dempsey Aideen Long Institute of Molecular Medicine Trinity College Dublin Trinity Centre for Health Sciences St James's Hospital Dublin Ireland School of Biomolecular and Biomedical Science Conway Institute University College Dublin Dublin Ireland

Hepatitis C imposes a significant burden on global healthcare. Chronic infection is associated with progressive inflammation of the liver which typically manifests in cirrhosis, organ failure and cancer. By virtue of elaborate evasion strategies, hepatitis C virus （HCV） succeeds as a persistent human virus. It has an extraordinary capacity to subvert the immune response enabling it to establish chronic infections and associated liver disease. Chemokines are low molecular weight chemotactic peptides that mediate the recruitment of inflammatory cells into tissues and back into the lymphatics and peripheral blood. Thus, they are central to the temporal and spatial distribution of effector and regulatory immune cells. The interactions between chemokines and their cognate receptors help shape the immune response and therefore, have a major influence on the outcome of infection. However, chemokines represent a target for modulation by viruses including the HCV. HCV is known to modulate chemokine expression in vitro and may therefore enable its survival by subverting the immune response in vivo through altered leukocyte chemotaxis resulting in impaired viral clearance and the establishment of chronic low-grade inflammation. In this review, the roles of chemokines in acute and chronic HCV infection are described with a particular emphasis placed on chemokine modulation as a means of immune subversion. We provide an in depth discussion of the part played by chemokines in mediating hepatic fibrosis while addressing the potential applications for these chemoattractants in prognostic medicine.

关键词： chemokine chemokine receptor hepatic fibrosis hepatitis C virus immune evasion

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Can inhibition of telomerase increase pancreatic cancer cell's susceptibility to chemotherapeutic reagents?

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Hepatobiliary & Pancreatic Diseases International 2002年第1期1卷 155-160页

作者： Thomas J.Ⅲ fahey Department of Surgery Cornell University Medical College New York NY USA

Objectives: To clarify the inhibition of pancreatic can-cer cells by interference with the hTR component of thetelomerase reverse transcriptase enzymatic complexand evaluate susceptibility of antisense hTR pancreaticcancer cells to chemotherapeutic ***: A 593 bp of full length hTR cDNA was sub-cloned into a mammalian expression vector pcDNA3.1(-) in antisense orientation to construct an antisensehTR expression plasmid. The plasmids were introducedinto Pancl cells, a human pancreatic carcinoma cellline, by lipofectin, and G418-resistant stable trans-formants were expanded. Resulting stable clones werescreened for the presence of hTR insert by PCR withT7 and BGH reverse primers located on the flanks ofthe multiclonal site of pcDNA3.1 vector. Cell growth rate,hTR expression, telomerase activity, and anchorage-in-dependent growth property were analyzed. Finally, sus-ceptibility of antisense hTR cells to chemotherapeuticreagents was ***: Significant downregulation of endogenous hTRwas evident in the antisense-hTR transformed cells,and telomerase activity was markedly decreased com-pared to control cells in standard TRAP assays. Fur-thermore, the proliferation and the anchorage-inde-pendent growth ability in antisense-hTR expressingcells were significantly decreased compared with thecontrol parental cells. However, no crisis or senescencephenomena was observed. Antisense hTR appears toincrease Pancl cell's susceptibility to chemotherapeuticreagent cDDP, but not to differentiation reagent DM-SO, COX2 inhibitor sulinbac, NS-398, curcumin, andchemotherapeutic reagent adriamycin(ADM).Conclusions: These data indicate that hTR is probablya critical component of human telomerase activity andthat downregulation of the RNA component of humantelomerase is an effective target for anticancer strategyand antisense hTR can increase Pancl cell's susceptibilityto cDDP.

关键词： Telomerase hTR Antisense Pancreatic carcinoma cellline chemotherapeutic reagents

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Glycaemic monitoring and control among high-risk patients with type 2 diabetes in Australian general practice during COVID-19

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Family Medicine and Community Health 2023年第3期11卷 62-85页

作者： Kirrilee Jane Barlow Paul P fahey Evan Atlantis School of Health Sciences Western Sydney UniversityKingswoodNew South WalesAustralia Discipline of Medicine Nepean Clinical SchoolFaculty of Medicine and HealthThe University of SydneyNepeanNew South WalesAustralia

Background The COVID-19 pandemic disrupted general practice worldwide,primarily due to public health measures that restricted access to care for chronic diseases,such as type 2 *** measures disproportionately affected higher risk groups with type 2 diabetes,such as older people and those with *** study aims to identify factors that may have influenced the rates of compliance with testing guidelines and target glycaemic control in Australian general practice settings during the COVID-19 *** We used a serial cross-sectional study design of patient record data from general practices representative of the Nepean Blue Mountains Local Health District between 2020 and *** patient records were analysed to determine percentages of subgroups with a blood glycaemic testing interval consistent with guidelines(≥1 within 15 months)and achieving target glycaemic control(by glycated haemoglobin of≤7%).Linear regression models were used to test the association between independent and dependent variables,and to generate regression coefficients and 95%CI,corrected for time *** Of the average 14356 patient records per month,55%were male,53%had a body mass index(BMI)<30 and 55%were aged 55–74 *** to testing guidelines slightly decreased(75–73%)but was positively associated with male sex(2.5%,95%CI 1.7%,3.4%),BMI≥30(9.6%,95%CI 8.8%,10.4%)and 55–74 years(7.5%,95%CI 6.6%,8.5%)and 75 years and over age groups(7.1%,95%CI 6.2%,7.9%).Mean percentage of patient records achieving target glycaemic control slightly increased and was negatively associated with male sex(-3.7%,95%CI-5.2%,–2.2%),but positively associated with 55–74 years(4.5%,95%CI 3.8%,5.1%)and 75 years and over age groups(12.2%,95%CI 4.5%,20.0%).Compliance to testing guidelines increased with each additional general practice per 10000 persons(8.4%,95%CI 4.9%,11.8%).Conclusions During the COVID-19 pandemic,people with type 2 diabetes in Australia continued to follow

关键词： patients testing slightly

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Epigenetics of gastroenteropancreatic neuroendocrine tumors:A clinicopathologic perspective

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World Journal of Gastrointestinal Oncology 2017年第9期9卷 341-353页

作者： Brendan M Finnerty Katherine D Gray Maureen D Moore Rasa Zarnegar Thomas J faheyⅢ Department of Surgery New York Presbyterian HospitalWeill Cornell MedicineNew YorkNY 10065United States

Gastroenteropancreatic neuroendocrine tumors(GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEPNET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microR NA and long non-coding RNA(lncR NA) differential expression profiles that are distinctive of GEPNETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.

关键词： Epigenetics Carcinoid Neuroendocrine MicroRNA Methylation Histone modifications Chromatin remodeling LncRNA

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Negative effects of tumor cell nitric oxide on anti-glioblastoma photodynamic therapy

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 675-689页

作者： Albert W.Girotti Jonathan M.fahey Witold Korytowski Department of Biochemistry Medical College of WisconsinMilwaukeeWI 53226United States Department of Biophysics Jagiellonian UniversityKrakow 30-387Poland

Glioblastomas are highly aggressive brain tumors that can persist after exposure to conventional chemotherapy or *** oxide(NO)produced by inducible NO synthase(iNOS/NOS2)in these tumors is known to foster malignant cell proliferation,migration,and invasion as well as resistance to chemo-and *** invasive photodynamic therapy(PDT)sensitized by 5-aminolevulinic acid(ALA)-induced protoporphyrin IX(PpIX)is a highly effective anti-glioblastoma modality,but it is also subject to NO-mediated *** by the authors have revealed that glioblastoma U87 and U251 cells use endogenous iNOS/NO to not only resist photokilling after an ALA/light challenge,but also to promote proliferation and migration/invasion of surviving ***-upregulated iNOS/NO was found to play a major role in these negative responses to PDT-like *** studies have revealed a tight network of upstream signaling events leading to iNOS induction in photostressed cells and transition to a more aggressive *** events include activation or upregulation of pro-survival/pro-expansion effector proteins such as NF-κB,phosphoinositide-3-kinase(PI3K),protein kinase-B(Akt),p300,Survivin,and *** addition to this upstream signaling and its regulation,pharmacologic approaches for directly suppressing iNOS at its activity *** level are *** highly effective agent in the latter category is bromodomain and extra-terminal(BET)inhibitor,JQ1,which was found to minimize iNOS upregulation in photostressed U87 *** acting similarly at the clinical level,a BET inhibitor such as JQ1 should markedly improve the efficacy of anti-glioblastoma PDT.

关键词： Glioblastoma photodynamic therapy nitric oxide inducible NO synthase

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Nitric oxide-elicited resistance to anti-glioblastoma photodynamic therapy

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Cancer Drug Resistance 2020年第3期3卷 401-414页

作者： Albert W.Girotti Jonathan M.fahey Witold Korytowski Department of Biochemistry Medical College of WisconsinMilwaukeeWI 53226USA. Department of Biophysics Jagiellonian UniversityKrakow 31-008Poland.

Glioblastoma multiforme is a highly aggressive primary brain malignancy that resists most conventional chemoand radiotherapeutic *** oxide(NO),a short lived free radical molecule produced by inducible NO synthase(iNOS)in glioblastomas and other tumors,is known to play a key role in tumor persistence,progression,and chemo/radiotherapy ***-specific and minimally invasive photodynamic therapy(PDT),based on oxidative damage resulting from non-ionizing photoactivation of a sensitizing agent,is highly effective against glioblastoma,but resistance also exists in this *** in the authors’laboratory have shown that much of the latter is mediated by iNOS/*** example,when glioblastoma U87 or U251 cells sensitized in mitochondria with 5-aminolevulinic acid-induced protoporphyrin IX were exposed to a moderate dose of visible light,the observed apoptosis was strongly enhanced by an iNOS activity inhibitor or NO scavenger,indicating that iNOS/NO had increased cell resistance to ***,cells that survived the photochallenge proliferated,migrated,and invaded more aggressively than controls,and these responses were also driven predominantly by iNOS/***-upregulated iNOS rather than basal enzyme was found to be responsible for all the negative effects *** of NO-mediated hyper-resistance/hyper-aggression in PDT-stressed glioblastoma has stimulated interest in how these responses can be prevented or at least minimized by pharmacologic adjuvants such as inhibitors of iNOS activity or *** developments along these lines and their clinical potential for improving anti-glioblastoma PDT are discussed.

关键词： Glioblastoma photodynamic therapy nitric oxide inducible nitric oxide synthase nitric oxide-mediated photodynamic therapy resistance anti-nitric oxide adjuvants

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Effect of thinning intensity on the stem CO_(2) efflux of Larix principis-rupprechtii Mayr

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Forest Ecosystems 2021年第4期8卷 841-855页

作者： Kuangji Zhao Timothy J.fahey Xiangzhen Wang Jie Wang Fang He Chuan Fan Zhongkui Jia Xianwei Li Sichuan Province Key Laboratory of Ecological Forestry Engineering on the Upper Reaches of the Yangtze River College of ForestrySichuan Agricultural University611130 ChengduChina Key Laboratory for Silviculture and Conservation of the Ministry of Education College of ForestryBeijing Forestry University100083 BeijingChina Department of Natural Resources Cornell University14853 New YorkUSA

Background:Stem CO_(2) efflux(E_(S))plays a critical role in the carbon budget of forest *** is a core practice for sustainable management of *** is therefore necessary and urgent to study the effect and mechanism of thinning intensity(TI)on E_(S).Methods:In this study,five TIs were applied in Larix principis-rupprechtii Mayr 21-,25-,and 41-year-old stands in North China in *** infrared gas analyzer(Li-8100 A)was used to measure ES and its association with environmental factors at monthly intervals from May to October in 2013 to *** addition,nutrients,wood structure and nonstructural carbon(NSC)data were measured in August ***:The results show that ES increased with increasing *** maximum ES values occurred at a TI of 35%(3.29,4.57 and 2.98μmol·m^(-2)·s^(-1))and were 1.54-,1.94-and 2.89-fold greater than the minimum E_(S) value in the CK stands(2.14,2.35 and 1.03μmol·m^(-2)·s^(-1))in July for the 21-,25-and 41-year-old forests,*** E_(S) of the trees in low-density stands was more sensitive to temperature than that of the trees in high-density *** sugars(SS)and temperature are the main factors affecting *** the stand density is low enough as 41-year-old ***-rupprechtii forests with TI 35%,bark thickness(BT)and humidity should be considered in addition to air temperature(T_(a)),wood temperature(T_(w)),sapwood width(SW),nitrogen concentration(N)and SS in the evaluation of *** a change in stand density is ignored,the CO_(2) released from individual 21-,25-and 41-year-old trees could be underestimated by 168.89%,101.94% and 200.49%,***_(2) release was estimated based on the stem equation in combination with the factors influencing ES for ***:We suggest that it is not sufficient to conventional models which quantify ES only by temperature and that incorporating the associated drivers(***,SS,SW and N)based on stand density into conventional model

关键词： Stem CO_(2)efflux Thinning intensity Environmental factors Nutrient content Wood structure Nonstructural carbon Larix principis-rupprechtii

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Stable expression of antisense hTR inhibits in vitro pancreatic cancer cell growth

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Chinese Medical Journal 2002年第8期115卷 1196-1200,152页

作者：滕理送陈石妹 Thomas J fahey Ⅲ 浙江大学医学院附属第一医院杭州310003 CornellUniversityMedicalCollege

OBJECTIVE: To clarify growth inhibition in pancreatic cancer cells by interference with the hTR component of the telomerase reverse transcriptase enzymatic complex. METHODS: A 593 bp full length hTR cDNA was subcloned into a mammalian expression vector pcDNA3.1(-) in the antisense orientation to construct an antisense hTR expression plasmid. These were introduced into panc1 cells, a human pancreatic carcinoma cell line, by lipofectin and G418-resistant stable transformants were expanded. Resulting stable clones were screened for the presence of the hTR insert by PCR with T7 and BGH reverse primers located on the flanks of the multiclonal site of the pcDNA3.1 vector. Cell growth rate, hTR expression, telomerase activity and anchorage-independent growth properties were analyzed. RESULTS: Significant downregulation of endogenous hTR was evident in the antisense-hTR transformed cells and telomerase activity was markedly decreased compared to control cells in standard TRAP assays. Furthermore, cell proliferation and the anchorage-independent growth ability in antisense-hTR expressing cells were significantly decreased compared with control parental cells. However, no crisis or senescence phenomena were observed. CONCLUSIONS: These data indicate that hTR may be a critical component of human telomerase activity and suggest that downregulation of the RNA component of human telomerase is a possible target for anticancer strategies.

关键词： DNA-Binding Proteins Humans Pancreatic Neoplasms RNA, Antisense Reverse Transcriptase Polymerase Chain Reaction Telomerase Tumor Cells, Cultured

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Shifts in the Holstein dairy cow milk fat globule membrane proteome that occur during the first week of lactation are affected by parity

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Journal of Animal Science and Biotechnology 2021年第2期12卷 534-548页

作者： Mallory C.Honan Megan J.fahey Amanda J.Fischer-Tlustos Michael A.Steele Sabrina L.Greenwood Department of Animal and Veterinary Sciences The University of VermontBurlingtonVT 05405USA Department of Animal Biosciences University of GuelphGuelphON N1G 2W1Canada Department of Agriculture Food&Nutritional ScienceUniversity of AlbertaEdmontonAB T6G 2P5Canada

Background:The milk fat globule membrane(MFGM)proteomes of colostrum and transition milk are rich sources of proteins that are likely important for neonatal calf *** addition,characterization of these proteomes could also yield valuable information regarding mammary gland physiology of the early postpartum lactating *** objectives of this research were to characterize the MFGM proteomes of colostrum and transition milk through sample collections at four timepoints postpartum,including the first milking(M1,colostrum),second milking(M2,transition milk),fourth milking(M4,transition milk),and fourteenth milking(M14,mature milk),and compare these proteomes between multiparous(MP;n=10)and primiparous(PP;n=10)Holstein dairy *** MFGM proteins were labeled using Tandem Mass tagging and analyzed using liquid chromatography-tandem mass spectrometry(LC-MS/MS).Protein identification was completed using MASCOT and Sequest in Proteome Discoverer *** scaled abundance values were analyzed using PROC MIXED in SAS to determine the effects of milking(MIL),parity(PAR),and MIL×*** adaptive false-discovery rate(FDR)-adjusted P values were determined using PROC *** characterization and bioinformatic analysis were completed using a combination of PANTHER,Blast,and ***:A total of 104 common proteins were identified in each of the MFGM *** analysis revealed that 70.2%of identified proteins were affected by *** these,78.1%were lower in M14 compared with M1,including immune-related proteins lactotransferrin,lactadherin and *** affected 44.2%of *** the proteins affected by PAR,84.8%were higher in MP cows compared with PP cows,including apolipoprotein E and histones 2A,2B,3,and 4 *** subfamily 1 member 1A and annexin 5 were higher in samples from PP ***×parity affected 32.7%of identified proteins,including lactotransferrin,gelsolin,vitamin D binding protein,and S100 ***

关键词： Colostrum LC-MS/MS Parity

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Management of hypertension in primary aldosteronism

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World Journal of Cardiology 2014年第5期6卷 227-233页

作者： Anna Aronova Thomas J fahey Ⅲ Rasa Zarnegar Department of Surgery Weill Cornell Medical College/New York Presbyterian Hospital New York NY 10021 United States

Hypertension causes significant morbidity and mortal-ity worldwide, owing to its deleterious effects on the cardiovascular and renal systems. Primary hyperaldo-steronism(PA) is the most common cause of revers-ible hypertension, affecting 5%-18% of adults with hypertension. PA is estimated to result from bilateral adrenal hyperplasia in two-thirds of patients, and from unilateral aldosterone-secreting adenoma in approxi-mately one-third. Suspected cases are initially screened by measurement of the plasma aldosterone-renin-ratio, and may be confirmed by additional noninvasive tests. Localization of aldostosterone hypersecretion is then determined by computed tomography imaging, and in selective cases with adrenal vein sampling. Solitary adenomas are managed by laparoscopic or robotic re-section, while bilateral hyperplasia is treated with min-eralocorticoid antagonists. Biochemical cure following adrenalectomy occurs in 99% of patients, and hemo-dynamic improvement is seen in over 90%, prompting a reduction in quantity of anti-hypertensive medica-tions in most patients. End-organ damage secondary to hypertension and excess aldosterone is significantly improved by both surgical and medical treatment, asmanifested by decreased left ventricular hypertrophy, arterial stiffness, and proteinuria, highlighting the im-portance of proper diagnosis and treatment of primary hyperaldosteronism. Although numerous independent predictors of resolution of hypertension after adrenalec-tomy for unilateral adenomas have been described, the Aldosteronoma Resolution Score is a validated multifac-torial model convenient for use in daily clinical practice.

关键词： Primary hyperaldosteronism Hypertension Adrenalectomy Aldosteronoma Treatment

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