|
1
|
Pewkliang Y, Thongsri P, Suthivanich P, Thongbaiphet N, Keatkla J, Pasomsub E, Anurathapan U, Borwornpinyo S, Wongkajornsilp A, Hongeng S, Sa-Ngiamsuntorn K. Immortalized hepatocyte-like cells: A competent hepatocyte model for studying clinical HCV isolate infection. PLoS One 2024; 19:e0303265. [PMID: 38739590 PMCID: PMC11090328 DOI: 10.1371/journal.pone.0303265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 04/23/2024] [Indexed: 05/16/2024] Open
Abstract
More than 58 million individuals worldwide are inflicted with chronic HCV. The disease carries a high risk of end stage liver disease, i.e., cirrhosis and hepatocellular carcinoma. Although direct-acting antiviral agents (DAAs) have revolutionized therapy, the emergence of drug-resistant strains has become a growing concern. Conventional cellular models, Huh7 and its derivatives were very permissive to only HCVcc (JFH-1), but not HCV clinical isolates. The lack of suitable host cells had hindered comprehensive research on patient-derived HCV. Here, we established a novel hepatocyte model for HCV culture to host clinically pan-genotype HCV strains. The immortalized hepatocyte-like cell line (imHC) derived from human mesenchymal stem cell carries HCV receptors and essential host factors. The imHC outperformed Huh7 as a host for HCV (JFH-1) and sustained the entire HCV life cycle of pan-genotypic clinical isolates. We analyzed the alteration of host markers (i.e., hepatic markers, cellular innate immune response, and cell apoptosis) in response to HCV infection. The imHC model uncovered the underlying mechanisms governing the action of IFN-α and the activation of sofosbuvir. The insights from HCV-cell culture model hold promise for understanding disease pathogenesis and novel anti-HCV development.
Collapse
Affiliation(s)
- Yongyut Pewkliang
- Faculty of Medicine Ramathibodi Hospital, Program in Translational Medicine, Mahidol University, Rama VI Road, Rajathevi, Bangkok, Thailand
| | - Piyanoot Thongsri
- Faculty of Medicine Ramathibodi Hospital, Program in Translational Medicine, Mahidol University, Rama VI Road, Rajathevi, Bangkok, Thailand
| | - Phichaya Suthivanich
- Faculty of Science, Excellent Center for Drug Discovery, Mahidol University, Rama VI Road, Rajathevi, Bangkok, Thailand
| | - Nipa Thongbaiphet
- Faculty of Medicine Ramathibodi Hospital, Department of Pathology, Virology Laboratory, Mahidol University, Rajathevi, Bangkok, Thailand
| | - Jiraporn Keatkla
- Faculty of Medicine Ramathibodi Hospital, Department of Pathology, Virology Laboratory, Mahidol University, Rajathevi, Bangkok, Thailand
| | - Ekawat Pasomsub
- Faculty of Medicine Ramathibodi Hospital, Department of Pathology, Virology Laboratory, Mahidol University, Rajathevi, Bangkok, Thailand
| | - Usanarat Anurathapan
- Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Mahidol University, Rajathevi, Bangkok, Thailand
| | - Suparerk Borwornpinyo
- Faculty of Science, Excellent Center for Drug Discovery, Mahidol University, Rama VI Road, Rajathevi, Bangkok, Thailand
- Faculty of Science, Department of Biotechnology, Mahidol University, Rajathevi, Bangkok, Thailand
| | - Adisak Wongkajornsilp
- Faculty of Medicine Siriraj Hospital, Department of Pharmacology, Mahidol University, Bangkok, Thailand
| | - Suradej Hongeng
- Faculty of Medicine Ramathibodi Hospital, Department of Pediatrics, Mahidol University, Rajathevi, Bangkok, Thailand
| | - Khanit Sa-Ngiamsuntorn
- Faculty of Pharmacy, Department of Biochemistry, Mahidol University, Rajathevi, Bangkok, Thailand
| |
Collapse
|
|
2
|
Wurcel AG, Chen G, Zubiago JA, Reyes J, Nowotny KM. Heterogeneity in Jail Nursing Medical Intake Forms: A Content Analysis. JOURNAL OF CORRECTIONAL HEALTH CARE 2021; 27:265-271. [PMID: 34724807 DOI: 10.1089/jchc.20.04.0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Despite high prevalence of infectious diseases and substance use disorders in jails, there are limited guidelines for the nursing intake process in this setting. We performed a content analysis of nursing intake forms used at each of the 14 Massachusetts county jails, focusing on infectious disease and substance use disorder. Only 85% of jails offered HIV testing during nursing intake and 50% of jails offered hepatitis C testing. Preventive interventions such as vaccines or pre-exposure prophylaxis therapy were infrequently offered during nursing intake. Screening for substance use disorder was present on the majority of intake forms, but only 23% of intake forms inquired about ongoing medication-assisted treatment for opioid use disorder. The results reflect heterogeneity in nursing intake forms, highlighting missed opportunities for public health interventions.
Collapse
Affiliation(s)
- Alysse G Wurcel
- Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA.,Department of Medicine, Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, USA
| | - Gang Chen
- Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Julia A Zubiago
- Department of Medicine, Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, USA
| | - Jessica Reyes
- Department of Medicine, Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, USA
| | | |
Collapse
|
|
3
|
Skyrme SL. The Lived Experience of Inequalities in the Provision of Treatment for Hepatitis C. FRONTIERS IN SOCIOLOGY 2021; 6:649838. [PMID: 34141735 PMCID: PMC8204130 DOI: 10.3389/fsoc.2021.649838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 05/18/2021] [Indexed: 06/12/2023]
Abstract
The issues of health, illness, stigma and inequalities in healthcare provision, areas that in my role as a social researcher were already of interest and concern, shifted to a different perspective when I was diagnosed with hepatitis C. From this altered position, my body and lifeworld were a nexus point for a range of ongoing challenges around staying as well as possible, and the struggle to get my healthcare needs met. There is a gap between the support provided for some ill and disabled people, and the help that they actually require. This is particularly so for conditions that are not well understood, that have a low public profile, limited funding, and/or are in some way stigmatised due to perceived differences to social norms. Hepatitis C is one such condition, it is a viral disease that is transmitted through blood-to-blood contact and it causes ongoing damage to the liver. Because of the systemic nature of the disease, individuals may struggle to cope with the demands of work and daily living, and their lifeworld and opportunities are frequently limited. It can be challenging for the patient to advocate for themselves due to low energy levels, self-blame for getting ill, and the stigma associated with the condition. The first generation of effective anti-viral drugs emerged from clinical trials in 2013, but in the United Kingdom context, access was only possible for those with advanced liver disease. Therefore, many patients felt compelled to purchase the anti-virals through Buyers Clubs, whereby generic versions of the drugs are imported for personal use at a fraction of the market cost. In this article I draw on my own lived experience of joining a Buyers Club as an example of how risks and benefits are weighed, and to explain the contexts in which decisions are shaped and made.
Collapse
|
|
4
|
Cozzani E, Herzum A, Burlando M, Parodi A. Cutaneous manifestations of HAV, HBV, HCV. Ital J Dermatol Venerol 2019; 156:5-12. [PMID: 31804053 DOI: 10.23736/s2784-8671.19.06488-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hepatotropic viral infections are a relevant global health problem and present multiple extrahepatic manifestations in addition to hepatic disease. Along with generic cutaneous symptoms correlated to the cholestatic liver disease that may arise during the infection, some cutaneous manifestations of hepatotropic viral infections are characteristic, enabling to suspect the underlying infection. This review will present the principal cutaneous manifestations of hepatotropic virus infection. Cutaneous manifestations are rare in HAV infections: these include urticaria, panniculitis, scarlatiniform eruption, evanescent skin rash, maculopapular prolonged rash, serum sickness-like illness rash, cutaneous vasculitis, cryoglobulinemia. The commonest cutaneous manifestation associated to HBV infection is serum sickness-like syndrome. Polyarteritis nodosa (PAN) is among the most common and serious cutaneous manifestations of HBV infection. In children, HBV infection may acutely manifest as papular acrodermatitis of childhood (Gianotti-Crosti Syndrome), with non-pruritic, non-coalescing, round papules. Patients with chronic HBV infection may also develop mixed cryoglobulinemia, that is, inter alia, the most documented extrahepatic manifestation of HCV infection. Cutaneous lichen planus has been associated to HBV and HCV infection. As for oral lichen planus, the association with HBV and HCV is more debated. Interestingly, patients with oral lichen planus with HCV have a higher risk of developing oral squamous cell carcinoma. Dermatologists should be aware of the possible cutaneous manifestations associated to viral hepatitis.
Collapse
Affiliation(s)
- Emanuele Cozzani
- Section of Dermatology, Department of Health Sciences (DISSAL), IRCCS San Martino University Hospital, Genoa, Italy -
| | - Astrid Herzum
- Section of Dermatology, Department of Health Sciences (DISSAL), IRCCS San Martino University Hospital, Genoa, Italy
| | - Martina Burlando
- Section of Dermatology, Department of Health Sciences (DISSAL), IRCCS San Martino University Hospital, Genoa, Italy
| | - Aurora Parodi
- Section of Dermatology, Department of Health Sciences (DISSAL), IRCCS San Martino University Hospital, Genoa, Italy
| |
Collapse
|
|
5
|
Kumari P, Ansari SN, Kumar R, Saini AK, Mobin SM. Design and Construction of Aroyl-Hydrazone Derivatives: Synthesis, Crystal Structure, Molecular Docking and Their Biological Activities. Chem Biodivers 2019; 16:e1900315. [PMID: 31532059 DOI: 10.1002/cbdv.201900315] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 09/17/2019] [Indexed: 01/10/2023]
Abstract
Here, we report the synthesis and characterization of four new aroyl-hydrazone derivatives L1 -L4 , and their structural as well as biological activities have been explored. In addition to docking with bovine serum albumin (BSA) and duplex DNA, the experimental results demonstrate the effective binding of L1 -L4 with BSA protein and calf thymus DNA (ct-DNA) which is in agreement with the docking results. Further biological activities of L1 -L4 have been examined through molecular docking with different proteins which are involved in the propagation of viral or cancer diseases. L1 shows best binding affinity with influenza A virus polymerase PB2 subunit (2VY7) with binding energy -11.42 kcal/mol and inhibition constant 4.23 nm, whereas L2 strongly bind with the hepatitis C virus NS5B polymerase (2WCX) with binding energy -10.47 kcal/mol and inhibition constant 21.06 nm. Ligand L3 binds strongly with TGF-beta receptor 1 (3FAA) and L4 with cancer-related EphA2 protein kinases (1MQB) with binding energy -10.61 kcal/mol, -10.02 kcal/mol and inhibition constant 16.67 nm and 45.41 nm, respectively. The binding energies of L1 -L4 are comparable with binding energies of their proven inhibitors. L1 , L3 and L4 can be considered as both 3FAA and 1MQB dual targeting anticancer agents, while L1 and L3 are both 2VY7 and 2WCX dual targeting antiviral agents. On the other side, L2 and L4 target only one virus related target (2WCX). Furthermore, the geometry optimizations of L1 -L4 were performed via density functional theory (DFT). Moreover, all four ligands (L1 -L4 ) were characterized by NMR, FT-IR, ESI-MS, elemental analysis and their molecular structures were validated by single crystal X-ray diffraction studies.
Collapse
Affiliation(s)
- Pratibha Kumari
- Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India
| | - Shagufi Naz Ansari
- Discipline of Chemistry, Indian Institute of Technology Indore, Simrol, Indore, 453552, India
| | - Ravi Kumar
- Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India
| | | | - Shaikh M Mobin
- Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India.,Discipline of Chemistry, Indian Institute of Technology Indore, Simrol, Indore, 453552, India.,Metallurgical Engineering and Material Science, Indian Institute of Technology Indore, Simrol, Indore, 453552, India
| |
Collapse
|
|
6
|
Wurcel AG, Burke DJ, Wang JJ, Engle B, Noonan K, Knox TA, Kim AY, Linas BP. The Burden of Untreated HCV Infection in Hospitalized Inmates: a Hospital Utilization and Cost Analysis. J Urban Health 2018; 95:467-473. [PMID: 30027427 PMCID: PMC6095754 DOI: 10.1007/s11524-018-0277-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) is highly prevalent in incarcerated populations. The high cost of HCV therapy places a major burden on correctional system healthcare budgets, but the burden of untreated HCV is not known. We investigated the economic impact of HCV through comparison of length of stay (LOS), frequency of 30-day readmission, and costs of hospitalizations in inmates with and without HCV using a 2004-2014 administrative claims database. Inmates with HCV had longer LOS, higher frequency of 30-day readmission, and increased cost of hospitalizations. Costs were higher in inmates with HCV even without advanced liver disease and in inmates with HIV/HCV compared to HCV alone. We conclude that although HCV treatment may not avert all of the observed increases in hospitalization, modest reductions in hospital utilization with HCV cure could help offset treatment costs. Policy discussions on HCV treatment in corrections should be informed by the costs of untreated HCV infection.
Collapse
Affiliation(s)
- Alysse G Wurcel
- Division of Geographic Medicine and Infectious Diseases, Department of Medicine, Tufts Medical Center, Boston, USA. .,Department of Public Health and Community Medicine, Tufts University School of Medicine, 136 Harrison Ave, M and V 2nd Floor, Room 234, Boston, MA, 02111, USA.
| | - Deirdre J Burke
- Division of Geographic Medicine and Infectious Diseases, Department of Medicine, Tufts Medical Center, Boston, USA
| | - Jianing J Wang
- Boston Medical Center, Boston University Schools of Medicine and Public Health, Boston, MA, USA
| | - Brian Engle
- Department of Public Health and Community Medicine, Tufts University School of Medicine, 136 Harrison Ave, M and V 2nd Floor, Room 234, Boston, MA, 02111, USA
| | | | - Tamsin A Knox
- Department of Public Health and Community Medicine, Tufts University School of Medicine, 136 Harrison Ave, M and V 2nd Floor, Room 234, Boston, MA, 02111, USA
| | - Arthur Y Kim
- Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Benjamin P Linas
- Boston Medical Center, Boston University Schools of Medicine and Public Health, Boston, MA, USA
| |
Collapse
|
|
7
|
Singh R, Garg N, Shukla G, Capalash N, Sharma P. Immunoprotective Efficacy of Acinetobacter baumannii Outer Membrane Protein, FilF, Predicted In silico as a Potential Vaccine Candidate. Front Microbiol 2016; 7:158. [PMID: 26904021 PMCID: PMC4751259 DOI: 10.3389/fmicb.2016.00158] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 01/29/2016] [Indexed: 11/22/2022] Open
Abstract
Acinetobacter baumannii is emerging as a serious nosocomial pathogen with multidrug resistance that has made it difficult to cure and development of efficacious treatment against this pathogen is direly needed. This has led to investigate vaccine approach to prevent and treat A. baumannii infections. In this work, an outer membrane putative pilus assembly protein, FilF, was predicted as vaccine candidate by in silico analysis of A. baumannii proteome and was found to be conserved among the A. baumannii strains. It was cloned and expressed in E. coli BL21(DE3) and purified by Ni-NTA chromatography. Immunization with FilF generated high antibody titer (>64,000) and provided 50% protection against a standardized lethal dose (108 CFU) of A. baumannii in murine pneumonia model. FilF immunization reduced the bacterial load in lungs by 2 and 4 log cycles, 12 and 24 h post infection as compared to adjuvant control; reduced the levels of pro-inflammatory cytokines TNF-α, IL-6, IL-33, IFN-γ, and IL-1β significantly and histology of lung tissue supported the data by showing considerably reduced damage and infiltration of neutrophils in lungs. These results demonstrate the in vivo validation of immunoprotective efficacy of a protein predicted as a vaccine candidate by in silico proteomic analysis and open the possibilities for exploration of a large array of uncharacterized proteins.
Collapse
Affiliation(s)
- Ravinder Singh
- Department of Microbiology, Panjab University Chandigarh, India
| | - Nisha Garg
- Department of Microbiology, Panjab University Chandigarh, India
| | - Geeta Shukla
- Department of Microbiology, Panjab University Chandigarh, India
| | - Neena Capalash
- Department of Biotechnology, Panjab University Chandigarh, India
| | - Prince Sharma
- Department of Microbiology, Panjab University Chandigarh, India
| |
Collapse
|
|
8
|
Harris M. "Three in the Room": Embodiment, Disclosure, and Vulnerability in Qualitative Research. QUALITATIVE HEALTH RESEARCH 2015; 25:1689-1699. [PMID: 25576481 DOI: 10.1177/1049732314566324] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
The researcher's body in qualitative research is often absented, an absence that can render deceptively tidy research accounts. In this article, I reflect on the interplay of embodiment and disclosure in the interview dynamic and the way in which my body became an object of inquiry in the research process. Three qualitative studies inform the article: the first exploring the experiences of 40 people living with hepatitis C in New Zealand and Australia, the second comprising life-history interviews with 38 people who inject drugs in London, and the third following 27 people through hepatitis C treatment in London. Bodily and verbal disclosures of my history, as someone with/without hepatitis C and a former heroin user, affected the energy of the interview dynamic, also embodied understandings of illness and drug use. Disclosure can enhance researcher vulnerability and I close with reflection on the ethical implications of "enhanced rapport" in the research situation.
Collapse
Affiliation(s)
- Magdalena Harris
- London School of Hygiene and Tropical Medicine, London, United Kingdom
| |
Collapse
|
|
9
|
Mosure KW, Knipe JO, Browning M, Arora V, Shu YZ, Phillip T, Mcphee F, Scola P, Balakrishnan A, Soars MG, Santone K, Sinz M. Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor. J Pharm Sci 2015; 104:2813-23. [DOI: 10.1002/jps.24356] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 12/23/2014] [Accepted: 12/23/2014] [Indexed: 12/11/2022]
|
|
10
|
Murphy SM, Dweik D, McPherson S, Roll JM. Association between hepatitis C virus and opioid use while in buprenorphine treatment: preliminary findings. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2015; 41:88-92. [PMID: 25490610 DOI: 10.3109/00952990.2014.983274] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND The prevalence of hepatitis-C-virus (HCV) infections is high among opioid-dependent individuals. Prior research on the simultaneous treatment of both conditions has primarily assessed success as it pertains to HCV. However, it has been noted that favorable substance use therapy outcomes may improve the likelihood of HCV-treatment initiation and success. Therefore, current guidelines for the treatment of HCV among illicit drug users suggest that treatment for addiction be given the highest priority. OBJECTIVES To determine whether opioid-dependent participants in a clinical trial of buprenorphine-treatment tapering regimens, who tested positive for the HCV antibody, experienced significantly different levels of opioid abstinence than those not infected. METHODS Data came from the National Drug Abuse Treatment Clinical Trial Network study 0003. 516 eligible opioid-dependent participants were randomized to either a 7-day or 28-day buprenorphine tapering schedule following a 4-week buprenorphine stabilization period. Generalized estimating equations were used to test the research question. RESULTS Participants with the HCV antibody were significantly less likely to submit opioid-negative urine analyses during and/or immediately following active treatment [OR = 0.69; CI = 0.51-0.93], indicating a higher rate of opioid use among this group. CONCLUSION Individualized opioid-dependence treatment strategies may be required for opioid-dependent individuals who test positive for the HCV antibody in order to ensure resources for both opioid-dependence and HCV therapies are used efficiently.
Collapse
Affiliation(s)
- Sean M Murphy
- Department of Health Policy and Administration, Washington State University , Spokane, Washington , USA
| | | | | | | |
Collapse
|
|
11
|
Abstract
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis and infects approximately three to four million people per year, about 170 million infected people in total, making it one of the major global health problems. In a minority of cases HCV is cleared spontaneously, but in most of the infected individuals infection progresses to a chronic state associated with high risk to develop liver cirrhosis, hepatocellular cancer, or liver failure. The treatment of HCV infection has evolved over the years. Interferon (IFN)-α in combination with ribavirin has been used for decades as standard therapy. More recently, a new standard-of-care treatment has been approved based on a triple combination with either HCV protease inhibitor telaprevir or boceprevir. In addition, various options for all-oral, IFN-free regimens are currently being evaluated. Despite substantial improvement of sustained virological response rates, some intrinsic limitations of these new direct-acting antivirals, including serious side effects, the risk of resistance development and high cost, urge the development of alternative or additional therapeutic strategies. Gene therapy represents a feasible alternative treatment. Small RNA technology, including RNA interference (RNAi) techniques and antisense approaches, is one of the potentially promising ways to investigate viral and host cell factors that are involved in HCV infection and replication. With this, newly developed gene therapy regimens will be provided to treat HCV. In this chapter, a comprehensive overview guides you through the current developments and applications of RNAi and microRNA-based gene therapy strategies in HCV treatment.
Collapse
|
|
12
|
Antony J, Celine TM. A Hospital-based Retrospective Study on Frequency and Distribution of Viral Hepatitis. J Glob Infect Dis 2014; 6:99-104. [PMID: 25191049 PMCID: PMC4147430 DOI: 10.4103/0974-777x.138499] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Viral hepatitis is a major public health problem throughout the world. It is the inflammation of the liver due to the infection of any of the five main hepatic viruses A to E and it affects the liver through different modes of transmission. This study mainly aims at the frequency and distribution of viral hepatitis based on age and sex during a time period of 5 years. MATERIALS AND METHODS This is a hospital-based retrospective study of 5 years at a tertiary level hospital in Kerala state in India. Medical records department of the hospital follow the guidelines of International Classification of Diseases-10 for coding the diseases. The data on frequency and distribution of viral hepatitis based on age and sex during a period of 5 years from April 2005 to March 2010 were collected and analyzed and 'z' test was used for finding out the difference in proportions. RESULT Out of 818 cases, 76.03% were males and 23.96% were females. The preponderance of males was apparent in all types of viral hepatitis infection. The high risk groups were the adults in the age group of 20-39 years. The main cause in the present study was hepatitis E virus (HEV) and followed by hepatitis A virus (HAV). Of total viral hepatitis cases, 31.54% were due to HAV, 6.35% hepatitis B virus, 0.85% hepatitis C virus and 61.24% were due to HEV respectively. In the present study, there was no case of hepatitis D virus has reported. The case fatality rate of viral hepatitis in the present study was minor than 1% (0.98%); whereas males were 0.96%; females of 1.02%. CONCLUSION Taking the safety measures including vaccination and proper management of waste materials are the only solution to control or eradicate this infection.
Collapse
Affiliation(s)
- Jimmy Antony
- Department of Community Medicine, M.O.S.C Medical College, Kolenchery, Ernakulam District, Kerala, India
| | - TM Celine
- Department of Community Medicine, M.O.S.C Medical College, Kolenchery, Ernakulam District, Kerala, India
| |
Collapse
|
|
13
|
Singer RA, Ragan JA, Bowles P, Chisowa E, Conway BG, Cordi EM, Leeman KR, Letendre LJ, Sieser JE, Sluggett GW, Stanchina CL, Strohmeyer H, Blunt J, Taylor S, Byrne C, Lynch D, Mullane S, O’Sullivan MM, Whelan M. Synthesis of Filibuvir. Part I. Diastereoselective Preparation of a β-Hydroxy Alkynyl Oxazolidinone and Conversion to a 6,6-Disubstituted 2H-Pyranone. Org Process Res Dev 2013. [DOI: 10.1021/op4002356] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Robert A. Singer
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - John A. Ragan
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Paul Bowles
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Esmort Chisowa
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Brian G. Conway
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Eric M. Cordi
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Kyle R. Leeman
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Leo J. Letendre
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Janice E. Sieser
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Gregory W. Sluggett
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Corey L. Stanchina
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Holly Strohmeyer
- Chemical Research and Development and ‡Analytical Research
and Development, Pfizer Worldwide Research and Development, Eastern
Point Road, Groton, 06340 Connecticut
| | - Jon Blunt
- Chemical Research and Development, Pfizer Process Development Facility Ramsgate Road, Sandwich, Kent, U.K
| | - Stuart Taylor
- Chemical Research and Development, Pfizer Process Development Facility Ramsgate Road, Sandwich, Kent, U.K
| | - Ciaran Byrne
- Pfizer Global Supply, Ringaskiddy, Cork County, Ireland
| | - Denis Lynch
- Pfizer Global Supply, Ringaskiddy, Cork County, Ireland
| | | | | | | |
Collapse
|
|
14
|
Hepatitis C Virus Load in Seropositive Liver and Kidney Transplant Recipients by Quantitative Real-Time PCR Before and After Transplantation. Jundishapur J Microbiol 2013. [DOI: 10.5812/jjm.7365] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
|
|
15
|
Zhou X, Zeng Y, Li J, Guo Y, Fu Y, He J, Sun S, Zhou Y. A novel helper-dependent adenovirus-based cell culture model for Hepatitis C virus replication and production. Virol J 2013; 10:273. [PMID: 23987099 PMCID: PMC3765914 DOI: 10.1186/1743-422x-10-273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Accepted: 08/26/2013] [Indexed: 12/16/2022] Open
Abstract
Background By using the hepatitis C virus (HCV) genotype 2a JFH-1 or its chimeric strains, a HCV infection system has been previously developed through several methods– such as in vitro-transcribed JFH1-RNA transfection or stable transfection of the JFH1 cDNA into human hepatoma Huh-7 cell line or its derivatives. However, other reliable methods for delivery of the HCV genome into cells are still worth trying. The helper-dependent adenovirus (HDAd) is devoid of all viral coding sequences and has a package capacity of 37 kb, which is suitably large for the delivery of the HCV genome. Here we report a new method for delivery of the HCV genome into Huh-7 and HepG2 cells by using the HDAd vector. Results Our results demonstrated that the infection of Huh-7 cells with the HDAdJFH1 virus led to efficient HCV replication and virion production. We found that the HCV viral RNA levels could reach 107 copies per milliliter (ml) in the culture medium. HDAdJFH1-infected Huh-7 cells could be cultured for 8 passages with the culture medium remaining infectious for naïve Huh-7 cells throughout this period. This infection system proved effective for evaluating the anti-HCV effects of IFN-α in Huh-7 cells. Co-infection of HepG2 cells with the HDAdJFH1 and HDAdmiR-122 virus also resulted in HCV expression and replication. Conclusion This is the first report of an HDAd-based strategy for HCV replication and production in vitro.
Collapse
Affiliation(s)
- Xiaojun Zhou
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Palomares-Jerez MF, Nemesio H, Franquelim HG, Castanho MARB, Villalaín J. N-terminal AH2 segment of protein NS4B from hepatitis C virus. Binding to and interaction with model biomembranes. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2013; 1828:1938-52. [PMID: 23639583 DOI: 10.1016/j.bbamem.2013.04.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Revised: 04/19/2013] [Accepted: 04/22/2013] [Indexed: 01/30/2023]
Abstract
HCV NS4B, a highly hydrophobic protein involved in the alteration of the intracellular host membranes forming the replication complex, plays a critical role in the HCV life cycle. NS4B is a multifunctional membrane protein that possesses different regions where diverse and significant functions are located. One of these important regions is the AH2 segment, which besides being highly conserved has been shown to play a significant role in NS4B functioning. We have carried out an in-depth biophysical study aimed at the elucidation of the capacity of this region to interact, modulate and disrupt membranes, as well as to study the structural and dynamic features relevant for that disruption. We show that a peptide derived from this region, NS4BAH2, is capable of specifically binding phosphatidyl inositol phosphates with high affinity, and its interfacial properties suggest that this segment could behave similarly to a pre-transmembrane domain partitioning into and interacting with the membrane depending on the membrane composition and/or other proteins. Moreover, NS4BAH2 is capable of rupturing membranes even at very low peptide-to-lipid ratios and its membrane-activity is modulated by lipid composition. NS4BAH2 is located in a shallow position in the membrane but it is able to affect the lipid environment from the membrane surface down to the hydrophobic core. The NS4B region where peptide NS4BAH2 resides might have an essential role in the membrane replication and/or assembly of the viral particle through the modulation of the membrane structure and hence the replication complex.
Collapse
|
|
17
|
Abstract
BACKGROUND Diagnostics that involve the use of oral fluids have become increasingly available commercially in recent years and are of particular interest because of their relative ease of use, low cost and noninvasive collection of oral fluid for testing. TYPES OF STUDIES REVIEWED The authors discuss the use of salivary diagnostics for virus detection with an emphasis on rapid detection of infection by using point-of-care devices. In particular, they review salivary diagnostics for human immunodeficiency virus, hepatitis C virus and human papillomavirus. Oral mucosal transudate contains secretory immunoglobulin (Ig) A, as well as IgM and IgG, which makes it a good source for immunodiagnostic-based devices. CLINICAL IMPLICATIONS Because patients often visit a dentist more regularly than they do a physician, there is increased discussion in the dental community regarding the need for practitioners to be aware of salivary diagnostics and to be willing and able to administer these tests to their patients.
Collapse
|
|
18
|
Prachi P, Biagini M, Bagnoli F. Vaccinology Is Turning into an Omics-Based Science. Drug Dev Res 2012. [DOI: 10.1002/ddr.21048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Prachi Prachi
- Novartis Vaccines; Research Center; via Fiorentina 1; 53100; Siena; Italy
| | | | - Fabio Bagnoli
- Novartis Vaccines; Research Center; via Fiorentina 1; 53100; Siena; Italy
| |
Collapse
|
|
19
|
Prevalence and risk factors associated with the presence of peripheral neuropathy in patients with hepatitis C virus infection. J Clin Neuromuscul Dis 2012; 4:109-14. [PMID: 19078700 DOI: 10.1097/00131402-200303000-00002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
OBJECTIVES To determine the frequency and risk factors associated with peripheral neuropathy in a population of patients with hepatitis C virus infection. METHODS Cross-sectional study. Electrophysiological assessment included bilateral motor and sensory conduction studies of four limbs. RESULTS Thirty-one cases and 31 control subjects were studied. Eighteen patients (58%) from the group of patients infected with the hepatitis C virus had evidence of neuropathy. Only 3 (10%) persons from the control group exhibited neuropathy. Among the risk factors for neuropathy in the patients infected with hepatitis C virus, we found the following: positive rheumatoid factor, cryoglobulinemia, and cirrhosis or active hepatitis. Other risk factors were advanced age, prolonged time of evolution, high viral load of the hepatitis C virus, and low complement. CONCLUSIONS The frequency of neuropathy encountered in our study was high (58%). In our study, a positive rheumatoid factor, cryoglobulins, and a high viral load were also associated with the presence of peripheral neuropathy. A high viral load could express possible direct viral damage.
Collapse
|
|
20
|
Characterization of lipid and lipoprotein metabolism in primary human hepatocytes. Biochim Biophys Acta Mol Cell Biol Lipids 2012; 1831:387-97. [PMID: 22951416 DOI: 10.1016/j.bbalip.2012.08.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Revised: 08/01/2012] [Accepted: 08/13/2012] [Indexed: 12/17/2022]
Abstract
Primary rodent hepatocytes and hepatoma cell lines are commonly used as model systems to elucidate and study potential drug targets for metabolic diseases such as obesity and atherosclerosis. However, if therapies are to be developed, it is essential that our knowledge gained from these systems is translatable to that of human. Here, we have characterized lipid and lipoprotein metabolism in primary human hepatocytes for comparison to rodent primary hepatocytes and human hepatoma cell lines. Primary human hepatocytes were maintained in collagen coated dishes in confluent monolayers for up to 3 days. We found primary human hepatocytes were viable, underwent lipid synthesis, and were able to secret lipoproteins up to 3 days in culture. Furthermore, the lipoprotein profile secreted by primary human hepatocytes was comparable to that found in human plasma; this contrasts with primary rodent hepatocytes and human hepatoma cells. We also investigated the pharmacological effects of nicotinic acid (niacin, NA), a potent dyslipidemic drug, on hepatic lipid synthesis and lipoprotein secretion. We found NA increased the expression of ATP-binding cassette transporter A1 in primary human hepatocytes, which may potentially explain how NA increases plasma high-density lipoproteins in humans. In conclusion, primary human hepatocytes are a more relevant model to study lipid synthesis and lipoprotein secretion than hepatoma cells or rodent primary hepatocyte models. Further research needs to be done to maintain liver specific functions of primary human hepatocytes in prolonged cultures for these cells to be a viable model.
Collapse
|
|
21
|
Palomares-Jerez MF, Nemesio H, Villalaín J. Interaction with membranes of the full C-terminal domain of protein NS4B from hepatitis C virus. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2012; 1818:2536-49. [PMID: 22749751 DOI: 10.1016/j.bbamem.2012.06.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 06/11/2012] [Accepted: 06/18/2012] [Indexed: 12/23/2022]
Abstract
Hepatitis C virus (HCV) NS4B protein is a transmembrane highly hydrophobic protein responsible for many key aspects of the viral replication process. The C-terminal part of NS4B is essential for replication and is a potential target for HCV replication inhibitors. In this work we have carried out a study of the binding to and interaction with model biomembranes of a peptide corresponding to the C-terminal domain of NS4B, NS4B(Cter). We show that NS4B(Cter) partitions into phospholipid membranes, is capable of rupturing membranes even at very low peptide-to-lipid ratios and its membrane-activity is modulated by lipid composition. NS4B(Cter) is located in a shallow position in the membrane but it is able to affect the lipid environment from the membrane surface down to the hydrophobic core. Our results identify the C-terminal region of the HCV NS4B protein as a membrane interacting domain, and therefore directly implicated in the HCV life cycle and possibly in the formation of the membranous web.
Collapse
|
|
22
|
Fournier PE, Raoult D. Prospects for the future using genomics and proteomics in clinical microbiology. Annu Rev Microbiol 2012; 65:169-88. [PMID: 21639792 DOI: 10.1146/annurev-micro-090110-102922] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The availability of genome sequences has revolutionized the fields of microbiology and infectious diseases. Indeed, more than 1,000 bacterial genomes and 3,000 viral genomes, including representatives of all significant human pathogens, have been sequenced to date. Owing to this tremendous amount of data, genomes are regarded as chimeras of sequence fragments from various origins. Coupled with novel proteomic analyses, genome sequencing has also resulted in unprecedented advances in pathogen diagnosis and genotyping and in the detection of virulence and antibiotic resistance. Herein, we review current achievements of genomics and proteomics and discuss potential developments for clinical microbiology laboratories.
Collapse
Affiliation(s)
- Pierre-Edouard Fournier
- Unité de Recherche sur les Maladies Infectieuses Tropicales et Emergentes, Université de la Méditerranée, Marseille Cedex 5, 13385 France.
| | | |
Collapse
|
|
23
|
Rutebemberwa A, Rosen HR. Of mice and men, calcineurin inhibitors and hepatitis C. Liver Transpl 2012; 18:1-4. [PMID: 22034173 DOI: 10.1002/lt.22458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
24
|
Yoshida T, Takayama K, Kondoh M, Sakurai F, Tani H, Sakamoto N, Matsuura Y, Mizuguchi H, Yagi K. Use of human hepatocyte-like cells derived from induced pluripotent stem cells as a model for hepatocytes in hepatitis C virus infection. Biochem Biophys Res Commun 2011; 416:119-24. [PMID: 22093821 DOI: 10.1016/j.bbrc.2011.11.007] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 11/02/2011] [Indexed: 12/14/2022]
Abstract
Host tropism of hepatitis C virus (HCV) is limited to human and chimpanzee. HCV infection has never been fully understood because there are few conventional models for HCV infection. Human induced pluripotent stem cell-derived hepatocyte-like (iPS-Hep) cells have been expected to use for drug discovery to predict therapeutic activities and side effects of compounds during the drug discovery process. However, the suitability of iPS-Hep cells as an experimental model for HCV research is not known. Here, we investigated the entry and genomic replication of HCV in iPS-Hep cells by using HCV pseudotype virus (HCVpv) and HCV subgenomic replicons, respectively. We showed that iPS-Hep cells, but not iPS cells, were susceptible to infection with HCVpv. The iPS-Hep cells expressed HCV receptors, including CD81, scavenger receptor class B type I (SR-BI), claudin-1, and occludin; in contrast, the iPS cells showed no expression of SR-BI or claudin-1. HCV RNA genome replication occurred in the iPS-Hep cells. Anti-CD81 antibody, an inhibitor of HCV entry, and interferon, an inhibitor of HCV genomic replication, dose-dependently attenuated HCVpv entry and HCV subgenomic replication in iPS-Hep cells, respectively. These findings suggest that iPS-Hep cells are an appropriate model for HCV infection.
Collapse
Affiliation(s)
- Takeshi Yoshida
- Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Martin SW, Glunz P, Beno BR, Bergstrom C, Romine JL, Scott Priestley E, Newman M, Gao M, Roberts S, Rigat K, Fridell R, Qiu D, Knobloh G, Wang YK. The Synthesis and evaluation of a novel class of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid Hepatitis C virus polymerase NS5B inhibitors. Bioorg Med Chem Lett 2011; 21:2869-72. [DOI: 10.1016/j.bmcl.2011.03.086] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Revised: 03/18/2011] [Accepted: 03/22/2011] [Indexed: 12/20/2022]
|
|
26
|
Scott JP, Alam M, Bremeyer N, Goodyear A, Lam T, Wilson RD, Zhou G. Mitsunobu Inversion of a Secondary Alcohol with Diphenylphosphoryl azide. Application to the Enantioselective Multikilogram Synthesis of a HCV Polymerase Inhibitor. Org Process Res Dev 2011. [DOI: 10.1021/op200002u] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Jeremy P. Scott
- Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K
| | - Mahbub Alam
- Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K
| | - Nadine Bremeyer
- Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K
| | - Adrian Goodyear
- Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K
| | - Thientu Lam
- Department of Chemical Process Development and Commercialisation, Merck and Co. Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
| | - Robert D. Wilson
- Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, U.K
| | - George Zhou
- Department of Chemical Process Development and Commercialisation, Merck and Co. Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
| |
Collapse
|
|
27
|
Yoshida T, Kondoh M, Ojima M, Mizuguchi H, Yamagishi Y, Sakamoto N, Yagi K. Adenovirus vector-mediated assay system for hepatitis C virus replication. Nucleic Acids Res 2011; 39:e64. [PMID: 21306994 PMCID: PMC3105406 DOI: 10.1093/nar/gkr047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The efficient delivery of the hepatitis C virus (HCV) RNA subgenomic replicon into cells is useful for basic and pharmaceutical studies. The adenovirus (Ad) vector is a convenient and efficient tool for the transduction of foreign genes into cells in vitro and in vivo. However, an Ad vector expressing the HCV replicon has never been developed. In the present study, we developed Ad vector containing an RNA polymerase (pol) I-dependent expression cassette and a tetracycline-controllable RNA pol I-dependent expression system. We prepared a hybrid promoter from the tetracycline-responsive element and the RNA pol I promoter. Ad vector particles coding the hybrid promoter-driven HCV replicon could be amplified, and interferon, an inhibitor of HCV replication, reduced HCV replication in cells transduced with the Ad vector coding HCV replicon. This is the first report of the development of an Ad vector-mediated HCV replicon system.
Collapse
Affiliation(s)
- Takeshi Yoshida
- Laboratory of Bio-Functional Molecular Chemistry, Department of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | | | | | | | | | | | | |
Collapse
|
|
28
|
van der Laan LJW, Wang Y, Tilanus HW, Janssen HLA, Pan Q. AAV-mediated gene therapy for liver diseases: the prime candidate for clinical application? Expert Opin Biol Ther 2011; 11:315-27. [PMID: 21204741 DOI: 10.1517/14712598.2011.548799] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
|
|
29
|
Yang X, Haurigot V, Zhou S, Luo G, Couto LB. Inhibition of hepatitis C virus replication using adeno-associated virus vector delivery of an exogenous anti-hepatitis C virus microRNA cluster. Hepatology 2010; 52:1877-87. [PMID: 20931557 DOI: 10.1002/hep.23908] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2010] [Accepted: 08/02/2010] [Indexed: 12/27/2022]
Abstract
UNLABELLED RNA interference (RNAi) is being evaluated as an alternative therapeutic strategy for hepatitis C virus (HCV) infection. The use of viral vectors encoding short hairpin RNAs (shRNAs) has been the most common strategy employed to provide sustained expression of RNAi effectors. However, overexpression and incomplete processing of shRNAs has led to saturation of the endogenous miRNA pathway, resulting in toxicity. The use of endogenous microRNAs (miRNAs) as scaffolds for short interfering (siRNAs) may avoid these problems, and miRNA clusters can be engineered to express multiple RNAi effectors, a feature that may prevent RNAi-resistant HCV mutant generation. We exploited the endogenous miRNA-17-92 cluster to generate a polycistronic primary miRNA that is processed into five mature miRNAs that target different regions of the HCV genome. All five anti-HCV miRNAs were active, achieving up to 97% inhibition of Renilla luciferase (RLuc) HCV reporter plasmids. Self-complementary recombinant adeno-associated virus (scAAV) vectors were chosen for therapeutic delivery of the miRNA cluster. Expression of the miRNAs from scAAV inhibited the replication of cell culture-propagated HCV (HCVcc) by 98%, and resulted in up to 93% gene silencing of RLuc-HCV reporter plasmids in mouse liver. No hepatocellular toxicity was observed at scAAV doses as high as 5 × 10(11) vector genomes per mouse, a dose that is approximately five-fold higher than doses of scAAV-shRNA vectors that others have shown previously to be toxic in mouse liver. CONCLUSION We have demonstrated that exogenous anti-HCV miRNAs induce gene silencing, and when expressed from scAAV vectors inhibit the replication of HCVcc without inducing toxicity. The combination of an AAV vector delivery system and exploitation of the endogenous RNAi pathway is a potentially viable alternative to current HCV treatment regimens.
Collapse
Affiliation(s)
- Xiao Yang
- Division of Hematology and Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | | | | | | | | |
Collapse
|
|
30
|
McCance-Katz EF. Drug interactions associated with methadone, buprenorphine, cocaine, and HIV medications: implications for pregnant women. Life Sci 2010; 88:953-8. [PMID: 20965297 DOI: 10.1016/j.lfs.2010.09.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Revised: 07/20/2010] [Accepted: 08/24/2010] [Indexed: 10/18/2022]
Abstract
Pregnancy in substance-abusing women with HIV/AIDS presents a complex clinical challenge. Opioid-dependent women need treatment with opioid therapy during pregnancy to protect the health of mother and developing fetus. However, opioid therapies, methadone and buprenorphine, may have drug interactions with some HIV medications that can have adverse effects leading to suboptimal clinical outcomes. Further, many opioid-dependent individuals have problems with other forms of substance abuse, for example, cocaine abuse, that could also contribute to poor clinical outcomes in a pregnant woman. Physiological changes, including increased plasma volume and increased hepatic and renal blood flow, occur in the pregnant woman as the pregnancy progresses and may alter medication needs with the potential to exacerbate drug interactions, although there is sparse literature on this issue. Knowledge of possible drug interactions between opioids, other abused substances such as cocaine, HIV therapeutics, and other frequently required medications such as antibiotics and anticonvulsants is important to assuring the best possible outcomes in the pregnant woman with opioid dependence and HIV/AIDS.
Collapse
Affiliation(s)
- Elinore F McCance-Katz
- Department of Psychiatry, University of California San Francisco, San Francisco General Hospital, United States.
| |
Collapse
|
|
31
|
Li H, Tatlock J, Linton A, Gonzalez J, Jewell T, Patel L, Ludlum S, Drowns M, Rahavendran SV, Skor H, Hunter R, Shi ST, Herlihy KJ, Parge H, Hickey M, Yu X, Chau F, Nonomiya J, Lewis C. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 2010; 52:1255-8. [PMID: 19209845 DOI: 10.1021/jm8014537] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.
Collapse
Affiliation(s)
- Hui Li
- Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Kim BS, Kim BT, Hwang KJ. The Synthesis of Diverse Adenosine 5'-phosphonate Analogues as Chain Terminators against Hepatitis C Virus (HCV). B KOREAN CHEM SOC 2010. [DOI: 10.5012/bkcs.2010.31.6.1643] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
33
|
Despins S, Issur M, Bougie I, Bisaillon M. Deciphering the molecular basis for nucleotide selection by the West Nile virus RNA helicase. Nucleic Acids Res 2010; 38:5493-506. [PMID: 20421212 PMCID: PMC2938200 DOI: 10.1093/nar/gkq276] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The West Nile virus RNA helicase uses the energy derived from the hydrolysis of nucleotides to separate complementary strands of RNA. Although this enzyme has a preference for ATP, the bias towards this purine nucleotide cannot be explained on the basis of specific protein–ATP interactions. Moreover, the enzyme does not harbor the characteristic Q-motif found in other helicases that regulates binding to ATP. In the present study, we used structural homology modeling to generate a model of the West Nile virus RNA helicase active site that provides instructive findings on the interaction between specific amino acids and the ATP substrate. In addition, we evaluated both the phosphohydrolysis and the inhibitory potential of a collection of 30 synthetic purine analogs. A structure-guided alanine scan of 16 different amino acids was also performed to clarify the contacts that are made between the enzyme and ATP. Our study provides a molecular rationale for the bias of the enzyme for ATP by highlighting the specific functional groups on ATP that are important for binding. Moreover, we identified three new essential amino acids (Arg-185, Arg-202 and Asn-417) that are critical for phosphohydrolysis. Finally, we provide evidence that a region located upstream of motif I, which we termed the nucleotide specificity region, plays a functional role in nucleotide selection which is reminiscent to the role exerted by the Q-motif found in other helicases.
Collapse
Affiliation(s)
- Simon Despins
- RNA Group/Groupe ARN, Département de Biochimie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | | | | | | |
Collapse
|
|
34
|
Yoshizato K, Tateno C. In vivo modeling of human liver for pharmacological study using humanized mouse. Expert Opin Drug Metab Toxicol 2010; 5:1435-46. [PMID: 19715443 DOI: 10.1517/17425250903216664] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The liver occupies a central place in the treatment of the substances taken into the body. If we could devise an in vivo or in vitro model that perfectly mimics the naturally-created human (h) liver, the work required for making effective and safe medicines would become easier and could be undertaken more cost effectively than it is currently. Considering the advantages of in vivo modeling over in vitro modeling under the current technological state of life sciences research, we have created an experimentally workable in vivo h-liver model, a liver-humanized mouse, in which host hepatocytes are largely replaced with healthy normal h-hepatocytes. Xenogenic h-hepatocytes are capable of constructing a histologically normal liver by collaborating with mouse-nonparenchymal cells in an elaborately organized manner. Considering its potential use for drug development, we have extensively characterized the mouse regarding the infectivity toward h-hepatitis viruses, activities of h-enzymes in Phase I and II of drug metabolisms, and h-hepatocyte-related drug transporters. These studies indicate that the humanized mouse liver mimics h-phenotypes at a level appropriate for pharmacological studies, and, thus, can be used not only for developing new medicines, but also for examining biological and pathological mechanisms in the h-liver.
Collapse
|
|
35
|
Harris M. Troubling biographical disruption: narratives of unconcern about hepatitis C diagnosis. SOCIOLOGY OF HEALTH & ILLNESS 2009; 31:1028-1042. [PMID: 19659739 DOI: 10.1111/j.1467-9566.2009.01172.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
This paper explores the impact of hepatitis C diagnosis among participants of a recent qualitative study based in New Zealand and Australia. The findings of this research were unique with regard to the small amount of existing literature on the topic. Whilst most social research indicates that diagnosis with hepatitis C is a disruptive or distressing experience, study participants were almost evenly divided between those who reported being distressed by diagnosis and those who described contracting hepatitis C as 'no big deal'. The varied nature of participants' narratives about their hepatitis C diagnosis indicates that the experience of biographical disruption is contextual: dependent upon previous experiences of illness, marginalisation or hardship, and the extent to which hepatitis C is an unknown entity or normalised within community networks. This paper draws on the theoretical frameworks of biographical disruption, normalisation and dys-appearance to illuminate these and other contextual issues informing participants' narratives of unconcern about hepatitis C diagnosis.
Collapse
Affiliation(s)
- Magdalena Harris
- National Centre in HIV Social Research, University of New South Wales, Australia.
| |
Collapse
|
|
36
|
Yoshizato K, Tateno C. A human hepatocyte-bearing mouse: an animal model to predict drug metabolism and effectiveness in humans. PPAR Res 2009; 2009:476217. [PMID: 19884982 PMCID: PMC2768028 DOI: 10.1155/2009/476217] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2009] [Accepted: 07/13/2009] [Indexed: 01/16/2023] Open
Abstract
Preclinical studies to predict the efficacy and safety of drugs have conventionally been conducted almost exclusively in mice and rats as rodents, despite the differences in drug metabolism between humans and rodents. Furthermore, human (h) viruses such as hepatitis viruses do not infect the rodent liver. A mouse bearing a liver in which the hepatocytes have been largely repopulated with h-hepatocytes would overcome some of these disadvantages. We have established a practical, efficient, and large-scale production system for such mice. Accumulated evidence has demonstrated that these hepatocyte-humanized mice are a useful and reliable animal model, exhibiting h-type responses in a series of in vivo drug processing (adsorption, distribution, metabolism, excretion) experiments and in the infection and propagation of hepatic viruses. In this review, we present the current status of studies on chimeric mice and describe their usefulness in the study of peroxisome proliferator-activated receptors.
Collapse
|
|
37
|
Martin Hernando J, Ontoria J, Malancona S, Attenni B, Fiore F, Bonelli F, Koch U, Di Marco S, Colarusso S, Ponzi S, Gennari N, Vignetti S, del Rosario Rico Ferreira M, Habermann J, Rowley M, Narjes F. Optimization of Thienopyrrole-Based Finger-Loop Inhibitors of the Hepatitis C Virus NS5B Polymerase. ChemMedChem 2009; 4:1695-713. [DOI: 10.1002/cmdc.200900184] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
|
|
38
|
Goto K, Watashi K, Inoue D, Hijikata M, Shimotohno K. Identification of cellular and viral factors related to anti-hepatitis C virus activity of cyclophilin inhibitor. Cancer Sci 2009; 100:1943-50. [PMID: 19659609 PMCID: PMC11159858 DOI: 10.1111/j.1349-7006.2009.01263.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We have so far reported that an immunosuppressant cyclosporin A (CsA), a well-known cyclophilin (CyP) inhibitor (CPI), strongly suppressed hepatitis C virus (HCV) replication in cell culture, and that CyPB was a cellular cofactor for viral replication. To further investigate antiviral mechanisms of CPI, we here developed cells carrying CsA-resistant HCV replicons, by culturing the HCV subgenomic replicon cells for 4 weeks in the presence of CsA with G418. Transfection of total RNA from the isolated CsA-resistant cells to naïve Huh7 cells conferred CsA resistance, suggesting that the replicon RNA itself was responsible for the resistant phenotype. Of the identified amino acid mutations, D320E in NS5A conferred the CsA resistance. The replicon carrying the D320E mutation was sensitive to interferon-alpha, but was resistant to CsA and other CPIs including NIM811 and sanglifehrin A. Knockdown of individual CyP subtypes revealed CyP40, in addition to CyPA and CyPB, contributed to viral replication, and CsA-resistant replicons acquired independence from CyPA for efficient replication. These data provide important evidence on the mechanisms underlying the regulation of HCV replication by CyP and for designing novel and specific anti-HCV strategies with CPIs.
Collapse
Affiliation(s)
- Kaku Goto
- Laboratory of Human Tumor Viruses, Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto, Japan
| | | | | | | | | |
Collapse
|
|
39
|
Guillén J, González-Alvarez A, Villalaín J. A membranotropic region in the C-terminal domain of hepatitis C virus protein NS4B interaction with membranes. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2009; 1798:327-37. [PMID: 19631190 DOI: 10.1016/j.bbamem.2009.07.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2009] [Revised: 07/05/2009] [Accepted: 07/08/2009] [Indexed: 01/06/2023]
Abstract
We have identified a membrane-active region in the HCV NS4B protein by studying membrane rupture induced by a NS4B-derived peptide library on model membranes. This segment corresponds to one of two previously predicted amphipathic helix and define it as a new membrane association domain. We report the binding and interaction with model membranes of a peptide patterned after this segment, peptide NS4B(H2), and show that NS4B(H2) strongly partitions into phospholipid membranes, interacts with them, and is located in a shallow position in the membrane. Furthermore, changes in the primary sequence cause the disruption of the hydrophobicity along the structure and prevent the resulting peptide from interacting with the membrane. Our results suggest that the region where the NS4B(H2) is located might have an essential role in the membrane replication and/or assembly of the viral particle through the modulation of the replication complex. Our findings therefore identify an important region in the HCV NS4B protein which might be implicated in the HCV life cycle and possibly in the formation of the membranous web.
Collapse
Affiliation(s)
- Jaime Guillén
- Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, E-03202, Elche-Alicante, Spain
| | | | | |
Collapse
|
|
40
|
Pan Q, Tilanus HW, Janssen HLA, van der Laan LJW. Prospects of RNAi and microRNA-based therapies for hepatitis C. Expert Opin Biol Ther 2009; 9:713-24. [DOI: 10.1517/14712590902989970] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
41
|
Scotto G, Fazio V, Fornabaio C, Tartaglia A, Di Tullio R, Saracino A, Angarano G. Peg-interferon alpha-2a versus Peg-interferon alpha-2b in nonresponders with HCV active chronic hepatitis: a pilot study. J Interferon Cytokine Res 2009; 28:623-9. [PMID: 18778199 DOI: 10.1089/jir.2007.0116] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The efficacy and tolerability of Peg-Interferon alpha-2a (Peg-IFNalpha-2a) versus Peg-Interferon alpha-2b (Peg-IFNalpha-2b) were compared in a patient cohort with hepatitis C virus (HCV)-related active chronic hepatitis, unresponsive to previous antiviral treatment with standard IFN (6 MU three times/week) plus ribavirin (10.6 mg/kg/day) for a period of at least 3 months. PATIENTS AND METHODS A total of 143 patients were enrolled and randomized into two treatment groups (A-B). Group A (71 patients) received one vial of Peg-IFNalpha-2a weekly (180 microg) subcutaneously whereas Group B (72 patients) received 1.5 microg/kg of Peg-IFNalpha-2b weekly subcutaneously. Interferon was combined with ribavirin (15 mg/kg/day) in both groups and all patients who demonstrated nondetectable HCV-RNA or a >or=2(log) reduction in viral load at week 12, were treated for 48 weeks, with a 24-week follow up. RESULTS Group A (10/71) and Group B (8/72) patients discontinued treatment due to severe side effects. At the end of therapy, HCV-RNA was undetectable in 17/71 (23.9%) Group A and in 19/72 (26.4%) of Group B patients. When terminating follow up, a sustained virological response was observed in 14/71 in Group A (19.7%) and 13/72 in Group B (18.0%). CONCLUSIONS Within the limits of the relatively small sample size, Peg-IFNalpha-2a and Peg-IFNalpha-2b demonstrated nonstatistically significant differences in effectiveness in patients nonresponsive to previous antiviral treatment.
Collapse
Affiliation(s)
- Gaetano Scotto
- Clinic of Infectious Diseases, University of Foggia, Foggia, Italy.
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Habermann J, Capitò E, Ferreira MDRR, Koch U, Narjes F. Discovery of pentacyclic compounds as potent inhibitors of hepatitis C virus NS5B RNA polymerase. Bioorg Med Chem Lett 2009; 19:633-8. [DOI: 10.1016/j.bmcl.2008.12.039] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Revised: 12/05/2008] [Accepted: 12/07/2008] [Indexed: 10/21/2022]
|
|
43
|
Omland LH, Jepsen P, Skinhøj P, Jørgensen HL, Münster AMB, Bangsborg J, Fenger M, Sørensen HT, Obel N. The impact of HIV-1 co-infection on long-term mortality in patients with hepatitis C: a population-based cohort study. HIV Med 2009; 10:65-71. [DOI: 10.1111/j.1468-1293.2008.00652.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
|
|
44
|
Bambini S, Rappuoli R. The use of genomics in microbial vaccine development. Drug Discov Today 2009; 14:252-60. [PMID: 19150507 PMCID: PMC7108364 DOI: 10.1016/j.drudis.2008.12.007] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Revised: 12/09/2008] [Accepted: 12/09/2008] [Indexed: 01/13/2023]
Abstract
Vaccination is one of the most effective tools for the prevention of infectious diseases. The availability of complete genome sequences, together with the progression of high-throughput technologies such as functional and structural genomics, has led to a new paradigm in vaccine development. Pan-genomic reverse vaccinology, with the comparison of sequence data from multiple isolates of the same species of a pathogen, increases the opportunity of the identification of novel vaccine candidates. Overall, the conventional empiric approach to vaccine development is being replaced by vaccine design. The recent development of synthetic genomics may provide a further opportunity to design vaccines.
Collapse
|
|
45
|
Mohebbi M, Mahmoodi M, Wolfe R, Nourijelyani K, Mohammad K, Zeraati H, Fotouhi A. Geographical spread of gastrointestinal tract cancer incidence in the Caspian Sea region of Iran: spatial analysis of cancer registry data. BMC Cancer 2008; 8:137. [PMID: 18479519 PMCID: PMC2397428 DOI: 10.1186/1471-2407-8-137] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2007] [Accepted: 05/14/2008] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND High incidence rates of gastrointestinal tract cancers have been reported in the Caspian region of Iran. This study aimed to: 1) describe the geographical spatial patterns of gastrointestinal tract cancer incidence based on cancer registry data and, 2) determine whether geographical clusters of statistical significance exist. METHODS The Babol Cancer Registry, which covers the two major northern Iranian provinces of Mazandaran and Golestan (total population = 4,484,622) was used to identify new gastrointestinal tract cancer cases during 2001 to 2005. Age-specific cancer incidence rates were calculated for 7 gastrointestinal tract cancer sites in 26 wards of the Mazandaran and Golestan provinces. Spatial autocorrelation indices, hierarchical Bayesian Poisson models, and spatial scan statistics were used in measuring the geographic pattern and clusters. RESULTS There were non-random spatial patterns in esophageal and stomach cancers that were similar for both sexes. Clusters of high incidence were identified in esophageal, stomach, colorectal and liver cancer for both sexes, as well as a possible cluster of pancreas cancer in males. CONCLUSION Gastrointestinal tract cancers exhibit significant spatial clustering of risk in northern Iran. Further work is needed to relate these geographical patterns to information on potential life-style and environmental factors.
Collapse
Affiliation(s)
- Mohammadreza Mohebbi
- 1Department of Epidemiology and Biostatistics, Tehran University of Medical Sciences, Tehran, Iran.
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Relative replication capacity and selective advantage profiles of protease inhibitor-resistant hepatitis C virus (HCV) NS3 protease mutants in the HCV genotype 1b replicon system. Antimicrob Agents Chemother 2007; 52:1101-10. [PMID: 18086851 DOI: 10.1128/aac.01149-07] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We characterized the selective advantage profiles of a panel of hepatitis C virus (HCV) NS3 protease mutants with three HCV protease inhibitors (PIs), BILN-2061, ITMN-191, and VX-950, using a genotype 1b HCV replicon system. Selective advantage curves were generated by a novel mathematical method that factors in the degree of drug susceptibility provided by the mutation, the base-level replication capacity of the mutant in the absence of drugs, and the overall viral replication levels as a function of drug concentration. Most of the mutants showed significantly increased selective advantages over the wild-type species upon drug treatment. Each drug is associated with unique selective advantage profiles that reflect its antiviral activity and mutant susceptibility. Five mutants (R155K/Q, A156T, and D168A/V) showed significant levels of selective advantage after treatment with >10 nM ( approximately 7 times the wild-type 50% effective concentration [EC50]) of BILN-2061. R155K displayed dominant levels of selective advantage over the other mutants upon treatment with ITMN-191 over a broad range of concentrations. Upon VX-950 treatment, various mutants (A156T, A156S, R155K, T54A, V170A, V36M/R155K, and R155Q) exhibited high levels of selective advantage in different drug concentration ranges, with A156T and A156S being the dominant mutants at >3 microM ( approximately 10 times the wild-type EC50) of VX-950. This method provides more accurate estimates of the behavior of various mutants under drug pressure than replication capacity analysis. We noted that the R155K mutant shows reduced susceptibility to all three PIs and significant selective advantage, raising concern over the potential emergence of R155K as a multidrug-resistant, highly fit mutant in HCV patients treated with PIs.
Collapse
|
|
47
|
Pan QW, Henry SD, Scholte BJ, Tilanus HW, Janssen HLA, van der Laan LJW. New therapeutic opportunities for Hepatitis C based on small RNA. World J Gastroenterol 2007; 13:4431-6. [PMID: 17724797 PMCID: PMC4611574 DOI: 10.3748/wjg.v13.i33.4431] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, anti-sense oligonucleotides (ASO), or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA (miR-122) in viral replication and discuss its potential for HCV molecular therapy.
Collapse
Affiliation(s)
- Qiu-Wei Pan
- Erasmus MC-University Medical Centre, Department of Gastroenterology, Room L458, sGravendijkwal 230, 3015 CE, Rotterdam, The Netherlands
| | | | | | | | | | | |
Collapse
|
|
48
|
Li H, Linton A, Tatlock J, Gonzalez J, Borchardt A, Abreo M, Jewell T, Patel L, Drowns M, Ludlum S, Goble M, Yang M, Blazel J, Rahavendran R, Skor H, Shi S, Lewis C, Fuhrman S. Allosteric inhibitors of hepatitis C polymerase: discovery of potent and orally bioavailable carbon-linked dihydropyrones. J Med Chem 2007; 50:3969-72. [PMID: 17658778 DOI: 10.1021/jm0704447] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.
Collapse
Affiliation(s)
- Hui Li
- Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
McCance-Katz EF, Moody DE, Smith PF, Morse GD, Friedland G, Pade P, Baker J, Alvanzo A, Jatlow P, Rainey PM. Interactions between buprenorphine and antiretrovirals. II. The protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir. Clin Infect Dis 2007; 43 Suppl 4:S235-46. [PMID: 17109310 DOI: 10.1086/508188] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
We examined drug interactions between buprenorphine, an opioid partial agonist available by prescription for treatment of opioid dependence, and the protease inhibitors (PIs) nelfinavir (NFV), ritonavir (RTV), and lopinavir/ritonavir (LPV/R). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per PI) participated in 24-h pharmacokinetic studies, before and after administration of each PI. Symptoms of opiate withdrawal and excess were determined before and after PI administration. PI pharmacokinetics were determined and compared between opiate-dependent participants and healthy control participants (n=15 per PI). Administration of RTV, but not of NFV or LPV/R, resulted in a significant increase in the buprenorphine area under the concentration-time curve (AUC). Symptoms of opiate excess, however, were not observed. Buprenorphine had no significant effects on PI AUC. Adjustments of doses of either buprenorphine or NFV, LPV/R, or RTV are not likely to be necessary when these drugs are administered for the treatment of opioid dependence and HIV disease.
Collapse
|
|
50
|
He Y, Duan W, Tan SL. Emerging host cell targets for hepatitis C therapy. Drug Discov Today 2007; 12:209-17. [PMID: 17331885 DOI: 10.1016/j.drudis.2007.01.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2006] [Revised: 01/03/2007] [Accepted: 01/24/2007] [Indexed: 12/23/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is a major burden on humanity. The current HCV therapy has limited efficacy, and there is pressing need for new and more effective therapies. Host cell factors that are required for HCV infection, replication and/or pathogenesis represent potential therapeutic targets. Of particular interest are cellular receptors that mediate HCV entry, factors that facilitate HCV replication and assembly, and intracellular pathways involving lipid biosynthesis, oxidative stress and innate immune response. A crucial challenge now is to manipulate such cellular targets pharmacologically for chronic HCV treatment, without being limited by side effects.
Collapse
Affiliation(s)
- Yupeng He
- Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
| | | | | |
Collapse
|