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Hepatitis c: Treatment of difficult to treat patients

World Journal of Hepatology 2015年第15期7卷 1953-1963页

作者： Eric G Hilgenfeldt Alex Schlachterman Roberto J Firpi Department of Internal Medicine University of Florida College of Medicine Department of Gastroen-terology Hepatology and Nutrition University of Florida College of Medicine Section of Hepatobiliary Diseases and Trans-plantation University of Florida

Over the past several years, more so recently, treatment options for hepatitis c virus(HcV) have seemed to exponentially grow. Up until recently, the regimen of pegylated interferon(peg-IFN) and ribavirin(RBV) stood as the standard of care. Direct acting antivirals, which target nonstructural proteins involved in replication and infection of HcV were first approved in 2011 as an addition to the peg-IFN and RBV regimen and with them have come increased sustained virological response rates(SVR). The previously reported 50%-70% SVR rates using the combination of peg-IFN and RBV are no longer the standard of care with direct acting antiviral(DAA) based regimens now achieving SVR of 70%-90%. PegIFN free as well as "all oral" regimens are also available. The current randomized controlled trials available show favorable SVRs in patients who are naive to treatment, non-cirrhotic, and not human immunodeficiency virus(HIV)-co-infected. What about patients who do not fit into these categories? In this review, we aim to discuss the currently approved and soon to be approved DAAs while focusing on their roles in patients that are treatment experienced, cirrhotic, or co-infected with HIV. In this discussion, review of the clinical trials leading to recent consensus guidelines as well as discussion of barriers to treatment will occur. A case will attempt will be made that social services, including financial support and drug/alcohol treatment, should be provided to all HcV infected patients to improve chances of cure and thus prevention of late stage sequela.

关键词： Hepatitis c virus Direct acting antiviral Human immunodeficiency virus cirrhosis Treatmentexperienced

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Down Regulated Protein c Plasma Levels in the Absence of Factor V Leiden Mutation in HIV Patients: An Observational Study in Maiduguri, North-Eastern Nigeria

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World Journal of AIDS 2015年第2期5卷 76-82页

作者： Simon O. Obi Ballah Akawu Denue Ifeanyi chukwu O. Martin Marycelin M. Baba Grace I. Amilo Salihu Aliyu Kwayabura Obi Ejeatulu Department of Medical Lab Science College of Medicine University of Maiduguri Maiduguri Nigeria Department of Medicine University of Maiduguri Teaching Hospital Maiduguri Nigeria Department of Immunology Faculty of Medicine Nnamdi Azikiwe University Awka Nigeria Department of Haematology Faculty of Medicine Nnamdi Azikiwe University Awka Nigeria Department of Obstetrics and Gynaecology University of Maiduguri Teaching Hospital Maiduguri Nigeria Department of Pharmacology Faculty of Medicine Nnamdi Azikiwe University Awka Nigeria

Background: As life expectancy of HIV-infected patients increases with use of highly active antiretroviral therapy (HAART), protean haematologic manifestation including decreased activity of natural anticoagulants such as protein c may occur in the absence of genetic risk factors. Based on this preposition, we assessed the plasma level of protein c, and prevalence of factor V Leiden mutation among HIV-infected individuals. Our cohort consisted of 499 HIV-infected patients, of which 250 had AIDS, while 249 were either asymptomatic or had minor mucocutaneous infection consistent with WHO clinical stages I and II without features of AIDS. We also evaluated 251 healthy, HIV-negative subjects as controls. All participants were tested for plasma protein c levels and factor V Leiden (FVL) mutation (Arg 506 Gln) by automation and amplification created restriction enzyme site (AcRES) polymerase chain reaction, respectively. The prevalence of reduced protein c plasma levels among HIV positive patients was 20%;it was more prevalent among those that had AIDS compared with those without features of AIDS, but within WHO clinical stage I and II, (93.3% vs 6.7%) respectively. None of the control patients had either reduced protein c nor FVL mutation. All participants that demonstrated reduced protein c plasma levels demonstrated normal FVL genotype (1691G/G). conclusion: Decreased protein c plasma levels can occur in HIV-infected patients in the absence of factor V Leiden mutation. The risk increases with severity of the disease. Deranged protein c plasma level increases the risk of hypercoagulable state in patients with advanced HIV disease;it should be considered among the causes of thrombo embolism in this group of patients.

关键词： HIV Infection Protein c Factor V Leiden Mutation

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Assessing cardiovascular risk in hepatitis c: An unmet need

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World Journal of Hepatology 2015年第19期7卷 2214-2219页

作者： Javier Ampuero Manuel Romero-Gómez Intercentre Unit of Digestive Diseases Virgen Macarena - Virgen del Rocio University Hospitals

chronic hepatitis c virus(HcV) is associated with significant morbidity and mortality, as a result of the progression towards cirrhosis and hepatocellular carcinoma. Additionally, HcV seems to be an independent risk factor for cardiovascular diseases(cVD) due to its association with insulin resistance, diabetes and steatosis. HcV infection represents an initial step in the chronic inflammatory cascade, showing a direct rolein altering glucose metabolism. After achieving sustained virological response, the incidence of insulin resistance and diabetes dramatically decrease. HcV core protein plays an essential role in promoting insulin resistance and oxidative stress. On the other hand, atherosclerosis is a common disease in which the artery wall thickens due to accumulation of fatty deposits. The main step in the formation of atherosclerotic plaques is the oxidation of low density lipoprotein particles, together with the increased production of proinflammatory markers [tumor necrosis factor-α, interleukin(IL)-6, IL-18 or c-reactive protein]. The advent of new direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis c infection. In this scenario, the cardiovascular risk has emerged and represents a major concern after the eradication of the virus. consequently, the number of studies evaluating this association is growing. Data derived from these studies have demonstrated the strong link between HcV infection and the atherogenic process, showing a higher risk of coronary heart disease, carotid atherosclerosis, peripheral artery disease and, ultimately, cVD-related mortality.

关键词： Hepatitis c Atherosclerosis coronary artery diseas

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Inhibition of Hepatitis c Virus Genotype 1a Non-Structural Proteins by Small Interference RNA in Human Hepatoma cell Lines

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Pharmacology & Pharmacy 2015年第11期6卷 502-517页

作者： Imran Shahid Waleed Hassan AlMalki Shaia Saleh R. Almalki Ismail Muhammad AlTurkestany Hassan Ali AlGhamdi Saleh Ali AlMenshawi Applied and Functional Genomics Laboratory Center of Excellence in Molecular Biology University of the Punjab Lahore Pakistan Department of Pharmacology and Toxicology College of Pharmacy Umm Al Qura University Makkah Saudi Arabia Laboratory Medicine Faculty of Applied Medical Sciences Albaha University Albaha Saudi Arabia Infection Control Pilgrims City Hospital Madina Saudi Arabia Toxicology Center Jeddah Saudi Arabia Toxiology Research Center Ministry of Interior Jeddah Saudi Arabia

Hepatitis c virus (HcV) infection and associated liver diseases are still challenging and represent a significant health care burden around the world. Although, the treatment strategies have been improved by the development of novel direct-acting antivirals, but such therapeutic options are still expensive and beyond the financial range of the most infected individuals in developing or even in resource replete countries. It demands an urgent need to search novel and improved alternate treatment strategies to treat the infection. The present study was aimed to develop an in vitro stable cell culture system, persistently expressing HcV genotype 1a non-structural genes and to characterize the inhibitory effects of synthetic siRNAs (short interference RNA) directed against the most conserved regions of nonstructural genes in an in vitro cell culture model. The continuous expression of nonstructural genes for more than 30 days post transfection was detected by reverse transcription polymerase chain reaction (RT-PcR) and Western blot analysis in stable human hepatoma cell line (Huh-7). The gene expression studies revealed significantly reduced gene expression of HcV nonstructural genes (i.e., NS2, NS4A and NS5A) both at mRNA and protein levels when treated against genome specific synthetic siRNAs in stable cell lines (51%, 47% and 54% respectively, p < 0.05). Similarly, a vivid decrease in HcV viral titer was exhibited by synthetic siRNAs in an in vitro viral replicate cell culture model (58%, 48% and 50%, respectively, p < 0.05) determined by quantitative Real-Time PcR (qPcR). Our data indicate that siRNA mediated gene silencing may be considered a promising alternate treatment strategy against HcV in combination with other effective therapeutic regimens in future.

关键词： Hepatitis c Virus Non-Structural Proteins Stable cell Line Anti-HcV Drugs Short Interference RNA

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c/EBP Mediates TNF--Induced cancer cell Migration by Inducing MMP Expression Dependent on p38 MAPK

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JOURNAL OF cELLULAR BIOcHEMISTRY 2015年第12期116卷 2766-2777页

作者： Xia, Peiyi Zhang, Rui Ge, Gaoxiang Chinese Acad Sci Key Lab Syst Biol Inst Biochem & Cell Biol Shanghai Inst Biol Sci Shanghai 200031 Peoples R China

Tumor necrosis factor (TNF)- is a pleiotropic cytokine that triggers cell proliferation, cell death, or inflammation. Besides its cytotoxic effect on cancer cells, TNF- exerts tumor promoting activity. Aberrant TNF- signaling promotes cancer cell motility, invasiveness, and enhances cancer metastasis. Exaggerated tumor cell migration, invasion, and metastasis by TNF- has been attributed to the activation of NF-B signaling. It is yet to be elucidated if other signaling pathways and effector molecules are involved in TNF--induced cancer cell migration and metastasis. Expression of c/EBP, a transcription factor involved in metabolism, inflammation, and cancer, is increased upon TNF- treatment. TNF- induces c/EBP expression by enhancing its transcription and protein stability. Activation of p38 MAPK, but not NF-B or JNK, is responsible for TNF--induced stabilization of c/EBP protein. c/EBP is involved in TNF--induced cancer cell migration. Knockdown of c/EBP inhibits TNF--induced cell migration, while overexpression of c/EBP increases migration of cancer cells. c/EBP is translated into transcriptional activator LAP1 and LAP2 and transcriptional repressor LIP utilizing alternative in-frame translation start sites. Despite TNF- induces expression of all three isoforms, LAP1/2, but not LIP, promote cancer cell migration. TNF- induced MMP1/3 expression, which was abrogated by c/EBP knockdown or p38 MAPK inhibition. MMP inhibitor or knockdown of MMP1/3 diminished TNF-- and c/EBP-induced cell migration. Thus, c/EBP mediates TNF--induced cancer cell migration by inducing MMP1/3 expression, and may participate in the regulation of inflammation-associated cancer metastasis. J. cell. Biochem. 116: 2766-2777, 2015. (c) 2015 Wiley Periodicals, Inc.

关键词： TNF- cELL MIGRATION c EBP MMP p38 MAPK INFLAMMATION

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SOFRITAS: Serializable Ordering-Free Regions for Increasing Thread Atomicity Scalably 18

SOFRITAS: Serializable Ordering-Free Regions for Increasing ...

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23rd International conference on Architectural Support for Programming Languages and Operating Systems (ASPLOS)

作者： DeLozier, christian Lucia, Brandon Eizenberg, Ariel Devietti, Joseph Univ Penn Philadelphia PA 19104 USA Carnegie Mellon Univ Pittsburgh PA 15213 USA

ISBN: (纸本)9781450349116

correctly synchronizing multithreaded programs is challenging and errors can lead to program failures such as atomicity violations. Existing strong memory consistency models rule out some possible failures, but are limited by depending on programmer-defined locking code. We present the new Ordering-Free Region (OFR) serializability consistency model that ensures atomicity for OFRs, which are spans of dynamic instructions between consecutive ordering constructs (e.g., barriers), without breaking atomicity at lock operations. Our platform, Serializable Ordering-Free Regions for Increasing Thread Atomicity Scalably (SOFRITAS), ensures a c/c++ program's execution is equivalent to a serialization of OFRs by default. We build two systems that realize the SOFRITAS idea: a concurrency bug finding tool for testing called SofriTest, and a production runtime system called SoPro. SofriTest uses OFRs to find concurrency bugs, including a multi-critical-section atomicity violation in memcached that weaker consistency models will miss. If OFRs are too coarse-grained, SofriTest suggests refinement annotations automatically. Our software-only SoPro implementation has high performance, scales well with increased parallelism, and prevents failures despite bugs in locking code. SoPro has an average overhead of just 1.59x on a single-threaded execution and 1.51x on sixteen threads, despite pthreads' much weaker memory model.

关键词： atomicity region serializability data races c c plus

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Is the use of IL28B genotype justified in the era of interferon-free treatments for hepatitis c?

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World Journal of Virology 2015年第3期4卷 178-184页

作者： Tatsuo Kanda Shingo Nakamoto Osamu Yokosuka Department of Gastroenterology and Nephrology Chiba UniversityGraduate School of Medicine

In 2009, several groups reported that interleukin-28B(IL28B) genotypes are associated with the response to peginterferon plus ribavirin therapy for chronic hepatitis c virus(HcV) infection in a genome-wide association study, although the mechanism of this association is not yet well understood. However, in recent years, tremendous progress has been made in the treatment of HcV infection. In Japan, some patients infected with HcV have the IL28 B major genotype, which may indicate a favorable response to interferon-including regimens; however, certain patients within this group are also interferon-intolerant or ineligible. In Japan, interferonfree 24-wk regimens of asunaprevir and daclatasvir are now available for HcV genotype 1b-infected patients who are interferon-intolerant or ineligible or previous treatment null-responders. The treatment response to interferon-free regimens appears better, regardless of IL28 B genotype. Maybe other interferon-free regimens will widely be available soon. In conclusion, although some HcV-infected individuals have IL28 B favorable alleles, importance of IL28 B will be reduced with availability of oral interferon free regimen.

关键词： Hepatitis c virus Interleukin-28B Interferon Japan Sustained virologic response

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Impact of Post Hepatitis c chronic Liver Disease and Hepatocellular carcinoma on Health Related Quality of Life

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Advances in Aging Research 2015年第6期4卷 177-186页

作者： Somaia M. Ebeid Safaa H. Ali Heba Y. Kamel Ahmed A. Elbaz Hazem M. El-Hariri Departments of Geriatric Medicine Faculty of Medicine Ain Shams University Cairo Egypt Departments of Tropical Medicine Faculty of Medicine Ain Shams University Cairo Egypt Department of Community Medicine Research National Research Center Cairo Egypt

Background: Post hepatitis c virus chronic liver disease (cLD) is prevalent among the Egyptian population with a bad impact upon their quality of life (QOL). Hepatocellular carcinoma (Hcc) is one of the long term and fatal complications of cLD and it also has its negative impact on patient’s quality of life. Aim: To assess impact of cLD and Hcc on the quality of life of group of hospitalized elderly patients. Methodology: Ninety elderly patients were divided into three groups: 30 elderly with post hepatitis c virus cLD, 30 elderly with Hcc and 30 others free of liver disease as control group (cn), all were recruited from the in-patient ward and the outpatient clinic of the Geriatric Department, Ain-Shams University Hospital. After giving consent, comprehensive geriatric assessment was done with assessment of their quality of life by using the Short Form-36 health survey (SF-36). Investigations including liver enzymes, serum albumin, serum bilirubin and abdominal ultrasound were done. Results: All QOL domains were the highest among control group, followed by Hcc group and the least among cLD group. The differences were statistically significant in most subscales and total score [Mean of cn = 81.9 ± 12.4, Mean of cLD = 47.5 ± 21.9, Mean of Hcc = 62.3 ± 16.1;P cn/cLD ≤ 0.001, P cn/Hcc ≤ 0.001, P cLD/Hcc = 0.004]. Albumin was the only biochemical marker correlated positively with total SF score and two subscales (PF and EF) [r = 0.408;P = 0.025]. conclusion & Recommendation: Our study showed a decrease in the QOL of Egyptian post hepatitis c virus cLD and Hcc patients compared with Egyptian population norms. The results showed that cLD were more affected than Hcc patients. This had a particularly serious negative impact on their life. The findings indicate a need for updated counseling and educational materials designed to provide adequate information and consistent healthcare service to this patient setting.

关键词： Post Hepatitis c Virus chronic Liver Diseases Hepatocellular carcinoma Quality of Life Short Form-36 Health Survey

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New treatment strategies for hepatitis c infection

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World Journal of Hepatology 2015年第17期7卷 2100-2109页

作者： Fatih Ermis Elif Senocak Department of Gastroenterology Duzce University Faculty of Medicine Department of Internal Medicine Duzce University Faculty of Medicine

Hepatitis c infection can lead to cirrhosis and hepatocellular carcinoma and it is an important cause of mortality and morbidity. Achieving a sustained virological response has been the major aim for decades. Interferon treatment was the primarily developed therapy against the infection. Addition of the guanosine analog ribavirin to stop viral RNA synthesis increased the response rates as well as the adverse effects of the treatment. The increasing demands for alternative regimens led to the development of direct-acting antivirals(DAAs). The approval of sofosbuvir and simeprevir signaled a new era of antiviral treatment for hepatitis c infection. Although the majority of studies have been performed with DAAs in combination with interferon and resulted in a decrease in treatment duration and increase in response rates, the response rates achieved with interferon-free regimens provided hope for patients ineligible for therapy with interferon. Most DAA studies are in phase Ⅱ leading to phase Ⅲ. In the near future more DAAs are expected to be approved. The main disadvantage of the therapy remains the cost of the drugs. Here, we focus on new treatment strategies for hepatitis c infection as well as agents targeting hepatitis c virus replication that are in clinical development.

关键词： Direct-acting antivirals Eradication Genotype Hepatitis c virus infection Interferon-free Treatment

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An Approach for Knowledge Extraction from Source code (KNESc) of Typed Programming Languages 6th

An Approach for Knowledge Extraction from Source Code (KNESC...

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World conference on Information Systems and Technologies (WorldcIST)

作者： Jiomekong, Azanzi camara, Gaoussou Univ Yaounde I Fac Sci UMMISCO Yaounde Cameroon Univ Alioune Diop Bambey EIR IMTICE Bambey Senegal

ISBN: (纸本)9783319777023;9783319777030

Knowledge extraction is the discovery of knowledge from structured and/or unstructured sources. This knowledge can be used to build or enrich a domain ontology. Source code is rarely used. But implementation platforms evolve faster than business logic and these evolutions are usually integrated directly into source code without updating the conceptual model. In this paper, we present a generic approach for knowledge extraction from source code of typed programming languages using Hidden Markov Models. This approach consist of the definition of the HMMso that it can be used to extract any type of knowledge from the source code. The method is experimented on EPIcAM and GeoServer developed in Java and on MapServer developed in c/c++. Structural evaluation shows that source code contains a structure that permit to build a domain ontology and functional evaluation shows that source code contains more knowledge than those contained in both databases and meta-models.

关键词： Knowledge extraction Ontology learning Hidden Markov Models Source code JAVA c c plus

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