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Golob-Schwarzl, Nicole,Krassnig, Stefanie,Toeglhofer, Anna M.,Park, Young Nyun,Gogg-Kamerer, Margit,Vierlinger, Klemens,Schrö,der, Fabian,Rhee, Hyungjn,Schicho, Rudolf,Fickert, Peter,Haybaeck, Joh Elsevier 2017 European journal of cancer Vol.83 No.-
<P><B>Abstract</B></P> <P>Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The initiation of protein translation is an important rate-limiting step in eukaryotes and is crucial in many viral infections. Eukaryotic translation initiation factors (eIFs) are involved in the initiation step of protein translation and are linked to the phosphatidylinositol-3-kinases PI3K/AKT/mTOR pathway. Therefore we aimed to investigate a potential role of eIFs in HCC. We herein report on the immunohistochemical expression of the various eIF subunits in 235 cases of virus-related human HCC. Additionally, we used immunoblot analysis to investigate the expression of virus-related HCC and non-virus-related HCC in comparison to controls. Mammalian target of rapamycin (or mechanistic target of rapamycin as it is known now (mTOR) and activated mTOR were significantly increased in chronic hepatitis C (HCV)-associated HCC, in HCC without a viral background, in alcoholic liver disease and Wilson disease. pPTEN, phosphatase and tensin homologue (PTEN) and pAKT showed a significant increase in HBV- and HCV-associated HCC, chronic hepatitis B, HCC without a viral background, alcoholic steatohepatitis (ASH) and Wilson disease. Phosphorylated (p)-eIF2α, eIF2α, eiF3B, eIF3D, eIF3J, p-eIF4B, eIF4G and eIF6 were upregulated in HCV-associated HCC. eIF2α, p-eIF4B, eIF5 and various eIF3 subunits were significantly increased in chronic hepatitis B (HBV)-associated HCC. HCC without viral background displayed a significant increase for the eIF subunits p-2α, 3C, 3I, 4E and 4G. We noticed engraved differences in the expression pattern between chronic hepatitis B and C, HBV- and HCV-associated HCC and non-virus-related HCC.</P> <P><B>Highlights</B></P> <P> <UL> <LI> mTOR and activated mammalian target of rapamycin (mTOR) were significantly increased in liver cancer. </LI> <LI> Various eukaryotic translation initiation factor (eIF) subunits were increased in liver cancer. </LI> </UL> </P>
The Arabidopsis ClpB/Hsp100 family of proteins: chaperones for stress and chloroplast development
Lee, Ung,Rioflorido, Ignatius,Hong, Suk-Whan,Larkindale, Jane,Waters, Elizabeth R.,Vierling, Elizabeth Blackwell Publishing Ltd 2007 The Plant journal Vol.49 No.1
<P>Summary</P><P> The Casein lytic proteinase/heat shock protein 100 (Clp/Hsp100) proteins are chaperones that act to remodel/disassemble protein complexes and/or aggregates using the energy of ATP. In plants, one of the best-studied proteins from this family is cytosolic ClpB1 (At1g74310), better known in Arabidopsis as <I>At</I>Hsp101, which is a heat shock protein required for acclimation to high temperatures. Three other ClpB homologues have been identified in the Arabidopsis genome (ClpB2, ClpB3 and ClpB4; At4g14670, At5g15450 and At2g25140). To define further the roles of these chaperones in plants we investigated their intracellular localization, evolutionary relationships, patterns of expression and the phenotypes of corresponding T-DNA insertion mutants. We first found that ClpB2 was misannotated; there is no functional ClpB/Hsp100 gene at this locus. By fusing the putative transit peptides of ClpB3 and ClpB4 with GFP, we showed that these proteins are targeted to the chloroplast and mitochondrion, respectively, and we therefore designated them as ClpB-p and ClpB-m. Phylogenetic analysis supports two major lineages of ClpB proteins in plants, an ‘eukaryotic’, cytosol/nuclear-localized group containing <I>At</I>Hsp101, and an organelle-localized lineage, containing both ClpB-p and ClpB-m. Although <I>At</I>Hsp101, ClpB-p and ClpB-m transcripts all accumulate dramatically at high temperatures, the T-DNA insertion mutants of ClpB-p and ClpB-m show no evidence of seedling heat stress phenotypes similar to those observed in <I>At</I>Hsp101 mutants. Strikingly, ClpB-p knockouts were seedling lethals, failing to accumulate chlorophyll or properly develop chloroplasts. Thus, in plants, the function of ClpB/Hsp100 proteins is not restricted to heat stress, but a specific member of the family provides housekeeping functions that are essential to chloroplast development.</P>
( Paul Kwo ),( Stefan Zeuzem ),( Steven L. Flamm ),( Myron Tong ),( John M Vierling ),( Stephen Pianko ),( Peter Buggisch ),( Victor de Lédinghen ),( Robert H. Hyland ),( Xiaoru Wu ),( Evguenia S. Sva 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: DAAs provide safe and highly efficacious therapies for HCV infection. However, the small proportion of patients who do not achieve a sustained virologic response with DAA-based regimens represent a population with an unmet medical need. Sofosbuvir(SOF) and velpatasvir(VEL) are pangenotypic inhibitors of the HCV NS5B and NS5A proteins, respectively, and voxilaprevir(VOX) is a pangenotypic HCV NS3/4A protease inhibitor. This study evaluates treatment with a SOF/VEL/VOX for 12weeks and a SOF/VEL for 12weeks as salvage regimens in DAA-experienced patients who had not previously received an NS5A inhibitor. Methods: Patients with genotypes 1-3 were randomized 1:1 to receive open-label SOF/VEL/VOX or SOF/VEL for 12weeks, stratified according to genotype and cirrhosis status. Patients of all other genotypes were assigned to receive SOF/VEL/VOX for 12weeks. DAA-experienced patients who previously were treated with an NS5A inhibitor or with only an NS3/4A protease inhibitor in combination with ribavirin and Peg-IFN were excluded. The primary endpoint evaluates the superiority of the SVR12 of each treatment to a prespecified goal of 85%. Results: Of the 333 patients who were randomized and treated, 77% were male, 19% had the IL28B CC genotype, 46% had compensated cirrhosis and 43% had genotype 1 infection. Most patients had prior DAA experience with either an NS5B inhibitor alone(73%) or an N5SB inhibitor and an NS3/4A protease inhibitor(25%); the most common prior treatment regimens were SOF with ribavirin ±Peg-IFN and SOF combined with simeprevir. Treatment was well tolerated.No SAE was assessed to be attributable to study drug. Overall, SVR12 was achieved in 97%(177/182) of patients treated with SOF/VEL/VOX and 90%(136/151) patients treated with SOF/VEL. SOF/VEL/VOX met the prespecified 85% SVR12 performance goal(p<0.001); SOF/VEL did not. Conclusions: SOF/VEL/VOX for 12 weeks provides a safe, well tolerated and effective retreatment options for patients who did not previously achieve SVR following treatment with non-NS5A inhibitor-containing DAA regimens.
( Do Young Kim ),( Won Young Tak ),( Stefan Zeuzem ),( Lawrence Serfaty ),( John M. Vierling ),( Wendy Cheng ),( Jacob George ),( Jan Sperl ),( Simone I. Strasser ),( Hiromitsu Kumada ),( Peggy Hwang 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: GT1b is the most common HCV genotype globally, accounting for the largest proportion of infections in Europe, Latin America, Russia, Turkey, and East Asia. We report the efficacy of 12 weeks of once-daily elbasvir/grazoprevir (50 mg/100 mg) (NS5A inhibitor/ NS3/4 protease inhibitor) in HCV GT1b-infected patients enrolled in the clinical development program. Methods: This analysis of treatment-naïve and treatment-experienced GT1b-infected patients used data pooled from 11 trials involving 30 countries and included 1070 patients with/without cirrhosis, chronic kidney disease (CKD), and HIV co-infection. Cirrhosis (F4, compensated) was confirmed by either liver biopsy or noninvasive tests. Patients with Stage 4 or Stage 5 CKD on hemodialysis were included. HIV/HCV co-infected patients were required to be on a stable antiretroviral regimen (ARV) (tenofovir or abacavir, emtricitabine or lamivudine, and either raltegrevir, dolutegravir, or rilpivirine) with CD4 >200/μL and HIV viral load undetectable, or if not on ARVs, have CD4 >500/μL and viral load < 50,000 IU/mL. The primary endpoint was the proportion of patients with HCV RNA below the lower limit of quantitation 12 weeks after treatment (SVR12). Efficacy data are presented for the full analysis set (FAS), which includes all patients who received at least one dose of study medication, and for the per-protocol (PP) population, which excludes nonvirologic failures. Results: A total of 1,070 patients were included in the analysis. Mean patient age was 53.7 years (range, 19-80); 50% were male; 47% were white, 43% were Asian, and 9% were black or African American; 20% were treatment-experienced; 39% had a baseline viral load >2,000,000 IU/mL; and 18% had evidence of cirrhosis. SVR12 was 97% (1040/1070) in the FAS; 15 patients (1.4%) were categorized as virologic failures and 15 (1.4%) were categorized as nonvirologic failures (lost-to-follow-up or withdrawal). Excluding the nonvirologic failures, SVR12 was 99% (1040/1055) in the PP analysis. There were no notable differences in subgroup analyses: SVR12 was 97% in both treatment-naïve and treatment-experienced patients; 99% in cirrhotics and 97% in noncirrhotics; 98% in patients with a baseline viral load < 2,000,000 IU/mL and 97% in patients with a baseline viral >2,000,000 IU/mL; 94% in HIV/HCV co-infected patients; and 100% and 95% in patients with Stage 4 or 5 CKD, respectively. Conclusions: High efficacy was achieved in the GT1b-infected population treated with elbasvir/grazoprevir for 12 weeks, with comparable efficacy across subgroups, including those with cirrhosis, high baseline viral load, and prior treatment failures.
( Won Choong Choi ),( Walid C. Arnaout ),( Federico G. Villamil ),( Achilles A. Demetriou ),( John M. Vierling ) 대한내과학회 2007 The Korean Journal of Internal Medicine Vol.22 No.2
Background: Distinguishing those patients with fulminant hepatic failure (FHF) and who require transplantation from those FHF patients who will survive with receiving only intensive medical care remains problematic, and this distinction is important because of the chronic shortage of donor livers. Methods: To assess the applicability of two prognostic scoring systems, referred to as the London and Clichy criteria, we compared using both systems, at the time of admission, for 43 FHF patients (15 M/28 F; age: 3716 yrs). Acetaminophen (ACM) was the etiology for 16 patients, while the remaining 27 had other etiologies. All the patients received intensive care, and 18 (8 ACM/10 non-ACM) had investigational BAL support. Results: For the ACM toxicity, neither the London nor the Clichy criteria exhibited acceptable sensitivity (71 vs 86%, respectively), specificity (78 vs 56%, respectively), a positive predictive value (71 vs 60%, respectively), a negative predictive value (78 vs 83%, respectively) or predictive accuracy (75 vs 69%, respectively) to predict patient survival without transplantation. In contrast, applying the London and Clichy criteria to the FHF patients with non-ACM etiologies showed a sensitivity of 96 vs 80%, respectively, a specificity of 100 vs 100%, respectively, a positive predictive value of 100 vs 100%, respectively a negative predictive value of 67 vs 29%, respectively and a predictive accuracy of 96% vs 82%, respectively. Conclusions: Overall, the London criteria more accurately predicted the need for transplantation, and neither the London criteria nor the Clichy prognostic criteria accurately predicted the outcome of those patients who suffered with FHF due to ACM. BAL support may have contributed to the survival of the patients with ACM toxicity and who didn`t undergo transplantation, and this survival exceeded the predictions of both prognostic systems. Additional multicenter studies should be conducted to refine these prognostic scoring systems, and this will help physicians rapidly identify those FHF patients who can survive without undergoing liver transplantation.