bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regression of fibrosis after HBV antiviral therapy. Is cirrhosis reversible?
Authors: Calvaruso Vincenza , Craxì Antonio 
Published: December 2013

AbstractLong‐lasting HBV‐DNA suppression is considered to be the best surrogate end‐point of antiviral therapy in patients with hepatitis B virus (HBV) related chronic hepatitis or cirrhosis, and it is a prerequisite to prevent liver‐related complications and improve survival. Treatment with oral antiviral drugs in patients with HBV cirrhosis is effective in restoring liver function and improving survival even in those with decompensated cirrhosis. These agents are generally well‐tolerated for long‐term treatment, and several evidences have demonstrated that they are able to reverse liver fibrosis and prevent the occurrence of HCC.
Optimizing treatment for HCV genotype 4: PEG‐IFN alfa 2a vs. PEG‐IFN alfa 2b; the debate continues
Authors: Esmat Gamal , El Kassas Mohamed , Hassany Mohamed , Gamil Mohamed , El Raziky Maissa 
Published: December 2013

AbstractHepatitis C virus (HCV) remains one of the leading causes of morbidity and mortality worldwide. Combined therapy with pegylated interferon (PEG‐IFN) and ribavirin is the current standard of care treatment for HCV genotype 4. Two types of PEG‐IFN are commercially available. The limited number of trials that were conducted for HCV genotype 4 and the few head to head comparisons make it impossible to know which is the best option? In this article we review all available PEG‐IFN trials performed worldwide for HCV genotype 4 since 2004. Unless another molecule is developed as a standalone for the treatment of HCV, PEG‐IFN will continue to be a source of debate.
HBeAg‐positive chronic hepatitis B: why do I treat my patients with pegylated interferon?
Authors: Kao Jia‐Horng 
Published: December 2013

AbstractAlthough chronic hepatitis B (CHB) is a global health threat, it is now a preventable and treatable disease. Seven agents have been approved for the treatment of CHB. Although many patients prefer potent long‐term nucleos(t)ide analogues (NAs) as the first‐line therapy because they are convenient to use and well‐tolerated, a finite duration of pegylated interferon (PEG‐IFN) is still an attractive strategy because it provides higher rates of off‐therapy host immune control over hepatitis B virus (HBV) compared with NAs. In addition, the rates of HBeAg/HBsAg loss or seroconversion increase over time in patients who respond to PEG‐IFN therapy. Nevertheless, these benefits are limited to 30% of all patients, and significant adverse effects are still a concern. Therefore, patients who can benefit most from PEG‐IFN therapy should be more carefully selected according to baseline host and viral predictors, such as age, ALT level, viral load, HBV genotype and HBV mutants. In addition, on‐treatment predictors including HBV DNA, HBeAg and HBsAg kinetics, can help decide who should continue or discontinue PEG‐IFN and shift to NA. Understanding these factors can help determine personalized PEG‐IFN therapy for CHB patients. In the near future, the treatment paradigm of CHB should be tailored on the basis of viral (HBV DNA level, HBV genotype and HBV mutants) and host (age, gender, ALT level and host genetic polymorphisms) factors, disease status (stage of fibrosis and comorbidities) and the selection of antiviral agents (immunomodulatory effect, antiviral potency, adverse effects and rate of drug resistance).
Treatment of hepatitis C virus genotype 3‐infection
Authors: Pol Stanislas , Vallet‐Pichard Anaïs , Corouge Marion 
Published: December 2013

AbstractThe treatment of hepatitis C virus (HCV) infection with pegylated interferon (PEG‐IFN) alfa and ribavirin (800 mg daily) (RBV) is the standard of care (SOC) for hepatitis C virus genotype 3‐infection leading to a sustained virological response (SVR) in around 65% of patients.A better understanding of the HCV life‐cycle has recently resulted in the development of several potential direct‐acting antiviral drugs (DAAs) targeting viral proteins (NS3/4A protease, NS5B nucleos(t)idic and non‐nucleos(t)idic polymerase, NS5A viral replication complex). First generation protease inhibitors in combination with PEG‐IFN/RBV are not efficient in genotype 3‐infected patients. The combination of PEG‐IFN/RBV with Daclatasvir, a NS5A inhibitor for 12–24 weeks results in a SVR in around 75% while the triple combination of PEG‐IFN/RBV with the oral nucleotidic polymerase inhibitor Sofosbuvir (GS‐7977) for 12 weeks in naïve patients results in a SVR in more than 95%. The results of the first oral combination of Sofosbuvir and RBV for 12 weeks in genotype 3‐infected patients have been rather disappointing with a slightly lower SVR than after 24 weeks of PEG‐IFN: around 60%, and only 30% in patients with cirrhosis. Extending treatment from 12 to 16 weeks in treatment experienced patients doubled the SVR rate and an 80% SVR rate is expected by extending treatment to 24 weeks. The best oral combination of new DAAs is probably the combination of Sofosbuvir and a NS5A inhibitor (Daclatasvir, Ledipasvir…) for 24 weeks, which resulted in a 100% SVR rate in a limited series. The use of cyclophilin inhibitors, a host‐targeted antiviral, in association with DAAs and/or RBV may also be of interest.The oral combination of new DAAs (dual or triple combination of different antivirals) or of DAAs and host targets such as cyclophilin will probably become the SOC for genotype 3‐infected treatment‐naïve or ‐experienced patients.
Is there still a role for PEG IFN+RBV therapy in patients with HCV genotype 1?
Authors: Serfaty Lawrence 
Published: December 2013

AbstractBoceprevir and telaprevir‐based triple therapy is now the standard of care for the treatment of genotype 1 patients. However, dual therapy with pegylated interferon and ribavirin should be discussed in treatment‐naïve patients with good predictors of response. A recent published trial has shown in non‐cirrhotic patients with low viral load at baseline, similar efficacy of a 24‐week course of dual therapy vs a 24‐week course of boceprevir‐based triple therapy in case of rapid virological response. Accordingly, addition of protease inhibitor should be discussed after 4 weeks of dual therapy in this easy‐to‐treat population.
A brief history of hepatitis milestones
Authors: Trepo Christian 
Published: December 2013

AbstractHepatitis has been a major plague of mankind. The history of the discovery of causative viruses is one of the most fascinating scientific adventures of this half century. Individualization of several types of hepatitis only emerged after world war two. Their identification has been associated with milestones which revolutionized medicine and public health. The discovery of HBV brought the first ever vaccine not prepared by tissue culture but initially directly from plasma and soon the first vaccine produced by genetic engineering. HBV vaccine proved to be the first “anti‐cancer” vaccine by preventing hepatocellular carcinoma and practically eradicating it from childhood in Taiwan. Successful vaccines became also available for HAV and more recently HEV. The discovery of HCV in 1989 opened a new era since it was the first virus was identified by a direct molecular approach. Two billion people are infected with HBV and 350 million are chronic carriers of the virus. The extraordinary effectiveness of HBV vaccination was best illustrated in Taiwan and Singapore where in less than 2 decades HBs Ag carriers dropped from 9,1% to 2,7% and HCC from 27% to 17%. Successful development of nucleos(t)ides analogs make it now possible to fully control disease progression with a daily pill long term therapy. The progress in HCV therapy has been even more spectacular and successful treatment jumped from 6 % with interferon alone in 1986 to more than 80% in 2013 with triple combination therapies. Remarkably chronic hepatitis C is the only chronic disease which is curable. It will be soon possible to eradicate HCV infection with, an all oral, daily single pill (containing several molecules) for 3 to 6 months which will cure over 90% of patients. This unprecedented therapeutic victory benefiting hundred millions of people matches the triumphs over small pox, polio and tuberculosis. The next 10 years should undoubtedly witness cure or full control over all forms of acute and chronic hepatitis.
HCV direct‐acting antiviral agents: the best interferon‐free combinations
Authors: Schinazi Raymond , Halfon Philippe , Marcellin Patrick , Asselah Tarik 
Published: December 2013

AbstractFor HCV infection, there have been major advancements during last several years with large numbers of ongoing trials with various direct‐acting antivirals (DAA) showing high potency, favourable tolerability profile, higher barrier to resistance, shortened treatment duration, all oral regimen, pan‐genotypic, fewer drug interactions and reduced pill burden. By 2014, several DAAs are anticipated to complete successful phase III trials and will be commercially available. Initially, a wave of IFN‐based regimen (sofosbuvir, faldaprevir and simeprevir) will be available for treatment of HCV genotype 1. In the near future, combination of antiviral agents with additive potency that lack cross‐resistance with good safety profile will likely be the new recommended regimens, making HCV, the first chronic viral infection to be eradicated worldwide with a finite duration of combination DAA therapy without IFN or ribavirin. The aim of this review was to summarize the results obtained from recent DAA combination studies without IFN.
K2O‐rich trapped melt in olivine in the Nakhla meteorite: Implications for petrogenesis of nakhlites and evolution of the Martian mantle
Authors: Goodrich Cyrena Anne , Treiman Allan H. , Filiberto Justin , Gross Juliane , Jercinovic Michael 
Published: December 2013

AbstractWe used new analytical and theoretical methods to determine the major and minor element compositions of the primary trapped liquid (PTLs) represented by melt inclusions in olivine and augite in the Martian clinopyroxenite, Nakhla, for comparison with previously proposed compositions for the Nakhla (or nakhlite) parent magma. We particularly focused on obtaining accurate K2O contents, and on testing whether high K2O contents and K2O/Na2O ratios obtained in previous studies of melt inclusions in olivine in Nakhla could have been due to unrepresentative sampling, systematic errors arising from electron microprobe techniques, late alteration of the inclusions, and/or boundary layer effects. Based on analyses of 35 melt inclusions in olivine cores, the PTL in olivine, PTLoliv, contained (by wt) approximately 47% SiO2, 6.3% Al2O3, 9.6% CaO, 1.8% K2O, and 0.9% Na2O, with K2O/Na2O = 2.0. We infer that the high K2O content of PTLoliv is not due to boundary layer effects and represents a real property of the melt from which the host olivine crystallized. This melt was cosaturated with olivine and augite. Its mg# is model‐dependent and is constrained only to be ≥19 (equilibrium Fo = 40). Based on analyses of 91 melt inclusions in augite cores, the PTL in augite, PTLaug, contained (by wt) 53–54% SiO2, 7–8% Al2O3, 0.8–1.1% K2O, and 1.1–1.4% Na2O, with K2O/Na2O = 0.7–0.8. This K2O content and K2O/Na2O ratio are significantly higher than inferred in studies of melt inclusions in augite in Nakhla by experimental rehomogenization. PTLaug was saturated only with augite, and in equilibrium with augite cores of mg# 62. PTLaug represents the Nakhla parent magma, and does not evolve to PTLoliv by fractional crystallization. We therefore conclude that olivine cores in Nakhla (and, by extension, other nakhlites) are xenocrystic. We propose that PTLoliv and PTLaug were generated from the same source region. PTLoliv was generated first and emplaced to form olivine‐rich cumulate rocks. Shortly thereafter, PTLaug was generated and ascended through these olivine‐rich cumulates, incorporating fragments of wallrock that became the xenocrystic olivine cores in Nakhla. The Nakhla (nakhlite) mantle source region was pyroxenitic with some olivine, and could have become enriched in K relative to Na via metasomatism. A high degree of melting of this source produced the silica‐poor, alkali‐rich magma PTLoliv. Further ascension and decompression of the source led to generation of the silica‐rich, relatively alkali‐poor magma PTLaug. Potassium‐rich magmas like those involved in the formation of the nakhlites represent an important part of the diversity of Martian igneous rocks.
Zinc isotopic composition of iron meteorites: Absence of isotopic anomalies and origin of the volatile element depletion
Authors: Chen Heng , Nguyen Bach Mai , Moynier Frédéric 
Published: December 2013

AbstractHigh‐precision Zn isotopic compositions measured by MC‐ICP‐MS are documented for 32 iron meteorites from various fractionally crystallized and silicate‐bearing groups. The δ66Zn values range from −0.59‰ up to +5.61‰ with most samples being slightly enriched in the heavier isotopes compared with carbonaceous chondrites (0 < δ66Zn < 0.5). The δ66Zn versus δ68Zn plot of all samples defines a common linear fractionation line, which supports the hypothesis that Zn was derived from a single reservoir or from multiple reservoirs linked by mass‐dependent fractionation processes. Our data for Redfields fall on a mass fractionation line and therefore refute a previous claim of it having an anomalous isotopic composition due to nonmixing of nucleosynthetic products. The negative correlation between δ66Zn and the Zn concentration of IAB and IIE is consistent with mass‐dependent isotopic fractionation due to evaporation with preferential loss of lighter isotopes in the vapor phase. Data for the Zn concentrations and isotopic compositions of two IVA samples demonstrate that volatile depletion in the IVA parent body is not likely the result of evaporation. This is important evidence that favors the incomplete condensation origin for the volatile depletion of the IVA parent body.
Multicentre surveillance study on feasibility, safety and efficacy of antifungal combination therapy for proven or probable invasive fungal diseases in haematological patients: the SEIFEM real‐life combo study
Authors: Candoni A. , Caira M. , Cesaro S. , Busca A. , Giacchino M. , Fanci R. , Delia M. , Nosari A. , Bonini A. , Cattaneo C. , Melillo L. , Caramatti C. , Milone G. , Scime’ R. , Picardi M. , Fanin R. , Pagano L. 
Published: December 2013

SummaryThis multicentre observational study evaluated the feasibility, efficacy and toxicity of antifungal combination therapy (combo) as treatment of proven or probable invasive fungal diseases (IFDs) in patients with haematological malignancies. Between January 2005 and January 2010, 84 cases of IFDs (39 proven and 45 probable) treated with combo were collected in 20 Hematological Italian Centres, in patients who underwent chemotherapy or allogeneic haematopoietic stem cell transplantation for haematological diseases. Median age of patients was 34 years (range 1–73) and 37% had less than 18 years. Acute leukaemia was the most common underlying haematological disease (68/84; 81%). The phase of treatment was as follows: first induction in 21/84 (25%), consolidation phase in 18/84 (21%) and reinduction/salvage in 45/84 (54%). The main site of infection was lung with or without other sites. The principal fungal pathogens were as follows: Aspergillus sp. 68 cases (81%), Candida sp. six cases (8%), Zygomycetes four cases (5%) and Fusarium sp. four cases (5%). The most used combo was caspofungin+voriconazole 35/84 (42%), caspofungin + liposomal amphotericin B (L‐AmB) 20/84 (24%) and L‐AmB+voriconazole 15/84 (18%). The median duration of combo was 19 days (range 3–180). The overall response rate (ORR) was 73% (61/84 responders) without significant differences between the combo regimens. The most important factor that significantly influenced the response was granulocyte (PMN) recovery (P 0.009). Only one patient discontinued therapy (voriconazole‐related neurotoxicity) and 22% experienced mild and reversible adverse events (hypokalaemia, ALT/AST increase and creatinine increase). The IFDs‐attributable mortality was 17%. This study indicates that combo was both well tolerated and effective in haematological patients. The most used combo regimens were caspofungin + voriconazole (ORR 80%) and caspofungin + L‐AmB (ORR 70%). The ORR was 73% and the mortality IFD related was 17%. PMN recovery during combo predicts a favourable outcome. Clinical Trials Registration: NCT00906633.
Impaired copper and iron metabolism in blood cells and muscles of patients affected by copper deficiency myeloneuropathy
Authors: Spinazzi Marco , Sghirlanzoni Angelo , Salviati Leonardo , Angelini Corrado 
Published: December 2013

AimsSevere copper deficiency leads in humans to a treatable multisystem disease characterized by anaemia and degeneration of spinal cord and nerves, but its mechanisms have not been investigated. We tested whether copper deficit leads to alterations in fundamental copper‐dependent proteins and in iron metabolism in blood and muscles of patients affected by copper deficiency myeloneuropathy, and if these metabolic abnormalities are associated with compensatory mechanisms for copper maintenance.MethodsWe evaluated the expression of critical copper enzymes, of iron‐related proteins, and copper chaperones and transporters in blood and muscles from five copper‐deficient patients presenting with subacute sensory ataxia, muscle paralysis, liver steatosis and variable anaemia. Severe copper deficiency was caused by chronic zinc intoxication in all of the patients, with an additional history of gastrectomy in two cases.ResultsThe antioxidant enzyme SOD1 and subunit 2 of cytochrome c oxidase were significantly decreased in blood cells and in muscles of copper‐deficient patients compared with controls. In muscle, the iron storage protein ferritin was dramatically reduced despite normal serum ferritin, and the expression of the haem‐proteins cytochrome c and myoglobin was impaired. Muscle expression of the copper transporter CTR1 and of the copper chaperone CCS, was strikingly increased, while antioxidant protein 1 was diminished.Conclusionscopper‐dependent enzymes with critical functions in antioxidant defences, in mitochondrial energy production, and in iron metabolism are affected in blood and muscles of patients with profound copper deficiency leading to myeloneuropathy. Homeostatic mechanisms are strongly activated to increase intracellular copper retention.
Synthetic TAL effectors for targeted enhancement of transgene expression in plants
Authors: Liu Wusheng , Rudis Mary R. , Peng Yanhui , Mazarei Mitra , Millwood Reginald J. , Yang Jian‐Ping , Xu Wenzhi , Chesnut Jonathan D. , Stewart Charles Neal 
Published: December 2013

SummaryTranscription activator‐like effectors (TALEs), secreted by the pathogenic bacteria Xanthomonas, specifically activate expression of targeted genes in plants. Here, we designed synthetic TALEs that bind to the flanking regions of the TATA‐box motif on the CaMV 35S promoter for the purpose of understanding the engineerable ‘hot‐spots’ for increasing transgene expression. We demonstrated that transient expression of de novo‐engineered TALEs using agroinfiltration could significantly increase reporter gene expression in stable transgenic tobacco expressing the orange fluorescent protein reporter gene pporRFP under the control of synthetic inducible, minimal or full‐length 35S promoters. Moreover, the additive effects of a combination of two different synthetic TALEs could significantly enhance the activation effects of TALEs on reporter gene expression more than when each TALE was used individually. We also studied the effects of the C‐terminal domain and the activation domain of synthetic TALEs, as well as the best ‘hot‐spots’ on the 35S promoter on targeted transgene activation. Furthermore, TALE activation of the Arabidopsis MYB transcription factor AtPAP1 (PRODUCTION OF ANTHOCYANIN PIGMENT 1) in stable transgenic tobacco gave rise to a dark purple colour on infiltrated leaves when driven by four copies of cis‐regulatory elements of pathogenesis‐related gene (PR1) with enhancer motifs B and A1 from the 35S promoter. These results provide novel insights into the potential applications of synthetic TALEs for targeted gene activation of transgenes in plants.
Interactions between the jasmonic and salicylic acid pathway modulate the plant metabolome and affect herbivores of different feeding types
Authors: SCHWEIGER R. , HEISE A.‐M. , PERSICKE M. , MÜLLER C. 
Published: December 2013

AbstractThe phytohormones jasmonic acid (JA) and salicylic acid (SA) mediate induced plant defences and the corresponding pathways interact in a complex manner as has been shown on the transcript and proteine level. Downstream, metabolic changes are important for plant–herbivore interactions. This study investigated metabolic changes in leaf tissue and phloem exudates of Plantago lanceolata after single and combined JA and SA applications as well as consequences on chewing‐biting (Heliothis virescens) and piercing‐sucking (Myzus persicae) herbivores. Targeted metabolite profiling and untargeted metabolic fingerprinting uncovered different categories of plant metabolites, which were influenced in a specific manner, indicating points of divergence, convergence, positive crosstalk and pronounced mutual antagonism between the signaling pathways. Phytohormone‐specific decreases of primary metabolite pool sizes in the phloem exudates may indicate shifts in sink–source relations, resource allocation, nutrient uptake or photosynthesis. Survival of both herbivore species was significantly reduced by JA and SA treatments. However, the combined application of JA and SA attenuated the negative effects at least against H. virescens suggesting that mutual antagonism between the JA and SA pathway may be responsible. Pathway interactions provide a great regulatory potential for the plant that allows triggering of appropriate defences when attacked by different antagonist species.
Wood properties of Populus and Betula in long‐term exposure to elevated CO2 and O3
Authors: KOSTIAINEN KATRI , SARANPÄÄ PEKKA , LUNDQVIST SVEN‐OLOF , KUBISKE MARK E. , VAPAAVUORI ELINA 
Published: December 2013

AbstractWe studied the interactive effects of elevated concentrations of CO2 and O3 on radial growth and wood properties of four trembling aspen (Populus tremuloides Michx.) clones and paper birch (Betula papyrifera Marsh.) saplings. The material for the study was collected from the Aspen FACE (free‐air CO2 enrichment) experiment in Rhinelander (WI, USA). Trees had been exposed to four treatments [control, elevated CO2 (560 ppm), elevated O3 (1.5 times ambient) and combined CO2 + O3] during growing seasons 1998–2008. Most treatment responses were observed in the early phase of experiment. Our results show that the CO2‐ and O3‐exposed aspen trees displayed a differential balance between efficiency and safety of water transport. Under elevated CO2, radial growth was enhanced and the trees had fewer but hydraulically more efficient larger diameter vessels. In contrast, elevated O3 decreased radial growth and the diameters of vessels and fibres. Clone‐specific decrease in wood density and cell wall thickness was observed under elevated CO2. In birch, the treatments had no major impacts on wood anatomy or wood density. Our study indicates that short‐term impact studies conducted with young seedlings may not give a realistic view of long‐term ecosystem responses.