bluuebunny/crossref_metadata_2025 huggingface dataset:
Leukocyte cell-derived chemotaxin 2 antagonizes MET receptor activation to suppress hepatocellular carcinoma vascular invasion by protein tyrosine phosphatase 1B recruitment
Authors: Chen Chi-Kuan , Yang Ching-Yao , Hua Kuo-Tai , Ho Ming-Chih , Johansson Gunnar , Jeng Yung-Ming , Chen Chiung-Nien , Chen Min-Wei , Lee Wei-Jiunn , Su Jen-Liang , Lai Tsung-Ching , Chou Chi-Chi , Ho Bing-Ching , Chang Chuan-Fa , Lee Po-Huang , Chang King-Jen , Hsiao Michael , Lin Ming-Tsan , Kuo Min-Liang
Published: October 2013

Leukocyte cell-derived chemotoxin 2 (LECT2) has been shown to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the underlying mechanism has not yet been completely defined. Here, we employ a LECT2-affinity column plus liquid chromatography coupled with tandem mass spectrometry to identify LECT2-binding proteins and found that MET receptor strongly interacted with LECT2 protein. Despite the presence of hepatocyte growth factor, the LECT2 binding causes an antagonistic effect to MET receptor activation through recruitment of protein tyrosine phosphatase 1B. The antagonistic effect of LECT2 on MET activation also mainly contributes to the blockage of vascular invasion and metastasis of HCC. Furthermore, serial deletions and mutations of LECT2 showed that the HxGxD motif is primarily responsible for MET receptor binding and its antagonistic effects. Conclusion: These findings reveal a novel, specific inhibitory function of LECT2 in HCC by the direct binding and inactivation of MET, opening a potential avenue for treating MET-related liver cancer. (HEPATOLOGY 2014;59:974-985)
On-treatment alpha-fetoprotein is a specific tumor marker for hepatocellular carcinoma in patients with chronic hepatitis B receiving entecavir
Authors: Wong Grace L.H. , Chan Henry L.Y. , Tse Yee-Kit , Chan Hoi-Yun , Tse Chi-Hang , Lo Angeline O.S. , Wong Vincent W.S.
Published: October 2013

Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) surveillance, which is criticized as neither sensitive nor specific in active hepatitis and liver cirrhosis. The aim of this study was to determine the performance of AFP as a tumor marker for HCC in entecavir-treated patients with chronic hepatitis B (CHB). This was a retrospective-prospective cohort study of 1,531 entecavir-treated patients under regular HCC surveillance with AFP and ultrasonography. Mean age was 52 ± 12 years; 1,099 (72%) patients were male and 332 (21.7%) had clinical evidence of cirrhosis. At a mean follow-up of 51 ± 13 months, 57 (2.9%) patients developed HCC (median size: 3.3 cm). AFP fluctuated with alanine aminotransferase (ALT) and peaked at the time of starting entecavir, then gradually decreased after. AFP started to increase 6 months before the diagnosis of HCC. The receiver operator characteristic curve (AUROC) of AFP was highest at the time of HCC diagnosis (0.85; 95% confidence interval [CI]: 0.73-0.98) and remained satisfactory at 3 (0.82; 95% CI: 0.73-0.91) and 6 months (0.79; 95% CI: 0.69-0.89) before the diagnosis. Using the conventional AFP cut-off (20 μg/L) at month 0, the sensitivity and specificity to diagnose HCC were 38.6% and 98.9%, respectively. Adopting the lower cut-off value (6 μg/L) of AFP level at month 0, sensitivity was increased to 80.7%, whereas specificity was decreased to 80.4%. Conclusion: On-treatment AFP is a specific tumor marker for HCC in CHB patients receiving entecavir therapy. Adopting a lower cut-off value of AFP level at 6 μg/L would significantly increase the sensitivity for HCC detection. (HEPATOLOGY 2014;59:986–995)
Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: Updated criteria and genotype assignment web resource
Authors: Smith Donald B. , Bukh Jens , Kuiken Carla , Muerhoff Scott A. , Rice Charles M. , Stapleton Jack T. , Simmonds Peter
Published: October 2013

The 2005 consensus proposal for the classification of hepatitis C virus (HCV) presented an agreed and uniform nomenclature for HCV variants and the criteria for their assignment into genotypes and subtypes. Since its publication, the available dataset of HCV sequences has vastly expanded through advancement in nucleotide sequencing technologies and an increasing focus on the role of HCV genetic variation in disease and treatment outcomes. The current study represents a major update to the previous consensus HCV classification, incorporating additional sequence information derived from over 1,300 (near-)complete genome sequences of HCV available on public databases in May 2013. Analysis resolved several nomenclature conflicts between genotype designations and using consensus criteria created a classification of HCV into seven confirmed genotypes and 67 subtypes. There are 21 additional complete coding region sequences of unassigned subtype. The study additionally describes the development of a Web resource hosted by the International Committee for Taxonomy of Viruses (ICTV) that maintains and regularly updates tables of reference isolates, accession numbers, and annotated alignments (
http://talk.ictvonline.org/links/hcv/hcv-classification.htm
). The Flaviviridae Study Group urges those who need to check or propose new genotypes or subtypes of HCV to contact the Study Group in advance of publication to avoid nomenclature conflicts appearing in the literature. While the criteria for assigning genotypes and subtypes remain unchanged from previous consensus proposals, changes are proposed in the assignment of provisional subtypes, subtype numbering beyond “w,” and the nomenclature of intergenotypic recombinant.

Conclusion :

This study represents an important reference point for the consensus classification of HCV variants that will be of value to researchers working in clinical and basic science fields.
Infection of common marmosets with hepatitis C virus/GB virus-B chimeras
Authors: Li Tingting , Zhu Shaomei , Shuai Lifang , Xu Yuxia , Yin Sen , Bian Yixin , Wang Yuanzhan , Zuo Bingfeng , Wang Wenjing , Zhao Shuoxian , Zhang Ling , Zhang Jingang , Gao George F. , Allain Jean-Pierre , Li Chengyao
Published: October 2013

The development of vaccination and novel therapy for hepatitis C virus (HCV) has been hampered by the lack of suitable small-animal models. GB virus B (GBV-B), closely related to HCV, causes viral hepatitis in common marmosets (Callithrix jacchue jacchus) and might represent an attractive surrogate model for HCV infection. However, differences exist between GBV-B and HCV in spite of a short genetic distance between the two viruses. Here we report common marmosets infected with two HCV/GBV-B chimeras containing HCV structural genes coding for either whole core and envelope proteins (CE1E2p7) or full envelope proteins (E1E2p7) substituted for the counterpart elements of GBV-B. Naïve animals intrahepatically injected with chimeric RNA transcripts or intravenously injected with sera from primary infected animals produced high levels of circulating infectious chimeric viruses and they developed chronic infection. Tacrolimus-treated marmosets inoculated with a CE1E2p7 chimera had higher viral loads and long-term persistent infection. A moderate elevation of serum aspartate aminotransferase (AST) levels was observed in parallel with viral replication. Chimeras recovered from liver samples revealed 1/958 adaptive viral mutations. Histopathological changes typical of viral hepatitis were observed in liver tissues from all types of HCV chimeras-infected marmosets. HCV core and E2 proteins were detected in liver tissues from infected animals by immunohistochemical staining. Fluctuations of chimeric virus replication in marmosets with spontaneous and sporadic viral clearance might be related to specific antibody and T-cell response to HCV proteins in vivo. Replication of CE1E2p7 chimera was observed in primary hepatocyte cultures by immunofluorescent staining in vitro. Conclusion: Infectious HCV chimeras causing chronic hepatitis in marmosets might constitute a small primate model suitable for evaluation of virus-cell interaction, vaccination, and antiviral therapy against HCV infection. (HEPATOLOGY 2014;59:789–802)
G-protein-coupled receptor 30/adenylyl cyclase/protein kinase A pathway is involved in estradiol 17ß-D-glucuronide-induced cholestasis
Authors: Zucchetti Andrés E. , Barosso Ismael R. , Boaglio Andrea C. , Basiglio Cecilia L. , Miszczuk Gisel , Larocca Cecilia M. , Ruiz Laura M. , Davio Carlos A. , Roma Marcelo G. , Crocenzi Fernando A. , Sánchez Pozzi Enrique J.
Published: October 2013

Estradiol-17ß-D-glucuronide (E17G) activates different signaling pathways (e.g., Ca2+-dependent protein kinase C, phosphoinositide 3-kinase/protein kinase B, mitogen-activated protein kinases [MAPKs] p38 and extracellular signal-related kinase 1/2, and estrogen receptor alpha) that lead to acute cholestasis in rat liver with retrieval of the canalicular transporters, bile salt export pump (Abcb11) and multidrug resistance-associated protein 2 (Abcc2). E17G shares with nonconjugated estradiol the capacity to activate these pathways. G-protein-coupled receptor 30 (GPR30) is a receptor implicated in nongenomic effects of estradiol, and the aim of this study was to analyze the potential role of this receptor and its downstream effectors in E17G-induced cholestasis. In vitro, GPR30 inhibition by G15 or its knockdown with small interfering RNA strongly prevented E17G-induced impairment of canalicular transporter function and localization. E17G increased cyclic adenosine monophosphate (cAMP) levels, and this increase was blocked by G15, linking GPR30 to adenylyl cyclase (AC). Moreover, AC inhibition totally prevented E17G insult. E17G also increased protein kinase A (PKA) activity, which was blocked by G15 and AC inhibitors, connecting the links of the pathway, GPR30-AC-PKA. PKA inhibition prevented E17G-induced cholestasis, whereas exchange protein activated directly by cyclic nucleotide/MAPK kinase, another cAMP downstream effector, was not implicated in cAMP cholestatic action. In the perfused rat liver model, inhibition of the GPR30-AC-PKA pathway totally prevented E17G-induced alteration in Abcb11 and Abcc2 function and localization. Conclusion: Activation of GPR30-AC-PKA is a key factor in the alteration of canalicular transporter function and localization induced by E17G. Interaction of E17G with GPR30 may be the first event in the cascade of signaling activation. (HEPATOLOGY 2014;59:1016–1029)
Liver regeneration by stem/progenitor cells
Authors: Itoh Tohru , Miyajima Atsushi
Published: October 2013

The liver is renowned for its strong, robust regenerative capacity, employing different modes of regeneration according to type and extent of injury. The process of compensatory hypertrophy of the liver upon partial hepatectomy has been standing as a classical model for studying organ regeneration in mammals and a subject of exhaustive analyses. Meanwhile, in view of the physiological relevance for many of the human liver pathologies induced upon toxic insults or hepatitis, other injury models have recently drawn increasing attention. In those damaged livers where hepatocyte proliferation is compromised, adult liver stem/progenitor cells (LPCs) are activated and differentiate to hepatocytes and cholangiocytes, leading to functional recovery of the organ. Here, we summarize and discuss recent findings on the mechanisms underlying the regeneration process of the liver. Whereas the primary focus of this article is on those related to LPC-mediated regeneration, we also introduce topics on compensatory hypertrophy, where application of new technologies and molecular genetics approaches in mice has gained a paradigm shift. Identification of various markers for LPC populations has expedited their characterization and enabled us to examine their differentiation potential in vivo using genetic lineage-tracing approaches. Comprehensive studies regarding intercellular signaling pathways and their modes of action have succeeded in elucidating novel frameworks for the LPC-niche interaction functioning in the regenerating liver. Conclusion: Advancing our understanding of the cellular and molecular mechanisms for liver regeneration should provide a basis for developing therapeutic strategies to treat patients with liver disease. (HEPATOLOGY 2014;59:1617-1626)
Donor PNPLA3 rs738409 Genotype Affects Fibrosis Progression in Liver Transplantation for Hepatitis C
Authors: Dunn Winston , O'Neil Maura , Zhao Jie , Wu Chuang Hong , Roberts Benjamin , Chakraborty Shweta , Sherman Craig , Weaver Brandy , Taylor Ryan , Olson Jody , Olyaee Mojtaba , Gilroy Richard , Schmitt Timothy , Yvonne Wan Yu-Jui , Weinman Steven A.
Published: October 2013

The rs738409 G>C single nucleotide polymorphism occurring in the patatin-like phospholipase 3 gene has been identified as a novel genetic marker for hepatic steatosis. Recent studies also associated rs738409 with fibrosis in hepatitis C (HCV). Therefore, we sought to determine the impact of donor and recipient rs738409 genotype on the progression of fibrosis after liver transplantation for HCV. This cohort study included 101 patients infected with HCV who underwent liver transplantation between January 2008, and June 2011. Donor and recipient rs738409 genotypes were determined from donor wedge biopsies and recipient explants. The time to Ishak stage 3 fibrosis, or HCV-related mortality/graft loss was analyzed by the Cox model adjusting for HCV-Donor Risk Index, warm ischemic time, pretransplant Model for Endstage Liver Disease (MELD) and viral load. The rs738409 CC variant was present in 56% of donors and 57% of recipients. The median follow-up period was 620 days. A total of 39 patients developed the primary outcome of ≥stage 3 fibrosis or HCV-related mortality/graft loss, the time to which differed by donor (

P

= 0.019) but not recipient (

P

= 0.89) genotype. In the multivariate model, donor GC or GG variants had 2.53 times the risk (95% confidence interval [CI] 1.25–5.02,

P

= 0.008) compared to CC variants. In the alternative endpoint: stage 3 fibrosis or all-cause mortality/graft loss, the effect of donor genotype was attenuated but remained significant at 1.98 (95% CI 1.11–3.53).

Conclusions

: The rs738409 genotype is an important predictor of posttransplant outcome in HCV. Liver, and not adipocytes, is the site at which this effect occurs. Our finding may be useful in donor selection for liver transplantation with HCV, and may guide decisions regarding early antiviral treatment. (Hepatology 2014;59:453–460)
Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis
Authors: Yang Ju Dong , Abdelmalek Manal F. , Pang Herbert , Guy Cynthia D. , Smith Alastair D. , Diehl Anna Mae , Suzuki Ayako
Published: October 2013

Estrogens inhibit stellate cell activation and fibrogenesis. Thus, gender and reproductive states may influence the degree of fibrosis in patients with nonalcoholic steatohepatitis (NASH). To investigate the association between gender, menopause, and the severity of liver fibrosis in patients with NASH, we analyzed 541 adult patients enrolled from our Duke Liver Clinics (n = 338) and the Duke Metabolic and Weight Loss Surgery Program (n = 203) who had a histologic diagnosis of NASH. Multiple ordinal logistic regression models were used to assess the association between gender, menopause, and severity of liver fibrosis. Overall, men, premenopausal, and postmenopausal women composed 35.1%, 28.4%, and 36.5% of the population, respectively. The mean age was 48 years and 22% had advanced fibrosis. After adjusting for covariates (enrolling site, grades of portal inflammation, and hepatocyte ballooning) and potential confounders (race, body mass index, diabetes/prediabetes, hypertension), adjusted cumulative odd ratio (ACOR) and 95% confidence interval (CI) for greater fibrosis severity was 1.4 (0.9, 2.1) (P = 0.17) for postmenopausal women and 1.6 (1.0, 2.5) (P = 0.03) for men, having premenopausal women as a reference. There was borderline interaction between gender and age group divided by age 50, the average age at menopause in the U.S. (P = 0.08): ACOR and 95% CI of having greater fibrosis severity in men compared to women was 1.8 (1.1, 2.9) for patients with age <50 years (P = 0.02) and 1.2 (0.7, 2.1) for patients with age ≥50 years (P = 0.59). Conclusion: Men are at a higher risk of having more severe fibrosis compared to women before menopause, while postmenopausal women have a similar severity of liver fibrosis compared to men. These findings may be explained by the protective effects of estrogen against fibrogenesis. (HEPATOLOGY 2014;59:1406-1414)
Epigenetic regulation of connective tissue growth factor by MicroRNA-214 delivery in exosomes from mouse or human hepatic stellate cells
Authors: Chen Li , Charrier Alyssa , Zhou Yu , Chen Ruju , Yu Bo , Agarwal Kitty , Tsukamoto Hidekazu , Lee James L. , Paulaitis Michael E. , Brigstock David R.
Published: October 2013

Connective tissue growth factor (CCN2) drives fibrogenesis in hepatic stellate cells (HSC). Here we show that CCN2 up-regulation in fibrotic or steatotic livers, or in culture-activated or ethanol-treated primary mouse HSC, is associated with a reciprocal down-regulation of microRNA-214 (miR-214). By using protector or reporter assays to investigate the 3′-untranslated region (UTR) of CCN2 mRNA, we found that induction of CCN2 expression in HSC by fibrosis-inducing stimuli was due to reduced expression of miR-214, which otherwise inhibited CCN2 expression by directly binding to the CCN2 3′-UTR. Additionally, miR-214 was present in HSC exosomes, which were bi-membrane vesicles, 50-150 nm in diameter, negatively charged (−26 mV), and positive for CD9. MiR-214 levels in exosomes but not in cell lysates were reduced by pretreatment of the cells with the exosome inhibitor, GW4869. Coculture of either quiescent HSC or miR-214-transfected activated HSC with CCN2 3′-UTR luciferase reporter-transfected recipient HSC resulted in miR-214- and exosome-dependent regulation of a wild-type CCN2 3′-UTR reporter but not of a mutant CCN2 3′-UTR reporter lacking the miR-214 binding site. Exosomes from HSC were a conduit for uptake of miR-214 by primary mouse hepatocytes. Down-regulation of CCN2 expression by miR-214 also occurred in human LX-2 HSC, consistent with a conserved miR-214 binding site in the human CCN2 3′-UTR. MiR-214 in LX-2 cells was shuttled by way of exosomes to recipient LX-2 cells or human HepG2 hepatocytes, resulting in suppression of CCN2 3′-UTR activity or expression of CCN2 downstream targets, including alpha smooth muscle actin or collagen. Experimental fibrosis in mice was associated with reduced circulating miR-214 levels. Conclusion: Exosomal transfer of miR-214 is a paradigm for the regulation of CCN2-dependent fibrogenesis and identifies fibrotic pathways as targets of intercellular regulation by exosomal miRs. (HEPATOLOGY 2014;59:1118–1129)
Creatinine- versus cystatine C-based equations in assessing the renal function of candidates for liver transplantation with cirrhosis
Authors: De Souza Vandréa , Hadj-Aissa Aoumeur , Dolomanova Olga , Rabilloud Muriel , Rognant Nicolas , Lemoine Sandrine , Radenne Sylvie , Dumortier Jérôme , Chapuis-Cellier Colette , Beyerle Françoise , Bon Chantal , Iwaz Jean , Selistre Luciano , Dubourg Laurence
Published: October 2013

Renal dysfunction is frequent in liver cirrhosis and is a strong prognostic predictor of orthotopic liver transplantation (OLT) outcome. Therefore, an accurate evaluation of the glomerular filtration rate (GFR) is crucial in pre-OLT patients. However, in these patients plasma creatinine (Pcr) is inaccurate and the place of serum cystatine C (CystC) is still debated. New GFR-predicting equations, based on standardized assays of Pcr and/or CystC, have been recently recommended in the general population but their performance in cirrhosis patients has been rarely studied. We evaluated the performance of the recently published Chronic Kidney Disease Epidemiology Collaboration equations (CKD-EPI-Pcr, CKD-EPI-CystC, and CKD-EPI-Pcr-CystC) and the more classical ones (4- and 6-variable MDRD and Hoek formulas) in cirrhosis patients referred for renal evaluation before OLT. Inulin clearance was performed in 202 consecutive patients together with the determination of Pcr and CystC with assays traceable to primary reference materials. The performance of the GFR-predicting equations was evaluated according to ascites severity (no, moderate, or refractory) and to hepatic and renal dysfunctions (MELD score ≤ or >15 and KDOQI stages, respectively). In the whole population, CystC-based equations showed a better performance than Pcr-based ones (lower bias and higher 10% and 30% accuracies). CKD-EPI-CystC equation showed the best performance whatever the ascites severity and in presence of a significant renal dysfunction (GFR <60 mL/min/1.73 m2). Conclusion: Pcr-based GFR predicting equations are not reliable in pre-OLT patients even when an IDMS-traceable enzymatic Pcr assay is used. Whenever a CystC-assay traceable to primary reference materials is performed and when a true measurement of GFR is not possible, CystC-based equations, especially CKD-EPI-CystC, may be recommended to evaluate renal function and for KDOQI staging. (HEPATOLOGY 2014;59:1522-1531)
A New Role for IKK-α in Hepatitis C Virus-Induced Lipogenesis
Authors: Douglas Mark W. , Esmaili Saeed , George Jacob
Published: October 2013

Hepatitis C virus (HCV) interacts extensively with host factors to not only establish productive infection but also trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IκB kinase-α (IKK-α) is a crucial host factor for HCV. Here we describe a new nuclear factor κB (NF-κB)-independent and kinase-mediated nuclear function of IKK-α in HCV assembly. HCV, through its 3′ untranslated region, interacts with DEAD box polypeptide 3, X-linked (DDX3X) to activate IKK-α, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving sterol regulatory element-binding proteins (SREBPs). This innate pathway induces lipogenic genes and enhances core-associated lipid droplet formation to facilitate viral assembly. Chemical inhibitors of IKK-α suppress HCV infection and IKK-α-induced lipogenesis, offering a proof-of-concept approach for new HCV therapeutic development. Our results show that HCV uses a novel mechanism to exploit intrinsic innate responses and hijack lipid metabolism, which may contribute to high chronicity rates and the pathological hallmark of steatosis in HCV infection.
Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients
Authors: Hsu Yao-Chun , Lin Jaw-Town , Ho Hsiu J. , Kao Yu-Hsi , Huang Yen-Tsung , Hsiao Nai-Wan , Wu Ming-Shiang , Liu Yi-Ya , Wu Chun-Ying
Published: October 2013

Hepatitis C virus (HCV) infection is causally associated with insulin resistance and diabetes mellitus. This population-based cohort study aimed to investigate whether antiviral therapy for HCV infection was associated with improved clinical outcomes related to diabetes. From the Taiwan National Health Insurance Research Database, 2,267,270 Taiwanese residents diagnosed with diabetes mellitus were screened for eligibility. HCV infection was defined by a specific diagnosis code and measurement of serum antibody. After excluding patients with serious comorbidity, we enrolled a total of 1,411 eligible patients who received pegylated interferon plus ribavirin (treated cohort), and matched them 1:1 with 1,411 untreated controls by propensity scores (untreated cohort). We also matched the treated cohort 1:4 with 5,644 diabetic patients without HCV infection (uninfected cohort). Participants were followed up for the occurrence of endstage renal disease (ESRD), ischemic stroke, and acute coronary syndrome (ACS) after receiving antiviral treatment or the corresponding calendar date. From 2003 to 2011, the 8-year cumulative incidences of ESRD in the treated, untreated, and uninfected cohorts were 1.1% (95% confidence interval [CI], 0.3-2.0%), 9.3% (95% CI, 5.9-12.7%), and 3.3% (95% CI, 2.3-4.3%), respectively (P < 0.001); those of stroke were 3.1% (95% CI, 1.1-5.0%), 5.3% (95% CI, 3.0-7.5%), and 6.1% (95% CI, 4.8-7.4%), respectively (P = 0.01); and those for ACS were 4.1% (95% CI, 2.1-6.1%), 6.6% (95% CI, 3.7-9.5%), and 7.4% (95% CI, 5.9-9.0%), respectively (P = 0.05). As compared with the untreated cohort, antiviral treatment was associated with multivariate-adjusted hazard ratios of 0.16 (95% CI, 0.07-0.33%) for ESRD, 0.53 (95% CI, 0.30-0.93) for ischemic stroke, and 0.64 (95% CI, 0.39-1.06) for ACS. Conclusion: Antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. (HEPATOLOGY 2014;59:1293-1302)
The combined expression of VPREB3 and ID3 represents a new helpful tool for the routine diagnosis of mature aggressive B‐cell lymphomas
Authors: Soldini Davide , Georgis Antoin , Montagna Chiara , Schüffler Peter Johannes , Martin Vittoria , Curioni‐Fontecedro Alessandra , Martinez Antonio , Tinguely Marianne
Published: October 2013

Genomic studies, such as gene expression profiling and next‐generation sequencing studies, have provided new insights into the phenotypic characteristics and pathogenesis of mature aggressive B‐cell lymphomas. In particular, mutations in the transcription factors ID3 and TCF3, leading to overexpression of B‐cell receptor components such as VPREB3, have been shown to be specific for Burkitt lymphoma (BL) and play an important tumourigenic role by mediating the activation of the pro‐survival phosphatidylinositol‐3‐OH kinase pathway. We performed immunohistochemical analysis by applying commercially available anti‐VPREB3 antibody to a large cohort of 185 genetically and immunophenotypically characterized mature aggressive B‐cell lymphomas and analyzed these results together with recent data on ID3 expression. The combined expression of both VPREB3 and ID3 was associated with a diagnosis of BL with high sensitivity (0.77), high specificity (0.75) and high negative predictive values (0.96), however, with lower positive predictive value (0.30). Double negative cases were absent in the group of BLs but could be found in approximately one third of the remaining cases of mature aggressive B‐cell lymphomas. Further, we could not identify a correlation with MYC, BCL2 or BCL6 aberrations with neither VPREB3 nor ID3 expression in each of the diagnostic groups analyzed. Our results, which are in line with recently discovered mutations in next‐generation sequencing studies, suggest that the combined immunohistochemical detection of VPREB3 and ID3 is applicable to the routine diagnostic in case of mature aggressive B‐cell lymphomas. In particular, it represents a useful and routinely applicable diagnostic tool to exclude BL diagnosis in case of single positive or double negative cases. Copyright © 2013 John Wiley & Sons, Ltd.
Treatment of gastric marginal zone B‐cell lymphoma of the mucosa‐associated lymphoid tissue with rituximab, cyclophosphamide, vincristine and prednisone
Authors: Aguiar‐Bujanda David , Llorca‐Mártinez Ignacio , Rivero‐Vera José C. , Blanco‐Sánchez María J. , Jiménez‐Gallego Pedro , Mori‐De Santiago Marta , Limeres‐Gonzalez Miguel A. , Cabrera‐Marrero José C. , Hernández‐Sosa María , Galván‐Ruíz Saray , Hernández‐Sarmiento Samuel , Saura Grau Salvador , Bohn‐Sarmiento Uriel
Published: October 2013

There is no standard treatment for patients with gastric marginal zone B‐cell lymphoma of the mucosa‐associated lymphoid tissue (MALT lymphoma) who are resistant to, or ineligible for, anti‐Helicobacter pylori (anti‐HP) therapy. In this study, we investigated the activity of the rituximab, cyclophosphamide, vincristine and prednisone (R‐CVP) regimen in patients with gastric MALT lymphoma. Patients were included provided they had untreated gastric MALT lymphoma (except for anti‐HP therapy) and were resistant to, or ineligible for, anti‐HP therapy. Treatment plan consisted of six to eight 21‐day cycles of the R‐CVP chemotherapy regimen. Toxicity, response, relapse and survival were evaluated. Twenty patients (12 women and 8 men) were included in the analyses with median age of 59 years. Thirteen patients (65%) had stage I tumours, and seven patients (35%) had stages II–IV tumours. The overall response rate was 100%, with 19 (95%) complete responses and one (5%) partial response. Regimen toxicity was mild and mainly hematological, and no cases of gastric bleeding or perforation occurred. After a median follow‐up of 56.3 months, three patients had relapsed, and 19 patients remained alive (specific lymphoma survival 100%), of whom 17 had no evidence of disease. In our experience, the R‐CVP regimen is a well‐tolerated and effective treatment for patients with gastric MALT lymphoma who are resistant to, or ineligible for, anti‐HP therapy. Copyright © 2013 John Wiley & Sons, Ltd.
The effects of user fees on quality and utilization of primary health‐care services in Afghanistan: a quasi‐experimental health financing pilot study in a post‐conflict setting
Authors: Steinhardt Laura C. , Rao Krishna D. , Hansen Peter M. , Alam Sahibullah , Peters David H.
Published: October 2013

Background

After the fall of the Taliban regime, most clinics in Afghanistan were charging fees to patients. The government invested in monitoring and evaluation systems for its newly rebuilt primary care system, but little was known about the effects of user fees. This study was undertaken to provide evidence on user fees' effects on quality and service utilization and to help inform development of health financing policy and strategy.

Methods

A quasi‐experimental health financing pilot study was implemented in 2005. Forty‐seven facilities were randomized to implement a standardized user fee intervention, offer free services, or serve as controls, continuing current cost‐sharing systems. Revenues were co‐managed by staff and community leaders for facility improvement. Baseline and follow‐up facility assessments, exit interviews, and household surveys, as well as routine data were used to evaluate user fee effects over 2 years.

Results

Observed and perceived quality improved at most facilities but did not differ by study group. Utilization increased in all groups, but the increase was 682 to 748 visits per month larger in facilities randomized to free services compared with those randomized to fees or controls (p < 0.01).

Conclusion

User fees demonstrated few beneficial effects and slowed the rate of increase of service utilization in Afghanistan. In 2008, the government abolished primary care fees, citing results of this study. Copyright © 2013 John Wiley & Sons, Ltd.
Effects of Nanofluid on Peristaltic Flow of a Carreau Fluid Model in an Inclined Magnetic Field
Authors: Akram Safia
Published: October 2013

In the present article we talk about the influence of a nanofluid on the peristaltic flow of a Carreau fluid model in the presence of an inclined channel and magnetic field. The mathematical modeling of the proposed problem is given for the two‐ dimensional and directional flow. The governing highly nonlinear coupled equations are simplified by means of the assumptions of long wavelength and low Reynolds number approximation. The solutions of the simplified coupled nonlinear equations are calculated using an analytical approach. At the end, graphical results are displayed to show the effects of various emerging parameters of interest. © 2013 Wiley Periodicals, Inc. Heat Trans Asian Res, 43(4): 368–383, 2014; Published online 3 October 2013 in Wiley Online Library (wileyonlinelibrary.com/journal/htj). DOI 10.1002/htj.21082
Unsteady MHD Mixed Convective Boundary‐Layer Slip Flow and Heat Transfer with Thermal Radiation and Viscous Dissipation
Authors: Ibrahim Wubshet , Shanker Bandari
Published: October 2013

A numerical analysis has been carried out to investigate the problem of MHD boundary‐layer flow and heat transfer of a viscous incompressible fluid over a moving vertical permeable stretching sheet with velocity and temperature slip boundary condition. A problem formulation is developed in the presence of radiation, viscous dissipation, and buoyancy force. A similarity transformation is used to reduce the governing boundary‐layer equations to coupled higher‐order nonlinear ordinary differential equations. These equations are solved numerically using the fourth‐order Runge–Kutta method along with shooting technique. The effects of the governing parameters such as Prandtl number, buoyancy parameter, slip parameter, magnetic parameter, Eckert Number, suction, and radiation parameter on the velocity and temperature profiles are discussed and shown by plotting graphs. It is found that the temperature is a decreasing function of the slip parameter ST. The results also indicate that the cooling rate of the sheet can be improved by increasing the buoyancy parameter. In addition the numerical results for the local skin friction coefficient and local Nusselt number are computed and presented in tabular form. The numerical results are compared and found to be in good agreement with previously published results on special cases of the problem. © 2013 Wiley Periodicals, Inc. Heat Trans Asian Res, 43(5): 412–426, 2014; Published online 3 October 2013 in Wiley Online Library (wileyonlinelibrary.com/journal/htj). DOI 10.1002/htj.21086
MHD Mixed Convection and Mass Transfer Due to Unsteady Stretching Sheet
Authors: Mishra Upendra , Singh Gurminder
Published: October 2013

Heat and mass transfer in the flow of a viscous incompressible fluid along a vertical isothermal unsteady stretching sheet in the presence of heat generation and a transverse magnetic field is investigated. The governing equations of continuity, momentum, energy, and species concentration are transformed into a system of nonlinear ordinary differential equations and solved numerically by using the Runge–Kutta fourth‐order method with shooting technique. The velocity, temperature, and concentration distributions are discussed numerically and shown through graphs. The expressions of skin‐friction coefficient, Nusselt number, and Sherwood number at the sheet are discussed numerically and their variations are presented through tables. © 2013 Wiley Periodicals, Inc. Heat Trans Asian Res, 43(5): 447–458, 2014; Published online 3 October 2013 in Wiley Online Library (wileyonlinelibrary.com/journal/htj). DOI 10.1002/htj.21088
Water balance of a burned and unburned forested boreal peatland
Authors: Thompson Dan K. , Benscoter Brian W. , Waddington James M.
Published: October 2013

We examined the water balance of a forested ombrotrophic peatland and adjacent burned peatland in the boreal plain of western Canada over a 3‐year period. Complete combustion of foliage and fine branches dramatically increased shortwave radiation inputs to the peat surface while halting all tree transpiration at the burned site. End‐of‐winter snowpack was 7–25% higher at the burned site likely due to decreased ablation from the tree canopy at the unburned site. Shrub regrowth at the burned site was rapid post‐fire, and shading by the shrub canopy in the burned site approached that of the unburned site within 3 years after fire. Site‐averaged surface resistance to evaporation was not different between sites, though surface resistance in hollows was lower in the burned site. Water loss at both burned and unburned sites is largely driven by surface evaporative losses. Evaporation at the burned site marginally exceeded the sum of pre‐fire transpiration and interception at the unburned site, suggesting that evapotranspiration during the growing season was 20–40 mm greater at the burned peatland. Although the net change in water storage during the growing season was largely unchanged by fire, the lack of low‐density surface peat in the burned site appears to have decreased specific yield, leading to greater water table decline at the burned site despite similar net change in storage. Copyright © 2013 John Wiley & Sons, Ltd.
The impact of the South–North Water Transfer Project (CTP)'s central route on groundwater table in the Hai River basin, North China
Authors: Ye Aizhong , Duan Qingyun , Chu Wei , Xu Jing , Mao Yuna
Published: October 2013

The central route of the South–North Water Transfer Project (CTP) is designed to divert approximately 9.5 billion m3 of water per year from the Han River, a major tributary of the Yangtze River, to the Hai River basin in the north China. The main purpose of this study is to assess the impact of CTP on groundwater table in the Hai River basin. Our study features a large‐scale distributed hydrological model that couples a physically based groundwater module, which is sub‐basin‐based, with a conceptual surface water module, which is grid‐based. There are several grids in each sub‐basin and water exchange among grid that are considered. Our model couples surface water module and groundwater module and calculates human water use at the same time. The simulation results indicate that even with the water supply by CTP, the groundwater table will continue to decline in the Hai River basin. However, the CTP water can evidently reduce the decline rate, helping alleviate groundwater overexploitation in Hai River region. Copyright © 2013 John Wiley & Sons, Ltd.
GLUE: 20 years on
Authors: Beven Keith , Binley Andrew
Published: October 2013

This paper reviews the use of the Generalized Likelihood Uncertainty Estimation (GLUE) methodology in the 20 years since the paper by Beven and Binley in Hydrological Processes in (1992), which is now one of the most highly cited papers in hydrology. The original conception, the on‐going controversy it has generated, the nature of different sources of uncertainty and the meaning of the GLUE prediction uncertainty bounds are discussed. The hydrological, rather than statistical, arguments about the nature of model and data errors and uncertainties that are the basis for GLUE are emphasized. The application of the Institute of Hydrology distributed model to the Gwy catchment at Plynlimon presented in the original paper is revisited, using a larger sample of models, a wider range of likelihood evaluations and new visualization techniques. It is concluded that there are good reasons to reject this model for that data set. This is a positive result in a research environment in that it requires improved models or data to be made available. In practice, there may be ethical issues of using outputs from models for which there is evidence for model rejection in decision making. Finally, some suggestions for what is needed in the next 20 years are provided. © 2013 The Authors.Hydrological Processespublished by John Wiley & Sons, Ltd.
Process‐based modelling of a headwater catchment in a semi‐arid area: the influence of macropore flow
Authors: van Schaik N. L. M. B. , Bronstert A. , de Jong S. M. , Jetten V. G. , van Dam J. C. , Ritsema C. J. , Schnabel S.
Published: October 2013

Subsurface stormflow is thought to occur mainly in humid environments with steep terrains. However, in semi‐arid areas, preferential flow through macropores can also result in a significant contribution of subsurface stormflow to catchment runoff for varying catchment conditions. Most hydrological models neglect this important subsurface preferential flow. Here, we use the process‐oriented hydrological model Hillflow‐3D, which includes a macropore flow approach, to simulate rainfall‐runoff in the semi‐arid Parapuños catchment in Spain, where macropore flow was observed in previous research. The model was extended for this study to account for sorptivity under very dry soil conditions. The results of the model simulations with and without macropore flow are compared. Both model versions give reasonable results for average rainfall situations, although the approach with the macropore concept provides slightly better results. The model results for scenarios of extreme rainfall events (>13.3 mm 30 min−1) however show large differences between the versions with and without macropores. These model results compared with measured rainfall‐runoff data show that the model with the macropore concept is better. Our conclusion is that preferential flow is important in controlling surface runoff in case of specific, high intensity rainfall events. Therefore, preferential flow processes must be included in hydrological models where we know that preferential flow occurs. Hydrological process models with a less detailed process description may fit observed average events reasonably well but can result in erroneous predictions for more extreme events. Copyright © 2013 John Wiley & Sons, Ltd.
Size relationships of water discharge in rivers: scaling of discharge with catchment area, main‐stem length and precipitation
Authors: Burgers H. E. (Robin) , Schipper Aafke M. , Jan Hendriks A.
Published: October 2013

Scaling relationships between water turnover or discharge and water system size may help to reveal and understand general patterns and processes in regional and global hydrological systems. In the present study, we derived global as well as climate‐specific scaling relationships between average or maximum river discharge and catchment area, main‐stem length and precipitation, based on data from 663 monitoring stations worldwide. Data were retrieved from a Global Runoff Data Centre (GRDC) database. The scaling relationships were established with ordinary least square (OLS) and standard major axis (SMA) regressions. The focus was on the SMA regressions because this method provides better estimates of the slope.

The overall empirical regressions derived were highly significant (p < 0.01). Average discharge (Q) and maximum discharge (Qmax) scaled to catchment area (A) with SMA slopes of 1.23 (r2 = 0.40) and 0.99 (r2 = 0.41), respectively. Average discharge (Q) scaled to length (L) with a slope of 2.16 (r2 = 0.40), while catchment area (A) scaled to main‐stem length (L) with a slope of 1.76 (r2 = 0.91). The addition of precipitation (P), yielding a multiple regression of discharge versus catchment area and precipitation, improved the explained variability to r2 = 0.56 and r2 = 0.52 for average and maximum discharge, respectively. Slopes of climate zone‐specific regressions tended to be similar to the slopes of the overall relationships. The uncertainties of the regressions were discussed and, where possible, compared to regressions derived in other studies. Copyright © 2013 John Wiley & Sons, Ltd.
Evidence for a Role of Executive Functions in Learning Biology
Authors: Rhodes Sinéad M. , Booth Josephine N. , Campbell Lorna Elise , Blythe Richard A. , Wheate Nial J. , Delibegovic Mirela
Published: October 2013

Research examining cognition and science learning has focused on working memory, but evidence implicates a broader set of executive functions. The current study examined executive functions and learning of biology in young adolescents. Fifty‐six participants, aged 12–13 years, completed tasks of working memory (Spatial Working Memory), inhibition (Stop‐Signal), attention set‐shifting (ID/ED) and planning (Stockings of Cambridge), from the Cambridge Neuropsychological Test Automated Battery. They also participated in a biology teaching session, practical and assessment on the topic of DNA designed specifically for the current study that measured (a) memory for biology facts taught and (b) understanding of information learned in the practical. Linear regression analysis revealed that planning ability predicted performance on the factual assessment, and both spatial working memory and planning were predictive of performance on the conceptual assessment. The findings suggest that planning ability is important in learning biological facts but that a broader set of executive functions are important for conceptual learning, highlighting the role of executive functions in understanding and applying knowledge about what is learned within science teaching. Copyright © 2013 John Wiley & Sons, Ltd.
Relative contribution of IL‐1α, IL‐1β and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG
Authors: Bourigault Marie‐Laure , Segueni Noria , Rose Stéphanie , Court Nathalie , Vacher Rachel , Vasseur Virginie , Erard François , Le Bert Marc , Garcia Irene , Iwakura Yoichiro , Jacobs Muazzam , Ryffel Bernhard , Quesniaux Valerie F. J.
Published: October 2013

TNF and IL‐1 are major mediators involved in severe inflammatory diseases against which therapeutic neutralizing antibodies are developed. However, both TNF and IL‐1 receptor pathways are essential for the control of Mycobacterium tuberculosis infection, and it is critical to assess the respective role of IL‐1α, IL‐1β, and TNF. Using gene‐targeted mice we show that absence of both IL‐1α and IL‐1β recapitulates the uncontrolled M. tuberculosis infection with increased bacterial burden, exacerbated lung inflammation, high IFNγ, reduced IL‐23 p19 and rapid death seen in IL‐1R1‐deficient mice. However, presence of either IL‐1α or IL‐1β in single‐deficient mice is sufficient to control acute M. tuberculosis infection, with restrained bacterial burden and lung pathology, in conditions where TNF deficient mice succumbed within 4 weeks with overwhelming infection. Systemic infection by attenuated M. bovis BCG was controlled in the absence of functional IL‐1 pathway, but not in the absence of TNF. Therefore, although both IL‐1α and IL‐1β are required for a full host response to virulent M. tuberculosis, the presence of either IL‐1α or IL‐1β allows some control of acute M. tuberculosis infection, and IL‐1 pathway is dispensable for controlling M. bovis BCG acute infection. This is in sharp contrast with TNF, which is essential for host response to both attenuated and virulent mycobacteria and may have implications for anti‐inflammatory therapy with IL‐1β neutralizing antibodies.
Serpin B5 is a CEA‐interacting biomarker for colorectal cancer
Authors: Baek Ji Yeon , Yeo Hyun Yang , Chang Hee Jin , Kim Kyung‐Hee , Kim Sun Young , Park Ji Won , Park Sung Chan , Choi Hyo Seong , Kim Dae Yong , Oh Jae Hwan
Published: October 2013

Serpin B5 is a candidate tumour suppressor, but its oncogenic activity has also been reported. Its function may be affected by protein interactions. The aim of this study was to assess the relationship between serpin B5 and carcinoembryonic antigen (CEA) expression in colorectal cancer (CRC). We also analysed the clinicopathological significance of serpin B5 expression in patients with CRC. Downregulation of serpin B5 was identified in a CEA‐suppressed LoVo cell line using two‐dimensional gel electrophoresis (2‐DE) and matrix‐associated laser desorption ionisation‐mass spectrometry (MALDI‐MS). The specific interaction and co‐localisation of serpin B5 with CEA were confirmed by co‐immunoprecipitation and confocal microscopy. Western blot analysis and ELISAs revealed significant positive correlations between levels of serpin B5 and CEA in human colon cancer cell lines and in the blood of patients with CRC. Tissue expression of serpin B5 in 377 patients with CRC was significantly associated with serum CEA, histological grade, stage, lymph node metastasis, lymphatic and perineural invasion, and infiltrative border. Strong expression of serpin B5 was also associated with a reduced DFS (p = 0.001) and OS (p = 0.017). Together, these findings describe a relationship between serpin B5 and CEA expression in CRC. Strong expression of serpin B5 was associated with a worse prognosis in patients with CRC and its expression may correlate with CEA levels in CRC.