bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein
Authors: Wu Yun-li , Peng Xian-e , Zhu Yi-bing , Yan Xiao-li , Chen Wan-nan , Lin Xu 
Published: December 2015

ABSTRACT
Hepatitis B virus (HBV) has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of HBV-associated hepatic steatosis still remain elusive. Our prior work has revealed that the expression level of liver fatty acid binding protein 1 (FABP1), a key regulator of hepatic lipid metabolism, was elevated in HBV-producing hepatoma cells. In this study, the effects of HBV X protein (HBx) mediated FABP1 regulation on hepatic steatosis and the underlying mechanism were determined. mRNA and protein levels of FABP1 were measured by quantitative RT-PCR (qPCR) and Western blotting. HBx-mediated FABP1 regulation was evaluated by luciferase assay, coimmunoprecipitation, and chromatin immunoprecipitation. Hepatic lipid accumulation was measured by using Oil-Red-O staining and the triglyceride level. It was found that expression of FABP1 was increased in HBV-producing hepatoma cells, the sera of HBV-infected patients, and the sera and liver tissues of HBV-transgenic mice. Ectopic overexpression of HBx resulted in upregulation of FABP1 in HBx-expressing hepatoma cells, whereas HBx abolishment reduced FABP1 expression. Mechanistically, HBx activated the FABP1 promoter in an HNF3β-, C/EBPα-, and PPARα-dependent manner, in which HBx increased the gene expression of HNF3β and physically interacted with C/EBPα and PPARα. On the other hand, knockdown of FABP1 remarkably blocked lipid accumulation both in long-chain free fatty acids treated HBx-expressing HepG2 cells and in a high-fat diet-fed HBx-transgenic mice. Therefore, FABP1 is a key driver gene in HBx-induced hepatic lipid accumulation via regulation of HNF3β, C/EBPα, and PPARα. FABP1 may represent a novel target for treatment of HBV-associated hepatic steatosis.

IMPORTANCE
Accumulating evidence from epidemiological and experimental studies has indicated that chronic HBV infection is associated with hepatic steatosis. However, the molecular mechanism underlying HBV-induced pathogenesis of hepatic steatosis still remains to be elucidated. In this study, we found that expression of liver fatty acid binding protein (FABP1) was dramatically increased in the sera of HBV-infected patients and in both sera and liver tissues of HBV-transgenic mice. Forced expression of HBx led to FABP1 upregulation, whereas knockdown of FABP1 remarkably diminished lipid accumulation in both
in vitro
and
in vivo
models. It is possible that HBx promotes hepatic lipid accumulation through upregulating FABP1 in the development of HBV-induced nonalcoholic fatty liver disease. Therefore, inhibition of FABP1 might have therapeutic value in steatosis-associated chronic HBV infection.
ORF33 and ORF38 of Kaposi's Sarcoma-Associated Herpesvirus Interact and Are Required for Optimal Production of Infectious Progeny Viruses
Authors: Wu Jian-jun , Avey Denis , Li Wenwei , Gillen Joseph , Fu Bishi , Miley Wendell , Whitby Denise , Zhu Fanxiu 
Published: December 2015

ABSTRACT

We recently showed that the interaction between Kaposi's sarcoma-associated herpesvirus (KSHV) tegument proteins ORF33 and ORF45 is crucial for progeny virion production, but the exact functions of KSHV ORF33 during lytic replication were unknown (J. Gillen, W. Li, Q. Liang, D. Avey, J. Wu, F. Wu, J. Myoung, and F. Zhu, J Virol
89:
4918–4931, 2015,
http://dx.doi.org/10.1128/JVI.02925-14
). Therefore, here we investigated the relationship between ORF33 and ORF38, whose counterparts in both alpha- and betaherpesviruses interact with each other. Using specific monoclonal antibodies, we found that both proteins are expressed during the late lytic cycle with similar kinetics and that both are present in mature virions as components of the tegument. Furthermore, we confirmed that ORF33 interacts with ORF38. Interestingly, we observed that ORF33 tightly associates with the capsid, whereas ORF38 associates with the envelope. We generated ORF33-null, ORF38-null, and double-null mutants and found that these mutants apparently have identical phenotypes: the mutations caused no apparent effect on viral gene expression but reduced the yield of progeny virion by about 10-fold. The progeny virions also lack certain virion component proteins, including ORF45. During viral lytic replication, the virions associate with cytoplasmic vesicles. We also observed that ORF38 associates with the membranes of vesicles and colocalizes with the Golgi membrane or early endosome membrane. Further analyses of ORF33/ORF38 mutants revealed the reduced production of virion-containing vesicles, suggesting that ORF33 and ORF38 are involved in the transport of newly assembled viral particles into cytoplasmic vesicles, a process important for viral maturation and egress.

IMPORTANCE
Herpesvirus assembly is an essential step in virus propagation that leads to the generation of progeny virions. It is a complicated process that depends on the delicate regulation of interactions among virion proteins. We previously revealed an essential role of ORF45-ORF33 binding for virus assembly. Here, we report that ORF33 and its binding partner, ORF38, are required for infectious virus production due to their important role in the tegumentation process. Moreover, we found that both ORF33 and ORF38 are involved in the transportation of virions through vesicles during maturation and egress. Our results provide new insights into the important roles of ORF33 and ORF38 during viral assembly, a process critical for virus propagation that is intimately linked to KSHV pathobiology.
A Highly Conserved Residue of the HIV-1 gp120 Inner Domain Is Important for Antibody-Dependent Cellular Cytotoxicity Responses Mediated by Anti-cluster A Antibodies
Authors: Ding Shilei , Veillette Maxime , Coutu Mathieu , Prévost Jérémie , Scharf Louise , Bjorkman Pamela J. , Ferrari Guido , Robinson James E. , Stürzel Christina , Hahn Beatrice H. , Sauter Daniel , Kirchhoff Frank , Lewis George K. , Pazgier Marzena , Finzi Andrés 
Published: December 2015

ABSTRACT
Previous studies have shown that sera from HIV-1-infected individuals contain antibodies able to mediate antibody-dependent cellular cytotoxicity (ADCC). These antibodies preferentially recognize envelope glycoprotein (Env) epitopes induced upon CD4 binding. Here, we show that a highly conserved tryptophan at position 69 of the gp120 inner domain is important for ADCC mediated by anti-cluster A antibodies and sera from HIV-1-infected individuals.
Equine Infectious Anemia Virus Gag Assembly and Export Are Directed by Matrix Protein through
trans
-Golgi Networks and Cellular Vesicles
Authors: Zhang Zeli , Ma Jian , Zhang Xiang , Su Chao , Yao Qiu-Cheng , Wang Xiaojun 
Published: December 2015

ABSTRACT

Gag intracellular assembly and export are very important processes for lentiviruses replication. Previous studies have demonstrated that equine infectious anemia virus (EIAV) matrix (MA) possesses distinct phosphoinositide affinity compared with HIV-1 MA and that phosphoinositide-mediated targeting to peripheral and internal membranes is a critical factor in EIAV assembly and release. In this study, we compared the cellular assembly sites of EIAV and HIV-1. We observed that the assembly of EIAV particles occurred on interior cellular membranes, while HIV-1 was targeted to the plasma membrane (PM) for assembly. Then, we determined that W7 and K9 in the EIAV MA N terminus were essential for Gag assembly and release but did not affect the cellular distribution of Gag. The replacement of EIAV MA with HIV-1 MA directed chimeric Gag to the PM but severely impaired Gag release. MA structural analysis indicated that the EIAV and HIV-1 MAs had similar spatial structures but that helix 1 of the EIAV MA was closer to loop 2. Further investigation indicated that EIAV Gag accumulated in the
trans
-Golgi network (TGN) but not the early and late endosomes. The 9 N-terminal amino acids of EIAV MA harbored the signal that directed Gag to the TGN membrane system. Additionally, we demonstrated that EIAV particles were transported to the extracellular space by the cellular vesicle system. This type of EIAV export was not associated with multivesicular bodies or microtubule depolymerization but could be inhibited by the actin-depolymerizing drug cytochalasin D, suggesting that dynamic actin depolymerization may be associated with EIAV production.

IMPORTANCE
In previous studies, EIAV Gag was reported to localize to both the cell interior and the plasma membrane. Here, we demonstrate that EIAV likely uses the TGN as the assembly site in contrast to HIV-1, which is targeted to the PM for assembly. These distinct assembly features are determined by the MA domain. We also identified two sites in the N terminus of EIAV MA that were important for Gag assembly and release. Furthermore, the observation of EIAV transport by cellular vesicles but not by multivesicular bodies sheds light on the mechanisms underlying EIAV cellular replication.
Control of PD-L1 Expression by Oncogenic Activation of the AKT–mTOR Pathway in Non–Small Cell Lung Cancer
Authors: Lastwika Kristin J. , Wilson Willie , Li Qing Kay , Norris Jeffrey , Xu Haiying , Ghazarian Sharon R. , Kitagawa Hiroshi , Kawabata Shigeru , Taube Janis M. , Yao Sheng , Liu Linda N. , Gills Joell J. , Dennis Phillip A. 
Published: December 2015

Abstract
Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT–mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT–mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells. Cancer Res; 76(2); 227–38. ©2015 AACR.
Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis
Authors: Marusiak Anna A. , Stephenson Natalie L. , Baik Hayeon , Trotter Eleanor W. , Li Yaoyong , Blyth Karen , Mason Susan , Chapman Phil , Puto Lorena A. , Read Jon A. , Brassington Claire , Pollard Hannah K. , Phillips Chris , Green Isabelle , Overman Ross , Collier Matthew , Testoni Ewelina , Miller Crispin J. , Hunter Tony , Sansom Owen J. , Brognard John 
Published: December 2015

Abstract
MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers, including frequently in colorectal cancer, where their function and pathobiological importance have been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant-negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain tumorigenic phenotypes, we reconstituted its signaling axis in colon cancer cells harboring MLK4-inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3, and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor-suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer. Cancer Res; 76(3); 724–35. ©2015 AACR.
A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer
Authors: Scarbrough Peter M. , Weber Rachel Palmieri , Iversen Edwin S. , Brhane Yonathan , Amos Christopher I. , Kraft Peter , Hung Rayjean J. , Sellers Thomas A. , Witte John S. , Pharoah Paul , Henderson Brian E. , Gruber Stephen B. , Hunter David J. , Garber Judy E. , Joshi Amit D. , McDonnell Kevin , Easton Doug F. , Eeles Ros , Kote-Jarai Zsofia , Muir Kenneth , Doherty Jennifer A. , Schildkraut Joellen M. 
Published: December 2015

Abstract
Background: DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility.
Methods: We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling.
Results: We identified three susceptibility DNA repair genes, RAD51B (P &lt; 5.09 × 10−6), MSH5 (P &lt; 5.09 × 10−6), and BRCA2 (P = 5.70 × 10−6). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways.
Conclusions: Only three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways.
Impact: Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria. Cancer Epidemiol Biomarkers Prev; 25(1); 193–200. ©2015 AACR.
Comparing Patient-Derived Xenograft and Computational Response Prediction for Targeted Therapy in Patients of Early-Stage Large Cell Lung Cancer
Authors: Li Jian , Ye Changkun , Mansmann Ulrich R. 
Published: December 2015

Abstract
Purpose: Targeted therapy (TT) provides highly effective cancer treatment for appropriately selected individuals. A major challenge of TT is to select patients who would benefit most.
Experimental Design: The study uses cancer material from 25 patients primarily diagnosed with non–small cell lung cancer (NSCLC). Patient-derived xenografts (PDXs) are treated with cetuximab and erlotinib. Treatment response is measured by tumor shrinkage comparing tumor volume at day 25 (V25) with tumor volume at baseline (V0). Shrinkage below 40% is considered as treatment response: V25/V0 &lt; 0.4 (&lt;40%). Furthermore, RNA-seq data from each tumor sample are used to predict tumor response to either treatment using an in silico molecular signaling map (MSM) approach.
Results: PDX response was 40% (10/25; 95% CI [21.13%, 61.34%]) under cetuximab and 20% (5/25; 95% CI [6.83%, 40.70%]) under erlotinib. MSM predicted response was 48% (12/25; 95% CI [27.8%, 68.7%]) under cetuximab and 40% (10/25; 95% CI [21.13%, 61.34%]) under erlotinib. Agreement between PDX and MSM response prediction is substantial under cetuximab and erlotinib: 84% (21/25, P = 0.001) and 80% (20/25, P = 0.003). A total of 5 from the 25 patients have been treated with cetuximab showing a clinical response identical to both predictions.
Conclusions: For NSCLC patients, this proof-of-concept study shows a considerable agreement in response prediction from MSM and PDX approaches, but MSM saves time and laboratory resources. Our result indicates the potential of MSM-based approach for clinical decision making when selecting cancer TTs. Clin Cancer Res; 22(9); 2167–76. ©2015 AACR.
Impact of Metformin on Advanced Pancreatic Cancer Survival: Too Little, Too Late?
Authors: Yang Yu-Xiao , Rustgi Anil K. 
Published: December 2015

Abstract
Metformin offers no survival advantage in patients with metastatic pancreatic cancer. Despite promising experimental evidence suggesting an antitumor effect of metformin, its impact on the survival of advanced pancreatic cancer is likely very limited. Future studies may need to consider its role in early-stage pancreatic cancer. Clin Cancer Res; 22(5); 1031–3. ©2015 AACR.
See related article by Reni et al., p. 1076
Construction and validation of a hybrid model to measure perceived public service quality (PSQ)
Authors: Guenoun Marcel , Goudarzi Kiane , Chandon Jean-Louis 
Published: December 2015

Today, public organizations make extensive use of marketing methods and concepts to design, implement and assess the services they deliver to their beneficiaries. The quality of the services offered is at the heart of their concerns. Public sector marketing requires tools that are adapted to the specific characteristics of the context. The main contribution of this research is to propose the construction of a hybrid model to measure perceived public service quality (PSQ), mixing public and private dimensions. It is based on a quantitative study conducted on a sample of 760 inhabitants of the French town of Besançon. Points for practitioners Service quality is a cornerstone of government modernization. However, public service quality adds another dimension to the notion of service quality. In addition to those found in the private sector, dimensions specific to the public sector have a significant impact on how the beneficiaries perceive public services. In this article we develop a model to measure Public Service Quality that incorporates the public and private dimensions in a single conceptualization. This research provides practitioners with an operational measurement tool to survey their beneficiaries on public service quality.
Overcoming the tensions between values: a challenge for French public service managers and their training schools
Authors: Larat Fabrice , Chauvigné Christian 
Published: December 2015

While there is universal recognition of their important role in the functioning of administrations and for the motivation of public officials, the values that serve as a reference for the public service are witnessing a change in the way they are understood and implemented in practice, particularly with regard to the new requirements of public management. The analysis developed in this article centres on the interplay between various dimensions relating to the perception and use of the key values of the French civil service and highlights the tensions that prevail despite the apparent preservation of the axiological reference universe of those concerned. It raises the question of the role of schools in the training of values management. It draws on the results of a survey conducted in France by the network of civil service schools (Réseau des écoles de service public; RESP) among managers undergoing training and their teachers and supervisory staff. Points for practitioners The study shows that organizations that are responsible for the initial or continuing training of civil servants offer a breeding ground for the (re)production of public service values. However, for civil service managers to be able to deal with the potential tensions between values (no clear hierarchy, apparent contradictions) it is necessary to develop their capacities for reflective analysis and practical application that will allow a critical distance and promote a contextualized ethical approach.
Public accountability and the Public Expenditure and Financial Accountability tool: an assessment
Authors: Loozekoot André , Dijkstra Geske 
Published: December 2015

Since 2005, the Public Expenditure and Financial Accountability tool has been widely used in developing countries and emerging economies to evaluate the performance of public financial management systems. In this article, we assess the strengths and weaknesses of the Public Expenditure and Financial Accountability instrument tool for evaluating public financial accountability. We examine the theoretical literature on public accountability in order to derive a suitable normative framework to assess the Public Expenditure and Financial Accountability tool. However, given that this literature is based on experiences in developed countries, we must extend it to also take into account the political cultures and practices in developing countries. Using this extended framework, we assess the Public Expenditure and Financial Accountability indicators related to, in particular, parliamentary committees for financial oversight and Supreme Audit Institutions. We conclude that the Public Expenditure and Financial Accountability tool could devote more attention to the independence of Supreme Audit Institutions, the nature of accountability debates, democratic inclusion and horizontal accountability mechanisms Points for practitioners The Public Expenditure and Financial Accountability tool has been applied in more than 116 countries and its reports offer valuable information for practitioners and researchers around the world. It is the only publicly available data set that measures the performance of financial committees of parliament and Supreme Audit Institutions. The strengths and weaknesses revealed in this article should be taken into account when using the Public Expenditure and Financial Accountability tool for research or for evaluating the quality of financial accountability systems in particular countries. The international financial institutions and donor agencies governing the Public Expenditure and Financial Accountability Secretariat can use the recommendations of this article to further improve the framework.