bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2
Authors: Wang Fang , Yuan Ji-Hang , Wang Shao-Bing , Yang Fu , Yuan Sheng-Xian , Ye Chen , Yang Ning , Zhou Wei-Ping , Li Wen-Lin , Li Wen , Sun Shu-Han
Published: July 2014

Many protein-coding oncofetal genes are highly expressed in murine and human fetal liver and silenced in adult liver. The protein products of these hepatic oncofetal genes have been used as clinical markers for the recurrence of hepatocellular carcinoma (HCC) and as therapeutic targets for HCC. Herein we examined the expression profiles of long noncoding RNAs (lncRNAs) found in fetal and adult liver in mice. Many fetal hepatic lncRNAs were identified; one of these, lncRNA-mPvt1, is an oncofetal RNA that was found to promote cell proliferation, cell cycling, and the expression of stem cell-like properties of murine cells. Interestingly, we found that human lncRNA-hPVT1 was up-regulated in HCC tissues and that patients with higher lncRNA-hPVT1 expression had a poor clinical prognosis. The protumorigenic effects of lncRNA-hPVT1 on cell proliferation, cell cycling, and stem cell-like properties of HCC cells were confirmed both in vitro and in vivo by gain-of-function and loss-of-function experiments. Moreover, mRNA expression profile data showed that lncRNA-hPVT1 up-regulated a series of cell cycle genes in SMMC-7721 cells. By RNA pulldown and mass spectrum experiments, we identified NOP2 as an RNA-binding protein that binds to lncRNA-hPVT1. We confirmed that lncRNA-hPVT1 up-regulated NOP2 by enhancing the stability of NOP2 proteins and that lncRNA-hPVT1 function depends on the presence of NOP2. Conclusion: Our study demonstrates that the expression of many lncRNAs is up-regulated in early liver development and that the fetal liver can be used to search for new diagnostic markers for HCC. LncRNA-hPVT1 promotes cell proliferation, cell cycling, and the acquisition of stem cell-like properties in HCC cells by stabilizing NOP2 protein. Regulation of the lncRNA-hPVT1/NOP2 pathway may have beneficial effects on the treatment of HCC. (Hepatology 2014;60:1278–1290)
LI‐RADS (Liver Imaging Reporting and Data System): Summary, discussion, and consensus of the LI‐RADS Management Working Group and future directions
Authors: Mitchell Donald G. , Bruix Jordi , Sherman Morris , Sirlin Claude B.
Published: July 2014

To improve standardization and consensus regarding performance, interpreting, and reporting computed tomography (CT) and magnetic resonance imaging (MRI) examinations of the liver in patients at risk for hepatocellular carcinoma (HCC), LI‐RADS (Liver Imaging Reporting and Data System) was launched in March 2011 and adopted by many clinical practices throughout the world. LI‐RADS categorizes nodules recognized at CT or MRI, in patients at high risk of HCC, as definitively benign, probably benign, intermediate probability of being HCC, probably HCC, and definitively HCC (corresponding to LI‐RADS categories 1‐5). The LI‐RADS Management Working Group, consisting of internationally recognized medical and surgical experts on HCC management, as well as radiologists involved in the development of LI‐RADS, was convened to evaluate management implications related to radiological categorization of the estimated probability that a lesion will be ultimately diagnosed as HCC. In this commentary, we briefly review LI‐RADS and the initial consensus of the LI‐RADS Management Working Group reached during its deliberations in 2013. We then focus on initial discordance of LI‐RADS with American Association for the Study of Liver Diseases and Organ Procurement Transplant Network guidelines, the basis for these differences, and how they are being addressed going forward to optimize reporting of CT and MRI findings in patients at risk for HCC and to increase consensus throughout the international community of physicians involved in the diagnosis and treatment of HCC. (Hepatology 2015;61:1056–1065)
CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis
Authors: Wang Lifeng , Sun Ying , Zhang Zheng , Jia Yiqiong , Zou Zhengsheng , Ding Jinbiao , Li Yuanyuan , Xu Xiangsheng , Jin Lei , Yang Tao , Li Zhiwei , Sun Yanling , Zhang Ji‐yuan , Lv Sa , Chen Liming , Li Baosen , Gershwin M. Eric , Wang Fu‐Sheng
Published: July 2014

There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5+CD4+ Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for 1 year. We report herein several key observations. First, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (P < 0.05) and HC (P < 0.01). Second, the function of circulating Tfh cells from PBC patients, including interleukin (IL)‐21 production (P < 0.05), the ability to promote B‐cell maturation, and autoantibody production, were greater than HC. Third, the frequency of these cells was significantly decreased in ursodeoxycholic acid (UDCA) responders compared to UDCA‐treated nonresponders, in both cross‐sectional (P = 0.023) and longitudinal studies (P = 0.036), respectively. Indeed, similar increases of Tfh cells were noted in liver and spleen. Conclusion: These results significantly extend our understanding of lymphoid subpopulations in PBC and their relative role in disease expression. Our data also provide a novel biomarker for evaluation of the effectiveness of new therapeutic approaches. (Hepatology 2015;61:627‐638)
Phylogenetic clustering of hepatitis C virus among people who inject drugs in Vancouver, Canada
Authors: Jacka Brendan , Applegate Tanya , Krajden Mel , Olmstead Andrea , Harrigan Richard P. , Marshall Brandon D.L. , DeBeck Kora , Milloy M.-J. , Lamoury Francois , Pybus Oliver G. , Lima Viviane D. , Magiorkinis Gkikas , Montoya Vincent , Montaner Julio , Joy Jeffrey , Woods Conan , Dobrer Sabina , Dore Gregory J. , Poon Art F.Y. , Grebely Jason
Published: July 2014

Little is known about factors associated with hepatitis C virus (HCV) transmission among people who inject drugs (PWID). Phylogenetic clustering and associated factors were evaluated among PWID in Vancouver, Canada. Data were derived from the Vancouver Injection Drug Users Study. Participants who were HCV antibody-positive at enrolment and those with HCV antibody seroconversion during follow-up (1996 to 2012) were tested for HCV RNA and sequenced (Core-E2 region). Phylogenetic trees were inferred using maximum likelihood analysis and clusters were identified using ClusterPicker (90% bootstrap threshold, 0.05 genetic distance threshold). Factors associated with clustering were assessed using logistic regression. Among 655 eligible participants, HCV genotype prevalence was: G1a: 48% (n = 313), G1b: 6% (n = 41), G2a: 3% (n = 20), G2b: 7% (n = 46), G3a: 33% (n = 213), G4a: <1% (n = 4), G6a: 1% (n = 8), G6e: <1% (n = 1), and unclassifiable: 1% (n = 9). The mean age was 36 years, 162 (25%) were female, and 164 (25%) were HIV+. Among 501 participants with HCV G1a and G3a, 31% (n = 156) were in a pair/cluster. Factors independently associated with phylogenetic clustering included: age <40 (versus age ≥40, adjusted odds ratio [AOR] = 1.64; 95% confidence interval [CI] 1.03, 2.63), human immunodeficiency virus (HIV) infection (AOR = 1.82; 95% CI 1.18, 2.81), HCV seroconversion (AOR = 3.05; 95% CI 1.40, 6.66), and recent syringe borrowing (AOR 1.59; 95% CI 1.07, 2.36).

Conclusion

: In this sample of PWID, one-third demonstrated phylogenetic clustering. Factors independently associated with phylogenetic clustering included younger age, recent HCV seroconversion, prevalent HIV infection, and recent syringe borrowing. Strategies to enhance the delivery of prevention and/or treatment strategies to those with HIV and recent HCV seroconversion should be explored, given an increased likelihood of HCV transmission in these subpopulations. (Hepatology 2014;60:1571–1580)
Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis
Authors: Song Ruipeng , Song Huiwen , Liang Yingjian , Yin Dalong , Zhang Heng , Zheng Tongsen , Wang Jiabei , Lu Zhaoyang , Song Xuan , Pei Tiemin , Qin Youyou , Li Yuejin , Xie Changming , Sun Boshi , Shi Huawen , Li Shuai , Meng Xianzhi , Yang Guangchao , Pan Shangha , Zhu Jiyuan , Qi Shuyi , Jiang Hongchi , Zhang Zhiyong , Liu Lianxin
Published: July 2014

Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent extrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effects of ATPase inhibitory factor 1 (IF1), an inhibitor of the mitochondrial H(+)-adenosine triphosphate (ATP) synthase, on HCC angiogenesis and metastasis. We found that increased expression of IF1 in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and metastasis, expressed high levels of IF1. Invasive tumors overexpressing IF1 were featured by active epithelial-mesenchymal transition (EMT) and increased angiogenesis, whereas silencing IF1 expression attenuated EMT and invasion of HCC cells. Mechanistically, IF1 promoted Snai1 and vascular endothelial growth factor (VEGF) expression by way of activating nuclear factor kappa B (NF-κB) signaling, which depended on the binding of tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) to NF-κB-inducing kinase (NIK) and the disruption of NIK association with the TRAF2-cIAP2 complex. Suppression of the NF-κB pathway interfered with IF1-mediated EMT and invasion. Chromatin immunoprecipitation assay showed that NF-κB can bind to the Snai1 promoter and trigger its transcription. IF1 was directly transcribed by NF-κB, thus forming a positive feedback signaling loop. There was a significant correlation between IF1 expression and pp65 levels in a cohort of HCC biopsies, and the combination of these two parameters was a more powerful predictor of poor prognosis.

Conclusion

: IF1 promotes HCC angiogenesis and metastasis by up-regulation of Snai1 and VEGF transcription, thereby providing new insight into HCC progression and IF1 function. (Hepatology 2014;60:1659–1673)
Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis
Authors: Zhang Jun , Zhang Weici , Leung Patrick S.C. , Bowlus Christopher L. , Dhaliwal Sandeep , Coppel Ross L. , Ansari Aftab A. , Yang Guo-Xiang , Wang Jinjun , Kenny Thomas P. , He Xiao-Song , Mackay Ian R. , Gershwin Eric M.
Published: July 2014

The serologic hallmark of primary biliary cirrhosis (PBC), the antimitochondrial response to the E2 component of the pyruvate dehydrogenase complex (PDC-E2), has unique features, including continuous high titers of immunoglobulin M (IgM) and IgG reactivity throughout all stages of disease, capable not only of target enzyme inhibition, but also crossreactive with chemical xenobiotics that share molecular homology with the inner lipoyl domain of PDC-E2; such chemicals have been proposed as potential etiological agents. We used flow cytometry and enzyme-linked immunospot assay (ELISPOT) to examine B-cell subsets in 59 subjects, including 28 with PBC, 13 with primary sclerosing cholangitis (PSC), and 18 healthy controls. Strikingly, in PBC, although there were no significant differences in B-cell phenotype subpopulations, 10% of the total IgG and IgA plasmablast population and 23% of the IgM plasmablast population were uniquely reactive with PDC-E2, detected in the CXCR7+CCR10low plasmablast population. In contrast, plasmablast reactivity to a control antigen, tetanus toxoid, was minimal and similar in all groups. Additionally, we isolated plasmablast-derived polyclonal antibodies and compared reactivity with plasma-derived antibodies and noted a distinct noncirculating tissue source of xenobiotic crossreacting antibodies. The high levels of autoantigen specific peripheral plasmablasts indicate recent activation of naive or memory B cells and a continuous and robust activation. The presence of CXCR7+CCR10low PDC-E2-specific ASCs suggests a mechanistic basis for the migration of circulating antigen specific plasmablasts to the mucosal epithelial ligands CXCL12 and CCL28.

Conclusion

: Our findings suggest a sustained rigorous B-cell response in PBC, likely activated and perpetuated by cognate autoantigen. (Hepatology 2014;60:1708–1716)
Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network
Authors: Navarro Victor J. , Barnhart Huiman , Bonkovsky Herbert L. , Davern Timothy , Fontana Robert J. , Grant Lafaine , Reddy Rajender K. , Seeff Leonard B. , Serrano Jose , Sherker Averell H. , Stolz Andrew , Talwalkar Jayant , Vega Maricruz , Vuppalanchi Raj
Published: July 2014

The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity caused by conventional medications as well as herbals and dietary supplements (HDS). To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight U.S. referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury caused by HDS. Hepatotoxicity caused by HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments, including death and liver transplantation (LT), were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury caused by bodybuilding HDS, 85 by nonbodybuilding HDS, and 709 by medications. Liver injury caused by HDS increased from 7% to 20% (P < 0.001) during the study period. Bodybuilding HDS caused prolonged jaundice (median, 91 days) in young men, but did not result in any fatalities or LT. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women, and, more frequently, led to death or transplantation, compared to injury from medications (13% vs. 3%; P < 0.05). Conclusions: The proportion of liver injury cases attributed to HDS in DILIN has increased significantly. Liver injury from nonbodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes (death and transplantation). (Hepatology 2014;60:1399–1408)
Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles
Authors: Lemoinne Sara , Cadoret Axelle , Rautou Pierre‐Emmanuel , El Mourabit Haquima , Ratziu Vlad , Corpechot Christophe , Rey Colette , Bosselut Nelly , Barbu Véronique , Wendum Dominique , Feldmann Gérard , Boulanger Chantal , Henegar Corneliu , Housset Chantal , Thabut Dominique
Published: July 2014

Liver fibrosis expanding from portal tracts and vascular remodeling are determinant factors in the progression of liver diseases to cirrhosis. In the present study, we examined the potential contribution of portal myofibroblasts (PMFs) to the vascular changes leading to cirrhosis. The analyses of liver cells based on the transcriptome of rat PMFs, compared to hepatic stellate cell HSC‐derived myofibroblasts in culture, identified collagen, type XV, alpha 1 (COL15A1) as a marker of PMFs. Normal liver contained rare COL15A1‐immunoreactive cells adjacent to the bile ducts and canals of Hering in the portal area. A marked increase in COL15A1 expression occurred together with that of the endothelial marker, von Willebrand factor, in human and rat liver tissue, at advanced stages of fibrosis caused by either biliary or hepatocellular injury. In cirrhotic liver, COL15A1‐expressing PMFs adopted a perivascular distribution outlining vascular capillaries proximal to reactive ductules, within large fibrotic septa. The effect of PMFs on endothelial cells (ECs) was evaluated by in vitro and in vivo angiogenesis assays. PMF‐conditioned medium increased the migration and tubulogenesis of liver ECs as well as human umbilical vein ECs and triggered angiogenesis within Matrigel plugs in mice. In coculture, PMFs developed intercellular junctions with ECs and enhanced the formation of vascular structures. PMFs released vascular endothelial growth factor (VEGF)A‐containing microparticles, which activated VEGF receptor 2 in ECs and largely mediated their proangiogenic effect. Cholangiocytes potentiated the angiogenic properties of PMFs by increasing VEGFA expression and microparticle shedding in these cells. Conclusion: PMFs are key cells in hepatic vascular remodeling. They signal to ECs through VEGFA‐laden microparticles and act as mural cells for newly formed vessels, driving scar progression from portal tracts into the parenchyma. (Hepatology 2015;61:1041–1055)
Epunctanone, a New Benzophenone, and Further Secondary Metabolites from Garcinia epunctataStapf (Guttiferae)
Authors: Fotso Ghislain W. , Ntumy Aku N. , Ngachussi Eliette , Dube Mthandazo , Mapitse Renameditswe , Kapche Gilbert D. W. F. , Andrae‐Marobela Kerstin , Ngadjui Bonaventure T. , Abegaz Berhanu M.
Published: July 2014

A new polyprenylated benzophenone, named epunctanone (1), was isolated from the stem bark of Garcinia epunctata Stapf, together with eight known compounds, 7‐epiisogarcinol (2), 2,6‐dimethoxy‐p‐benzoquinone (3), friedelin (4), lupeol (5), 16β‐hydroxylupeol (6), betulin (7), stigmasterol (8), and rheediaxanthone A (9). The structure of epunctanone (1) was established by detailed analysis of its spectroscopic data, especially 1D‐ and 2D‐NMR, and HR‐MS data. All these compounds were evaluated for their antimicrobial and anti‐protozoan activities. They were also assayed to determine if any of the compounds were nonpeptide agonist ligands for nematodal G‐protein‐coupled receptors, which would be an indication of potential antinematodal activity. Among the isolated compounds, 7‐epiisogarcinol (2) was the most active against Candida albicans.
Anthraquinone Derivatives and an Orsellinic Acid Ester from the Marine Alga‐Derived Endophytic Fungus Eurotium cristatum EN‐220
Authors: Du Feng‐Yu , Li Xiao‐Ming , Song Ji‐Ying , Li Chun‐Shun , Wang Bin‐Gui
Published: July 2014

Cultivation of the fungal strain Eurotium cristatum EN‐220, an endophyte obtained from the marine alga Sargassum thunbergii, resulted in the isolation of one new anthraquinone glycoside, 3‐O‐(α‐D‐ribofuranosyl)questinol (1) and one new orsellinic acid ester, cristatumside A (2), together with three known aromatic glycosides, 3‐O‐(α‐D‐ribofuranosyl)questin (3), isotorachrysone 6‐O‐α‐D‐ribofuranoside (4), and asperflavin ribofuranoside (5), as well as three anthraquinone derivatives, asperflavin (6), eurorubrin (7), and (+)‐variecolorquinone A (8). The structures of these compounds were determined by extensive analysis of their spectroscopic data, as well as by their comparison with those in the literature. Each of the isolated compounds was evaluated for its antimicrobial activity and brine shrimp lethality.
The relative role of soil type and tree cover on water storage and transmission in northern headwater catchments
Authors: Geris Josie , Tetzlaff Doerthe , McDonnell Jeffrey , Soulsby Chris
Published: July 2014

Soil water storage and stable isotopes dynamics were investigated in dominant soil–vegetation assemblages of a wet northern headwater catchment (3.2 km2) with limited seasonality in precipitation. We determined the relative influence of soil and vegetation cover on storage and transmission processes. Forested and non‐forested sites were compared, on poorly drained histosols in riparian zones and freely draining podzols on steeper hillslopes. Results showed that soil properties exert a much stronger influence than vegetation on water storage dynamics and fluxes, both at the plot and catchment scale. This is mainly linked to the overall energy‐limited climate, restricting evaporation, in conjunction with high soil water storage capacities. Threshold behaviour in runoff responses at the catchment scale was associated with differences in soil water storage and transmission dynamics of different hydropedological units. Linear input–output relationships occurred when runoff was generated predominantly from the permanently wet riparian histosols, which show only small dynamic storage changes. In contrast, nonlinear runoff generation was related to transient periods of high soil wetness on the hillslopes. During drier conditions, more marked differences in soil water dynamics related to vegetation properties emerged, in terms of evaporation and impacts on temporarily increasing dynamic storage potential. Overall, our results suggest that soil type and their influence on runoff generation are dominant over vegetation effects in wet, northern headwater catchments with low seasonality in precipitation. Potential increase of subsurface storage by tree cover (e.g. for flood management) will therefore be spatially distributed throughout the landscape and limited to rare and extreme dry conditions. Copyright © 2014 John Wiley & Sons, Ltd.
Radar rainfall uncertainty modelling influenced by wind
Authors: Dai Qiang , Han Dawei , Rico‐Ramirez Miguel A. , Zhuo Lu , Nanding Nergui , Islam Tanvir
Published: July 2014

Radar‐based estimates of rainfall are affected by many sources of uncertainties, which would propagate through the hydrological model when radar rainfall estimates are used as input or initial conditions. An elegant solution to quantify these uncertainties is to model the empirical relationship between radar measurements and rain gauge observations (as the ‘ground reference’). However, most current studies only use a fixed and uniform model to represent the uncertainty of radar rainfall, without consideration of its variation under different synoptic regimes. Wind is such a typical weather factor, as it not only induces error in rain gauge measurements but also causes the raindrops observed by weather radar to drift when they reach the ground. For this reason, as a first attempt, this study introduces the wind field into the uncertainty model and designs the radar rainfall uncertainty model under different wind conditions. We separate the original dataset into three subsamples according to wind speed, which are named as WDI (0–2 m/s), WDII (2–4 m/s) and WDIII (>4 m/s). The multivariate distributed ensemble generator is introduced and established for each subsample. Thirty typical events (10 at each wind range) are selected to explore the behaviours of uncertainty under different wind ranges. In each time step, 500 ensemble members are generated, and the values of 5th to 95th percentile values are used to produce the uncertainty bands. Two basic features of uncertainty bands, namely dispersion and ensemble bias, increase significantly with the growth of wind speed, demonstrating that wind speed plays a considerable role in influencing the behaviour of the uncertainty band. On the basis of these pieces of evidence, we conclude that the radar rainfall uncertainty model established under different wind conditions should be more realistic in representing the radar rainfall uncertainty. This study is only a start in incorporating synoptic regimes into rainfall uncertainty analysis, and a great deal of more effort is still needed to build a realistic and comprehensive uncertainty model for radar rainfall data. Copyright © 2014 John Wiley & Sons, Ltd.
Venous thromboembolism risk prediction in ambulatory cancer patients: Clinical significance of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio
Authors: Ferroni Patrizia , Riondino Silvia , Formica Vincenzo , Cereda Vittore , Tosetto Livia , La Farina Francesca , Valente Maria Giovanna , Vergati Matteo , Guadagni Fiorella , Roselli Mario
Published: July 2014

Neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) ratios might represent a yet unrecognized risk factor for venous thromboembolism (VTE) in cancer out‐patients receiving chemotherapy. Accordingly, this study was aimed at analyzing the significance of these novel markers in the risk prediction of a first VTE episode in a population representative of a general practice cohort. To this purpose, a mono‐institutional cohort study was conducted to retrospectively analyze NLR and PLR in 810 consecutive cancer out‐patients with primary or relapsing solid cancer at the start of a new chemotherapy regimen. Over a median follow‐up of 9.2 months, VTE occurred in 6.7% of patients. Incidental VTE was diagnosed at time of restaging in 47% of cases. Median pre‐chemotherapy NLR (p = 0.015) and PLR (p = 0.040) were significantly higher in patients with intermediate risk class who developed symptomatic VTE with a twofold increased VTE risk for both inflammation‐based markers (NLR: p = 0.022; PLR: p = 0.037) and a worst 1‐year VTE‐free survival for patients with high NLR or PLR. However, only PLR (HR = 2.4, p = 0.027) confirmed to be an independent predictor of future VTE in patients in the intermediate risk class in multivariate analysis, together with ECOG performance status (HR = 3.4, p = 0.0002) and bevacizumab use (HR = 4.7, p = 0.012). We may, thus, conclude that PLR, but to a lesser extent NLR, could represent useful clinical predictors of VTE, especially in selected categories of patients such as those in the intermediate risk class in whom the assessment of PLR could allow a better risk stratification of VTE without additional costs to the national health systems.
Penicillin‐binding protein 2a of methicillin‐resistant Staphylococcus aureus
Authors: Fishovitz Jennifer , Hermoso Juan A. , Chang Mayland , Mobashery Shahriar
Published: July 2014

High‐level resistance to β‐lactam antibiotics in methicillin‐resistant Staphylococcus aureus (MRSA) is due to expression of penicillin‐binding protein 2a (PBP2a), a transpeptidase that catalyzes cell‐wall crosslinking in the face of the challenge by β‐lactam antibiotics. The activity of this protein is regulated by allostery at a site 60 Å distant from the active site, where crosslinking of cell wall takes place. This review discusses the state of knowledge on this important enzyme of cell‐wall biosynthesis in MRSA. © 2014 IUBMB Life, 66(8):572–577, 2014
The Developmental Basis of Epigenetic Regulation of HTR2A and Psychiatric Outcomes
Authors: Paquette Alison G. , Marsit Carmen J.
Published: July 2014

The serotonin receptor 5‐HT2A (encoded by HTR2A) is an important regulator of fetal brain development and adult cognitive function. Environmental signals that induce epigenetic changes of serotonin response genes, including HTR2A, have been implicated in adverse mental health outcomes. The objective of this perspective article is to address the medical implications of HTR2A epigenetic regulation, which has been associated with both infant neurobehavioral outcomes and adult mental health. Ongoing research has identified a region of the HTR2A promoter that has been associated with a number of medical outcomes in adults and infants, including bipolar disorder, schizophrenia, chronic fatigue syndrome, borderline personality disorder, suicidality, and neurobehavioral outcomes. Epigenetic regulation of HTR2A has been studied in several different types of tissues, including the placenta. The placenta is an important source of serotonin during fetal neurodevelopment, and placental epigenetic variation of HTR2A has been associated with infant neurobehavioral outcomes, which may represent the basis of adult mental health disorders. Further analysis is needed to identify intrinsic and extrinsic factors that modulate HTR2A methylation, and the mechanism by which this epigenetic variation influences fetal growth and leads to altered brain development, manifesting in psychiatric disorders. J. Cell. Biochem. 115: 2065–2072, 2014. © 2014 Wiley Periodicals, Inc.
Unexpected Transcellular Protein Crossover Occurs During Canonical DNA Transfection
Authors: Arsenault Jason , Cuijpers Sabine A.G. , Niranjan Dhevahi , Davletov Bazbek
Published: July 2014

Transfection of DNA has been invaluable for biological sciences, yet the effects upon membrane homeostasis are far from negligible. Here, we demonstrate that Neuro2A cells transfected using Lipofectamine LTX with the fluorescently coupled Botulinum serotype A holoenzyme (EGFP‐LcA) cDNA express this SNAP25 protease that can, once translated, escape the transfected host cytosol and become endocytosed into untransfected cells, without its innate binding and translocation domains. Fluorescent readouts revealed moderate transfection rates (30–50%) while immunoblotting revealed a surprisingly total enzymatic cleavage of SNAP25; the transgenic protein acted beyond the confines of its host cell. Using intracellular dyes, no important cytotoxic effects were observed from reagent treatment alone, which excluded the possibility of membrane ruptures, though noticeably, intracellular acidic organelles were redistributed towards the plasma membrane. This drastic, yet frequently unobserved, change in protein permeability and endosomal trafficking following reagent treatment highlights important concerns for all studies using transient transfection. J. Cell. Biochem. 115: 2047–2054, 2014. © 2014 Wiley Periodicals, Inc.
The Use of Dialectical Behavior Therapy Skills Training as Stand‐Alone Treatment: A Systematic Review of the Treatment Outcome Literature
Authors: Valentine Sarah E. , Bankoff Sarah M. , Poulin Renée M. , Reidler Esther B. , Pantalone David W.
Published: July 2014

Objective

Dialectical behavior therapy (DBT) skills training is currently being administered as stand‐alone treatment across a variety of clinical settings, serving diverse client populations. However, there is little empirical support for this use.

Method

In this systematic review, we identified 17 trials employing a treatment that included DBT skills training in the absence of the other DBT modalities.

Results

While the literature reviewed provides preliminary evidence of the utility of DBT skills training to address a range of mental health and behavioral problems, methodological limitations of published studies preclude us from drawing strong conclusions about the efficacy of skills training as a stand‐alone treatment.

Conclusion

We present an overview of the implementation of DBT skills training across clinical settings and populations. We found preliminary evidence supporting the use of DBT skills training as a method of addressing a range of behaviors. We provide recommendations for future research.
THE ROLE OF SLEEP IN THE RELATION BETWEEN COMMUNITY VIOLENCE EXPOSURE AND DELINQUENCY AMONG LATINO ADOLESCENTS
Authors: Rubens Sonia L. , Fite Paula J. , Cooley John L. , Canter Kimberly S.
Published: July 2014

Little is known about factors that account for the link between community violence exposure (CVE) and delinquency among adolescents. Sleep is one factor that warrants attention, given the poor sleep habits found among many adolescents and its relation to CVE and delinquent behaviors. Further, given the growing rate of Latino youth in the United States, and their risk for CVE, examining factors that account for this relation among Latino youth is essential for developing culturally sensitive interventions. This study evaluated whether sleep problems accounted for the link between CVE and delinquency among a sample of 144 Latino adolescents (54% male; ages 14­–19 years). CVE and sleep problems were uniquely related to delinquency. Further, Meeker's test of indirect effects indicated that sleep problems partially accounted for the relation between CVE and delinquency. Interventions targeting sleep problems in Latino adolescents may aid in reducing delinquency among Latino adolescents, particularly for those with CVE.
Derivation of Phase 3 dosing for peginterferon lambda‐1a in chronic hepatitis C, Part 1: Modeling optimal treatment duration and sustained virologic response rates
Authors: Wang Xiaodong , Hruska Matthew , Chan Phyllis , Ahmad Alaa , Freeman Jeremy , Horga Maria Arantxa , Hillson Jan , Kansra Vikram , Lopez‐Talavera Juan‐Carlos
Published: July 2014

Peginterferon lambda‐1a (Lambda) is under clinical development for the treatment of chronic hepatitis B and C virus (HBV, HCV, respectively) infection. This is the first of two manuscripts detailing the pharmacodynamic derivation of Lambda dosing and treatment durations for Phase 3 studies in HCV, based on Phase 2 data. We describe here the derivation of a population model of Lambda exposure; the adaptation of a previously published viral dynamic model for Lambda treatment and host genotype, and its use to simulate sustained virologic responses (SVR). Lambda population pharmacokinetics was described by a one‐compartment model with first‐order absorption, and 33.0 L per day clearance with 47% interindividual (36% intra‐individual) variability. Weight explained a negligible proportion of the variability. Based on SVR predictions, optimum treatment durations were 48 weeks for HCV genotypes 1 or 4 (SVR estimates for 120, 180, and 240 μg Lambda: 58%, 54%, 47%, respectively) and 24 weeks for genotypes 2 or 3 (75%, 72%, 67%). SVR predictions for 240 μg were lower due to dropout predictions. The SVR model established the optimum treatment duration for Phase 3 studies but did not differentiate between 120 and 180 μg dosing. A companion manuscript describes dose selection based on exposure–response/safety modeling.
Evidence for ca. 7‐ka maximum Holocene transgression on the Peninsular Malaysia east coast
Authors: PARHAM PETER R. , SAITO YOSHIKI , SAPON NORAISYAH , SURIADI ROKIAH , MOHTAR NOOR AZARIYAH
Published: July 2014

In situ fossil coral and shelly marine deposits occur up to 50 cm above mean sea level in north‐east Peninsular Malaysia. The fossil reef comprises over 15 coral species and associated molluscs. Radiocarbon ages of corals range from 7238 to 6909 cal a BP. The reef occurs adjacent to bedrock hills that formed a mainland peninsula when the coral was living. Abundant well‐preserved fossil molluscs with bivalves commonly articulated occur in ditch tailings from coastal plains flanking these hills. Landward, a sand ridge represents part of the maximum transgression shoreline. When alive, the fossil coral reef required clear water and full marine conditions seaward of the peninsula. The maximum transgression here occurred ca. 7 ka with stable environmental conditions persisting long enough for diverse coral reef development. Assuming a similar tidal range to today, relative sea level ca. 7 ka would have been between 1.4 and 3 m above present. Between then and ca. 6 ka, abundant sediment supply resulted in barrier‐beach construction seaward of the coral reef, converting the area to a lagoonal environment unsuitable for coral and burial by muddy deposits. Assuming that regional relative sea‐level data indicate maximum Holocene highstand up to +5 m between 6 and 4 ka are correct, then the maximum transgression preceded maximum sea level by at least 1000 years.
Climate over mainland Southeast Asia 10.5–5 ka
Authors: CHABANGBORN AKKANEEWUT , WOHLFARTH BARBARA
Published: July 2014

We assembled and evaluated Holocene palaeo‐vegetation records regarding semi‐quantitative precipitation and temperature for mainland Southeast Asia and compared these with precipitation reconstructions for the Indian Ocean (IOM) and East Asian (EAM) monsoon sub‐systems. Our results indicate that temperatures and precipitation in mainland Southeast Asia generally exceeded 18 °C and 1100 mm a−1 during the Holocene. Mainland Southeast Asia experienced cool/wet climatic conditions between 10.5 and 10 ka BP, a warmer/drier climate between 10 and 9 ka BP, cooler/wetter conditions between 9 and 7 ka BP, and moderately warmer/drier conditions since 7 ka BP. The reconstructed summer monsoon intensity compares well with the reconstructed hydroclimate for the EAM region, but diverges from that of the IOM region between 10.5 and 9 ka BP and 7–6.5 ka BP. This discrepancy is explained by differences in land–sea configuration, and regional sea‐level history. A strengthening/weakening of the Asian summer monsoon between 9 and 7 ka BP and after 6.5 ka BP, respectively, is observed across the whole Asian monsoon region. Our new data sets support an asynchronous onset of the Asian summer monsoon optimum.
The effects of contact area and applied load on the morphology of in vitro worn ultra‐high molecular weight knee prostheses: a micro‐Raman and gravimetric study
Authors: Tozzi Silvia , Modena Enrico , Falcioni Stefano , Sudanese Alessandra , Affatato Saverio , Taddei Paola
Published: July 2014

Ultra‐high molecular weight polyethylene knee prostheses of two different sizes (i.e. characterised by different contact areas) were run on a knee wear simulator in two tests differing for the applied load. Gravimetric and micro‐Raman spectroscopic analyses were performed to investigate at macroscopic and molecular levels the effects of contact area and applied load on the morphology of the knee components. The larger prostheses showed a higher mass loss in both tests, while Raman spectroscopy showed a more significant polymer degradation in the smaller prostheses, suggesting that a lower contact area is responsible for a higher wear at the molecular wear, but for a lower gravimetric wear. Raman measurements showed that in the second test (using a higher applied load), the wear mechanism changed with respect to the first test: the less severe conditions used in the latter resulted in an increase in the orthorhombic content, while the more severe conditions used in the former determined an increase and rearrangement of the amorphous phase. The results here reported allow to gain more insights into the effects of contact area, applied load and contact stress on wear. Preliminary micro‐Raman analyses on in vivo worn knee prostheses confirmed the results obtained in vitro: the retrievals of smaller size were found more degraded at molecular level than those of larger size. These findings showed that the conditions used in the in vitro tests well simulate the knee kinematics of the knee joint and thus the in vivo wear. Copyright © 2014 John Wiley & Sons, Ltd.
Expression of EpCAM and prognosis in early‐stage glottic cancer treated by radiotherapy
Authors: Murakami Naoya , Mori Taisuke , Yoshimoto Seiichi , Ito Yoshinori , Kobayashi Kazuma , Ken Harada , Kitaguchi Mayuka , Sekii Shuhei , Takahashi Kana , Yoshio Kotaro , Inaba Koji , Morota Madoka , Sumi Minako , Itami Jun
Published: July 2014

Objectives/Hypothesis

Treatment of head and neck squamous cell carcinoma (HNSCC) often requires radiotherapy, but relapse can occur. There is, therefore, an urgent need for the identification of a predictive novel biomarker for radiosensitivity. The epithelial cell adhesion molecule (EpCAM) has been shown to promote the transformation of malignant tumors, and EpCAM may have prognostic significance, but it is not known if EpCAM determines prognosis, especially with respect to radiotherapy. Therefore, we determined the incidence of the expression of EpCAM in HNSCC and analyzed the prognostic value in patients with early‐stage glottic cancer treated with radiotherapy.

Study Design

Retrospective analysis.

Methods

All patients with HNSCCs examined in our hospital between January 2012 and February 2013 were analyzed prospectively for the expression of EpCAM. T1–2N0 glottic cancer patients who were primarily treated by radiation therapy between 1995 and 2008 were retrospectively investigated. Patients with or without local recurrence after radical radiation therapy were extracted. The relationship between local recurrence and histopathologic EpCAM expression was compared within these two groups.

Results

One hundred eighteen patients with HNSCCs from the nasopharynx, oropharynx, hypopharynx, larynx, oral cavity, paranasal cavity, unknown primary, and other sites were analyzed. Positive expression of EpCAM was noted in the oropharynx, hypopharynx, and larynx (72%, 90%, and 58%, respectively). Seventeen and 22 patients with or without local recurrence were extracted, respectively. There was no difference between two groups, with the exception of EpCAM expression.

Conclusions

The expression of EpCAM in HNSCC was investigated. Patients with strong EpCAM expression were associated with local recurrence after primary radiation therapy.

Level of Evidence

NA Laryngoscope, 124:E431–E436, 2014
On the influence of second order uniformly elliptic operators in nonlinear problems
Authors: Montenegro Marcos , de Moura Renato J.
Published: July 2014

The purpose of the present paper is to discuss the role of second order elliptic operators of the type on the existence of a positive solution for the problem involving critical exponent

urn:x-wiley:equation:mana201300249:equation:mana201300249-math-0002where Ω is a smooth bounded domain in , , and λ is a real parameter. In particular, we show that if the function has an interior global minimum point x0 such that is comparable to , where and is the identity matrix of order n, then the range of values of λ for which the problem above has a positive solution can change drastically from to .
Deuterium‐labeled phylloquinone fed to α‐tocopherol‐injected rats demonstrates sensitivity of low phylloquinone‐containing tissues to menaquinone‐4 depletion
Authors: Farley Sherry M. , Leonard Scott W. , Stevens Jan F. , Traber Maret G.
Published: July 2014

Scope

The influence of excess α‐tocopherol (α‐T) on tissue depletion of phylloquinone (PK) and menaquinone‐4 (MK‐4) was evaluated.

Methods and results

Rats (n = 5 per group) were fed deuterium‐labeled PK (2 μmol/kg diet) for 17 days, thereby labeling the conversion from deuterium‐labeled PK to d4‐MK‐4. Then they were injected subcutaneously daily for the last 7 days with saline, vehicle, or α‐T (100 mg/kg body weight). α‐T injections (i) increased α‐T concentrations by tenfold in liver, doubled them in plasma and most tissues, but they were unchanged in brain; (ii) increased the α‐T metabolite, carboxyethyl hydroxychromanol (α‐CEHC) concentrations: >25‐fold in liver and kidney, tenfold in plasma and lung, and 50‐fold in heart; brain contained detectable α‐CEHC (0.26 ± 0.03 nmol/g) only in α‐T‐injected animals; and (iii) depleted most tissues’ vitamin K. Compared with vehicle‐injected rats, brains from α‐T rats contained half the total vitamin K (10.3 ± 0.5 versus 21 ± 2 pmol/g, p = 0.0002) and one‐third the d4‐MK‐4 (5.8 ± 0.5 versus 14.6 ± 1.7 pmol/g, p = 0.0002). Tissues with high PK concentrations (liver, 21–30 pmol/g and heart, 28–50 pmol/g) were resistant to K depletion.

Conclusion

We propose that α‐T‐dependent vitamin K depletion is likely mediated at an intermediate step in MK‐4 production; thus, tissues with high PK are unaffected.
Docosahexaenoic acid reduces linoleic acid induced monocyte chemoattractant protein‐1 expression via PPARγ and nuclear factor‐κB pathway in retinal pigment epithelial cells
Authors: Fang I‐Mo , Yang Chang‐Hao , Yang Chung‐May
Published: July 2014

Scope

To investigate whether docosahexaenoic acid (DHA) could inhibit linoleic acid (LA) induced monocyte chemoattractant protein (MCP)‐1 expression in human retinal pigment epithelial (RPE) cells.

Methods and results

ARPE‐19 cells were pretreated with DHA and then exposed to LA. The expression of MCP‐1 and PPARγ  was examined using RT‐PCR and Western blot analysis. LA at 10, 25, or 50 μM induced expression of MCP ARPE‐19 cells in a dose‐dependent manner (p < 0.05). DHA at 50 and 100 μM effectively inhibited LA‐induced MCP‐1 expression and production (p < 0.05) and NF‐κB activation. In addition, the culture medium from LA‐stimulated ARPE‐19 cells could induce tube formation in choroidal endothelial cells (RF6A), whereas 100 μM DHA inhibited tube formation. DHA at 100 μM increased the expression and activity of PPARγ (p < 0.05). Pretreatment with PPARγ inhibitor (GW9662) abolished the inhibitory effect of DHA (100 μM) on LA‐induced IκB degradation, p65 translocation, and MCP‐1 expression in ARPE‐19 cells (p < 0.05), as well as tube formation in RF6A.

Conclusion

DHA reduced LA‐induced MCP‐1 expression via a PPARγ‐ and NF‐κB‐dependent pathway in ARPE‐19 cells. These results suggest the molecular mechanisms underlying the beneficial effects of increased consumption of DHA and reduced consumption of LA on age‐related macular degeneration.
Phenylpropenoic acid glucoside augments pancreatic beta cell mass in high‐fat diet‐fed mice and protects beta cells from ER stress‐induced apoptosis
Authors: Mathijs Iris , Da Cunha Daniel A. , Himpe Eddy , Ladriere Laurence , Chellan Nireshni , Roux Candice R. , Joubert Elizabeth , Muller Christo , Cnop Miriam , Louw Johan , Bouwens Luc
Published: July 2014

Scope

A major goal of diabetes therapy is to identify novel drugs that preserve or expand pancreatic beta cell mass. Here, we examined the effect of a phenylpropenoic acid glucoside (PPAG) on the beta cell mass, and via which mechanism this effect is established.

Methods and results

Mice were fed a high‐fat and fructose‐containing diet to induce obesity and hyperglycemia. PPAG treatment protected obese mice from diet‐induced hyperglycemia and resulted in a tripling of beta cell mass. The effect of the phytochemical on beta cell mass was neither due to increased proliferation, as determined by Ki67 immunostaining, nor to neogenesis, which was assessed by genetic lineage tracing. TUNEL staining revealed suppressed apoptosis in PPAG‐treated obese mice. In vitro, PPAG protected beta cells from palmitate‐induced apoptosis. It protected beta cells against ER stress by increasing expression of antiapoptotic B‐cell lymphoma 2 (BCL2) protein without affecting proapoptotic signals.

Conclusions

We identified an antidiabetic phytochemical that protects pancreatic beta cells from ER stress and apoptosis induced by high‐fat diet/lipotoxicity. At the tissue level, this led to a tripling of beta cell mass. At the molecular level, the protective effect of the phytochemical was mediated by increasing BCL2 expression in beta cells.
Transcriptome analysis reveals a dynamic and differential transcriptional response to sulforaphane in normal and prostate cancer cells and suggests a role for Sp1 in chemoprevention
Authors: Beaver Laura M. , Buchanan Alex , Sokolowski Elizabeth I. , Riscoe Allison N. , Wong Carmen P. , Chang Jeff H. , Löhr Christiane V. , Williams David E. , Dashwood Roderick H. , Ho Emily
Published: July 2014

Scope

Epidemiological studies provide evidence that consumption of cruciferous vegetables, like broccoli, can reduce the risk of cancer development. Sulforaphane (SFN) is a phytochemical derived from cruciferous vegetables that induces anti‐proliferative and pro‐apoptotic responses in prostate cancer cells, but not in normal prostate cells. The mechanisms responsible for this cancer‐specific cytotoxicity remain unclear.

Methods and results

We utilized RNA sequencing and determined the transcriptomes of normal prostate epithelial cells, androgen‐dependent prostate cancer cells, and androgen‐independent prostate cancer cells treated with SFN. SFN treatment dynamically altered gene expression and resulted in distinct transcriptome profiles depending on prostate cell line. SFN also down‐regulated the expression of genes that were up‐regulated in prostate cancer cells. Network analysis of genes altered by SFN treatment revealed that the transcription factor Specificity protein 1 (Sp1) was present in an average of 90.5% of networks. Sp1 protein was significantly decreased by SFN treatment in prostate cancer cells and Sp1 may be an important mediator of SFN‐induced changes in expression.

Conclusion

Overall, the data show that SFN alters gene expression differentially in normal and cancer cells with key targets in chemopreventive processes, making it a promising dietary anti‐cancer agent.