bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polyomavirus Large T Antigen Binds Symmetrical Repeats at the Viral Origin in an Asymmetrical Manner
Authors: Harrison Celia , Jiang Tao , Banerjee Pubali , Meinke Gretchen , D'Abramo Claudia M. , Schaffhausen Brian , Bohm Andrew 
Published: October 2013

ABSTRACT

Polyomaviruses have repeating sequences at their origins of replication that bind the origin-binding domain of virus-encoded large T antigen. In murine polyomavirus, the central region of the origin contains four copies (P1 to P4) of the sequence G(A/G)GGC. They are arranged as a pair of inverted repeats with a 2-bp overlap between the repeats at the center. In contrast to simian virus 40 (SV40), where the repeats are nonoverlapping and all four repeats can be simultaneously occupied, the crystal structure of the four central murine polyomavirus sequence repeats in complex with the polyomavirus origin-binding domain reveals that only three of the four repeats (P1, P2, and P4) are occupied. Isothermal titration calorimetry confirms that the stoichiometry is the same in solution as in the crystal structure. Consistent with these results, mutation of the third repeat has little effect on DNA replication
in vivo
. Thus, the apparent 2-fold symmetry within the DNA repeats is not carried over to the protein-DNA complex. Flanking sequences, such as the AT-rich region, are known to be important for DNA replication. When the orientation of the central region was reversed with respect to these flanking regions, the origin was still able to replicate and the P3 sequence (now located at the P2 position with respect to the flanking regions) was again dispensable. This highlights the critical importance of the precise sequence of the region containing the pentamers in replication.
Type I Interferon and NF-κB Activation Elicited by Herpes Simplex Virus gH/gL via αvβ3 Integrin in Epithelial and Neuronal Cell Lines
Authors: Gianni Tatiana , Leoni Valerio , Campadelli-Fiume Gabriella 
Published: October 2013

ABSTRACT

αvβ3 integrin represents a novel sensing system which detects herpes simplex virus (HSV) and bacterial constituents. In cooperation with Toll-like receptor 2 (TLR2), it elicits an innate response that leads to activation of type I interferon (IFN), NF-κB, and a specific set of cytokines. We report that this defensive branch is functional in cells which represent experimental models of epithelial, including keratinocytic, and neuronal cells. These are the major targets of HSV
in vivo
. HSV entered the three cell lines via distinct routes. Hence, the defensive response was independent of the route of virus entry. Soluble gH/gL sufficed to elicit type I IFN and NF-κB activation and represents the viral pathogen-associated molecular pattern (PAMP) of this defense system.
Evolution of the Hemagglutinin Protein of the New Pandemic H1N1 Influenza Virus: Maintaining Optimal Receptor Binding by Compensatory Substitutions
Authors: de Vries Robert P. , de Vries Erik , Martínez-Romero Carles , McBride Ryan , van Kuppeveld Frank J. , Rottier Peter J. M. , García-Sastre Adolfo , Paulson James C. , de Haan Cornelis A. M. 
Published: October 2013

ABSTRACT
Pandemic influenza A H1N1 (pH1N1) virus emerged in 2009. In the subsequent 4 years, it acquired several genetic changes in its hemagglutinin (HA). Mutations may be expected while virus is adapting to the human host or upon evasion from adaptive immune responses. However, pH1N1 has not displayed any major antigenic changes so far. We examined the effect of the amino acid substitutions found to be most frequently occurring in the pH1N1 HA protein before 1 April 2012 on the receptor-binding properties of the virus by using recombinant soluble HA trimers. Two changes (S186P and S188T) were shown to increase the receptor-binding avidity of HA, whereas two others (A137T and A200T) decreased binding avidity. Construction of an HA protein tree revealed the worldwide emergence of several HA variants during the past few influenza seasons. Strikingly, two major variants harbor combinations of substitutions (S186P/A137T and S188T/A200T, respectively) with opposite individual effects on binding. Stepwise reconstruction of the HA proteins of these variants demonstrated that the mutations that increase receptor-binding avidity are compensated for by the acquisition of subsequent mutations. The combination of these substitutions restored the receptor-binding properties (avidity and specificity) of these HA variants to those of the parental virus. The results strongly suggest that the HA of pH1N1 was already optimally adapted to the human host upon its emergence in April 2009. Moreover, these results are in agreement with a recent model for antigenic drift, in which influenza A virus mutants with high and low receptor-binding avidity alternate.
Measles Virus Fusion Machinery Activated by Sialic Acid Binding Globular Domain
Authors: Talekar Aparna , Moscona Anne , Porotto Matteo 
Published: October 2013

ABSTRACT

Paramyxoviruses, including the human pathogen measles virus (MV) and the avian Newcastle disease virus (NDV), enter host cells through fusion of the viral envelope with the target cell membrane. This fusion is driven by the concerted action of two viral envelope glycoproteins: the receptor binding protein and the fusion protein (F). The MV receptor binding protein (hemagglutinin [H]) attaches to proteinaceous receptors on host cells, while the receptor binding protein of NDV (hemagglutinin-neuraminidase [HN]) interacts with sialic acid-containing receptors. The receptor-bound HN/H triggers F to undergo conformational changes that render it competent to mediate fusion of the viral and cellular membranes. The mechanism of fusion activation has been proposed to be different for sialic acid-binding viruses and proteinaceous receptor-binding viruses. We report that a chimeric protein containing the NDV HN receptor binding region and the MV H stalk domain can activate MV F to fuse, suggesting that the signal to the stalk of a protein-binding receptor binding molecule can be transmitted from a sialic acid binding domain. By engineering the NDV HN globular domain to interact with a proteinaceous receptor, the fusion activation signal was preserved. Our findings are consistent with a unified mechanism of fusion activation, at least for the
Paramyxovirinae
subfamily, in which the receptor binding domains of the receptor binding proteins are interchangeable and the stalk determines the specificity of F activation.
Activation of the Endoplasmic Reticulum Calcium Sensor STIM1 and Store-Operated Calcium Entry by Rotavirus Requires NSP4 Viroporin Activity
Authors: Hyser Joseph M. , Utama Budi , Crawford Sue E. , Broughman James R. , Estes Mary K. 
Published: October 2013

ABSTRACT
Rotavirus nonstructural protein 4 (NSP4) induces dramatic changes in cellular calcium homeostasis. These include increased endoplasmic reticulum (ER) permeability, resulting in decreased ER calcium stores and activation of plasma membrane (PM) calcium influx channels, ultimately causing a 2- to 4-fold elevation in cytoplasmic calcium. Elevated cytoplasmic calcium is absolutely required for virus replication, but the underlying mechanisms responsible for calcium influx remain poorly understood. NSP4 is an ER-localized viroporin, whose activity depletes ER calcium, which ultimately leads to calcium influx. We hypothesized that NSP4-mediated depletion of ER calcium activates store-operated calcium entry (SOCE) through activation of the ER calcium sensor stromal interaction molecule 1 (STIM1). We established and used a stable yellow fluorescent protein-expressing STIM1 cell line (YFP-STIM1) as a biosensor to assess STIM1 activation (puncta formation) by rotavirus infection and NSP4 expression. We found that STIM1 is constitutively active in rotavirus-infected cells and that STIM1 puncta colocalize with the PM-localized Orai1 SOCE calcium channel. Expression of wild-type NSP4 activated STIM1, resulting in PM calcium influx, but an NSP4 viroporin mutant failed to induce STIM1 activation and did not activate the PM calcium entry pathway. Finally, knockdown of STIM1 significantly reduced rotavirus yield, indicating STIM1 plays a critical role in virus replication. These data demonstrate that while rotavirus may ultimately activate multiple calcium channels in the PM, calcium influx is predicated on NSP4 viroporin-mediated activation of STIM1 in the ER. This is the first report of viroporin-mediated activation of SOCE, reinforcing NSP4 as a robust model to understand dysregulation of calcium homeostasis during virus infections.
Nonhuman Transferrin Receptor 1 Is an Efficient Cell Entry Receptor for Ocozocoautla de Espinosa Virus
Authors: Caì Yíngyún , Yú Shuĭqìng , Mazur Steven , Dŏng Lián , Janosko Krisztina , Zhāng Téngfēi , Müller Marcel A. , Hensley Lisa E. , Bavari Sina , Jahrling Peter B. , Radoshitzky Sheli R. , Kuhn Jens H. 
Published: October 2013

ABSTRACT
Ocozocoautla de Espinosa virus (OCEV) is a novel, uncultured arenavirus. We found that the OCEV glycoprotein mediates entry into grivet and bat cells through transferrin receptor 1 (TfR1) binding but that OCEV glycoprotein precursor (GPC)-pseudotyped retroviruses poorly entered 53 human cancer cell lines. Interestingly, OCEV and Tacaribe virus could use bat, but not human, TfR1. Replacing three human TfR1 amino acids with their bat ortholog counterparts transformed human TfR1 into an efficient OCEV and Tacaribe virus receptor.
Safely and effectively reducing inpatient length of stay: a controlled study of the General Internal Medicine Care Transformation Initiative
Authors: McAlister Finlay A , Bakal Jeffrey A , Majumdar Sumit R , Dean Stafford , Padwal Rajdeep S , Kassam Narmin , Bacchus Maria , Colbourne Ann 
Published: October 2013

PurposeWhether improving the efficiency of hospital care will worsen post-discharge outcomes is unclear. We designed this study to evaluate the General Internal Medicine (GIM) Care Transformation Initiative implemented at one of the seven teaching hospitals in the Canadian province of Alberta.MethodsControlled before–after study of GIM patients hospitalised at the University of Alberta Hospital (UAH, intervention site, n=1896) or the six other teaching hospitals in Alberta—three in Edmonton (intra-regional controls (IRC), n=4550) and three in Calgary (extra-regional controls (ERC), n=4095). The primary effectiveness outcome was risk-adjusted length of stay (LOS) and the primary safety outcome was ‘mortality during index hospitalisation or all-cause readmission or death within 30-days of discharge’.ResultsLOS for GIM patients decreased by 0.68 days at Alberta teaching hospitals between 2009 and 2012; GIM patients hospitalised at the UAH exhibited a further 20% relative decline in adjusted LOS (total reduction=1.43 days, 95% CI 0.94 to 1.92 days) from PRE to POST. Interrupted time series (ITS) confirmed that the 1.43 day reduction at the UAH was statistically significant (level change p=0.003), while the declines at the IRC (p=0.37) and ERC (p=0.45) were not. Our safety outcome did not change for UAH patients (18.4% PRE-intervention vs 17.8% POST-intervention, adjusted OR 1.02 (95%CI 0.80 to 1.31), p=0.42 on ITS), nor for those hospitalised at the IRC (p=0.33) or the ERC (p=0.73) sites.ConclusionsThe Care Transformation Initiative was associated with substantial reductions in LOS without increasing post-discharge events commonly quoted as proxies for quality.
Changing frequency of equivocal HER-2/neu scores and factors predictive of negative HER 2/neu fluorescent in situ hybridisation in invasive carcinomas of the breast
Authors: Boulos Fouad , Farra Chantal G , Saad Aldin Ehab M , Masaad Cleo , Hassoun Yasmin , Fedda Faysal , Doumiati Hassan , Tawil Ayman N , Nasser Zeina , Nahleh Zeina , Tfayli Arafat 
Published: October 2013

BackgroundAnalysis of human epidermal growth factor receptor 2 (HER-2) status has become standard of care in breast cancer patients due to its important prognostic and therapeutic implications. Immunohistochemistry (IHC) is the most commonly used primary method for detection of HER-2 overexpression. Controversy exists on the interpretation of samples that are equivocal for HER 2 status (IHC 2+). Recent guidelines state that samples equivocal for HER 2 status require validation with fluorescent in situ hybridisation (FISH). The use of FISH, however, despite higher accuracy comes at a higher cost that is not affordable to all patients.MethodsThis study is a retrospective study conducted at the American University of Beirut Medical Center, including women diagnosed with breast cancer with equivocal IHC scores presenting between 2009 and 2011. We attempted to correlate clinicopathological characteristics of patients diagnosed with breast cancer that can influence conclusions made on HER 2 status when analysing IHC equivocal samples in an effort to decrease the need for FISH testing. 113 patients in our records were included; charts were reviewed for different patient clinical characteristics and samples were analysed for pathological characteristics.ResultsUsing logistic regression, progesterone receptor status and HER-2 staining of the normal glands around the tumour by IHC were the two statistically significant variables that showed association with FISH results. The strength of progesterone receptor status positivity and HER-2 staining of the normal glands around the tumour were proportional to the likelihood of a negative FISH. Also, the presence of strong and diffuse hormone receptor positivity in low-grade tumours was predictive of negative HER-2 status.ConclusionsIn countries where resources are strained, oncologists need to think of measures to minimise the increasing financial burden of cancer care. Our study serves to highlight a few clinicopathological characteristics that might eliminate the need for further testing through FISH.
Targeting Blockage of STAT3 in Hepatocellular Carcinoma Cells Augments NK Cell Functions via Reverse Hepatocellular Carcinoma–Induced Immune Suppression
Authors: Sun Xiaoxia , Sui Qiangjun , Zhang Cai , Tian Zhigang , Zhang Jian 
Published: October 2013

Abstract
STAT3 is an important transcriptional factor for cell growth, differentiation, and apoptosis. Although evidence suggests a positive role for STAT3 in cancer, the inhibitory effects of tumor STAT3 on natural killer (NK) cell functions in human hepatocellular carcinoma are unclear. In this study, we found that blocking STAT3 in hepatocellular carcinoma cells enhanced NK-cell antitumor function. In the case of STAT3-blocked hepatocellular carcinoma cells, NKG2D ligands were upregulated, which promoted recognition by NK cells. Importantly, the cytokine profile of hepatocellular carcinoma cells was altered; in particular, TGF-β and interleukin 10 (IL-10) expression was reduced, and type I interferon (IFN) was induced, thus facilitating NK-cell activation. Indeed, the cytotoxicity of NK cells treated with supernatant from STAT3-blocked hepatocellular carcinoma cells was augmented, with a concomitant elevation of molecules associated with NK cytolysis. Further experiments confirmed that the recovery of NK cells depended on the downregulation of TGF-β and upregulation of type I IFN derived from STAT3-blocked hepatocellular carcinoma cells. These findings demonstrated a pivotal role for STAT3 in hepatocellular carcinoma-mediated NK-cell dysfunction, and highlighted the importance of STAT3 blockade for hepatocellular carcinoma immunotherapy, which could restore NK-cell cytotoxicity in addition to its direct influence on tumor cells. Mol Cancer Ther; 12(12); 2885–96. ©2013 AACR.
BRAF V600E Is a Determinant of Sensitivity to Proteasome Inhibitors
Authors: Zecchin Davide , Boscaro Valentina , Medico Enzo , Barault Ludovic , Martini Miriam , Arena Sabrina , Cancelliere Carlotta , Bartolini Alice , Crowley Emily H. , Bardelli Alberto , Gallicchio Margherita , Di Nicolantonio Federica 
Published: October 2013

Abstract
A critical step toward defining tailored therapy in patients with cancer is the identification of genetic interactions that may impair—or boost—the efficacy of selected therapeutic approaches. Cell models able to recapitulate combinations of genetic aberrations are important to find drug–genotype interactions poorly affected by the heterogeneous genetics of human tumors. In order to identify novel pharmacogenomic relationships, we employed an isogenic cell panel that reconstructs cancer genetic scenarios. We screened a library of 43 compounds in human hTERT-HME1 epithelial cells in which PTEN or RB1 were silenced in combination with the targeted knockin of cancer-associated mutations in EGFR, KRAS, BRAF, or PIK3CA oncogenes. Statistical analysis and clustering algorithms were applied to display similar drug response profiles and mutation-specific patterns of activity. From the screen, we discovered that proteasome inhibitors show selectivity toward BRAF V600E–mutant cells, irrespective of PTEN or RB1 expression. Preferential targeting of BRAF-mutant cells by proteasome inhibitors was corroborated in a second BRAF V600E isogenic model, as well as in a panel of colorectal cancer cell lines by the use of the proteasome inhibitor carfilzomib. Notably, carfilzomib also showed striking in vivo activity in a BRAF-mutant human colorectal cancer xenograft model. Vulnerability to proteasome inhibitors is dependent on persistent BRAF signaling, because BRAF V600E blockade by PLX4720 reversed sensitivity to carfilzomib in BRAF-mutant colorectal cancer cells. Our findings indicated that proteasome inhibition might represent a valuable targeting strategy in BRAF V600E–mutant colorectal tumors. Mol Cancer Ther; 12(12); 2950–61. ©2013 AACR.
Molecular Predictors of Sensitivity to the Insulin-like Growth Factor 1 Receptor Inhibitor Figitumumab (CP-751,871)
Authors: Pavlicek Adam , Lira Maruja E. , Lee Nathan V. , Ching Keith A. , Ye Jingjing , Cao Joan , Garza Scott J. , Hook Kenneth E. , Ozeck Mark , Shi Stephanie T. , Yuan Jing , Zheng Xianxian , Rejto Paul A. , Kan Julie L.C. , Christensen James G. 
Published: October 2013

Abstract
Figitumumab (CP-751,871), a potent and fully human monoclonal anti–insulin-like growth factor 1 receptor (IGF1R) antibody, has been investigated in clinical trials of several solid tumors. To identify biomarkers of sensitivity and resistance to figitumumab, its in vitro antiproliferative activity was analyzed in a panel of 93 cancer cell lines by combining in vitro screens with extensive molecular profiling of genomic aberrations. Overall response was bimodal and the majority of cell lines were resistant to figitumumab. Nine of 15 sensitive cell lines were derived from colon cancers. Correlations between genomic characteristics of cancer cell lines with figitumumab antiproliferative activity revealed that components of the IGF pathway, including IRS2 (insulin receptor substrate 2) and IGFBP5 (IGF-binding protein 5), played a pivotal role in determining the sensitivity of tumors to single-agent figitumumab. Tissue-specific differences among the top predictive genes highlight the need for tumor-specific patient selection strategies. For the first time, we report that alteration or expression of the MYB oncogene is associated with sensitivity to IGF1R inhibitors. MYB is dysregulated in hematologic and epithelial tumors, and IGF1R inhibition may represent a novel therapeutic opportunity. Although growth inhibitory activity with single-agent figitumumab was relatively rare, nine combinations comprising figitumumab plus chemotherapeutic agents or other targeted agents exhibited properties of synergy. Inhibitors of the ERBB family were frequently synergistic and potential biomarkers of drug synergy were identified. Several biomarkers of antiproliferative activity of figitumumab both alone and in combination with other therapies may inform the design of clinical trials evaluating IGF1R inhibitors. Mol Cancer Ther; 12(12); 2929–39. ©2013 AACR.
S100A14: Novel Modulator of Terminal Differentiation in Esophageal Cancer
Authors: Chen Hongyan , Ma Jianlin , Sunkel Benjamin , Luo Aiping , Ding Fang , Li Yi , He Huan , Zhang Shuguang , Xu Chengshan , Jin Qinge , Wang Qianben , Liu Zhihua 
Published: October 2013

Abstract
Aberrant keratinocyte differentiation is a key mechanism in the initiation of cancer. Because activities regulating differentiation exhibit altered or reduced capacity in esophageal cancer cells, it is vital to pinpoint those genes that control epidermal proliferation and terminal differentiation to better understand esophageal carcinogenesis. S100A14 is a member of the S100 calcium-binding protein family and has been suggested to be involved in cell proliferation, apoptosis, and invasion. The present study used immunohistochemistry analysis of S100A14 in clinical specimens of esophageal squamous cell carcinoma (ESCC) to show that decreased S100A14 is strongly correlated with poor differentiation. Furthermore, both mRNA and protein expression of S100A14 was drastically increased upon 12-O-tetra-decanoylphorbol-13-acetate (TPA) and calcium-induced esophageal cancer cell differentiation. Overexpression of S100A14 resulted in a G1-phase cell cycle arrest and promoted calcium-inhibited cell growth. Conversely, decreasing S100A14 expression significantly promoted G1–S transition and prevented the morphologic changes associated with calcium-induced cell differentiation. Molecular investigation demonstrated that S100A14 altered the calcium-induced expression of late markers of differentiation, with the most prominent effect on involucrin (IVL) and filaggrin (FLG). Finally, it was determined that S100A14 is transcriptionally regulated by JunB and that S100A14 and JunB status significantly correlated in ESCC tissue. In summary, these data demonstrate that S100A14 is transcriptionally regulated by JunB and involved in ESCC cell differentiation.
Implications: This study further differentiates the molecular mechanism controlling the development and progression of esophageal cancer. Mol Cancer Res; 11(12); 1542–53. ©2013 AACR.
A systematic review of model-based economic evaluations of diagnostic and therapeutic strategies for lower extremity artery disease
Authors: Vaidya Anil , Joore Manuela A. , Cate-Hoek Arina J. ten , Kleinegris Marie-Claire , Cate Hugo ten , Severens Johan L. 
Published: October 2013

SummaryLower extremity artery disease (LEAD) is a sign of wide spread atherosclerosis also affecting coronary, cerebral and renal arteries and is associated with increased risk of cardiovascular events. Many economic evaluations have been published for LEAD due to its clinical, social and economic importance. The aim of this systematic review was to assess modelling methods used in published economic evaluations in the field of LEAD. Our review appraised and compared the general characteristics, model structure and methodological quality of published models. Electronic databases MEDLINE and EMBASE were searched until February 2013 via OVID interface. Cochrane database of systematic reviews, Health Technology Assessment database hosted by National Institute for Health research and National Health Services Economic Evaluation Database (NHSEED) were also searched. The methodological quality of the included studies was assessed by using the Philips’ checklist. Sixteen model-based economic evaluations were identified and included. Eleven models compared therapeutic health technologies; three models compared diagnostic tests and two models compared a combination of diagnostic and therapeutic options for LEAD. Results of this systematic review revealed an acceptable to low methodological quality of the included studies. Methodological diversity and insufficient information posed a challenge for valid comparison of the included studies. In conclusion, there is a need for transparent, methodologically comparable and scientifically credible modelbased economic evaluations in the field of LEAD. Future modelling studies should include clinically and economically important cardiovascular outcomes to reflect the wider impact of LEAD on individual patients and on the society.