bluuebunny/crossref_metadata_2025 huggingface dataset:
Measles Virus Fusion Machinery Activated by Sialic Acid Binding Globular Domain
Authors: Talekar Aparna , Moscona Anne , Porotto Matteo
Published: October 2013

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

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

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.
Ameloblastoma: an aggressive lesion of the mandible
Authors: Suma M S , Sundaresh K J , Shruthy R , Mallikarjuna Rachappa
Published: October 2013

Ameloblastoma is a benign locally invasive epithelial odontogenic tumour comprising 1% of all tumours and cysts arising in the jaws. It is commonly found in the third and fourth decade in the molar ramus region of the mandible. Among all types of ameloblastoma, multicystic ameloblastoma is believed to be locally aggressive lesion that has the tendency for recurrence. In this report we present a large multicystic ameloblastoma in the left body-ramus region of the mandible in a 55-year-old woman. This large lesion was diagnosed with the help of CT and was successfully managed by hemimandibulectomy with simultaneous reconstruction using iliac crest bone.
Management of ST elevation myocardial infarction in pregnancy
Authors: Constantine Andrew Harry , Mozid Abdul M , Aggarwal Rajesh
Published: October 2013

A 33-year-old lady in the second trimester of pregnancy presented to the emergency department having suffered a cardiac arrest at home. An emergency caesarean section was performed in the resuscitation area. On return of spontaneous circulation, a 12-lead ECG showed anterior ST elevation myocardial infarction. She was transferred to our tertiary centre for an emergency coronary angiography and was successfully treated, making a full recovery. This case report examines the relatively rare entity of myocardial infarction in pregnancy and looks at the mechanisms underlying this.
Barefoot running: an evaluation of current hypothesis, future research and clinical applications
Authors: Tam Nicholas , Astephen Wilson Janie L , Noakes Timothy D , Tucker Ross
Published: October 2013

Barefoot running has become a popular research topic, driven by the increasing prescription of barefoot running as a means of reducing injury risk. Proponents of barefoot running cite evolutionary theories that long-distance running ability was crucial for human survival, and proof of the benefits of natural running. Subsequently, runners have been advised to run barefoot as a treatment mode for injuries, strength and conditioning. The body of literature examining the mechanical, structural, clinical and performance implications of barefoot running is still in its infancy. Recent research has found significant differences associated with barefoot running relative to shod running, and these differences have been associated with factors that are thought to contribute to injury and performance. Crucially, long-term prospective studies have yet to be conducted and the link between barefoot running and injury or performance remains tenuous and speculative. The injury prevention potential of barefoot running is further complicated by the complexity of injury aetiology, with no single factor having been identified as causative for the most common running injuries. The aim of the present review was to critically evaluate the theory and evidence for barefoot running, drawing on both collected evidence as well as literature that have been used to argue in favour of barefoot running. We describe the factors driving the prescription of barefoot running, examine which of these factors may have merit, what the collected evidence suggests about the suitability of barefoot running for its purported uses and describe the necessary future research to confirm or refute the barefoot running hypotheses.
How to minimise the health risks to athletes who compete in weight-sensitive sports review and position statement on behalf of the Ad Hoc Research Working Group on Body Composition, Health and Performance, under the auspices of the IOC Medical Commission
Authors: Sundgot-Borgen Jorunn , Meyer Nanna L , Lohman Timothy G , Ackland Timothy R , Maughan Ronald J , Stewart Arthur D , Müller Wolfram
Published: October 2013

A focus on low body weight and body fat content, combined with regulations in some weight-sensitive sports, are considered risk factors for extreme dieting, eating disorders (EDs) and related health consequences among athletes. At present there are, from a health perspective, no generally accepted optimum values for body weight or percentage of fat mass in different sports and there is no ‘gold standard’ method for body composition assessment in athletes. On the basis of health considerations as well as performance, medical support teams should know how to approach elite athletes who seek to achieve an unrealistic body composition and how to prevent restrictive eating practices from developing into an ED. In addition, these teams must know when to raise the alarm and how to advice athletes who are affected by extreme dieting or clinical EDs. However, there is no consensus on when athletes struggling with extreme dieting or EDs should be referred for specialist medical treatment or removed from competition. Based on the present review, we conclude that there is a need for (1) sport-specific and gender-specific preventive programmes, (2) criteria for raising alarm and ‘does not start’ (DNS) for athletes with EDs and (3) modifications to the regulations in some sports. Further, the key areas for research identified include the development of standard methods for body composition assessment in elite athletes; screening measures for EDs among athletes; development and testing of prevention programmes; investigating the short and long-term effects of extreme dieting; and EDs on health and performance.
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

Purpose

Whether 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.

Methods

Controlled 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’.

Results

LOS 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.

Conclusions

The 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

Background

Analysis 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.

Methods

This 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.

Results

Using 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.

Conclusions

In 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.
EQUIVALENT FORCES IN NEWTON EQUATION FROM TWIST DEFORMATIONS AND NON-INERTIAL COORDINATE FRAMES
Authors: DASZKIEWICZ MARCIN
Published: October 2013

We compare two ways of forces generated in the model of nonrelativistic particle moving in the presence of constant field force F. One of them uses the twist-deformed N-enlarged Newton–Hooke quantum spacetimes while the other incorporates the Coriolis transformations of classical space. In particular, we find the conditions for which both treatments provide the same forces. The presented investigations are performed by analogy to the schemes and ideas proposed in Ref. 1.
STRUCTURAL AND ELECTRONIC EVOLUTION FROM SiC SHEET TO SILICENE
Authors: LIU G. , WU M. S. , OUYANG C. Y. , XU B.
Published: October 2013

The evolution of the structural and electronic properties from SiC sheet to silicene is studied by using first-principles density functional theory. It is found that the planar configurations of the Si – C monolayer systems are basically kept except for the increase of the buckling of the planar structure when the substitution ratio of Si increases. Band gaps of the Si – C monolayer system decrease gradually when the substitution ratio of Si atoms ranges from 0% to 100%. The energy and type of the band gaps are closely related with the substitution ratio of Si atoms and the Si – C order. Further analysis of density of states reveals the orbital contribution of Si and C atoms near the Fermi level. The discussion of the electronic evolution from SiC sheet to silicene would widen the application of the Si – C monolayer systems in the optoelectronic field in the future nanotechnology.
THE PLANCK MISSION: RECENT RESULTS, COSMOLOGICAL AND FUNDAMENTAL PHYSICS PERSPECTIVES
Authors: MANDOLESI NAZZARENO , BURIGANA CARLO , GRUPPUSO ALESSANDRO , NATOLI PAOLO
Published: October 2013

We provide a description of the latest status and performance of the Planck satellite, focusing on the final predicted sensitivity of Planck. The optimization of the observational strategy for the additional surveys following the nominal 15 months of integration (about two surveys) originally allocated and the limitation represented by astrophysical foreground emissions are presented. An outline of early and intermediate astrophysical results from the Planck Collaboration is provided. A concise view of some fundamental cosmological results that will be achieved by exploiting Planck's full set of temperature and polarization data are presented. Finally, the perspectives opened by Planck in answering some key questions in fundamental physics, with particular attention to parity symmetry analyses, are described.
A ROBUST FUZZY CLASSIFICATION MAXIMUM LIKELIHOOD CLUSTERING FRAMEWORK
Authors: YANG MIIN-SHEN , LIN CHIH-YING , TIAN YI-CHENG
Published: October 2013

In 1993, Yang first extended the classification maximum likelihood (CML) to a so-called fuzzy CML, by combining fuzzy c-partitions with the CML function. Fuzzy c-partitions are generally an extension of hard c-partitions. It was claimed that this was more robust. However, the fuzzy CML still lacks some robustness as a clustering algorithm, such as its in-ability to detect different volumes of clusters, its heavy dependence on parameter initializations and the necessity to provide an a priori cluster number. In this paper, we construct a robust fuzzy CML clustering framework that has a robust clustering method. The eigenvalue decomposition of a covariance matrix is firstly considered using the fuzzy CML model. The Bayesian information criterion (BIC) is then used for model selection, in order to choose the best model with the optimal number of clusters. Therefore, the proposed robust fuzzy CML clustering framework exhibits clustering characteristics that are robust in terms of the parameter initialization, robust in terms of the cluster number and also in terms of its capability to detect different volumes of clusters. Numerical examples and real data applications with comparisons are provided, which demonstrate the effectiveness and superiority of the proposed method.
Nancy E. Beckage (1950–2012): Pioneer in Insect Host-Parasite Interactions
Authors: Riddiford Lynn M. , Webb Bruce A.
Published: October 2013

Nancy E. Beckage is widely recognized for her pioneering work in the field of insect host-parasitoid interactions beginning with endocrine influences of the tobacco hornworm, Manduca sexta, host and its parasitoid wasp Apanteles congregatus (now Cotesia congregata) on each other's development. Moreover, her studies show that the polydnavirus carried by the parasitoid wasp not only protects the parasitoid from the host's immune defenses, but also is responsible for some of the developmental effects of parasitism. Nancy was a highly regarded mentor of both undergraduate and graduate students and more widely of women students and colleagues in entomology. Her service both to her particular area and to entomology in general through participation on federal grant review panels and in the governance of the Entomological Society of America, organization of symposia at both national and international meetings, and editorship of several different journal issues and of several books is legendary. She has left behind a lasting legacy of increased understanding of multilevel endocrine and physiological interactions among insects and other organisms and a strong network of interacting scientists and colleagues in her area of entomology.
Daily exposure to a running wheel entrains circadian rhythms in mice in parallel with development of an increase in spontaneous movement prior to running-wheel access
Authors: Yamanaka Yujiro , Honma Sato , Honma Ken-ichi
Published: October 2013

Entrainment of circadian behavior rhythms by daily exposure to a running wheel was examined in mice under constant darkness. Spontaneous movement was individually monitored for more than 6 mo by a thermal sensor. After establishment of steady-state free running, mice were placed in a different cage equipped with a running-wheel for 3 h once per day at 6 AM. The daily exchange was continued for 80 days. The number of wheel revolutions during exposure to the running wheel was also measured simultaneously with spontaneous movement. In 13 out of 17 mice, circadian behavior rhythm was entrained by daily wheel exposure, showing a period indistinguishable from 24 h. The entrainment occurred in parallel with an increase in spontaneous movement immediately prior to the daily wheel exposure. A similar preexposure increase was observed in only one of four nonentrained mice. The preexposure increase appeared in 19.5 days on average after the start of daily wheel exposure and persisted for 36 days on average after the termination of the exposure schedule. The preexposure increase was detected only when daily wheel exposure came into the activity phase of the circadian behavior rhythm, which was accompanied by an increase in the number of wheel revolutions. These findings indicate that a novel oscillation with a circadian period is induced in mice by daily exposure to a running wheel at a fixed time of day and suggest that the oscillation is involved in the nonphotic entrainment of circadian rhythms in spontaneous movement.
Effects of the motor cortical quadripulse transcranial magnetic stimulation (QPS) on the contralateral motor cortex and interhemispheric interactions
Authors: Tsutsumi Ryosuke , Hanajima Ritsuko , Terao Yasuo , Shirota Yuichiro , Ohminami Shinya , Shimizu Takahiro , Tanaka Nobuyuki , Ugawa Yoshikazu
Published: October 2013

Corpus callosum connects the bilateral primary motor cortices (M1s) and plays an important role in motor control. Using the paired-pulse transcranial magnetic stimulation (TMS) paradigm, we can measure interhemispheric inhibition (IHI) and interhemispheric facilitation (IHF) as indexes of the interhemispheric interactions in humans. We investigated how quadripulse transcranial magnetic stimulation (QPS), one form of repetitive TMS (rTMS), on M1 affects the contralateral M1 and the interhemispheric interactions. QPS is able to induce bidirectional plastic changes in M1 depending on the interstimulus intervals (ISIs) of TMS pulses: long-term potentiation (LTP)-like effect by QPS-5 protocol, and long-term depression-like effect by QPS-50, whose numbers indicate the ISI (ms). Twelve healthy subjects were enrolled. We applied QPS over the left M1 and recorded several parameters before and 30 min after QPS. QPS-5, which increased motor-evoked potentials (MEPs) induced by left M1 activation, also increased MEPs induced by right M1 activation. Meanwhile, QPS-50, which decreased MEPs elicited by left M1 activation, did not induce any significant changes in MEPs elicited by right M1 activation. None of the resting motor threshold, active motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation, and short-interval intracortical inhibition in right M1 were affected by QPS. IHI and IHF from left to right M1 significantly increased after left M1 QPS-5. The degree of left first dorsal interosseous MEP amplitude change by QPS-5 significantly correlated with the degree of IHF change. We suppose that the LTP-like effect on the contralateral M1 may be produced by some interhemispheric interactions through the corpus callosum.
Central complex neurons exhibit behaviorally gated responses to visual motion inDrosophila
Authors: Weir Peter T. , Schnell Bettina , Dickinson Michael H.
Published: October 2013

Sensory systems provide abundant information about the environment surrounding an animal, but only a small fraction of that information is relevant for any given task. One example of this requirement for context-dependent filtering of a sensory stream is the role that optic flow plays in guiding locomotion. Flying animals, which do not have access to a direct measure of ground speed, rely on optic flow to regulate their forward velocity. This observation suggests that progressive optic flow, the pattern of front-to-back motion on the retina created by forward motion, should be especially salient to an animal while it is in flight, but less important while it is standing still. We recorded the activity of cells in the central complex of Drosophila melanogaster during quiescence and tethered flight using both calcium imaging and whole cell patch-clamp techniques. We observed a genetically identified set of neurons in the fan-shaped body that are unresponsive to visual motion while the animal is quiescent. During flight their baseline activity increases, and they respond to front-to-back motion with changes relative to this baseline. The results provide an example of how nervous systems selectively respond to complex sensory stimuli depending on the current behavioral state of the animal.
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

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

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

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

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

Lower 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.
Mediterranean and DASH Diet Scores and Mortality in Women With Heart Failure
Authors: Levitan Emily B. , Lewis Cora E. , Tinker Lesley F. , Eaton Charles B. , Ahmed Ali , Manson JoAnn E. , Snetselaar Linda G. , Martin Lisa W. , Trevisan Maurizio , Howard Barbara V. , Shikany James M.
Published: October 2013

Background—

Current dietary recommendations for patients with heart failure (HF) are largely based on data from non-HF populations; evidence on associations of dietary patterns with outcomes in HF is limited. We therefore evaluated associations of Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diet scores with mortality among postmenopausal women with HF.

Methods and Results—

Women’s Health Initiative participants were followed up from the date of HF hospitalization through the date of death or last participant contact before August 2009. Mediterranean and DASH diet scores were calculated from food-frequency questionnaires. Cox proportional hazards models adjusted for demographics, health behaviors, and health status were used to calculate hazard ratios and 95% confidence intervals (CI). For a median of 4.6 years of follow-up, 1385 of 3215 (43.1%) participants who experienced a HF hospitalization died. Multivariable-adjusted hazard ratios were 1 (reference), 1.05 (95% CI, 0.89–1.24), 0.97 (95% CI, 0.81–1.17), and 0.85 (95% CI, 0.70–1.02) across quartiles of the Mediterranean diet score (
P
trend=0.08) and 1 (reference), 1.04 (95% CI, 0.89–1.21), 0.83 (95% CI, 0.70–0.98), and 0.84 (95% CI, 0.70–1.00) across quartiles of the DASH diet score (
P
trend=0.01). Diet score components, vegetables, nuts, and whole grain intake, were inversely associated with mortality.

Conclusions—

Higher DASH diet scores were associated with modestly lower mortality in women with HF, and there was a nonsignificant trend toward an inverse association with Mediterranean diet scores. These data provide support for the concept that dietary recommendations developed for other cardiovascular conditions or general populations may also be appropriate in patients with HF.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00000611.
Enoyl Coenzyme A Hydratase Domain–Containing 2, a Potential Novel Regulator of Myocardial Ischemia Injury
Authors: Du Jianhai , Li Zhixin , Li Quan‐Zhen , Guan Tongju , Yang Qiuhui , Xu Hao , Pritchard Kirkwood A. , Camara Amadou K. S. , Shi Yang
Published: October 2013

Background

We reported previously that Brown Norway (
BN
) rats are more resistant to myocardial ischemia/reperfusion (I/R) injury than are Dahl S (
SS
) rats. To identify the unique genes differentially expressed in the hearts of these rats, we used
DNA
microarray analysis and observed that enoyl coenzyme A hydratase–containing domain 2 (
ECHDC
2) is highly expressed (≈18‐fold) in the
SS
hearts compared with the
BN
hearts.

Methods and Results

RT
‐
PCR
,
W
estern blot, and immunohistochemistry analyses verified that
ECHDC
2 was highly expressed in
SS
hearts compared with the
BN
hearts.

ECHDC
2

gene locates at chromosome 5 of rat and is expressed in mitochondria of the heart, mainly in cardiomyocytes but not in cardiofibroblasts. Overexpression of
ECHDC
2 in cells increased susceptibility to I/R injury while knockdown of
ECHDC
2 enhanced resistance to I/R injury. Furthermore, we observed that left anterior descending coronary artery ligation–induced myocardial infarction was more severe in the
SS
hearts than in the
BN
hearts or
SSBN
5 hearts, which was built on
SS
rats but had the substitution of chromosome 5 from
BN
rats. We also demonstrated that
ECHDC
2 did not alter mitochondrial O
2
consumption, metabolic intermediates and
ATP
production. By gas chromatography–mass spectrometry, we found that
ECHDC
2 overexpression increased the levels of the cellular branched chain amino acids leucine and valine.

Conclusion

ECHDC
2, a mitochondrial protein, may be involved in regulating cell death and myocardial injury. Its deficiency in
BN
rats contributes to their increased resistance to myocardial I/R compared with
SS
rats.
ECHDC
2 increases branched chain amino acid metabolism and appears to be a novel regulator linking cell metabolism with cardiovascular disease.
Authorship Attribution with Topic Models
Authors: Seroussi Yanir , Zukerman Ingrid , Bohnert Fabian
Published: October 2013

Authorship attribution deals with identifying the authors of anonymous texts. Traditionally, research in this field has focused on formal texts, such as essays and novels, but recently more attention has been given to texts generated by on-line users, such as e-mails and blogs. Authorship attribution of such on-line texts is a more challenging task than traditional authorship attribution, because such texts tend to be short, and the number of candidate authors is often larger than in traditional settings. We address this challenge by using topic models to obtain author representations. In addition to exploring novel ways of applying two popular topic models to this task, we test our new model that projects authors and documents to two disjoint topic spaces. Utilizing our model in authorship attribution yields state-of-the-art performance on several data sets, containing either formal texts written by a few authors or informal texts generated by tens to thousands of on-line users. We also present experimental results that demonstrate the applicability of topical author representations to two other problems: inferring the sentiment polarity of texts, and predicting the ratings that users would give to items such as movies.
Identification of Multiword Expressions by Combining Multiple Linguistic Information Sources
Authors: Tsvetkov Yulia , Wintner Shuly
Published: October 2013

We propose a framework for using multiple sources of linguistic information in the task of identifying multiword expressions in natural language texts. We define various linguistically motivated classification features and introduce novel ways for computing them. We then manually define interrelationships among the features, and express them in a Bayesian network. The result is a powerful classifier that can identify multiword expressions of various types and multiple syntactic constructions in text corpora. Our methodology is unsupervised and language-independent; it requires relatively few language resources and is thus suitable for a large number of languages. We report results on English, French, and Hebrew, and demonstrate a significant improvement in identification accuracy, compared with less sophisticated baselines.
Muʿtazilī Discussions of the Abrogation of the Torah Ibn Ḫallād (4th/10th century) and His Commentators*
Authors: Schmidtke Sabine , Adang Camilla
Published: October 2013

Abstract

Abū ʿAlī Muḥammad b. Ḫallād al-Baṣrī, a distinguished disciple of Abū Hāšim al-Ǧubbāʾī (d. 321/933), wrote a Kitāb al-Uṣūl together with an autocommentary, both of which are lost. Substantial portions of his Kitāb al-Uṣūl, though, have reached us embedded in two works by later Muʿtazilī authors, viz. the Kitāb Ziyādāt Šarḥ al-uṣūl by the Zaydī Imām al-Nāṭiq bi-l-Ḥaqq Abū Ṭālib Yaḥyā b. al-Ḥusayn b. Hārūn al-Buṭḥānī (d. 424/1033) and a second supercommentary or taʿlīq that was apparently composed by the Zaydī author ʿAlī b. al-Ḥusayn b. Muḥammad al-Daylamī Siyāh [Šāh] Sarīǧān [Sarbīǧān]. Both works provide valuable and supplementary information on Ibn Ḫallād’s original Kitāb al-Uṣūl/Šarḥ al-uṣūl. By way of example, the section on the abrogation of the Torah from the two commentaries is offered in a critical edition, and the similarities and discrepancies between the two works are discussed in detail on the basis of this section. The issue discussed here is one of the main arguments in polemics between Muslims and Jews.
Early Postoperative Results in Stapedectomy
Authors: Sperling Neil M. , Sury Krishna , Gordon Jessica , Cox Shaun
Published: October 2013

Objective

To measure early audiometric changes after primary stapedotomy.

Study Design

Case series with chart review.

Setting

Academic inner‐city hospitals.

Subjects and Methods

Consecutive patients operated on by the first author were included (only 1 ear in cases of bilateral surgery), and their audiometric results were reviewed. Data were analyzed from 45 ears. Air and bone audiometric measures were analyzed from 5 days post operation and 6 months post operation. Threshold shifts were quantified at 5 days and 6 months post operation.

Results

Overall results for the group were good, with 91% of patients achieving an air‐bone gap less than or equal to 10 dB by 6 months post operation. Threshold shifts in at least 1 frequency were common at 5 days (62% of patients), but less so at 6 months (36%). Patients with shifts did not have worse overall outcomes at 6 months than those with no shifts. No difference in results was observed for the 2 prostheses used in this series.

Conclusion

Early audiometric results after stapedectomy commonly reveal worsened bone conduction (postoperative threshold shifts), which may reflect cochlear trauma, but do not lead to poorer outcomes as measured by conventional methods.
Local Safety Concerns of Repited Dexamethasone Intravitreal Implant (Ozurdex®) For Macular Diseases
Authors: Gallego-Pinazo Roberto , Hernández-Martinez Pablo q , Hervás-Ontiveros Ana , Martínez-Castillo Sebastián , Dolz-Marco Rosa , Arévalo J. Fernando , Wu Lihteh , Díaz-Llopis Manuel
Published: October 2013

Introduction: The objective of the present study was to analyze the expanding indications for the dexamethasone intravitreal implant (Ozurdex®) in macular edema of varied diseases, and determine its safety concerns. 
Materials and Methods: We retrospectively reviewed the ophthalmic charts of patients treated with at least one intravitreal injection of Ozurdex® since April 2010 to October 2011. Data regarding complications of the procedure as well as the need for cataract surgery were collected. No patient with the diagnosis of glaucoma was included in the present study. Early recurrences where treated with laser photocoagulation or intravitreal ranibizumab at the discretion of the physician; late recurrences where treated with a new Ozurdex® injection. 
Results: The causative diseases of ME in the 214 eyes of our sample were: diabetic macular edema (101 eyes of 84 patients); branch retinal vein occlusion (27 eyes of 27 patients with superior temporal branch occlusion; 6 eyes of 6 patients with inferior temporal branch occlusion); central retinal vein occlusion (23 eyes of 23 patients); uveitic macular edema (13 eyes of 11 patients). Patients with other indications such as exudative age-related macular degeneration (27 eyes of 27 patients), and pseudophakic cystoid macular edema (7 eyes of 7 patients). Regarding complications, we found a rate of posterior cataract progression in 69.6% of phakic eyes after receiving a second intravitreal Ozurdex® for the treatment of ME. A significant IOP increase was evidenced in 21.18% of cases following the first Ozurdex® implant. Patients with uveitic macular edema (UME) showed the greatest rate of IOP increase (53.86%) following Ozurdex® implant. In addition, anterior chamber migration of the Ozurdex® implant was seen in 2 cases with lens posterior capsule rupture. 
Discussion: This is a descriptive study of 214 eyes of 189 patients treated with intravitreal Ozurdex® in real-life conditions, which adds an important value for the retinal physicians. Further long-term studies are warranted in order to establish a more accurate safety profile of Ozurdex® for retinal diseases.