bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping of Functional Domains of the Lipid Kinase Phosphatidylinositol 4-Kinase Type III Alpha Involved in Enzymatic Activity and Hepatitis C Virus Replication
Authors: Harak Christian , Radujkovic Danijela , Taveneau Cyntia , Reiss Simon , Klein Rahel , Bressanelli Stéphane , Lohmann Volker 
Published: June 2014

ABSTRACT

The lipid kinase phosphatidylinositol 4-kinase III alpha (PI4KIIIα) is an endoplasmic reticulum (ER)-resident enzyme that synthesizes phosphatidylinositol 4-phosphate (PI4P). PI4KIIIα is an essential host factor for hepatitis C virus (HCV) replication. Interaction with HCV nonstructural protein 5A (NS5A) leads to kinase activation and accumulation of PI4P at intracellular membranes. In this study, we investigated the structural requirements of PI4KIIIα in HCV replication and enzymatic activity. Therefore, we analyzed PI4KIIIα mutants for subcellular localization, reconstitution of HCV replication in PI4KIIIα knockdown cell lines, PI4P induction in HCV-positive cells, and lipid kinase activity
in vitro
. All mutants still interacted with NS5A and localized in a manner similar to that of the full-length enzyme, suggesting multiple regions of PI4KIIIα are involved in NS5A interaction and subcellular localization. Interestingly, the N-terminal 1,152 amino acids were dispensable for HCV replication, PI4P induction, and enzymatic function, whereas further N-terminal or C-terminal deletions were deleterious, thereby defining the minimal PI4KIIIα core enzyme at a size of ca. 108 kDa. Additional deletion of predicted functional motifs within the C-terminal half of PI4KIIIα also were detrimental for enzymatic activity and for the ability of PI4KIIIα to rescue HCV replication, with the exception of a proposed nuclear localization signal, suggesting that the entire C-terminal half of PI4KIIIα is involved in the formation of a minimal enzymatic core. This view was supported by structural modeling of the PI4KIIIα C terminus, suggesting a catalytic center formed by an N- and C-terminal lobe and an armadillo-fold motif, which is preceded by three distinct alpha-helical domains probably involved in regulation of enzymatic activity.

IMPORTANCE
The lipid kinase PI4KIIIα is of central importance for cellular phosphatidylinositol metabolism and is a key host cell factor of hepatitis C virus replication. However, little is known so far about the structure of this 240-kDa protein and the functional importance of specific subdomains regarding lipid kinase activity and viral replication. This work focuses on the phenotypic analysis of distinct PI4KIIIα mutants in different biochemical and cell-based assays and develops a structural model of the C-terminal enzymatic core. The results shed light on the structural and functional requirements of enzymatic activity and the determinants required for HCV replication.
Impaired Immune Response to Vaccination against Infection with Human Respiratory Syncytial Virus at Advanced Age
Authors: Guichelaar Teun , Hoeboer Jeroen , Widjojoatmodjo Myra N. , Reemers Sylvia S. N. , van Els Cécile A. C. M. , Otten Rob , van Remmerden Yvonne , Boes Jolande , Luytjes Willem 
Published: June 2014

ABSTRACTElderly humans are prone to severe infection with human respiratory syncytial virus (HRSV). The aging of today's human population warrants the development of protective vaccination strategies aimed specifically at the elderly. This may require special approaches due to deteriorating immune function. To design and test vaccination strategies tailored to the elderly population, we need to understand the host response to HRSV vaccination and infection at old age. Moreover, the preclinical need for testing of candidate vaccines requires translational models resembling susceptibility to the (unadapted) human pathogen. Here, we explored the effects of aging on immunity and protection induced by a model HRSV vaccine candidate in a translational aging model in cotton rats (Sigmodon hispidus) and examined possibilities to optimize vaccination concepts for the elderly. We immunized young and aged cotton rats with a live-attenuated recombinant HRSV vaccine candidate and analyzed the induced immune response to and protection against challenge with HRSV. In old cotton rats, HRSV infection persisted longer, and vaccination induced less protection against infection. Aged animals developed lower levels of vaccine-induced IgG, virus-neutralizing serum antibodies, and IgA in lungs. Moreover, booster responses to HRSV challenge were impaired in animals vaccinated at an older age. However, increased dose and reduced attenuation of vaccine improved protection even in old animals. This study shows that cotton rats provide a model for studying the effects of aging on the immune response to the human respiratory pathogen HRSV and possibilities to optimize vaccine concepts for the elderly.IMPORTANCEHRSV infection poses a risk for severe disease in the elderly. The aging of the population warrants increased efforts to prevent disease at old age, whereas HRSV vaccines are only in the developmental phase. The preclinical need for testing of candidate human vaccines requires translational models resembling susceptibility to the natural human virus. Moreover, we need to gain insight into waning immunity at old age, as this is a special concern in vaccine development. In this study, we explored the effect of age on protection and immunity against an experimental HRSV vaccine in aged cotton rats (Sigmodon hispidus), a rodent species that provides a model representing natural susceptibility to human viruses. Older animals generate fewer antibodies upon vaccination and require a higher vaccine dose for protection. Notably, during the early secondary immune response to subsequent HRSV infection, older animals showed less protection and a slower increase of the virus-neutralizing antibody titer.
Human and Host Species Transferrin Receptor 1 Use by North American Arenaviruses
Authors: Zong Min , Fofana Isabel , Choe Hyeryun 
Published: June 2014

ABSTRACT
At least five New World (NW) arenaviruses cause hemorrhagic fevers in South America. These pathogenic clade B viruses, as well as nonpathogenic arenaviruses of the same clade, use transferrin receptor 1 (TfR1) of their host species to enter cells. Pathogenic viruses are distinguished from closely related nonpathogenic ones by their additional ability to utilize human TfR1 (hTfR1). Here, we investigate the receptor usage of North American arenaviruses, whose entry proteins share greatest similarity with those of the clade B viruses. We show that all six North American arenaviruses investigated utilize host species TfR1 orthologs and present evidence consistent with arenavirus-mediated selection pressure on the TfR1 of the North American arenavirus host species. Notably, one of these viruses, AV96010151, closely related to the prototype Whitewater Arroyo virus (WWAV), entered cells using hTfR1, consistent with a role for a WWAV-like virus in three fatal human infections whose causative agent has not been identified. In addition, modest changes were sufficient to convert hTfR1 into a functional receptor for most of these viruses, suggesting that a minor alteration in virus entry protein may allow these viruses to use hTfR1. Our data establish TfR1 as a cellular receptor for North American arenaviruses, highlight an “arms race” between these viruses and their host species, support the association of North American arenavirus with fatal human infections, and suggest that these viruses have a higher potential to emerge and cause human diseases than has previously been appreciated.

IMPORTANCE
hTfR1 use is a key determinant for a NW arenavirus to cause hemorrhagic fevers in humans. All known pathogenic NW arenaviruses are transmitted in South America by their host rodents. North American arenaviruses are generally considered nonpathogenic, but some of these viruses have been tentatively implicated in human fatalities. We show that these North American arenaviruses use the TfR1 orthologs of their rodent host species and identify TfR1 polymorphisms suggesting an ongoing “arms race” between these viruses and their hosts. We also show that a close relative of a North American arenavirus suggested to have caused human fatalities, the Whitewater Arroyo species complex virus AV96010151, uses human TfR1. Moreover, we present data that imply that modest changes in other North American arenaviruses might allow these viruses to infect humans. Collectively, our data suggest that North American arenaviruses have a higher potential to cause human disease than previously assumed.
Locking and Blocking the Viral Landscape of an Alphavirus with Neutralizing Antibodies
Authors: Porta Jason , Jose Joyce , Roehrig John T. , Blair Carol D. , Kuhn Richard J. , Rossmann Michael G. 
Published: June 2014

ABSTRACTAlphaviruses are serious, sometimes lethal human pathogens that belong to the familyTogaviridae. The structures of human Venezuelan equine encephalitis virus (VEEV), an alphavirus, in complex with two strongly neutralizing antibody Fab fragments (F5 and 3B4C-4) have been determined using a combination of cryo-electron microscopy and homology modeling. We characterize these monoclonal antibody Fab fragments, which are known to abrogate VEEV infectivity by binding to the E2 (envelope) surface glycoprotein. Both of these antibody Fab fragments cross-link the surface E2 glycoproteins and therefore probably inhibit infectivity by blocking the conformational changes that are required for making the virus fusogenic. The F5 Fab fragment cross-links E2 proteins within one trimeric spike, whereas the 3B4C-4 Fab fragment cross-links E2 proteins from neighboring spikes. Furthermore, F5 probably blocks the receptor-binding site, whereas 3B4C-4 sterically hinders the exposure of the fusion loop at the end of the E2 B-domain.IMPORTANCEAlphaviral infections are transmitted mainly by mosquitoes. Venezuelan equine encephalitis virus (VEEV) is an alphavirus with a wide distribution across the globe. No effective vaccines exist for alphaviral infections. Therefore, a better understanding of VEEV and its associated neutralizing antibodies will help with the development of effective drugs and vaccines.
Association between childhood adversities and long-term suicidality among South Africans from the results of the South African Stress and Health study: a cross-sectional study
Authors: Bruwer Belinda , Govender Ravi , Bishop Melanie , Williams David R , Stein Dan J , Seedat Soraya 
Published: June 2014

ObjectiveSuicide and suicidal behaviours are significant public health problems and a leading cause of death worldwide and in South Africa. We examined the association between childhood adversities and suicidal behaviour over the life course.MethodsA national probability sample of 4351 South African adult participants (aged 18 years and older) in the South African Stress and Health (SASH) study was interviewed as part of the World Mental Health Surveys initiative. Respondents provided sociodemographic and diagnostic information, as well as an account of suicide-related thoughts and behaviours. Suicidality or suicidal behaviour were defined as were defined as suicide attempts and suicidal ideation in the total sample, and suicide plans and attempts among ideators. Childhood adversities included physical abuse, sexual abuse, parental death, parental divorce, other parental loss, family violence, physical illness and financial adversity. The association between suicidality and childhood adversities was examined using discrete-time survival models.ResultsMore than a third of the respondents with suicidal behaviour experienced at least one childhood adversity, with physical abuse, parental death and parental divorce being the most prevalent adversities. Physical abuse, sexual abuse and parental divorce were identified as significant risk markers for lifetime suicide attempts, while physical abuse and parental divorce were significantly correlated with suicidal ideation. Two or more childhood adversities were associated with a twofold higher risk of lifetime suicide attempts. Sexual abuse (OR 9.3), parental divorce (OR 3.1) and childhood physical abuse (OR 2.2) had the strongest associations with lifetime suicide attempts. The effect of childhood adversities on suicidal tendencies varied over thelife course.For example, sexual abuse was significantly associated with suicide attempts during childhood and teen years, but not during young and later adulthood.ConclusionsChildhood adversities, especially sexual abuse, physical abuse and parental divorce, are important risk factors for the onset and persistence of suicidal behaviour, with this risk being greatest in childhood and adolescence.
Weyl groups and vertex operator algebras generated by Ising vectors satisfying the (2B, 3C) condition
Authors: Chen Hsian-Yang , Lam Ching Hung 
Published: June 2014

In this paper, we construct explicitly certain moonshine type vertex operator algebras generated by a set of Ising vectors I such that(1) for any e ≠ f ∈ I, the subVOA VOA (e, f) generated by e and f is isomorphic to either U2Bor U3C; and(2) the subgroup generated by the corresponding Miyamoto involutions {τe| e ∈ I} is isomorphic to the Weyl group of a root system of type An, Dn, E6, E7or E8.The structures of the corresponding vertex operator algebras and their Griess algebras are also studied. In particular, the central charge of these vertex operator algebras are determined.
Predicted 25(OH)D Score and Colorectal Cancer Risk According to Vitamin D Receptor Expression
Authors: Jung Seungyoun , Qian Zhi Rong , Yamauchi Mai , Bertrand Kimberly A. , Fitzgerald Kathryn C. , Inamura Kentaro , Kim Sun A. , Mima Kosuke , Sukawa Yasutaka , Zhang Xuehong , Wang Molin , Smith-Warner Stephanie A. , Wu Kana , Fuchs Charles S. , Chan Andrew T. , Giovannucci Edward L. , Ng Kimmie , Cho Eunyoung , Ogino Shuji , Nishihara Reiko 
Published: June 2014

AbstractBackground: Despite accumulating evidence for the preventive effect of vitamin D on colorectal carcinogenesis, its precise mechanisms remain unclear. We hypothesized that vitamin D was associated with a lower risk of colorectal cancer with high-level vitamin D receptor (VDR) expression, but not with risk of tumor with low-level VDR expression.Methods: Among 140,418 participants followed from 1986 through 2008 in the Nurses' Health Study and the Health Professionals' Follow-up Study, we identified 1,059 incident colorectal cancer cases with tumor molecular data. The predicted 25-hydroxyvitamin D [25(OH)D] score was developed using the known determinants of plasma 25(OH)D. We estimated the HR for cancer subtypes using the duplication method Cox proportional hazards model.Results: A higher predicted 25(OH)D score was associated with a lower risk of colorectal cancer irrespective of VDR expression level (Pheterogeneity for subtypes = 0.75). Multivariate HRs (95% confidence intervals) comparing the highest with the lowest quintile of predicted 25(OH)D scores were 0.48 (0.30–0.78) for VDR-negative tumor and 0.56 (0.42–0.75) for VDR-positive tumor. Similarly, the significant inverse associations of the predicted 25(OH)D score with colorectal cancer risk did not significantly differ by KRAS, BRAF, or PIK3CA status (Pheterogeneity for subtypes ≥ 0.22).Conclusions: A higher predicted vitamin D score was significantly associated with a lower colorectal cancer risk, regardless of VDR status and other molecular features examined.Impact: The preventive effect of vitamin D on colorectal carcinogenesis may not totally depend on tumor factors. Host factors (such as local and systemic immunity) may need to be considered. Cancer Epidemiol Biomarkers Prev; 23(8); 1628–37. ©2014 AACR.
Tyrosine Phosphoproteomics Identifies Both Codrivers and Cotargeting Strategies for T790M-Related EGFR-TKI Resistance in Non–Small Cell Lung Cancer
Authors: Yoshida Takeshi , Zhang Guolin , Smith Matthew A. , Lopez Alex S. , Bai Yun , Li Jiannong , Fang Bin , Koomen John , Rawal Bhupendra , Fisher Kate J. , Chen Ann Y. , Kitano Michiko , Morita Yume , Yamaguchi Haruka , Shibata Kiyoko , Okabe Takafumi , Okamoto Isamu , Nakagawa Kazuhiko , Haura Eric B. 
Published: June 2014

Abstract
Purpose: Irreversible EGFR-tyrosine kinase inhibitors (TKI) are thought to be one strategy to overcome EGFR-TKI resistance induced by T790M gatekeeper mutations in non–small cell lung cancer (NSCLC), yet they display limited clinical efficacy. We hypothesized that additional resistance mechanisms that cooperate with T790M could be identified by profiling tyrosine phosphorylation in NSCLC cells with acquired resistance to reversible EGFR-TKI and harboring T790M.
Experimental Design: We profiled PC9 cells with TKI-sensitive EGFR mutation and paired EGFR-TKI–resistant PC9GR (gefitinib-resistant) cells with T790M using immunoaffinity purification of tyrosine-phosphorylated peptides and mass spectrometry–based identification/quantification. Profiles of erlotinib perturbations were examined.
Results: We observed a large fraction of the tyrosine phosphoproteome was more abundant in PC9- and PC9GR-erlotinib–treated cells, including phosphopeptides corresponding to MET, IGF, and AXL signaling. Activation of these receptor tyrosine kinases by growth factors could protect PC9GR cells against the irreversible EGFR-TKI afatinib. We identified a Src family kinase (SFK) network as EGFR-independent and confirmed that neither erlotinib nor afatinib affected Src phosphorylation at the activation site. The SFK inhibitor dasatinib plus afatinib abolished Src phosphorylation and completely suppressed downstream phosphorylated Akt and Erk. Dasatinib further enhanced antitumor activity of afatinib or T790M-selective EGFR-TKI (WZ4006) in proliferation and apoptosis assays in multiple NSCLC cell lines with T790M-mediated resistance. This translated into tumor regression in PC9GR xenograft studies with combined afatinib and dasatinib.
Conclusions: Our results identified both codrivers of resistance along with T790M and support further studies of irreversible or T790M-selective EGFR inhibitors combined with dasatinib in patients with NSCLC with acquired T790M. Clin Cancer Res; 20(15); 4059–74. ©2014 AACR.
Randomized Phase Ib/II Trial of Rilotumumab or Ganitumab with Panitumumab versus Panitumumab Alone in Patients with Wild-type KRAS Metastatic Colorectal Cancer
Authors: Van Cutsem Eric , Eng Cathy , Nowara Elzbieta , Świeboda-Sadlej Anna , Tebbutt Niall C. , Mitchell Edith , Davidenko Irina , Stephenson Joe , Elez Elena , Prenen Hans , Deng Hongjie , Tang Rui , McCaffery Ian , Oliner Kelly S. , Chen Lisa , Gansert Jennifer , Loh Elwyn , Smethurst Dominic , Tabernero Josep 
Published: June 2014

Abstract
Purpose: Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC.
Experimental Design: Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work.
Results: In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints.
Conclusions: Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC. Clin Cancer Res; 20(16); 4240–50. ©2014 AACR.
CARTs on the Road for Myeloma
Authors: Maus Marcela V. , June Carl H. 
Published: June 2014

Abstract
Chimeric antigen receptors redirect T cells to surface antigens. Discovery and validation of appropriate target antigens expands the possible indications for chimeric-antigen receptor (CAR) T cells. CS1 is expressed at high levels by multiple myeloma cells, but also to some extent on other lymphocytes. CS1 may be a viable target for CAR T cells in multiple myeloma. Clin Cancer Res; 20(15); 3899–901. ©2014 AACR.
Aspirin and Serum Estrogens in Postmenopausal Women: A Randomized Controlled Clinical Trial
Authors: Duggan Catherine , Wang Ching-Yun , Xiao Liren , McTiernan Anne 
Published: June 2014

Abstract
Epidemiologic studies suggest a reduced risk of breast cancer among women who use aspirin. A plausible mechanism is through aspirin's effect on estrogens, possibly mediated through interference with estrogen synthesis via reduction in inflammation, which is increased in adipose tissues, including breast. In a randomized placebo-controlled trial, we evaluated the effects of six-month administration of 325 mg/day aspirin on serum estrogens (estradiol, estrone, free estradiol, and bioavailable estradiol) and sex hormone–binding globulin (SHBG) in 144 healthy postmenopausal women. Eligible participants, recruited 2005–2007, were not taking nonsteroidal anti-inflammatory medication, including aspirin &gt;2 times/week or menopausal hormone therapy, and had a Breast Imaging-Reporting and Data System (BI-RADS) mammographic density classification of 2, 3, or 4. The intervention effects (intent-to-treat) were evaluated by differences in the geometric mean outcome changes at six months between aspirin and placebo groups using generalized estimating equations (GEE). Participants were a mean 59.4 (SD, 5.4) years of age, with a mean body mass index (BMI) of 26.4 (SD, 5.4) kg/m2. Between baseline and six months, none of the serum estrogens or SHBG changed substantially and there were no differences between groups. Stratifying by BMI did not change results. In conclusion, a single daily administration of 325 mg of aspirin for six months had no effect on serum estrogens or SHBG in postmenopausal women. Larger doses or longer duration of aspirin administration may be needed to affect circulating estrogens. Alternately, if aspirin influences breast cancer risk in postmenopausal women, it may do so through direct breast tissue effects, or through pathways other than estrogens. Cancer Prev Res; 7(9); 906–12. ©2014 AACR.