bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Reporter System for Positioning of Proteins at the Bacterial Pole
Authors: Fixen Kathryn R. , Janakiraman Anuradha , Garrity Sean , Slade Daniel J. , Gray Andrew N. , Karahan Nilay , Hochschild Ann , Goldberg Marcia B. 
Published: February 2012

ABSTRACT

Spatial organization within bacteria is fundamental to many cellular processes, although the basic mechanisms underlying localization of proteins to specific sites within bacteria are poorly understood. The study of protein positioning has been limited by a paucity of methods that allow rapid large-scale screening for mutants in which protein positioning is altered. We developed a genetic reporter system for protein localization to the pole within the bacterial cytoplasm that allows saturation screening for mutants in
Escherichia coli
in which protein localization is altered. Utilizing this system, we identify proteins required for proper positioning of the
Shigella
autotransporter IcsA. Autotransporters, widely distributed bacterial virulence proteins, are secreted at the bacterial pole. We show that the conserved cell division protein FtsQ is required for localization of IcsA and other autotransporters to the pole. We demonstrate further that this system can be applied to the study of proteins other than autotransporters that display polar positioning within bacterial cells.

IMPORTANCE
Many proteins localize to specific sites within bacterial cells, and localization to these sites is frequently critical to proper protein function. The mechanisms that underlie protein localization are incompletely understood, in part because of the paucity of methods that allow saturation screening for mutants in which protein localization is altered. We developed a genetic reporter assay that enables screening of bacterial populations for changes in localization of proteins to the bacterial pole, and we demonstrate the utility of the system in identifying factors required for proper localization of the polar
Shigella
autotransporter protein IcsA. Using this method, we identify the conserved cell division protein FtsQ as being required for positioning of IcsA to the bacterial pole. We demonstrate further that the requirement for FtsQ for polar positioning applies to other autotransporters and that the method can be applied to polar proteins other than autotransporters.
Evaluation of a systematic postal screening and treatment service for genitalChlamydia trachomatis, with remote clinic access via the internet: a cross-sectional study, East of England
Authors: Bracebridge Samantha , Bachmann Max Oscar , Ramkhelawon Krishna , Woolnough Alison 
Published: February 2012

ObjectiveEngland's National Chlamydia Screening Programme provides opportunistic testing for all 15–24-year-olds in healthcare and non-healthcare settings. The authors undertook an evaluation of a population service-based postal chlamydia screening and treatment service, with registration and access to the service via the internet, in order to target screening interventions more effectively in future.MethodsIndividuals aged between 18 and 24 years, within the North East Essex Primary Care Trust, were identified for chlamydia screening by the service between 1 December 2008 and 31 January 2009. Associations between test uptake and positivity, and individuals' personal characteristics, were examined. The efficacy of partner notification was estimated, and the costs of screening were compared with the national average.ResultsUptake of chlamydia screening was 11.5%, with lower response rates among men, individuals older than 20 years and those living in more deprived areas. The chlamydia positivity was 4.4% and higher in those reporting multiple sexual partners, individuals older than 20 years and those living in more deprived areas. The proportion of partners notified per index case was 0.17. The service contributed to 3431 of the overall 11 209 annual chlamydia screens of the Primary Care Trust in 2008–2009, at a cost of £78 per screening test completed and £1764 per case detected.ConclusionsOur evaluation shows that this service model can contribute substantially to the overall coverage of chlamydia screening tests. However, the costs of service provision per case detected and treated, using this model, were high compared to the National Chlamydia Screening Programme.
ON COHOMOLOGY OF NILPOTENT SYMPLECTIC LIE ALGEBRAS OF DIM. ≤ 6 AND DEFORMATION OF THOSE OF DIM. ≤ 4
Authors: MOUNA F. , BOUETOU T. B. , NGUIFFO M. B. 
Published: February 2012

This work is devoted to the result on symplectic nilpotent Lie algebras classified in a paper by [Y. Khakimdjanov, M. Goze and A. Medina, Symplectic or contact structures on Lie groups, Differential Geom. Appl. 21 (2004) 41–54]. We focus the attention on the investigation of their cohomology groups by using algebra tools. We give also an overview of deformation to those algebras of dim. ≤ 4.
A review of the Ediacaran to Early Cambrian (‘Infra-Cambrian’) evaporites and associated sediments of the Middle East
Authors: Smith A. G. 
Published: February 2012

Abstract

The paper reviews the age, location and extent of the late Neoproterozoic to Early Cambrian evaporite basins in the Middle East, NW India and Pakistan. The stratigraphic section discussed includes the largest inorganic negative δ
13
C excursion known (in the Shuram Formation); six cycles of alternating evaporites and carbonate (Ara Formation) and a unique formation in the middle of the Ara known as the Al Shomou silicilyte, which is a major hydrocarbon source. Tuff/volcanic horizons within the Ara are very well dated, with a precision of <0.15 myr. Extensional faulting was contemporaneous with the deposition of the evaporites, creating basins that at times showed density stratification and anoxia. The Buah Formation, which underlies the Ara, provides an insight into the development of Ediacaran carbonate ramp systems in the absence of bioturbation. A reconstruction of Gondwana brings the Ara and the Hormuz evaporites close to the evaporites of NW India and Pakistan, but leaves a small gap between them, which was probably occupied by a continental sliver, mostly likely part of the Lut block of central Iran. The Ara-Hormuz basins lie on the edge of a major continental collision between India and east Africa that was part of the amalgamation of east Gondwana.
Increased CD8+ T-cell Function following Castration and Immunization Is Countered by Parallel Expansion of Regulatory T Cells
Authors: Tang Shuai , Moore Miranda L. , Grayson Jason M. , Dubey Purnima 
Published: February 2012

Abstract
Although androgen ablation therapy is effective in treating primary prostate cancers, a significant number of patients develop incurable castration-resistant disease. Recent studies have suggested a potential synergy between vaccination and androgen ablation, yet the enhanced T-cell function is transient. Using a defined tumor antigen model, UV-8101-RE, we found that concomitant castration significantly increased the frequency and function of antigen-specific CD8+ T cells early after the immunization of wild-type mice. However, at a late time point after immunization, effector function was reduced to the same level as noncastrated mice and was accompanied by a concomitant amplification in CD4+CD25+Foxp3+ regulatory T cells (Treg) following immunization. We investigated whether Treg expansion occurred following castration of prostate tumor–bearing mice. In the prostate-specific Pten−/− mouse model of prostate cancer, we observed an accelerated Treg expansion in mice bearing the castration-resistant endogenous prostate tumor, which prevented effector responses to UV-8101-RE. Treg depletion together with castration elicited a strong CD8+ T-cell response to UV-8101-RE in Pten−/− mice and rescued effector function in castrated and immunized wild-type mice. In addition, Treg expansion in Pten−/− mice was prevented by in vivo interleukin (IL)-2 blockade suggesting that increased IL-2 generated by castration and immunization promotes Treg expansion. Our findings therefore suggest that although effector responses are augmented by castration, the concomitant expansion of Tregs is one mechanism responsible for only transient immune potentiation after androgen ablation. Cancer Res; 72(8); 1975–85. ©2012 AACR.
Intragenic ATM Methylation in Peripheral Blood DNA as a Biomarker of Breast Cancer Risk
Authors: Brennan Kevin , Garcia-Closas Montserrat , Orr Nick , Fletcher Olivia , Jones Michael , Ashworth Alan , Swerdlow Anthony , Thorne Heather , Riboli Elio , Vineis Paolo , Dorronsoro Miren , Clavel-Chapelon Francoise , Panico Salvatore , Onland-Moret N. Charlotte , Trichopoulos Dimitrios , Kaaks Rudolf , Khaw Kay-Tee , Brown Robert , Flanagan James M. 
Published: February 2012

Abstract
Few studies have evaluated the association between DNA methylation in white blood cells (WBC) and the risk of breast cancer. The evaluation of WBC DNA methylation as a biomarker of cancer risk is of particular importance as peripheral blood is often available in prospective cohorts and easier to obtain than tumor or normal tissues. Here, we used prediagnostic blood samples from three studies to analyze WBC DNA methylation of two ATM intragenic loci (ATMmvp2a and ATMmvp2b) and genome-wide DNA methylation in long interspersed nuclear element-1 (LINE1) repetitive elements. Samples were from a case–control study derived from a cohort of high-risk breast cancer families (KConFab) and nested case–control studies in two prospective cohorts: Breakthrough Generations Study (BGS) and European Prospective Investigation into Cancer and Nutrition (EPIC). Bisulfite pyrosequencing was used to quantify methylation from 640 incident cases of invasive breast cancer and 741 controls. Quintile analyses for ATMmvp2a showed an increased risk of breast cancer limited to women in the highest quintile [OR, 1.89; 95% confidence interval (CI), 1.36–2.64; P = 1.64 × 10−4]. We found no significant differences in estimates across studies or in analyses stratified by family history or menopausal status. However, a more consistent association was observed in younger than in older women and individually significant in KConFab and BGS, but not EPIC. We observed no differences in LINE1 or ATMmvp2b methylation between cases and controls. Together, our findings indicate that WBC DNA methylation levels at ATM could be a marker of breast cancer risk and further support the pursuit of epigenome-wide association studies of peripheral blood DNA methylation. Cancer Res; 72(9); 2304–13. ©2012 AACR.
Densely Granulated Murine NK Cells Eradicate Large Solid Tumors
Authors: Liu Rebecca B. , Engels Boris , Arina Ainhoa , Schreiber Karin , Hyjek Elizabeth , Schietinger Andrea , Binder David C. , Butz Eric , Krausz Thomas , Rowley Donald A. , Jabri Bana , Schreiber Hans 
Published: February 2012

AbstractNatural killer (NK) cells inhibit early stages of tumor formation, recurrence, and metastasis. Here, we show that NK cells can also eradicate large solid tumors. Eradication depended on the massive infiltration of proliferating NK cells due to interleukin 15 (IL-15) released and presented by the cancer cells in the tumor microenvironment. Infiltrating NK cells had the striking morphologic feature of being densely loaded with periodic acid-Schiff–positive, diastase-resistant granules, resembling uterine NK cells. Perforin-mediated killing by these densely granulated NK cells was essential for tumor eradication. Expression of the IL-15 receptor α on cancer cells was needed to efficiently induce granulated NK cells, and expression on host stromal cells was essential to prevent tumor relapse after near complete destruction. These results indicate that IL-15 released at the cancer site induces highly activated NK cells that lead to eradication of large solid tumors. Cancer Res; 72(8); 1964–74. ©2012 AACR.
Plasma Biomarkers as Predictors of Outcome in Patients with Advanced Hepatocellular Carcinoma
Authors: Llovet Josep M. , Peña Carol E.A. , Lathia Chetan D. , Shan Michael , Meinhardt Gerold , Bruix Jordi 
Published: February 2012

Abstract
Purpose: Validated biomarkers of prognosis and response to drug have not been identified for patients with hepatocellular carcinoma (HCC). One of the objectives of the phase III, randomized, controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial was to explore the ability of plasma biomarkers to predict prognosis and therapeutic efficacy.
Experimental Design: In SHARP, 602 patients with advanced HCC were randomized to receive either oral sorafenib 400 mg twice a day per os or matching placebo daily on a continuous basis. Ten plasma biomarkers implicated in the pathogenesis of HCC were measured in 491 patients at baseline and in 305 after 12 weeks of treatment. The candidate biomarkers were analyzed to identify correlates of prognosis or predictors of response to sorafenib.
Results: In both the entire patient population and the placebo cohort, baseline angiopoietin 2 (Ang2) and VEGF concentrations independently predicted survival. Clinical variables such as macroscopic vascular invasion, Eastern Cooperative Oncology Group (ECOG) performance status, and baseline α-fetoprotein and alkaline phosphatase concentrations also independently predicted survival in these groups. In the sorafenib cohort, trends toward enhanced survival benefit from sorafenib were observed in patients with high s-c-KIT or low hepatocyte growth factor concentration at baseline (P of interaction = 0.081 and 0.073, respectively).
Conclusions: The angiogenesis biomarkers Ang2 and VEGF were independent predictors of survival in patients with advanced HCC. In contrast, none of the biomarkers tested significantly predicted response to sorafenib. Clin Cancer Res; 18(8); 2290–300. ©2012 AACR.
Aurora A Inhibitor (MLN8237) plus Vincristine plus Rituximab Is Synthetic Lethal and a Potential Curative Therapy in Aggressive B-cell Non-Hodgkin Lymphoma
Authors: Mahadevan Daruka , Stejskal Amy , Cooke Laurence S. , Manziello Ann , Morales Carla , Persky Daniel O. , Fisher Richard I. , Miller Thomas P. , Qi Wenqing 
Published: February 2012

AbstractPurpose: Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Overexpression of Auroras promotes resistance to microtubule-targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 [M], an Aurora A inhibitor with either vincristine [MV] or docetaxel [MD] in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The addition of rituximab [R] to MV or MD was evaluated for synthetic lethality.Experimental Design: Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets, and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival, and mechanisms of response/relapse by gene expression profiling with protein validation.Results: MV is synergistic whereas MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of rituximab to MV is superior to MD, but both significantly induce apoptosis compared with doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single-agent activity for MLN8237, rituximab, docetaxel, and vincristine with tumor growth inhibition (TGI) of approximately 10% to 15%. Of the doublets, MV caused tumor regression, whereas TGI was observed with MD (approximately 55%–60%) and MR (approximately 25%–50%), respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, whereas MDR led to TGI of approximately 85%. Proliferation cell nuclear antigen, Aurora B, cyclin B1, cyclin D1, and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy.Conclusions: Addition of rituximab to MV is a novel therapeutic strategy for aggressive B-NHL and warrants clinical trial evaluation. Clin Cancer Res; 18(8); 2210–9. ©2012 AACR.
cMET and Phospho-cMET Protein Levels in Breast Cancers and Survival Outcomes
Authors: Raghav Kanwal P. , Wang Wenting , Liu Shuying , Chavez-MacGregor Mariana , Meng Xiaolong , Hortobagyi Gabriel N. , Mills Gordon B. , Meric-Bernstam Funda , Blumenschein George R. , Gonzalez-Angulo Ana M. 
Published: February 2012

Abstract
Purpose: To evaluate cMET (mesenchymal–epithelial transition factor gene) and phospho-cMET (p-cMET) levels in breast cancer subtypes and its impact on survival outcomes.
Experimental Design: We measured protein levels of cMET and p-cMET in 257 breast cancers using reverse phase protein array. Regression tree method and Martingale residual plots were applied to find best cutoff point for high and low levels. Kaplan–Meier survival curves were used to estimate relapse-free (RFS) and overall (OS) survival. Cox proportional hazards models were fit to determine associations of cMET/p-cMET with outcomes after adjustment for other characteristics.
Results: Median age was 51 years. There were 140 (54.5%) hormone receptor (HR) positive, 53 (20.6%) HER2 positive, and 64 (24.9%) triple-negative tumors. Using selected cutoffs, 181 (70.4%) and 123 (47.9%) cancers had high levels of cMET and p-cMET, respectively. There were no significant differences in mean expression of cMET (P &lt; 0.128) and p-cMET (P &lt; 0.088) by breast cancer subtype. Dichotomized cMET and p-cMET level was a significant prognostic factor for RFS [HR: 2.44, 95% confidence interval (CI): 1.34–4.44, P = 0.003 and HR: 1.64, 95% CI: 1.04–2.60, P = 0.033] and OS (HR: 3.18, 95% CI: 1.43–7.11, P = 0.003 and HR: 1.92, 95% CI: 1.08–3.44, P = 0.025). Within breast cancer subtypes, high cMET levels were associated with worse RFS (P = 0.014) and OS (P = 0.006) in HR-positive tumors, and high p-cMET levels were associated with worse RFS (P = 0.019) and OS (P = 0.014) in HER2-positive breast cancers. In multivariable analysis, patients with high cMET had a significantly higher risk of recurrence (HR: 2.06, 95% CI: 1.08–3.94, P = 0.028) and death (HR: 2.81, 95% CI: 1.19–6.64, P = 0.019). High p-cMET level was associated with higher risk of recurrence (HR: 1.79, 95% CI: 1.08–2.95.77, P = 0.020).
Conclusions: High levels of cMET and p-cMET were seen in all breast cancer subtypes and correlated with poor prognosis. Clin Cancer Res; 18(8); 2269–77. ©2012 AACR.
nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer
Authors: Frese Kristopher K. , Neesse Albrecht , Cook Natalie , Bapiro Tashinga E. , Lolkema Martijn P. , Jodrell Duncan I. , Tuveson David A. 
Published: February 2012

Abstract
Nanoparticle albumin-bound (nab)-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the coadministration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species–mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials.
Significance: This study provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer. Cancer Discovery; 2(3); 260–9. ©2012 AACR.
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Literature-Based Genetic Risk Scores for Coronary Heart Disease
Authors: Vaarhorst Anika A.M. , Lu Yingchang , Heijmans Bastiaan T. , Dollé Martijn E.T. , Böhringer Stefan , Putter Hein , Imholz Sandra , Merry Audrey H.H. , van Greevenbroek Marleen M. , Jukema J. Wouter , Gorgels Anton P.M. , van den Brandt Piet A. , Müller Michael , Schouten Leo J. , Feskens Edith J.M. , Boer Jolanda M.A. , Slagboom P. Eline 
Published: February 2012

Background—
Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD.

Methods and Results—

Incident cases (n=742), that is, participants who developed CHD during a median follow-up of 12.1 years (range, 0.0–16.9 years), were compared with a randomly selected subcohort of 2221 participants selected from the total cohort (n=21 148). We genotyped 179 SNPs previously associated with CHD or CHD RF in GWAS as published up to May 2, 2011. The allele-count GRS, composed of all SNPs, the 153 RF SNPs, or the 29 CHD SNPs were not associated with CHD independent of CHD RF. The weighted 29 CHD SNP GRS, with weights obtained from GWAS for every SNP, were associated with CHD independent of CHD RF (hazard ratio, 1.12 per weighted risk allele; 95% confidence interval, 1.04–1.21) and improved risk reclassification with 2.8% (
P
=0.031). As an exploratory approach to achieve weighting, we performed least absolute shrinkage and selection operator (LASSO) regression analysis on all SNPs and the CHD SNPs. The CHD LASSO GRS performed equal to the weighted CHD GRS, whereas the Overall LASSO GRS performed slightly better than the weighted CHD GRS.

Conclusions—
A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.