bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria
Authors: Shah Swati , Cannon Joe R. , Fenselau Catherine , Briken Volker 
Published: August 2015

ABSTRACT

The ESX-5 secretion system of
Mycobacterium tuberculosis
is important for bacterial virulence and for the secretion of the large PE/PPE protein family, whose genes constitute 10% of the
M. tuberculosis
genome. A four-gene region of the ESX-5 system is duplicated three times in the
M. tuberculosis
genome, but the functions of these duplicates are unknown. Here we investigated one of these duplicates: the region carrying the
esxI
,
esxJ
,
ppe15
, and
pe8
genes (ESX-5a). An ESX-5a deletion mutant in the model system
M. marinum
background was deficient in the secretion of some members of the PE/PPE family of proteins. Surprisingly, we also identified other proteins that are not members of this family, thus expanding the range of ESX-5 secretion substrates. In addition, we demonstrated that ESX-5a is important for the virulence of
M. marinum
in the zebrafish model. Furthermore, we showed the role of the
M. tuberculosis
ESX-5a region in inflammasome activation but not host cell death induction, which is different from the case for the
M. tuberculosis
ESX-5 system. In conclusion, the ESX-5a region is nonredundant with its ESX-5 paralog and is necessary for secretion of a specific subset of proteins in
M. tuberculosis
and
M. marinum
that are important for bacterial virulence of
M. marinum
. Our findings point to a role for the three ESX-5 duplicate regions in the selection of substrates for secretion via ESX-5, and hence, they provide the basis for a refined model of the molecular mechanism of this type VII secretion system.
Erythrocytic Iron Deficiency Enhances Susceptibility to Plasmodium chabaudi Infection in Mice Carrying a Missense Mutation in Transferrin Receptor 1
Authors: Lelliott Patrick M. , McMorran Brendan J. , Foote Simon J. , Burgio Gaetan 
Published: August 2015

ABSTRACT

The treatment of iron deficiency in areas of high malaria transmission is complicated by evidence which suggests that iron deficiency anemia protects against malaria, while iron supplementation increases malaria risk. Iron deficiency anemia results in an array of pathologies, including reduced systemic iron bioavailability and abnormal erythrocyte physiology; however, the mechanisms by which these pathologies influence malaria infection are not well defined. In the present study, the response to malaria infection was examined in a mutant mouse line,
Tfrc

MRI24910

, identified during an
N
-ethyl-
N
-nitrosourea (ENU) screen. This line carries a missense mutation in the gene for transferrin receptor 1 (TFR1). Heterozygous mice exhibited reduced erythrocyte volume and density, a phenotype consistent with dietary iron deficiency anemia. However, unlike the case in dietary deficiency, the erythrocyte half-life, mean corpuscular hemoglobin concentration, and intraerythrocytic ferritin content were unchanged. Systemic iron bioavailability was also unchanged, indicating that this mutation results in erythrocytic iron deficiency without significantly altering overall iron homeostasis. When infected with the rodent malaria parasite
Plasmodium chabaudi adami
, mice displayed increased parasitemia and succumbed to infection more quickly than their wild-type littermates. Transfusion of fluorescently labeled erythrocytes into malaria parasite-infected mice demonstrated an erythrocyte-autonomous enhanced survival of parasites within mutant erythrocytes. Together, these results indicate that TFR1 deficiency alters erythrocyte physiology in a way that is similar to dietary iron deficiency anemia, albeit to a lesser degree, and that this promotes intraerythrocytic parasite survival and an increased susceptibility to malaria in mice. These findings may have implications for the management of iron deficiency in the context of malaria.
Vibrio cholerae leuO Transcription Is Positively Regulated by ToxR and Contributes to Bile Resistance
Authors: Ante Vanessa M. , Bina X. Renee , Howard Mondraya F. , Sayeed Sameera , Taylor Dawn L. , Bina James E. 
Published: August 2015

ABSTRACT

Vibrio cholerae
is an aquatic organism and facultative human pathogen that colonizes the small intestine. In the small intestine,
V. cholerae
is exposed to a variety of antimicrobial compounds, including bile.
V. cholerae
resistance to bile is multifactorial and includes alterations in the membrane permeability barrier that are mediated by ToxR, a membrane-associated transcription factor. ToxR has also been shown to be required for activation of the LysR family transcription factor
leuO
in response to cyclic dipeptides. LeuO has been implicated in the regulation of multiple
V. cholerae
phenotypes, including biofilm production and virulence. In this study, we investigated the effects of bile on
leuO
expression. We show that
leuO
transcription increased in response to bile and bile salts but not in response to other detergents. The bile-dependent increase in
leuO
expression was dependent on ToxR, which was found to bind directly to the
leuO
promoter. The periplasmic domain of ToxR was required for basal
leuO
expression and for the bile-dependent induction of both
leuO
and
ompU
transcription.
V. cholerae
mutants that did not express
leuO
exhibited increased bile susceptibility, suggesting that LeuO contributes to bile resistance. Our collective results demonstrate that ToxR activates
leuO
expression in response to bile and that LeuO is a component of the ToxR-dependent responses that contribute to bile resistance.

IMPORTANCE
The success of
Vibrio cholerae
as a human pathogen is dependent upon its ability to rapidly adapt to changes in its growth environment. Growth in the human gastrointestinal tract requires the expression of genes that provide resistance to host antimicrobial compounds, including bile. In this work, we show for the first time that the LysR family regulator LeuO mediates responses in
V. cholerae
that contribute to bile resistance.
A cluster-randomised quality improvement study to improve two inpatient stroke quality indicators
Authors: Williams Linda , Daggett Virginia , Slaven James E , Yu Zhangsheng , Sager Danielle , Myers Jennifer , Plue Laurie , Woodward-Hagg Heather , Damush Teresa M 
Published: August 2015

BackgroundQuality indicator collection and feedback improves stroke care. We sought to determine whether quality improvement training plus indicator feedback was more effective than indicator feedback alone in improving inpatient stroke indicators.MethodsWe conducted a cluster-randomised quality improvement trial, randomising hospitals to quality improvement training plus indicator feedback versus indicator feedback alone to improve deep vein thrombosis (DVT) prophylaxis and dysphagia screening. Intervention sites received collaborative-based quality improvement training, external facilitation and indicator feedback. Control sites received only indicator feedback. We compared indicators pre-implementation (pre-I) to active implementation (active-I) and post-implementation (post-I) periods. We constructed mixed-effect logistic models of the two indicators with a random intercept for hospital effect, adjusting for patient, time, intervention and hospital variables.ResultsPatients at intervention sites (1147 admissions), had similar race, gender and National Institutes of Health Stroke Scale scores to control sites (1017 admissions). DVT prophylaxis improved more in intervention sites during active-I period (ratio of ORs 4.90, p<0.001), but did not differ in post-I period. Dysphagia screening improved similarly in both groups during active-I, but control sites improved more in post-I period (ratio of ORs 0.67, p=0.04). In logistic models, the intervention was independently positively associated with DVT performance during active-I period, and negatively associated with dysphagia performance post-I period.ConclusionQuality improvement training was associated with early DVT improvement, but the effect was not sustained over time and was not seen with dysphagia screening. External quality improvement programmes may quickly boost performance but their effect may vary by indicator and may not sustain over time.
Soluble Vascular Endothelial Growth Factor (sVEGF) and the Risk of Venous Thromboembolism in Patients with Cancer: Results from the Vienna Cancer and Thrombosis Study (CATS)
Authors: Posch Florian , Thaler Johannes , Zlabinger Gerhard-Johann , Königsbrügge Oliver , Koder Silvia , Zielinski Christoph , Pabinger Ingrid , Ay Cihan 
Published: August 2015

Abstract
Purpose: Cancer patients are at an increased risk of venous thromboembolism (VTE). VEGF promotes the growth of highly thrombogenic tumor vessels. Here, we explored the utility of soluble plasma VEGF-A (sVEGF) as a biomarker for the prediction of VTE in patients with cancer.
Experimental Design: Eight hundred four patients with newly diagnosed cancer or progression after remission were prospectively followed for 2 years until the occurrence of VTE or death [tumor sites: brain (n = 87), breast (n = 137), lung (n = 120), gastrointestinal (n = 143), pancreas (n = 53), prostate (n = 95), kidney (n = 22), myeloma and lymphoma (n = 99), and others (n = 48)]. Primary endpoint was symptomatic or fatal VTE. sVEGF was measured by immunoassay in baseline plasma.
Results: Fifty-five patients developed VTE (6.8%) and 364 patients (45.3%) died. Five-hundred and forty-two (68.3%) participants had sVEGF levels above the detection limit of 0.5 pg/mL. The median sVEGF level (25th–75th percentile) was 8.1 pg/mL (0–17.7). The cumulative 2-year incidence of VTE was 10.2% [95% confidence interval (CI), 6.4–14.9] in patients with sVEGF greater than the 75th percentile of the sVEGF distribution (Q3, cutoff: 17.7 pg/mL), and 5.9% (95% CI, 4.2–7.9) in patients with lower levels (P = 0.03). The corresponding 2-year risk of death was 52.8% (95% CI, 46.0–60.0) and 43.9% (95% CI, 40.0–48.0), respectively (P = 0.02). In univariable time-to-VTE regression, elevated sVEGF was associated with VTE [subhazard ratio (SHR) per 10 pg/mL increase, 1.04; 95% CI,1.00–1.09; P = 0.04)]. The association between sVEGF and risk of VTE prevailed after multivariable adjustment for high-risk tumor sites, age, gender, factor VIII, thrombin generation potential, and soluble P-Selectin (adjusted SHR, 1.04; 95% CI, 1.00–1.09, P = 0.05).
Conclusions: Elevated sVEGF is associated with an increased risk of VTE in patients with cancer. Clin Cancer Res; 22(1); 200–6. ©2015 AACR.
A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models
Authors: Ye Xiang S. , Fan Li , Van Horn Robert D. , Nakai Ryuichiro , Ohta Yoshihisa , Akinaga Shiro , Murakata Chikara , Yamashita Yoshinori , Yin Tinggui , Credille Kelly M. , Donoho Gregory P. , Merzoug Farhana F. , Li Heng , Aggarwal Amit , Blanchard Kerry , Westin Eric H. 
Published: August 2015

Abstract
Intervention of cancer cell mitosis by antitubulin drugs is among the most effective cancer chemotherapies. However, antitubulin drugs have dose-limiting side effects due to important functions of microtubules in resting normal cells and are often rendered ineffective by rapid emergence of resistance. Antimitotic agents with different mechanisms of action and improved safety profiles are needed as new treatment options. Mitosis-specific kinesin Eg5 represents an attractive anticancer target for discovering such new antimitotic agents, because Eg5 is essential only in mitotic progression and has no roles in resting, nondividing cells. Here, we show that a novel selective Eg5 inhibitor, LY2523355, has broad target-mediated anticancer activity in vitro and in vivo. LY2523355 arrests cancer cells at mitosis and causes rapid cell death that requires sustained spindle-assembly checkpoint (SAC) activation with a required threshold concentration. In vivo efficacy of LY2523355 is highly dose/schedule-dependent, achieving complete remission in a number of xenograft tumor models, including patient-derived xenograft (PDX) tumor models. We further establish that histone-H3 phosphorylation of tumor and proliferating skin cells is a promising pharmacodynamic biomarker for in vivo anticancer activity of LY2523355. Mol Cancer Ther; 14(11); 2463–72. ©2015 AACR.
Targeting G-Quadruplex DNA Structures by EMICORON Has a Strong Antitumor Efficacy against Advanced Models of Human Colon Cancer
Authors: Porru Manuela , Artuso Simona , Salvati Erica , Bianco Armandodoriano , Franceschin Marco , Diodoro Maria Grazia , Passeri Daniela , Orlandi Augusto , Savorani Francesco , D'Incalci Maurizio , Biroccio Annamaria , Leonetti Carlo 
Published: August 2015

Abstract
We previously identified EMICORON as a novel G-quadruplex (G4) ligand showing high selectivity for G4 structures over the duplex DNA, causing telomere damage and inhibition of cell proliferation in transformed and tumor cells. Here, we evaluated the antitumoral effect of EMICORON on advanced models of human colon cancer that could adequately predict human clinical outcomes. Our results showed that EMICORON was well tolerated in mice, as no adverse effects were reported, and a low ratio of sensitivity across human and mouse bone marrow cells was observed, indicating a good potential for reaching similar blood levels in humans. Moreover, EMICORON showed a marked therapeutic efficacy, as it inhibited the growth of patient-derived xenografts (PDX) and orthotopic colon cancer and strongly reduced the dissemination of tumor cells to lymph nodes, intestine, stomach, and liver. Finally, activation of DNA damage and impairment of proliferation and angiogenesis are proved to be key determinants of EMICORON antitumoral activity. Altogether, our results, performed on advanced experimental models of human colon cancer that bridge the translational gap between preclinical and clinical studies, demonstrated that EMICORON had an unprecedented antitumor activity warranting further studies of EMICORON-based combination treatments. Mol Cancer Ther; 14(11); 2541–51. ©2015 AACR.
Specific CP110 Phosphorylation Sites Mediate Anaphase Catastrophe after CDK2 Inhibition: Evidence for Cooperation with USP33 Knockdown
Authors: Hu Shanhu , Lu Yun , Orr Bernardo , Godek Kristina , Mustachio Lisa Maria , Kawakami Masanori , Sekula David , Compton Duane A. , Freemantle Sarah , Dmitrovsky Ethan 
Published: August 2015

Abstract
Chromosomal instability (CIN) is a hallmark of solid tumor biology and is implicated in carcinogenesis. Preferentially eliminating malignant cells by targeting CIN and aneuploidy is an attractive antineoplastic strategy. We previously reported that CDK2 antagonism causes lung cancer cells to undergo anaphase catastrophe and apoptosis through inhibition of phosphorylation of the centrosomal protein CP110. Cells with activating KRAS mutations were particularly sensitive to CDK2 inhibition due to downregulation of CP110 protein levels. This study investigated mechanisms of CDK2 antagonism that mediate anaphase catastrophe via changes in CP110 protein expression and how activated KRAS affects CP110 levels in lung cancers. Site-directed mutagenesis revealed candidate CDK phosphorylation sites of CP110 (residues Ser 170 and Thr 194) critical for conferring anaphase catastrophe by altering centrosome clustering in mitosis. Intriguingly, KRAS mutation can promote CP110 protein degradation by upregulating the ubiquitin ligase SCFcyclinF, which targets CP110 protein for destabilization. Finally, CDK2 inhibitor response was enhanced when combined with knockdown of the deubiquitinase USP33 that in turn accelerates CP110 protein degradation. Thus, this study provides molecular pharmacologic insights into how CP110 expression regulates response to CDK2 inhibition. An improved understanding of in vitro antineoplastic mechanisms of combining CDK2 antagonism with induced CP110 repression provides a rationale for exploring clinical consequences of this strategy. Taken together, preclinical findings obtained from combining CDK2 inhibition with USP33 repression have implications for treating patients with non–small cell lung cancers. Mol Cancer Ther; 14(11); 2576–85. ©2015 AACR.
Paired Box 5 Methylation Detection by Droplet Digital PCR for Ultra-Sensitive Deep Surgical Margins Analysis of Head and Neck Squamous Cell Carcinoma
Authors: Hayashi Masamichi , Guerrero-Preston Rafael , Sidransky David , Koch Wayne M. 
Published: August 2015

Abstract
Molecular deep surgical margin analysis has been shown to predict locoregional recurrences of head and neck squamous cell carcinoma (HNSCC). To improve the accuracy and versatility of the analysis, we used a highly tumor-specific methylation marker and highly sensitive detection technology to test DNA from surgical margins. Histologically cancer-negative deep surgical margin samples were prospectively collected from 82 eligible HNSCC surgeries by an imprinting procedure (n = 75) and primary tissue collection (n = 70). Bisulfite-treated DNA from each sample was analyzed by both conventional quantitative methylation-specific PCR (QMSP) and QMSP by droplet digital PCR (ddQMSP) targeting Paired box 5 (PAX5) gene promoter methylation. The association between the presence of PAX5 methylation and locoregional recurrence-free survival (LRFS) was evaluated. PAX5 methylation was found in 68.0% (51 of 75) of tumors in the imprint samples and 71.4% (50 of 70) in the primary tissue samples. Among cases that did not have postoperative radiation (n = 31 in imprint samples, n = 29 in tissue samples), both conventional QMSP and ddQMSP revealed that PAX5 methylation–positive margins was significantly associated with poor LRFS by univariate analysis. In particular, ddQMSP increased detection of the PAX5 marker from 29% to 71% in the nonradiated imprint cases. Also, PAX5 methylated imprint margins were an excellent predictor of poor LRFS [HR, 3.89; 95% confidence interval (CI), 1.19–17.52; P = 0.023] by multivariate analysis. PAX5 methylation appears to be an excellent tumor-specific marker for molecular deep surgical margin analysis of HNSCC. Moreover, the ddQMSP assay displays increased sensitivity for methylation marker detection. Cancer Prev Res; 8(11); 1017–26. ©2015 AACR.
PAK1 Promotes Intestinal Tumor Initiation
Authors: Dammann Kyle , Khare Vineeta , Harpain Felix , Lang Michaela , Kurtovic Azra , Mesteri Ildiko , Evstatiev Rayko , Gasche Christoph 
Published: August 2015

Abstractp21-activated kinase 1 (PAK1) is a serine/threonine kinase that is overexpressed in colorectal cancer. PAK1 is a target of mesalamine [5-aminosylicylic acid (5-ASA)], a common drug for the treatment of ulcerative colitis with prospective chemopreventive properties. Here, we investigated whether PAK1 deletion impedes tumorigenesis in murine intestinal cancer models. Ten-week-old APCmin or APCmin/PAK1−/− mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six- to 8-week-old PAK1−/− and wild-type (WT) mice received one 10 mg/kg intraperitoneal injection of azoxymethane (AOM) and four cycles of 1.7% dextran sodium sulfate (DSS) for 4 days followed by 14 days of regular water. Mice also received 5-ASA via diet. Tumor incidence and size was assessed via colonoscopy and pathology. Molecular targets of PAK1 and 5-ASA were evaluated via immunohistochemistry (IHC) in both models. PAK1 deletion reduced tumor multiplicity and tumor burden but did not alter average tumor size in APCmin mice. IHC revealed that PAK1 deletion reduced p-AKT, β-catenin, and c-Myc expression in APCmin adenomas. Colonoscopy and pathologic analysis revealed that PAK1 deletion reduced tumor multiplicity without affecting tumor size in AOM/DSS-treated mice. 5-ASA treatment and PAK1 deletion impeded tumor multiplicity and dysplastic lesions in AOM/DSS mice. IHC further revealed that 5-ASA blocked β-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis. Cancer Prev Res; 8(11); 1093–101. ©2015 AACR.
Urinary Metabolites of Prostanoids and Risk of Recurrent Colorectal Adenomas in the Aspirin/Folate Polyp Prevention Study (AFPPS)
Authors: Fedirko Veronika , Bradshaw Patrick T. , Figueiredo Jane C. , Sandler Robert S. , Barry Elizabeth L. , Ahnen Dennis J. , Milne Ginger L. , Bresalier Robert S. , Baron John A. 
Published: August 2015

Abstract
Aspirin has been shown to protect against colorectal neoplasms; however, the optimal chemopreventive dose and underlying mechanisms are unclear. We aimed to study the relationship between prostanoid metabolites and aspirin's effect on adenoma occurrence. We used data from the Aspirin/Folate Polyp Prevention Study, in which 1,121 participants with a recent adenoma were randomized to placebo or two doses of aspirin (81 or 325 mg/d) to be taken until the next surveillance colonoscopy, anticipated about 3 years later. Urinary metabolites of prostanoids (PGE-M, PGI-M, and dTxB2) were measured using liquid chromatography/mass spectrometry or GC/NICI-MS in 876 participants near the end of treatment follow-up. Poisson regression with a robust error variance was used to calculate relative risks and 95% confidence intervals. PGE-M, PGI-M, and dTxB2 levels were 28%, 37%, and 60% proportionately lower, respectively, in individuals who took 325 mg of aspirin compared with individuals who took placebo (all P &lt; 0.001). Similarly, among individuals who took 81 mg of aspirin, PGE-M, PGI-M, and dTxB2 were, respectively, 18%, 30%, and 57% proportionally lower compared with placebo (all P &lt; 0.005). None of the metabolites or their ratios were statistically significantly associated with the risk of adenoma occurrence. The effect of aspirin in reducing adenoma risk was independent of prostanoid levels. Aspirin use is associated with lower levels of urinary prostanoid metabolites. However, our findings do not support the hypothesis that these metabolites are associated with adenoma occurrence, suggesting that COX-dependent mechanisms may not completely explain the chemopreventive effect of aspirin on colorectal neoplasms. Cancer Prev Res; 8(11); 1061–8. ©2015 AACR.
Family history of venous thromboembolism as a risk factor and genetic research tool
Authors: Li Xinjun , Ohlsson Henrik , Ji Jianguang , Sundquist Jan , Sundquist Kristina , Zöller Bengt 
Published: August 2015

SummaryFamilial clustering of venous thromboembolism (VTE) was described as far back as 1905 by Briggs. Although Egeberg discovered inherited deficiency of antithrombin in 1965, it was not until Dahlback discovered resistance to activated protein C in 1993 that it became clear that genetic factors are common risk factors of VTE. Several genes have been linked to familial aggregation of VTE and genome-wide association studies have found several novel gene loci. Still, it has been estimated that much of the heritability for VTE remains to be discovered. Family history (FH) of VTE is therefore still important to determine whether a patient has an increased genetic risk of VTE. FH has the potential to represent the sum of effects and interactions between environmental and genetic factors. In this article the design, methodology, results, clinical and genetic implications of FH studies of VTE are reviewed. FH in first-degree relatives (siblings and/or parents) is associated with a 2–3 times increased familial relative risk (FRR). However, the FRR is dependent on age, number of affected relatives, and presentation of VTE (provoked/unprovoked). Especially high familial risks are observed in individuals with two or more affected siblings (FFR> 50). However, the familial risk for recurrent VTE is much lower or non-significant. Moreover, FH of VTE appears mainly to be important for venous diseases (i. e. VTE and varicose veins). The familial associations with other diseases are weaker. In conclusion, FH of VTE is an important research tool and a clinically potential useful risk factor for VTE.