bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxidative Stress Modulates the Nitric Oxide Defense Promoted by Escherichia coli Flavorubredoxin
Authors: Baptista Joana M. , Justino Marta C. , Melo Ana M. P. , Teixeira Miguel , Saraiva Lígia M. 
Published: May 2012

ABSTRACT

Mammalian cells of innate immunity respond to pathogen invasion by activating proteins that generate a burst of oxidative and nitrosative stress. Pathogens defend themselves from the toxic compounds by triggering a variety of detoxifying enzymes.
Escherichia coli
flavorubredoxin is a nitric oxide reductase that is expressed under nitrosative stress conditions. We report that in contrast to nitrosative stress alone, exposure to both nitrosative and oxidative stresses abolishes the expression of flavorubredoxin. Electron paramagnetic resonance (EPR) experiments showed that under these conditions, the iron center of the flavorubredoxin transcription activator NorR loses the ability to bind nitric oxide. Accordingly, triggering of the NorR ATPase activity, a requisite for flavorubredoxin activation, was impaired by treatment of the protein with the double stress. Studies of macrophages revealed that the contribution of flavorubredoxin to the survival of
E. coli
depends on the stage of macrophage infection and that the lack of protection observed at the early phase is related to inhibition of NorR activity by the oxidative burst. We propose that the time-dependent activation of flavorubredoxin contributes to the adaptation of
E. coli
to the different fluxes of hydrogen peroxide and nitric oxide to which the bacterium is subjected during the course of macrophage infection.
SalB Inactivation Modulates Culture Supernatant Exoproteins and Affects Autolysis and Viability in Enterococcus faecalis OG1RF
Authors: Shankar Jayendra , Walker Rachel G. , Wilkinson Mark C. , Ward Deborah , Horsburgh Malcolm J. 
Published: May 2012

ABSTRACT

The culture supernatant fraction of an
Enterococcus faecalis gelE
mutant of strain OG1RF contained elevated levels of the secreted antigen SalB. Using differential fluorescence gel electrophoresis (DIGE) the
salB
mutant was shown to possess a unique complement of exoproteins. Differentially abundant exoproteins were identified using matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry. Stress-related proteins including DnaK, Dps family protein, SOD, and NADH peroxidase were present in greater quantity in the OG1RF
salB
mutant culture supernatant. Moreover, several proteins involved in cell wall synthesis and cell division, including
d
-Ala-
d
-Lac ligase and EzrA, were present in reduced quantity in OG1RF
salB
relative to the parent strain. The
salB
mutant displayed reduced viability and anomalous cell division, and these phenotypes were exacerbated in a
gelE salB
double mutant. An epistatic relationship between
gelE
and
salB
was not identified with respect to increased autolysis and cell morphological changes observed in the
salB
mutant. SalB was purified as a six-histidine-tagged protein to investigate peptidoglycan hydrolytic activity; however, activity was not evident. High-pressure liquid chromatography (HPLC) analysis of reduced muropeptides from peptidoglycan digested with mutanolysin revealed that the
salB
mutant and OG1RF were indistinguishable.
Risk factors affecting inhospital mortality after hip fracture: retrospective analysis using the Japanese Diagnosis Procedure Combination Database
Authors: Shoda Naoko , Yasunaga Hideo , Horiguchi Hiromasa , Matsuda Shinya , Ohe Kazuhiko , Kadono Yuho , Tanaka Sakae 
Published: May 2012

ObjectiveTo identify risk factors for inhospital mortality in patients with hip fractures using the Japanese Diagnosis Procedure Combination (DPC) nationwide administrative claims database.DesignRetrospective observational study.SettingHospitals adopting the DPC system during 2007–2009.ParticipantsThe authors analysed a total of 80 800 eligible patients aged ≥60 years with a single hip fracture (International Classification of Diseases, 10th Revision codes: S72.0 and S72.1). The DPC database includes patients treated between July and December each year.Main outcome measuresInhospital mortality after hip fracture.ResultsThe overall inhospital mortality rate after hip fractures was 3.3%. Multivariate analysis indicated that inhospital mortality was significantly associated with male gender (OR 2.12, 95% CI 1.94 to 2.31), advancing age and number of comorbidities. Significantly higher mortality was observed in those treated conservatively (OR 4.25, 95% CI 3.92 to 4.61). Surgical delays of 5 days or more were significantly associated with higher rates of inhospital mortality (OR 1.34, 95% CI 1.20 to 1.50).ConclusionsIn patients with hip fractures, male gender, advancing age, high number of comorbidities, conservative treatment and the surgical delay of 5 days or more were associated with higher rates of inhospital mortality.
A cost-utility analysis of transcatheter aortic valve implantation in Belgium: focusing on a well-defined and identifiable population
Authors: Neyt Mattias , Van Brabandt Hans , Devriese Stephan , Van De Sande Stefaan 
Published: May 2012

BackgroundPatients with severe aortic stenosis and coexisting non-cardiac conditions may be at high risk for surgical replacement of the aortic valve or even be no candidates for surgery. In these patients, transcatheter aortic valve implantation (TAVI) is suggested as an alternative. Results of the PARTNER (Placement of AoRTic TraNscathetER Valve) trial comparing the clinical effectiveness of TAVI with surgical valve replacement and standard therapy were published. The authors assessed the cost-effectiveness of TAVI in Belgium.MethodsA Markov model of incremental costs, effects (survival and quality of life) and incremental cost-effectiveness of TAVI was developed. The impact on survival, number of events and quality of life was based on the PARTNER trial. Costs per event were context specific.ResultsIn high-risk operable patients, even if the minor differences in 30-day and 1-year mortality are taken into account, the incremental cost-effectiveness ratio (ICER) remains on average above €750 000 per quality-adjusted life-year (QALY) gained (incremental cost: €20 400; incremental effect: 0.03 QALYs). In inoperable patients, an ICER of €44 900 per QALY (incremental cost: €33 200; incremental effect: 0.74 QALYs) is calculated, including a life-long extrapolation of the mortality benefit. This result was sensitive to the assumed time horizon. The subgroup of anatomically inoperable patients had better outcomes than medically inoperable patients, with ICERs decreasing more than €10 000/QALY.ConclusionsIt is inappropriate to consider reimbursement of TAVI for high-risk operable patients. Reimbursing TAVI in inoperable patients in essence is a political decision. From an economic perspective, it would be prudent to first target patients that are inoperable because of anatomical prohibitive conditions. In the search for evidence, the authors identified non-published negative results from a randomised controlled TAVI trial. The study sponsor should be more willing to share this information to allow balanced evaluations and policy recommendations. Payers should require these data before taking reimbursement decisions.
Risk Factors for Alloimmunisation after red blood Cell Transfusions (R-FACT): a case cohort study
Authors: Zalpuri Saurabh , Zwaginga Jaap Jan , van der Bom J G 
Published: May 2012

IntroductionIndividuals exposed to red blood cell alloantigens through transfusion, pregnancy or transplantation may produce antibodies against the alloantigens. Alloantibodies can pose serious clinical problems such as delayed haemolytic reactions and logistic problems, for example, to obtain timely and properly matched transfusion blood for patients in which new alloantibodies are detected.ObjectiveThe authors hypothesise that the particular clinical conditions (eg, used medication, concomitant infection, cellular immunity) during which transfusions are given may contribute to the risk of immunisation. The aim of this research was to examine the association between clinical, environmental and genetic characteristics of the recipient of erythrocyte transfusions and the risk against erythrocyte alloimmunisation during that transfusion episode.Methods and analysis Study designIncident case–cohort study.SettingSecondary care, nationwide study (within the Netherlands) including seven hospitals, from January 2005 to December 2011.Study populationConsecutive red cell transfused patients at the study centres.InclusionThe study cohort comprises of consecutive red blood cell transfused patients at the study centre.ExclusionPatients with transfusions before the study period and/or pre-existing alloantibodies.Cases defined as first time alloantibody formers; Controls defined as transfused individuals matched (on number of transfusions) to cases and have not formed an alloantibody.Statistical analysisLogistic regression models will be used to assess the association between the risk to develop antibodies and potential risk factors, adjusted for other risk factors.Ethics and disseminationApproval at each local ethics regulatory committee will be obtained. Data will be coded for privacy reasons. Patients will be sent a letter and an information brochure explaining the purpose of the study. A consent form in presence of the study coordinator will be signed before the blood taking commences. Investigators will submit progress summary of the study to study sponsor regularly. Investigators will notify the accredited ethics board of the end of the study within a period of 8 weeks.
Endothelium-dependent vascular relaxation induced by Globularia alypum extract is mediated by EDHF in perfused rat mesenteric arterial bed
Authors: Chokri Aziz , El Abida Kaouakib , Zegzouti Younes Filali , Ben Cheikh Rachid 
Published: May 2012

The vasodilatory effect of Globularia alypum L. (GA) extract was evaluated in rat mesenteric arterial bed pre-contracted by continuous infusion of phenylephrine (2–4 ng/mL). Bolus injections of GA elicited dose–response vasodilation, which was abolished after endothelium removal. Addition of a nitric oxide synthase inhibitor, NG-nitro-l-arginine methyl ester (100 µmol/L), alone or in the presence of a cyclooxygenase inhibitor, indomethacin (10 µmol/L), did not significantly affect the vasodilation of the mesenteric arterial bed in response to GA extract. These results suggest that GA-induced vasodilation is endothelium dependent but nitric oxide and prostacyclin independent. In the presence of high K+ (60 mmol/L), the GA vasodilatory effect was completely abolished, suggesting that the vasodilation effect is mediated by hyperpolarization of the vascular cells. Also, pre-treatment with atropine (a muscarinic receptors antagonist) antagonized the GA-induced vasodilation, suggesting that the vasodilatory effect is mainly mediated by the endothelium-derived hyperpolarizing factor through activation of endothelial muscarinic receptors.
Carbohydrate- and lipid-enriched meals acutely disrupt glycemic homeostasis by inducing transient insulin resistance in rats
Authors: Campello Raquel Saldanha , Alves-Wagner Ana Barbara Teixeira , Abdulkader Fernando , Mori Rosana Cristina Tieko , Machado Ubiratan Fabres 
Published: May 2012

Chronic intake of high-carbohydrate or high-lipid diets is a well-known insulin resistance inducer. This study investigates the immediate effect (1–6 h) of a carbohydrate- or lipid-enriched meal on insulin sensitivity. Fasted rats were refed with standard, carbohydrate-enriched (C), or lipid-enriched (L) meal. Plasma insulin, glucose, and non-esterified fatty acids (NEFA) were measured at 1, 2, 4, and 6 h of refeeding. The glucose–insulin index showed that either carbohydrates or lipids decreased insulin sensitivity at 2 h of refeeding. At this time point, insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) detected insulin resistance in C rats, while GTT confirmed it in L rats. Reduced glycogen and phosphorylated AKT and GSK3 content revealed hepatic insulin resistance in C rats. Reduced glucose uptake in skeletal muscle subjected to the fatty acid concentration that mimics the high NEFA level of L rats suggests insulin resistance in these animals is mainly in muscle. In conclusion, carbohydrate- or lipid-enriched meals acutely disrupt glycemic homeostasis, inducing a transient insulin resistance, which seems to involve liver and skeletal muscle, respectively. Thus, the insulin resistance observed when those types of diets are chronically consumed may be an evolution of repeated episodes of this transient insulin resistance.
The Nedd8-Activating Enzyme Inhibitor MLN4924 Induces Autophagy and Apoptosis to Suppress Liver Cancer Cell Growth
Authors: Luo Zhongguang , Yu Guangyang , Lee Hyuk Woo , Li Lihui , Wang Lingyan , Yang Dongqin , Pan Yongfu , Ding Chan , Qian Jing , Wu Lijun , Chu Yiwei , Yi Jing , Wang Xiangdong , Sun Yi , Jeong Lak Shin , Liu Jie , Jia Lijun 
Published: May 2012

Abstract
Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy. Cancer Res; 72(13); 3360–71. ©2012 AACR.
FRMD4A Upregulation in Human Squamous Cell Carcinoma Promotes Tumor Growth and Metastasis and Is Associated with Poor Prognosis
Authors: Goldie Stephen J. , Mulder Klaas W. , Tan David Wei-Min , Lyons Scott K. , Sims Andrew H. , Watt Fiona M. 
Published: May 2012

Abstract
New therapeutic strategies are needed to improve treatment of head and neck squamous cell carcinoma (HNSCC), an aggressive tumor with poor survival rates. FRMD4A is a human epidermal stem cell marker implicated previously in epithelial polarity that is upregulated in SCC cells. Here, we report that FRMD4A upregulation occurs in primary human HNSCCs where high expression levels correlate with increased risks of relapse. FRMD4A silencing decreased growth and metastasis of human SCC xenografts in skin and tongue, reduced SCC proliferation and intercellular adhesion, and stimulated caspase-3 activity and expression of terminal differentiation markers. Notably, FRMD4A attenuation caused nuclear accumulation of YAP, suggesting a potential role for FRMD4A in Hippo signaling. Treatment with the HSP90 inhibitor 17-DMAG or ligation of CD44 with hyaluronan caused nuclear depletion of FRMD4A, nuclear accumulation of YAP and reduced SCC growth and metastasis. Together, our findings suggest FRMD4A as a novel candidate therapeutic target in HNSCC based on the key role in metastatic growth we have identified. Cancer Res; 72(13); 3424–36. ©2012 AACR.
CXCL10 Promotes Osteolytic Bone Metastasis by Enhancing Cancer Outgrowth and Osteoclastogenesis
Authors: Lee Jong-Ho , Kim Ha-Neui , Kim Kyung-Ok , Jin Won Jong , Lee Seungbok , Kim Hong-Hee , Ha Hyunil , Lee Zang Hee 
Published: May 2012

Abstract
Amplification of the chemokines CXCL10 and RANKL has been suggested to promote osteoclast differentiation and osteolytic bone metastasis, but a function for endogenous CXCL10 in these processes is not well established. In this study, we show that endogenous CXCL10 is critical to recruit cancer cells to bone, support osteoclast differentiation and promote for the formation of osteolytic bone metastases. Neutralizing CXCL10 antibody reduced migration of cancer cells expressing the CXCL10 receptor CXCR3, and loss of CXCR3 or CXCL10 decreased bone tumor burden in vivo. Bone colonization augmented host production of CXCL10, which was required for cancer growth and subsequent osteolysis. Direct interactions between cancer cells and macrophages further stimulated CXCL10 production from macrophages. Growth of bone metastases required CXCL10-stimulated adhesion of cancer cells to type I collagen as well as RANKL-mediated osteoclast formation. Together, our findings show that CXCL10 facilitates trafficking of CXCR3-expressing cancer cells to bone, which augments its own production and promotes osteoclastic differentiation. CXCL10 therefore may represent a therapeutic target for osteolytic bone metastasis. Cancer Res; 72(13); 3175–86. ©2012 AACR.
Engineering and Therapeutic Application of Single-Chain Bivalent TGF-β Family Traps
Authors: Zwaagstra John C. , Sulea Traian , Baardsnes Jason , Lenferink Anne E.G. , Collins Cathy , Cantin Christiane , Paul-Roc Béatrice , Grothe Suzanne , Hossain Sazzad , Richer Louis-Philippe , L'Abbé Denis , Tom Roseanne , Cass Brian , Durocher Yves , O'Connor-McCourt Maureen D. 
Published: May 2012

Abstract
Deregulation of TGF-β superfamily signaling is a causative factor in many diseases. Here we describe a protein engineering strategy for the generation of single-chain bivalent receptor traps for TGF-β superfamily ligands. Traps were assembled using the intrinsically disordered regions flanking the structured binding domain of each receptor as "native linkers" between two binding domains. This yields traps that are approximately threefold smaller than antibodies and consists entirely of native receptor sequences. Two TGF-β type II receptor-based, single-chain traps were designed, termed (TβRII)2 and (TβRIIb)2, that have native linker lengths of 35 and 60 amino acids, respectively. Both single-chain traps exhibit a 100 to 1,000 fold higher in vitro ligand binding and neutralization activity compared with the monovalent ectodomain (TβRII-ED), and a similar or slightly better potency than pan–TGF-β–neutralizing antibody 1D11 or an Fc-fused receptor trap (TβRII-Fc). Despite its short in vivo half-life (&lt;1 hour), which is primarily due to kidney clearance, daily injections of the (TβRII)2 trap reduced the growth of 4T1 tumors in BALB/c mice by 50%, an efficacy that is comparable with 1D11 (dosed thrice weekly). In addition, (TβRII)2 treatment of mice with established 4T1 tumors (100 mm3) significantly inhibited further tumor growth, whereas the 1D11 antibody did not. Overall, our results indicate that our rationally designed bivalent, single-chain traps have promising therapeutic potential. Mol Cancer Ther; 11(7); 1477–87. ©2012 AACR.
Bilateral Oophorectomy, Body Mass Index, and Mortality in U.S. Women Aged 40 Years and Older
Authors: McCarthy Anne Marie , Menke Andy , Ouyang Pamela , Visvanathan Kala 
Published: May 2012

Abstract
Bilateral oophorectomy is used as a risk reduction strategy in BRCA1/2 mutation carriers, although data on long-term side effects are not yet available. In the general population, oophorectomy, particularly at a young age, has been associated with increased overall and cardiovascular disease (CVD) mortality. The mechanisms for this association are not well understood. We examined the association between prior bilateral oophorectomy, obesity, and all-cause, cancer, and CVD mortality. Our study population included women ages 40 and above from the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative survey with enrollment from 1988 to 1994 and prospective mortality follow-up through December 31, 2006. We excluded women with a history of reproductive cancer or missing oophorectomy status, yielding a study population of 4,040. Cox proportional hazards modeling was used to estimate HR for all-cause and cause-specific mortality. In multivariate analyses, body mass index (BMI) significantly modified the association between oophorectomy and mortality (Pinteraction = 0.04). Women who were obese at the time of interview and who had an oophorectomy at less than 40 years were more than twice as likely to die [HR, 2.23; 95% confidence interval (CI), 1.25–3.98], particularly of CVD (HR, 2.77; 95% CI, 0.91–8.41), than nonobese women with intact ovaries. These associations persisted after excluding women who used estrogen therapy and women who had oophorectomy before 35 years of age. The joint effect of obesity and early oophorectomy on mortality was significantly greater than expected, given the independent effects of both exposures. Our results suggest that minimizing weight gain after oophorectomy and addressing cardiovascular risk factors could beneficially impact mortality. Cancer Prev Res; 5(6); 847–54. ©2012 AACR.
A Novel Sulindac Derivative that Potently Suppresses Colon Tumor Cell Growth by Inhibiting cGMP Phosphodiesterase and β-Catenin Transcriptional Activity
Authors: Whitt Jason D. , Li Nan , Tinsley Heather N. , Chen Xi , Zhang Wei , Li Yonghe , Gary Bernard D. , Keeton Adam B. , Xi Yaguang , Abadi Ashraf H. , Grizzle William E. , Piazza Gary A. 
Published: May 2012

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to inhibit tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for cancer chemoprevention. Here, we characterize a novel sulindac derivative referred to as sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human colon tumor cells. The basis for this activity appears to involve cyclic guanosine 3′,5′,-monophosphate phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in colon tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate cGMP-dependent protein kinase G at concentrations that suppress tumor cell growth. PDE5 was found to be essential for colon tumor cell growth as determined by siRNA knockdown studies, elevated in colon tumor cells as compared with normal colonocytes, and associated with the tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-catenin as evident by its ability to reduce β-catenin nuclear levels, Tcf (T-cell factor) transcriptional activity, and survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading isozymes can be targeted to develop safer and more efficacious NSAID derivatives for colorectal cancer chemoprevention. Cancer Prev Res; 5(6); 822–33. ©2012 AACR.