bluuebunny/crossref_metadata_2025_split huggingface dataset:
The LonA Protease Regulates Biofilm Formation, Motility, Virulence, and the Type VI Secretion System in Vibrio cholerae
Authors: Rogers Andrew , Townsley Loni , Gallego-Hernandez Ana L. , Beyhan Sinem , Kwuan Laura , Yildiz Fitnat H. 
Published: January 2016

ABSTRACT

The presence of the Lon protease in all three domains of life hints at its biological importance. The prokaryotic Lon protease is responsible not only for degrading abnormal proteins but also for carrying out the proteolytic regulation of specific protein targets. Posttranslational regulation by Lon is known to affect a variety of physiological traits in many bacteria, including biofilm formation, motility, and virulence. Here, we identify the regulatory roles of LonA in the human pathogen
Vibrio cholerae
. We determined that the absence of LonA adversely affects biofilm formation, increases swimming motility, and influences intracellular levels of cyclic diguanylate. Whole-genome expression analysis revealed that the message abundance of genes involved in biofilm formation was decreased but that the message abundances of those involved in virulence and the type VI secretion system were increased in a
lonA
mutant compared to the wild type. We further demonstrated that a
lonA
mutant displays an increase in type VI secretion system activity and is markedly defective in colonization of the infant mouse. These findings suggest that LonA plays a critical role in the environmental survival and virulence of
V. cholerae
.

IMPORTANCE
Bacteria utilize intracellular proteases to degrade damaged proteins and adapt to changing environments. The Lon protease has been shown to be important for environmental adaptation and plays a crucial role in regulating the motility, biofilm formation, and virulence of numerous plant and animal pathogens. We find that LonA of the human pathogen
V. cholerae
is in line with this trend, as the deletion of LonA leads to hypermotility and defects in both biofilm formation and colonization of the infant mouse. In addition, we show that LonA regulates levels of cyclic diguanylate and the type VI secretion system. Our observations add to the known regulatory repertoire of the Lon protease and the current understanding of
V. cholerae
physiology.
The harms of smoking and benefits of smoking cessation in women compared with men with type 2 diabetes: an observational analysis of the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial
Authors: Blomster Juuso I , Woodward Mark , Zoungas Sophia , Hillis Graham S , Harrap Stephen , Neal Bruce , Poulter Neil , Mancia Giuseppe , Chalmers John , Huxley Rachel 
Published: January 2016

ObjectivesIn general populations, the adverse effects of smoking on coronary risk have been demonstrated to be greater in women than in men; whether this is true for individuals with diabetes is unclear.DesignCohort study.Setting20 countries worldwide participating in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial.Participants11 140 patients with type 2 diabetes aged ≥55 years and in cardiovascular risk at the time of randomisation.Primary and secondary outcome measuresMajor cardiovascular events (death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction (MI)), all cardiovascular events (major cardiovascular event or peripheral arterial disease or transient ischaemic attack), and all-cause mortality. Secondary outcome measures were major coronary events (fatal and non-fatal MI), major cerebrovascular events (fatal and non-fatal stroke), nephropathy (new or worsening renal disease), and all cancer.ResultsAt baseline, 6466 (56% women) participants were never-smokers, 1550 (28% women) were daily smokers and 3124 (21% women) were former smokers. Median follow-up time was 5 years. In Cox regression models after multiple adjustments, compared with never smoking, daily smoking was associated with increased risk of all primary and secondary outcomes with the exception of major cerebrovascular disease. Only for major coronary events was there any evidence of a stronger effect in women than in men (ratio of the adjusted HRs women:men; 1.64 (0.83 to 3.26) p=0.08). For all other outcomes considered, the hazards of smoking were similar in men and women. Quitting smoking was associated with a 30% reduction in all-cause mortality (p=0.001) in both sexes.ConclusionsIn individuals with diabetes, the effects of smoking on all major forms of cardiovascular disease are equally as hazardous in women and men with the possible exception of major coronary events where there was some evidence of a greater hazard in women.Trial registration numberNCT00145925.
How safe is primary care? A systematic review
Authors: Panesar Sukhmeet Singh , deSilva Debra , Carson-Stevens Andrew , Cresswell Kathrin M , Salvilla Sarah Angostora , Slight Sarah Patricia , Javad Sundas , Netuveli Gopalakrishnan , Larizgoitia Itziar , Donaldson Liam J , Bates David W , Sheikh Aziz 
Published: January 2016

ImportanceImproving patient safety is at the forefront of policy and practice. While considerable progress has been made in understanding the frequency, causes and consequences of error in hospitals, less is known about the safety of primary care.ObjectiveWe investigated how often patient safety incidents occur in primary care and how often these were associated with patient harm.Evidence reviewWe searched 18 databases and contacted international experts to identify published and unpublished studies available between 1 January 1980 and 31 July 2014. Patient safety incidents of any type were eligible. Eligible studies were critically appraised using validated instruments and data were descriptively and narratively synthesised.FindingsNine systematic reviews and 100 primary studies were included. Studies reported between <1 and 24 patient safety incidents per 100 consultations. The median from population-based record review studies was 2–3 incidents for every 100 consultations/records reviewed. It was estimated that around 4% of these incidents may be associated with severe harm, defined as significantly impacting on a patient's well-being, including long-term physical or psychological issues or death (range <1% to 44% of incidents). Incidents relating to diagnosis and prescribing were most likely to result in severe harm.Conclusions and relevanceMillions of people throughout the world use primary care services on any given day. This review suggests that safety incidents are relatively common, but most do not result in serious harm that reaches the patient. Diagnostic and prescribing incidents are the most likely to result in avoidable harm.Systematic review registrationThis systematic review is registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42012002304).
Remote video auditing with real-time feedback in an academic surgical suite improves safety and efficiency metrics: a cluster randomised study
Authors: Overdyk Frank J , Dowling Oonagh , Newman Sheldon , Glatt David , Chester Michelle , Armellino Donna , Cole Brandon , Landis Gregg S , Schoenfeld David , DiCapua John F 
Published: January 2016

ImportanceCompliance with the surgical safety checklist during operative procedures has been shown to reduce inhospital mortality and complications but proper execution by the surgical team remains elusive.ObjectiveWe evaluated the impact of remote video auditing with real-time provider feedback on checklist compliance during sign-in, time-out and sign-out and case turnover times.Design, settingProspective, cluster randomised study in a 23-operating room (OR) suite.ParticipantsSurgeons, anaesthesia providers, nurses and support staff.ExposureORs were randomised to receive, or not receive, real-time feedback on safety checklist compliance and efficiency metrics via display boards and text messages, followed by a period during which all ORs received feedback.Main outcome(s) and measure(s)Checklist compliance (Pass/Fail) during sign-in, time-out and sign-out demonstrated by (1) use of checklist, (2) team attentiveness, (3) required duration, (4) proper sequence and duration of case turnover times.ResultsSign-in, time-out and sign-out PASS rates increased from 25%, 16% and 32% during baseline phase (n=1886) to 64%, 84% and 68% for feedback ORs versus 40%, 77% and 51% for no-feedback ORs (p<0.004) during the intervention phase (n=2693). Pass rates were 91%, 95% and 84% during the all-feedback phase (n=2001). For scheduled cases (n=1406, 71%), feedback reduced mean turnover times by 14% (41.4 min vs 48.1 min, p<0.004), and the improvement was sustained during the all-feedback period. Feedback had no effect on turnover time for unscheduled cases (n=587, 29%).Conclusions and relevanceOur data indicate that remote video auditing with feedback improves surgical safety checklist compliance for all cases, and turnover time for scheduled cases, but not for unscheduled cases.
Response to belimumab among patients with systemic lupus erythematosus in clinical practice settings: 24-month results from the OBSErve study in the USA
Authors: Collins C E , Dall'Era M , Kan H , Macahilig C , Molta C , Koscielny V , Chang D J 
Published: January 2016

ObjectiveTo examine disease activity and clinical outcomes, and describe overall patterns of systemic lupus erythematosus (SLE) care in patients who received belimumab in a real-world clinical setting.MethodsThis observational cohort study was conducted in US clinical practices. Rheumatologists (n=92) identified adults with SLE who had received ≥8 infusions of belimumab plus standard of care (SoC). Physicians assessed disease outcomes at 6-month intervals using patient medical charts, for up to 24 months. The primary outcome was physician-assessed change in SLE disease. Other outcomes included change in steroid use, laboratory tests and healthcare resource utilisation (HCRU).ResultsOf 501 patients (intent-to-treat population (ITT)), 446 were female, mean age was 43.3 years and 98% had moderate/severe disease activity at baseline (first dose of belimumab). Data for 277 patients who completed 24 months of belimumab treatment were available. Among the ITT, a ≥50% improvement in overall clinical response between baseline and month 6 was reported for 48.7% of patients; continued improvement was seen at all subsequent 6-month intervals relative to the previous timepoint. The percentage of patients with moderate/severe disease also decreased at each timepoint. At baseline, 77.0% of patients received steroids at a mean (SD) prednisone equivalent dose of 19.9 (14.39) mg/day, which decreased to 8.4 (7.35) mg/day at month 6 and 6.1 (9.31) mg/day at month 24. Abnormal laboratory values typically associated with SLE also demonstrated improvements at month 6, which continued through 24 months. HCRU decreased over the duration of the study.ConclusionsPatients with SLE who received belimumab plus SoC for up to 24 months demonstrated improvements in disease severity and laboratory values and a reduction in steroid use and HCRU as early as month 6. Improvements continued through 24 months, providing evidence of reduced disease activity among patients taking belimumab in real-world clinical practice.
Heart rate never lies: interventional cardiologist and Braude's quote revised
Authors: Cook Stéphane , Stauffer Jean-Christophe , Goy Jean-Jacques , Graf Denis , Puricel Serban , Frobert Aurélien , Muller Olivier , Togni Mario , Arroyo Diego 
Published: January 2016

BackgroundInterventional cardiologists may be immune to stress, allowing them to perform complex percutaneous interventions under pressure.ObjectivesTo assess heart rate (HR) variations as a surrogate marker of stress of interventional cardiologists during percutaneous cardiac procedures and in every-day life.DesignThis is a single-centre observational study including a total of six male interventional cardiologists performing coronary interventions and pacemaker implantations. Participants were asked to record their HR with the Apple Watch Device during procedures, every-day life and control activities such as outpatient consultations, sport, marital conflicts and sexual intercourse.ResultsAverage daily HR was 88±17 bpm. During work days, HR increased significantly during procedures (90±17 bpm) compared with days outside the cathlab (87±17 bpm, p=0.02). The average HR was higher during a regular week working (88±16 bpm) compared with weekends off (84±18 bpm, p=0.002). Complex cardiac procedures were associated with higher HR up to 122 bpm. Peak HR were higher during physical exertion. Of note, participants complained of hypersexuality and mania after night shifts.ConclusionsWork and especially percutaneous cardiac procedures increase HR independently of physical exertion suggesting that interventional cardiologists experience mental stress and emotions.
Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
Authors: Shono Yusuke , Tuckett Andrea Z. , Liou Hsiou-Chi , Doubrovina Ekaterina , Derenzini Enrico , Ouk Samedy , Tsai Jennifer J. , Smith Odette M. , Levy Emily R. , Kreines Fabiana M. , Ziegler Carly G.K. , Scallion Mary I. , Doubrovin Mikhail , Heller Glenn , Younes Anas , O'Reilly Richard J. , van den Brink Marcel R.M. , Zakrzewski Johannes L. 
Published: January 2016

AbstractNF-κB plays a variety of roles in oncogenesis and immunity that may be beneficial for therapeutic targeting, but strategies to selectively inhibit NF-κB to exert antitumor activity have been elusive. Here, we describe IT-901, a bioactive naphthalenethiobarbiturate derivative that potently inhibits the NF-κB subunit c-Rel. IT-901 suppressed graft-versus-host disease while preserving graft-versus-lymphoma activity during allogeneic transplantation. Further preclinical assessment of IT-901 for the treatment of human B-cell lymphoma revealed antitumor properties in vitro and in vivo without restriction to NF-κB–dependent lymphoma. This nondiscriminatory, antilymphoma effect was attributed to modulation of the redox homeostasis in lymphoma cells resulting in oxidative stress. Moreover, NF-κB inhibition by IT-901 resulted in reduced stimulation of the oxidative stress response gene heme oxygenase-1, and we demonstrated that NF-κB inhibition exacerbated oxidative stress induction to inhibit growth of lymphoma cells. Notably, IT-901 did not elicit increased levels of reactive oxygen species in normal leukocytes, illustrating its cancer selective properties. Taken together, our results provide mechanistic insight and preclinical proof of concept for IT-901 as a novel therapeutic agent to treat human lymphoid tumors and ameliorate graft-versus-host disease. Cancer Res; 76(2); 377–89. ©2016 AACR.
Activation of Hematopoietic Stem/Progenitor Cells Promotes Immunosuppression Within the Pre–metastatic Niche
Authors: Giles Amber Jin , Reid Caitlin Marie , Evans Justin DeWayne , Murgai Meera , Vicioso Yorleny , Highfill Steven Lorenz , Kasai Miki , Vahdat Linda , Mackall Crystal Lee , Lyden David , Wexler Leonard , Kaplan Rosandra Natasha 
Published: January 2016

Abstract
Metastatic tumors have been shown to establish microenvironments in distant tissues that are permissive to disseminated tumor cells. Hematopoietic cells contribute to this microenvironment, yet the precise initiating events responsible for establishing the pre-metastatic niche remain unclear. Here, we tracked the developmental fate of hematopoietic stem and progenitor cells (HSPC) in tumor-bearing mice. We show that a distant primary tumor drives the expansion of HSPCs within the bone marrow and their mobilization to the bloodstream. Treatment of purified HSPCs cultured ex vivo with tumor-conditioned media induced their proliferation as well as their differentiation into immunosuppressive myeloid cells. We furthered tracked purified HSPCs in vivo and found they differentiated into myeloid-derived suppressor cells in early metastatic sites of tumor-bearing mice. The number of CD11b+Ly6g+ cells in metastatic sites was significantly increased by HSPC mobilization and decreased if tumor-mediated mobilization was inhibited. Moreover, pharmacologic mobilization of HSPCs increased metastasis, whereas depletion of Gr1+ cells abrogated the metastasis-promoting effects of HSPC mobilization. Finally, we detected elevated levels of HSPCs in the circulation of newly diagnosed cancer patients, which correlated with increased risk for metastatic progression. Taken together, our results highlight bone marrow activation as one of the earliest steps of the metastatic process and identify circulating HSPCs as potential clinical indicators of metastatic niche formation. Cancer Res; 76(6); 1335–47. ©2015 AACR.
A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors
Authors: Zhong Haihong , Davis April , Ouzounova Maria , Carrasco Rosa A. , Chen Cui , Breen Shannon , Chang Yong S. , Huang Jiaqi , Liu Zheng , Yao Yihong , Hurt Elaine , Moisan Jacques , Fung Michael , Tice David A. , Clouthier Shawn G. , Xiao Zhan , Wicha Max S. , Korkaya Hasan , Hollingsworth Robert E. 
Published: January 2016

Abstract
Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for IL6 in promoting tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Notably, in tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2+ tumor cells by targeting the CD44+CD24− cancer stem cell population. Collectively, our findings extend the evidence of important pleiotropic roles of IL6 in tumorigenesis and drug resistance, and offer a preclinical proof of concept for the use of IL6 antibodies in combination regimens to heighten therapeutic responses and overcome drug resistance. Cancer Res; 76(2); 480–90. ©2016 AACR.
HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis
Authors: Choi Seo-Hyun , Nam Jae-Kyung , Kim Bu-Yeo , Jang Junho , Jin Young-Bae , Lee Hae-June , Park Seungwoo , Ji Young Hoon , Cho Jaeho , Lee Yoon-Jin 
Published: January 2016

Abstract
The endothelial-to-mesenchymal transition (EndMT) contributes to cancer, fibrosis, and other pathologic processes. However, the underlying mechanisms are poorly understood. Endothelial HSP1 (HSPB1) protects against cellular stress and has been implicated in cancer progression and pulmonary fibrosis. In this study, we investigated the role of HSPB1 in mediating the EndMT during the development of pulmonary fibrosis and lung cancer. HSPB1 silencing in human pulmonary endothelial cells accelerated emergence of the fibrotic phenotype after treatment with TGFβ or other cytokines linked to pulmonary fibrosis, suggesting that HSPB1 maintains endothelial cell identity. In mice, endothelial-specific overexpression of HSPB1 was sufficient to inhibit pulmonary fibrosis by blocking the EndMT. Conversely, HSPB1 depletion in a mouse model of lung tumorigenesis induced the EndMT. In clinical specimens of non–small cell lung cancer, HSPB1 expression was absent from tumor endothelial cells undergoing the EndMT. Our results showed that HSPB1 regulated the EndMT in lung fibrosis and cancer, suggesting that HSPB1-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases. Cancer Res; 76(5); 1019–30. ©2016 AACR.
Non–Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases
Authors: Isozaki Hideko , Ichihara Eiki , Takigawa Nagio , Ohashi Kadoaki , Ochi Nobuaki , Yasugi Masayuki , Ninomiya Takashi , Yamane Hiromichi , Hotta Katsuyuki , Sakai Katsuya , Matsumoto Kunio , Hosokawa Shinobu , Bessho Akihiro , Sendo Toshiaki , Tanimoto Mitsune , Kiura Katsuyuki 
Published: January 2016

Abstract
Crizotinib is the standard of care for advanced non–small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult. Cancer Res; 76(6); 1506–16. ©2015 AACR.