bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of CPAP to reduce arterial stiffness in moderate-to-severe obstructive sleep apnoea, without excessive daytime sleepiness (STIFFSLEEP): an observational cohort study protocol
Authors: Mineiro Maria Alexandra , Marques da Silva Pedro , Alves Marta , Virella Daniel , Marques Gomes Maria João , Cardoso João 
Published: July 2016

IntroductionSleepiness is a cardinal symptom in obstructive sleep apnoea (OSA) but most patients have unspecific symptoms. Arterial stiffness, evaluated by pulse wave velocity (PWV), is related to atherosclerosis and cardiovascular (CV) risk. Arterial stiffness was reported to be higher in patients with OSA, improving after treatment with continuous positive airway pressure (CPAP). This study aims to assess whether the same effect occurs in patients with OSA and without sleepiness.Methods and analysisThis observational study assesses the CV effect of CPAP therapy on a cohort of patients with moderate-to-severe OSA; the effect on the subcohorts of sleepy and non-sleepy patients will be compared. A systematic and consecutive sample of patients advised CPAP therapy will be recruited from a single outpatient sleep clinic (Centro Hospitalar de Lisboa Central—CHLC, Portugal). Eligible patients are male, younger than 65 years, with confirmed moderate-to-severe OSA and apnoea–hypopnea index (AHI) above 15/hour. Other sleep disorders, diabetes or any CV disease other than hypertension are exclusion criteria. Clinical evaluation at baseline includes Epworth Sleepiness Scale (ESS), and sleepiness is defined as ESS above 10. OSA will be confirmed by polygraphic study (cardiorespiratory, level 3). Participants are advised to undertake an assessment of carotid-femoral PWV (cf-PWV) and 24 hours evaluation of ambulatory blood pressure monitoring (ABPM), at baseline and after 4 months of CPAP therapy. Compliance and effectiveness of CPAP will be assessed. The main outcome is the variation of cf-PWV over time.Ethics and disseminationThis protocol was approved by the Ethics Committees of CHLC (reference number 84/2012) and NOVA Medical School (number36/2014/CEFCM), Lisbon. Informed, written consent will be obtained. Its results will be presented at conferences and published in peer-reviewed journals.Trial registration numberNCT02273089; Pre-results.
Geographic variation in the treatment of non-ST-segment myocardial infarction in the English National Health Service: a cohort study
Authors: Dondo T B , Hall M , Timmis A D , Yan A T , Batin P D , Oliver G , Alabas O A , Norman P , Deanfield J E , Bloor K , Hemingway H , Gale C P 
Published: July 2016

ObjectivesTo investigate geographic variation in guideline-indicated treatments for non-ST-elevation myocardial infarction (NSTEMI) in the English National Health Service (NHS).DesignCohort study using registry data from the Myocardial Ischaemia National Audit Project.SettingAll Clinical Commissioning Groups (CCGs) (n=211) in the English NHS.Participants357 228 patients with NSTEMI between 1 January 2003 and 30 June 2013.Main outcome measureProportion of eligible NSTEMI who received all eligible guideline-indicated treatments (optimal care) according to the date of guideline publication.ResultsThe proportion of NSTEMI who received optimal care was low (48 257/357 228; 13.5%) and varied between CCGs (median 12.8%, IQR 0.7–18.1%). The greatest geographic variation was for aldosterone antagonists (16.7%, 0.0–40.0%) and least for use of an ECG (96.7%, 92.5–98.7%). The highest rates of care were for acute aspirin (median 92.8%, IQR 88.6–97.1%), and aspirin (90.1%, 85.1–93.3%) and statins (86.4%, 82.3–91.2%) at hospital discharge. The lowest rates were for smoking cessation advice (median 11.6%, IQR 8.7–16.6%), dietary advice (32.4%, 23.9–41.7%) and the prescription of P2Y12inhibitors (39.7%, 32.4–46.9%). After adjustment for case mix, nearly all (99.6%) of the variation was due to between-hospital differences (median 64.7%, IQR 57.4–70.0%; between-hospital variance: 1.92, 95% CI 1.51 to 2.44; interclass correlation 0.996, 95% CI 0.976 to 0.999).ConclusionsAcross the English NHS, the optimal use of guideline-indicated treatments for NSTEMI was low. Variation in the use of specific treatments for NSTEMI was mostly explained by between-hospital differences in care. Performance-based commissioning may increase the use of NSTEMI treatments and, therefore, reduce premature cardiovascular deaths.Trial registration numberNCT02436187.
External validation of the emergency department assessment of chest pain score accelerated diagnostic pathway (EDACS-ADP)
Authors: Flaws Dylan , Than Martin , Scheuermeyer Frank Xavier , Christenson James , Boychuk Barbara , Greenslade Jaimi H , Aldous Sally , Hammett Christopher J , Parsonage William A , Deely Joanne M , Pickering John W , Cullen Louise 
Published: July 2016

ObjectiveThe emergency department assessment of chest pain score accelerated diagnostic pathway (EDACS-ADP) facilitates low-risk ED chest pain patients early to outpatient investigation. We aimed to validate this rule in a North American population.MethodsWe performed a retrospective validation of the EDACS-ADP using 763 chest pain patients who presented to St Paul's Hospital, Vancouver, Canada, between June 2000 and January 2003. Patients were classified as low risk if they had an EDACS <16, no new ischaemia on ECG and non-elevated serial 0-hour and 2-hour cardiac troponin concentrations. The primary outcome was the number of patients who had a predetermined major adverse cardiac event (MACE) at 30 days after presentation.ResultsOf the 763 patients, 317 (41.6%) were classified as low risk by the EDACS-ADP. The sensitivity, specificity, negative predictive value and positive predictive value of the EDACS-ADP for 30-day MACE were 100% (95% CI 94.2% to 100%), 46.4% (95% CI 42.6% to 50.2%), 100% (95% CI 98.5% to 100.0%) and 17.5% (95% CI 14.1% to 21.3%), respectively.ConclusionsThis study validated the EDACS-ADP in a novel context and supports its safe use in a North American population. It confirms that EDACS-ADP can facilitate progression to early outpatient investigation in up to 40% of ED chest pain patients within 2 hours.
Cardiovascular disease risk factors in relation to smoking behaviour and history: a population-based cohort study
Authors: Keto Jaana , Ventola Hanna , Jokelainen Jari , Linden Kari , Keinänen-Kiukaanniemi Sirkka , Timonen Markku , Ylisaukko-oja Tero , Auvinen Juha 
Published: July 2016

ObjectiveTo investigate how individual risk factors for cardiovascular disease (CVD) (blood pressure, lipid levels, body mass index, waist and hip circumference, use of antihypertensive or hypolipidemic medication, and diagnosed diabetes) differ in people aged 46 years with different smoking behaviour and history.MethodsThis population-based cohort study is based on longitudinal data from the Northern Finland Birth Cohort 1966 project. Data were collected at the 31-year and 46-year follow-ups, when a total of 5038 and 5974 individuals participated in clinical examinations and questionnaires. Data from both follow-ups were available for 3548 participants. In addition to individual CVD risk factors, Framingham and Systematic Coronary Risk Evaluation (SCORE) algorithms were used to assess the absolute risk of a CVD event within the next decade.ResultsThe differences in individual risk factors for CVD reached statistical significance for some groups, but the differences were not consistent or clinically significant. There were no clinically significant differences in CVD risk as measured by Framingham or SCORE algorithms between never smokers, recent quitters and former smokers (7.5%, 7.4%, 8.1% for men; 3.3%, 3.0%, 3.2% for women; p<0.001).ConclusionsThe effect of past or present smoking on individual CVD risk parameters such as blood pressure and cholesterol seems to be of clinically minor significance in people aged 46 years. In other words, smoking seems to be above all an independent risk factor for CVD in the working-age population. Quitting smoking in working age may thus reduce calculated CVD risk nearly to the same level with people who have never smoked.
Prospective observational study of point-of-care creatinine in trauma
Authors: Carden Anthony J , Salcedo Edgardo S , Tran Nam K , Gross Eric , Mattice Jennifer , Shepard Jan , Galante Joseph M 
Published: July 2016

BackgroundPatients with trauma are at risk for renal dysfunction from hypovolemia or urological injury. In austere environments, creatinine values are not available to guide resuscitation. A new portable device, the Stat Sensor Point-of-care (POC) Whole Blood Creatinine Analyzer, provides accurate results in <30 s and requires minimal training. This device has not been evaluated in trauma despite the theoretical benefit it provides. The purpose of this study is to determine the clinical impact of the POC device in trauma.Methods40 patients with trauma were enrolled in a prospective observational study. One drop of blood was used for creatinine determination on the Statsensor POC device. POC creatinine results were compared to the laboratory. Turnaround time (TAT) for POC and laboratory methods was calculated as well as time elapsed to CT scan if applicable.ResultsPatients (n=40) were enrolled between December 2014 and March 2015. POC creatinine values were similar to laboratory methods with a mean bias of 0.075±0.27 (p=0.08). Mean analytical TATs for the POC measurements were significantly faster than the laboratory method (11.6±10.0 min vs 78.1±27.9 min, n=40, p<0.0001). Mean elapsed time before arrival at the CT scanner was 52.9±34.2 min.ConclusionsThe POC device reported similar creatinine values to the laboratory and provided significantly faster results. POC creatinine testing is a promising development for trauma practice in austere environments and workup of a subset of stable patients with trauma. Further study is warranted to determine clinical impact, both in hospital-based trauma and austere environments.
Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2
Authors: Zhang Jia-Xing , Chen Zhen-Hua , Xu Yi , Chen Jie-Wei , Weng Hui-Wen , Yun Miao , Zheng Zou-San , Chen Cui , Wu Bing-Li , Li En-Min , Fu Jian-Hua , Ye Sheng , Xie Dan 
Published: July 2016

Abstract

Purpose:
We previously reported the oncogenic role of paired-like homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC.

Experimental Design:
Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy.

Results:
ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P &lt; 0.05). Gain- and loss-of-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. In addition, miR-644a dramatically suppressed self-renewal and stem cell–like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell–associated phenotype, at least partially, by inactivation of the Akt/GSK-3β/β-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC.

Conclusions:
Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. Clin Cancer Res; 23(1); 298–310. ©2016 AACR.
FDA Approval of Palbociclib in Combination with Fulvestrant for the Treatment of Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer
Authors: Walker Amanda J. , Wedam Suparna , Amiri-Kordestani Laleh , Bloomquist Erik , Tang Shengui , Sridhara Rajeshwari , Chen Wei , Palmby Todd R. , Fourie Zirkelbach Jeanne , Fu Wentao , Liu Qi , Tilley Amy , Kim Geoffrey , Kluetz Paul G. , McKee Amy E. , Pazdur Richard 
Published: July 2016

Abstract
On February 19, 2016, the FDA approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, AstraZeneca) for the treatment of women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2:1) to receive palbociclib plus fulvestrant (n = 347) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator-assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 months vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% confidence interval (CI), 0.36–0.59; P &lt; 0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (&gt;20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. Clin Cancer Res; 22(20); 4968–72. ©2016 AACR.
Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors
Authors: Singhi Aatur D. , Liu Ta-Chiang , Roncaioli Justin L. , Cao Dengfeng , Zeh Herbert J. , Zureikat Amer H. , Tsung Allan , Marsh J. Wallis , Lee Kenneth K. , Hogg Melissa E. , Bahary Nathan , Brand Randall E. , McGrath Kevin M. , Slivka Adam , Cressman Kristi L. , Fuhrer Kimberly , O'Sullivan Roderick J. 
Published: July 2016

AbstractPurpose: Pancreatic neuroendocrine tumors (PanNET) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing has identified recurrent mutations in the genes DAXX and ATRX, which correlate with loss of protein expression and alternative lengthening of telomeres (ALT). Both ALT and DAXX/ATRX loss were initially reported to be associated with a favorable prognosis; however, recent studies suggest the contrary. Our aims were to assess the prevalence and prognostic significance of ALT and DAXX/ATRX in both primary and metastatic PanNETs.Experimental Design: Telomere-specific FISH and DAXX/ATRX IHC was performed on a multi-institutional cohort of 321 patients with resected PanNET and 191 distant metastases from 52 patients. These results were correlated with clinicopathologic features, including disease-free survival (DFS) and disease-specific survival (DSS).Results: The prevalence of ALT and DAXX/ATRX loss in resected PanNETs was 31% and 26%, respectively, and associated with larger tumor size, higher WHO grade, lymph node metastasis, and distant metastasis (P &lt; 0.001). The 5-year DFS and 10-year DSS of patients with ALT-positive and DAXX/ATRX-negative PanNETs were 40% and 50%, respectively, as compared with 96% and 89%, respectively, for wild-type PanNETs. Among distant metastases, ALT and DAXX/ATRX loss was 67% and 52%, respectively, and only occurred in the setting of an ALT-positive and DAXX/ATRX-negative primary PanNET. By multivariate analysis, both ALT and DAXX/ATRX loss were negative, independent prognostic factors for DFS.Conclusions: ALT and DAXX/ATRX loss in PanNETs was associated with shorter DFS and DSS and likely plays a significant role in driving metastatic disease. Clin Cancer Res; 23(2); 600–9. ©2016 AACR.
MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer
Authors: Hernandez-Hoyos Gabriela , Sewell Toddy , Bader Robert , Bannink Jeannette , Chenault Ruth A. , Daugherty Mollie , Dasovich Maria , Fang Hang , Gottschalk Rebecca , Kumer John , Miller Robert E. , Ravikumar Padma , Wiens Jennifer , Algate Paul A. , Bienvenue David , McMahan Catherine J. , Natarajan Sateesh K. , Gross Jane A. , Blankenship John W. 
Published: July 2016

Abstract
Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ϵ to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID γ (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155–65. ©2016 AACR.
Concepts to Target MYC in Pancreatic Cancer
Authors: Wirth Matthias , Mahboobi Siavosh , Krämer Oliver H. , Schneider Günter 
Published: July 2016

Abstract
Current data suggest that MYC is an important signaling hub and driver in pancreatic ductal adenocarcinoma (PDAC), a tumor entity with a strikingly poor prognosis. No targeted therapies with a meaningful clinical impact were successfully developed against PDAC so far. This points to the need to establish novel concepts targeting the relevant drivers of PDAC, like KRAS or MYC. Here, we discuss recent developments of direct or indirect MYC inhibitors and their potential mode of action in PDAC. Mol Cancer Ther; 15(8); 1792–8. ©2016 AACR.
Mitochondrial β-Carotene 9′,10′ Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function
Authors: Gong Xiaoming , Marisiddaiah Raju , Zaripheh Susan , Wiener Doris , Rubin Lewis P. 
Published: July 2016

Abstract
Despite numerous inquiries into protective roles of lycopene in prostate cancer prevention or therapy, little is known about mechanisms by which lycopene or its metabolites inhibit prostate cancer. The enzyme β-carotene 9′,10′-oxygenase (BCO2), which catalyzes asymmetric cleavage of several carotenoids, is the principal regulator of lycopene metabolism, but the range of BCO2 biological functions is incompletely understood. This study investigated expression and functional roles of BCO2 in human prostate cancer. Expression of the bco2 gene is dramatically decreased in prostate cancer tissue and in a range of prostate cancer cell lines as compared with nonneoplastic prostate tissue and normal prostatic epithelial cells, respectively. Inhibition of DNA methyltransferase activity restored bco2 expression in prostate cancer cell lines tested. Treatment with lycopene or its metabolite, apo-10-lycopenal, also increased bco2 expression and reduced cell proliferation in androgen-sensitive cell lines, but lycopene neither altered bco2 expression nor cell growth in androgen-resistant cells. Notably, restoring bco2 expression in prostate cancer cells inhibited cell proliferation and colony formation, irrespective of lycopene exposure. Exogenous expression of either wild-type BCO2 or a mutant (enzymatically inactive) BCO2 in prostate cancer cells reduced NF-κB activity and decreased NF-κB nuclear translocation and DNA binding. Together, these results indicate epigenetic loss of BCO2 expression is associated with prostate cancer progression. Moreover, these findings describe previously unanticipated functions of BCO2 that are independent of its enzymatic role in lycopene metabolism.
Implications: This study identifies BCO2 as a tumor suppressor in prostate cancer. BCO2-mediated inhibition of NF-κB signaling implies BCO2 status is important in prostate cancer progression. Mol Cancer Res; 14(10); 966–75. ©2016 AACR.
Effectiveness of Left Atrial Appendage Exclusion Procedures to Reduce the Risk of Stroke: A Systematic Review of the Evidence
Authors: Noelck North , Papak Joel , Freeman Michele , Paynter Robin , Low Allison , Motu’apuaka Makalapua , Kondo Karli , Kansagara Devan 
Published: July 2016

Background—
Atrial fibrillation is an important cause of cardioembolic stroke. Oral anticoagulants (OAC) reduce stroke risk but increase the risk of serious bleeding. Left atrial appendage (LAA) procedures have been developed to isolate the LAA from circulating blood flow, as an alternative to OAC. We conducted a systematic review of the benefits and harms of surgical and percutaneous LAA exclusion procedures.

Methods and Results—
We searched multiple data sources, including Ovid MEDLINE, Cochrane, and Embase, through January 7, 2015. Of 2567 citations, 20 primary studies met prespecified inclusion criteria. We abstracted data on patient characteristics, stroke, mortality, and adverse effects. We assessed study quality and graded the strength of evidence using published criteria. Trials found low-strength evidence that percutaneous LAA exclusion confers similar risks of stroke and mortality as continued OAC, but this evidence was limited to the Watchman device in patients eligible for long-term OAC. Observational studies found moderate-strength evidence of serious harms with a variety of percutaneous LAA procedures. There is low-strength evidence that surgical LAA exclusion does not add significant harm during heart surgery for another indication, but evidence on stroke reduction is insufficient.

Conclusions—
There is limited evidence that the Watchman device may be noninferior to long-term OAC in selected patients. Data on effectiveness of LAA exclusion devices is lacking in patients ineligible for long-term OAC. Percutaneous LAA devices are associated with high rates of procedure-related harms. Although surgical LAA exclusion during heart surgery does not seem to add incremental harm, there is insufficient evidence of benefit.