bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nocturnal antihypertensive treatment in patients with type 1 diabetes with autonomic neuropathy and non-dipping of blood pressure during night time: protocol for a randomised, placebo-controlled, double-blind, two-way crossover study
Authors: Hjortkær Henrik , Jensen Tonny , Kofoed Klaus , Mogensen Ulrik , Køber Lars , Hilsted Karen Lisa , Corinth Helle , Theilade Simone , Hilsted Jannik 
Published: October 2014

IntroductionCardiac autonomic neuropathy (CAN) and elevated nocturnal blood pressure are independent risk factors for cardiovascular disease in patients with diabetes. Previously, associations between CAN, non-dipping of nocturnal blood pressure and coronary artery calcification have been demonstrated. The present protocol describes a trial to test the efficacy of bedtime dosing of the ACE inhibitor enalapril on night time blood pressure and left ventricular mass in patients with type 1 diabetes.Materials and methodsIn a randomised, double-blind, two-way cross-over study, 24 normoalbuminuric patients with type 1 diabetes with CAN will be treated for 12 weeks with either morning or bedtime dosing of 20 mg enalapril, followed by 12 weeks of switched treatment regimen. During each treatment period, two 24 h ambulatory blood pressure measurements will be performed and after each treatment period left ventricular mass will be determined by multisliced CT. Primary end points will be reduction in blood pressure and reduction in left ventricular mass.Ethics and disseminationThe study has been approved by the Danish Medicines Agency, the Scientific-Ethical Committee of the Capital Region of Denmark and the Danish Data Protection Agency. An external monitoring committee (the Good Clinical Practice Unit at Copenhagen University Hospital) will oversee the study. The results of the study will be presented at national and international scientific meetings and publications will be submitted to peer-reviewed journals.Trial registration numberEudraCT (2012- 002136-90).
Aligned genomic data compression via improved modeling
Authors: Ochoa Idoia , Hernaez Mikel , Weissman Tsachy 
Published: October 2014

With the release of the latest Next-Generation Sequencing (NGS) machine, the HiSeq X by Illumina, the cost of sequencing the whole genome of a human is expected to drop to a mere $1000. This milestone in sequencing history marks the era of affordable sequencing of individuals and opens the doors to personalized medicine. In accord, unprecedented volumes of genomic data will require storage for processing. There will be dire need not only of compressing aligned data, but also of generating compressed files that can be fed directly to downstream applications to facilitate the analysis of and inference on the data. Several approaches to this challenge have been proposed in the literature; however, focus thus far has been on the low coverage regime and most of the suggested compressors are not based on effective modeling of the data. We demonstrate the benefit of data modeling for compressing aligned reads. Specifically, we show that, by working with data models designed for the aligned data, we can improve considerably over the best compression ratio achieved by previously proposed algorithms. Our results indicate that the pareto-optimal barrier for compression rate and speed claimed by Bonfield and Mahoney (2013) [Bonfield JK and Mahoneys MV, Compression of FASTQ and SAM format sequencing data, PLOS ONE, 8(3):e59190, 2013.] does not apply for high coverage aligned data. Furthermore, our improved compression ratio is achieved by splitting the data in a manner conducive to operations in the compressed domain by downstream applications.
Mitochondrial DNA Copy Number and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Risk in Two Prospective Studies
Authors: Kim Christopher , Bassig Bryan A. , Seow Wei Jie , Hu Wei , Purdue Mark P. , Huang Wen-Yi , Liu Chin-San , Cheng Wen-Ling , Männistö Satu , Vermeulen Roel , Weinstein Stephanie J. , Lim Unhee , Hosgood H. Dean , Bonner Matthew R. , Caporaso Neil E. , Albanes Demetrius , Lan Qing , Rothman Nathaniel 
Published: October 2014

Abstract
Background: Mitochondrial DNA copy number (mtDNA CN) may be modified by mitochondria in response to oxidative stress. Previously, mtDNA CN was associated with non-Hodgkin lymphoma (NHL) risk, particularly chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We conducted a replication study in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study and pooled with published ATBC (Alpha-Tocopherol, Beta-Carotene) data.
Methods: In PLCO, 292 NHL cases (95 CLL/SLL cases) and 301 controls were pooled with 142 NHL cases (47 CLL/SLL cases) and 142 controls from ATBC. Subjects answered a questionnaire and provided blood. DNA was extracted from prediagnostic peripheral white blood, and mtDNA CN assayed by quantitative polymerase chain reaction. Unconditional logistic regression estimated mtDNA CN and NHL risk by odds ratios (OR) and 95% confidence intervals (95% CI).
Results: Greater mtDNA CN was associated with increased risk of CLL/SLL among males in PLCO (3rd vs. 1st tertile: OR, 2.21; 95% CI, 1.03–4.72; Ptrend: 0.049) and pooled (T3 vs. T1: OR, 3.12; 95% CI, 1.72–5.68; Ptrend: 0.0002). Association was stronger among male smokers (Ptrend: &lt;0.0001) and essentially identical for cases diagnosed &lt;6, &gt;6–8, and &gt;8 years from blood draw (pooled: Pinteraction: 0.65). mtDNA CN and risk of other NHL subtypes and multiple myeloma showed no association.
Conclusions and Impact: Mitochondrial DNA CN was associated with risk of CLL/SLL in males/male smokers. The risk was observed among cases diagnosed as long as 8 years after blood draw. These results suggest that higher mtDNA CN may reflect a process involved in CLL/SLL development. Cancer Epidemiol Biomarkers Prev; 24(1); 148–53. ©2014 AACR.
A Phase II Study of the Efficacy and Safety of the Combination Therapy of the MEK Inhibitor Refametinib (BAY 86-9766) Plus Sorafenib for Asian Patients with Unresectable Hepatocellular Carcinoma
Authors: Lim Ho Yeong , Heo Jeong , Choi Hye Jin , Lin Cheng-Yao , Yoon Jung-Hwan , Hsu Chiun , Rau Kun-Ming , Poon Ronnie T.P. , Yeo Winnie , Park Joong-Won , Tay Miah Hiang , Hsieh Wen-Son , Kappeler Christian , Rajagopalan Prabhu , Krissel Heiko , Jeffers Michael , Yen Chia-Jui , Tak Won Young 
Published: October 2014

Abstract
Purpose: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177).
Experimental Design: Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability.
Results: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients.
Conclusions: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination. Clin Cancer Res; 20(23); 5976–85. ©2014 AACR.
A Tissue Biomarker–Based Model That Identifies Patients with a High Risk of Distant Metastasis and Differential Survival by Length of Androgen Deprivation Therapy in RTOG Protocol 92-02
Authors: Pollack Alan , Dignam James J. , Diaz Dayssy A. , Wu Qian , Stoyanova Radka , Bae Kyounghwa , Dicker Adam P. , Sandler Howard , Hanks Gerald E. , Feng Felix Y. 
Published: October 2014

Abstract
Purpose: To examine the relationship between the expression of 7 promising apoptotic/cell proliferation proteins (Ki-67, p53, MDM2, bcl-2, bax, p16, and Cox-2) and risk of distant metastasis.
Experimental Design: RTOG 92-02 compared external beam radiotherapy (EBRT) to approximately 70 Gy + short-term androgen deprivation therapy (STADT) with EBRT + long-term ADT (LTADT). Immunohistochemical analysis was available for ≥4 biomarkers in 616 of 1,521 assessable cases. Biomarkers were evaluated individually and jointly via multivariable modeling of distant metastasis using competing risks hazards regression, adjusting for age, prostate-specific antigen, Gleason score, T stage, and treatment.
Results: Modeling identified four biomarkers (Ki-67, MDM2, p16 and Cox-2) that were jointly associated with distant metastasis. The c-index was 0.77 for the full model and 0.70 for the model without the biomarkers; a relative improvement of about 10% (likelihood ratio P &lt; 0.001). Subdivision of the patients into quartiles based on predicted distant metastasis risk identified a high-risk group with 10-year distant metastasis risk of 52.5% after EBRT + STADT and 31% with EBRT + LTADT; associated 10-year prostate cancer–specific mortality (PCSM) risks were 45.9% and 14.5% with STADT and LTADT.
Conclusion: Four biomarkers were found to contribute significantly to a model that predicted distant metastasis and identified a subgroup of patients at a particularly high risk of both distant metastasis and PCSM when EBRT + STADT was used. LTADT resulted in significant reductions in distant metastasis and improvements in PCSM, and there was a suggestion of greater importance in the very high risk subgroup. Clin Cancer Res; 20(24); 6379–88. ©2014 AACR.
Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer
Authors: Suryawanshi Swati , Huang Xin , Elishaev Esther , Budiu Raluca A. , Zhang Lixin , Kim SungHwan , Donnellan Nicole , Mantia-Smaldone Gina , Ma Tianzhou , Tseng George , Lee Ted , Mansuria Suketu , Edwards Robert P. , Vlad Anda M. 
Published: October 2014

Abstract
Purpose: Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear-cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC).
Experimental Design: RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n = 32), benign endometriosis (n = 30), atypical endometriosis (n = 15), and EAOC (n = 43). Serous tumors (n = 15) were included as nonendometriosis-associated controls. The immune microenvironment was profiled using Nanostring and the nCounter GX Human Immunology Kit, comprising probes for a total of 511 immune genes.
Results: One third of the patients with endometriosis revealed a tumor-like inflammation profile, suggesting that cancer-like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation.
Conclusions: These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC. Clin Cancer Res; 20(23); 6163–74. ©2014 AACR.
Dual HER2 Targeting Impedes Growth of HER2 Gene–Amplified Uterine Serous Carcinoma Xenografts
Authors: Groeneweg Jolijn W. , Hernandez Silvia F. , Byron Virginia F. , DiGloria Celeste M. , Lopez Hector , Scialabba Vanessa , Kim Minji , Zhang Ling , Borger Darrell R. , Tambouret Rosemary , Foster Rosemary , Rueda Bo R. , Growdon Whitfield B. 
Published: October 2014

Abstract
Purpose: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts.
Experimental Design: Immunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation.
Results: HER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models, and was associated with increased apoptosis and decreased proliferation.
Conclusions: Although trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation. Clin Cancer Res; 20(24); 6517–28. ©2014 AACR.
Tumor Genotype Is an Independent Prognostic Factor in Primary Gastrointestinal Stromal Tumors of Gastric Origin: A European Multicenter Analysis Based on ConticaGIST
Authors: Wozniak Agnieszka , Rutkowski Piotr , Schöffski Patrick , Ray-Coquard Isabelle , Hostein Isabelle , Schildhaus Hans-Ulrich , Le Cesne Axel , Bylina Elzbieta , Limon Janusz , Blay Jean-Yves , Siedlecki Janusz A. , Wardelmann Eva , Sciot Raf , Coindre Jean-Michel , Debiec-Rychter Maria 
Published: October 2014

Abstract
Purpose: Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response to treatment with tyrosine kinase inhibitors, the role of tumor genotype as a prognostic factor remains controversial. The ConticaGIST study sought to determine the pathologic and molecular factors associated with disease-free survival (DFS) in patients with operable, imatinib-naive GIST.
Experimental Design: Clinicopathologic and molecular data from 1,056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European ConticaGIST database were prospectively obtained and reviewed. Risk of tumor recurrence was stratified using the modified NIH criteria. The median follow-up was 52 months.
Results: On testing for potential prognostic parameters, the following were associated with inferior DFS on multivariable Cox model analysis: primary nongastric site, size &gt;10 cm, mitotic index &gt;10 mitoses per 50 high power field, and the KIT exon 9 duplication [hazard ratio (HR), 1.47; 95% confidence interval (CI), 0.9–2.5; P = 0.037] and KIT exon 11 deletions involving codons 557 and/or 558 [KITdel-inc557/558; HR, 1.45; 95% CI, 1.0–2.2; P = 0.004]. Conversely, PDGFRA exon 18 mutations were indicators of better prognosis [HR, 0.23; 95% CI, 0.1–0.6; P = 0.002]. KITdel-inc557/558 were an adverse indicator only in GIST localized in the stomach (P &lt; 0.001) but not in tumors with nongastric origin. In gastric GIST, all other mutations presented remarkably superior 5-year DFS.
Conclusions: In conclusion, tumor genotype is an independent molecular prognostic variable associated with gastric GIST and should be used for optimizing tailored adjuvant imatinib treatment. Clin Cancer Res; 20(23); 6105–16. ©2014 AACR.
Whole-Body Low-Dose Computed Tomography and Advanced Imaging Techniques for Multiple Myeloma Bone Disease
Authors: Pianko Matthew J. , Terpos Evangelos , Roodman G. David , Divgi Chaitanya R. , Zweegman Sonja , Hillengass Jens , Lentzsch Suzanne 
Published: October 2014

AbstractDetection of lytic bone lesions is crucial in the workup for multiple myeloma and very often dictates the decision to start treatment. Conventional radiography, despite decades of use, is often insufficient for detection of bone disease in multiple myeloma. Modern imaging techniques such as MRI, PET, and CT offer superior detection of myeloma bone disease and extramedullary manifestations of plasma cell dyscrasias. Novel whole-body low-dose computed tomography (WBLDCT) protocols allow for collection of superior image detail of the skeleton at doses of radiation similar to those used for conventional planar radiography. Several studies have shown that WBLDCT has a superior detection rate for lytic bone lesions compared with whole-body X-ray (WBXR), potentially leading to restaging and changes in therapy. MRI and PET provide imaging data important for assessing disease activity and prognostication. Because of several advantages over WBXR, WBLDCT is already the standard imaging technique for use in patients with multiple myeloma in many European institutions. However, the radiographic skeletal survey or WBXR is still the initial study of choice used to screen for myeloma bone disease in many institutions. In this review, we aim to explore the changing landscape of imaging for myeloma bone disease through use of modern imaging techniques. Clin Cancer Res; 20(23); 5888–97. ©2014 AACR.
Lycopene Attenuated Hepatic Tumorigenesis via Differential Mechanisms Depending on Carotenoid Cleavage Enzyme in Mice
Authors: Ip Blanche C. , Liu Chun , Ausman Lynne M. , von Lintig Johannes , Wang Xiang-Dong 
Published: October 2014

Abstract
Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10′-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9′,10′-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)–promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-κB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress–mediated unfolded protein response (ERUPR), through decreasing ERUPR-mediated protein kinase RNA-activated like kinase–eukaryotic initiation factor 2α activation, and inositol requiring 1α–X-box–binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, β-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression. Cancer Prev Res; 7(12); 1219–27. ©2014 AACR.
Multimodal 3 Tesla MRI Confirms Intact Arterial Wall in Acute Stroke Patients After Stent-Retriever Thrombectomy
Authors: Hsieh Kety , Verma Rajeev K. , Schroth Gerhard , Gratz Pascal P. , Kellner-Weldon Frauke , Gralla Jan , Zubler Christoph , Mordasini Pasquale , Jung Simon , Mattle Heinrich P. , El-Koussy Marwan 
Published: October 2014

Background and Purpose—
The aim of this prospective study was to assess vascular integrity after stent-retriever thrombectomy.

Methods—
Dissection, contrast medium extravasation, and vasospasm were evaluated in 23 patients after thrombectomy with biplane or 3D-digital subtraction angiography and 3-Tesla vessel wall MRI.

Results—
Vasospasm was detected angiographically in 10 patients, necessitating intra-arterial nimodipine in 2 of them. Contrast extravasation, intramural hemorrhage, or iatrogenic dissection were not detected on multimodal MRI in any patient even after Y-double stent-retriever technique.

Conclusions—
Our findings suggest that clinically relevant vessel wall injuries occur rarely after stent-retriever thrombectomy.
Socioeconomic Position and Survival After Stroke in Denmark 2003 to 2012
Authors: Andersen Klaus Kaae , Dalton Susanne Oksbjerg , Steding-Jessen Marianne , Olsen Tom Skyhøj 
Published: October 2014

Background and Purpose—
The risk for stroke is higher in low-income groups. It is not clear whether these groups also have a higher risk for death after a stroke.

Methods—
We studied survival in relation to income and level of education in all patients aged >40 years admitted to hospital for stroke in Denmark in 2003 to 2012. All Danish hospitals report data to the Danish Stroke Register for all patients admitted for acute stroke, including age, sex, stroke severity, subtype, and a cardiovascular risk profile. Information on income and education was obtained from Statistics Denmark; deaths from all causes from the Civil Registration Registry.

Results—
Information on education and disposable income was available for 56 581 Danes hospitalized for stroke during the 9.5-year study period. Median length of follow-up was 3.1 years. For the entire follow-up period, there was a significant, stepwise, independent relation between income and risk for death after stroke, which was 30% higher for the lowest than for the highest quintile income group (relative risk, 0.70, 95% confidence interval, 0.65–0.74). People aged <65 years with basic education had a slightly higher risk for death than those with the longest (relative risk, 1.15; 95% confidence interval, 1.02–1.30). Death within 1 month was not associated with income or education.

Conclusions—
The survival of patients with low income was reduced by 30% as compared with those with high income. Education had only a modest effect and only in patients aged <65 years. The impact of socioeconomic position was on late but not on early poststroke death.