bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Potential of DNA Methylation and Transcript Levels of HIF1A and EPAS1 in Colorectal Cancer
Authors: Rawłuszko-Wieczorek Agnieszka Anna , Horbacka Karolina , Krokowicz Piotr , Misztal Matthew , Jagodziński Paweł Piotr 
Published: May 2014

Abstract
Hypoxic conditions during the formation of colorectal cancer may support the development of more aggressive tumors. Hypoxia-inducible factor (HIF) is a heterodimeric complex, composed of oxygen-induced HIFα and constitutively expressed HIFβ subunits, which mediates the primary transcriptional response to hypoxic stress. Among HIFα isoforms, HIF1α (HIF1A) and endothelial PAS domain–containing protein 1 (EPAS1) are able to robustly activate hypoxia-responsive gene signatures. Although posttranslational regulation of HIFα subunits is well described, less is known about their transcriptional regulation. Here, molecular analysis determined that EPAS1 mRNA was significantly reduced in primary colonic adenocarcinoma specimens compared with histopathologically nonneoplastic tissue from 120 patients. In contrast, no difference in HIF1A mRNA levels was observed between cancerous and noncancerous tissue. Bisulfite DNA sequencing and high-resolution melting analysis identified significant DNA hypermethylation in the EPAS1 regulatory region from cancerous tissue compared with nonneoplastic tissue. Importantly, multivariate Cox regression analysis revealed a high HR for patients with cancer with low EPAS1 transcript levels (HR, 4.91; 95% confidence interval, CI, 0.42–56.15; P = 0.047) and hypermethylated EPAS1 DNA (HR, 33.94; 95% CI, 2.84–405.95; P = 0.0054). Treatment with a DNA methyltransferase inhibitor, 5-Aza-2′-deoxycytidine (5-aza-dC/Decitabine), upregulated EPAS1 expression in hypoxic colorectal cancer cells that were associated with DNA demethylation of the EPAS1 regulatory region. In summary, EPAS1 is transcriptionally regulated by DNA methylation in colorectal cancer.
Implications: DNA methylation and mRNA status of EPAS1 have novel prognostic potential for colorectal cancer. Mol Cancer Res; 12(8); 1112–27. ©2014 AACR.
Prostatic and Dietary Omega-3 Fatty Acids and Prostate Cancer Progression during Active Surveillance
Authors: Moreel Xavier , Allaire Janie , Léger Caroline , Caron André , Labonté Marie-Ève , Lamarche Benoît , Julien Pierre , Desmeules Patrice , Têtu Bernard , Fradet Vincent 
Published: May 2014

Abstract
The association between omega-3 (ω-3) fatty acids and prostate cancer has been widely studied. However, little is known about the impact of prostate tissue fatty acid content on prostate cancer progression. We hypothesized that compared with the estimated dietary ω-3 fatty acids intake and the ω-3 fatty acids levels measured in red blood cells (RBC), the prostate tissue ω-3 fatty acid content is more strongly related to prostate cancer progression. We present the initial observations from baseline data of a phase II clinical trial conducted in a cohort of 48 untreated men affected with low-risk prostate cancer, managed under active surveillance. These men underwent a first repeat biopsy session within 6 months after the initial diagnosis of low-risk prostate cancer, at which time 29% of the men had progressed from a Gleason score of 6 to a Gleason score of 7. At the first repeat biopsy session, fatty acid levels were assessed with a food-frequency questionnaire, and determined in the RBC and in the prostate tissue biopsy. We found that eicosapentaenoic acid (EPA) was associated with a reduced risk of prostate cancer progression when measured directly in the prostate tissue. Thus, this initial interim study analysis suggests that prostate tissue ω-3 fatty acids, especially EPA, may be protective against prostate cancer progression in men with low-risk prostate cancer. Cancer Prev Res; 7(7); 766–76. ©2014 AACR.
Urinary PGE-M Levels Are Associated with Risk of Colorectal Adenomas and Chemopreventive Response to Anti-Inflammatory Drugs
Authors: Bezawada Navya , Song Mingyang , Wu Kana , Mehta Raaj S. , Milne Ginger L. , Ogino Shuji , Fuchs Charles S. , Giovannucci Edward L. , Chan Andrew T. 
Published: May 2014

Abstract
Prostaglandin E2 (PGE2) promotes colorectal carcinogenesis. Overall, systemic PGE2 production can be assessed by measuring its major metabolite, PGE-M, in urine. We examined the potential role of PGE-M as a biomarker for colorectal adenoma risk and chemopreventive response to anti-inflammatory drugs. We conducted a prospective case–control study nested within the Nurses' Health Study. Among women who previously provided a urine sample, we identified 420 cases diagnosed with colorectal adenoma during follow-up and matched them to 420 endoscopy-negative controls. We measured urinary PGE-M using an LC/MS assay. Compared with women in the lowest quartile of urinary PGE-M, women in the highest quartile had a multivariate OR of 1.40 (95% confidence interval (CI), 0.92–2.14) for any adenoma; 0.91 (95% CI, 0.48–1.72) for low-risk adenoma (solitary adenoma &lt;1 cm in greatest diameter with tubular/unspecified histology); and 1.66 (95% CI, 1.04–2.67) for high-risk adenoma (adenoma ≥1 cm in greatest diameter and/or tubulovillous, villous or high-grade dysplasia histology or multiple adenomas of any size or histology). Regular use of anti-inflammatory drugs (≥2 standard tablets of aspirin/NSAIDs per week) was associated with a significant reduction in adenoma risk (multivariate OR, 0.61; 95% CI, 0.43–0.87) in women with high baseline PGE-M (quartiles 2–4), but not low PGE-M (quartile 1).Urinary PGE-M is associated with an increased risk of high-risk adenoma. Anti-inflammatory drugs seem to reduce adenoma risk among women with high, but not low PGE-M. Urinary PGE-M may serve as a biomarker to define subsets of the population who may obtain differential chemopreventive benefit from anti-inflammatory drugs. Cancer Prev Res; 7(7); 758–65. ©2014 AACR.
Decision Making for Destination Therapy Left Ventricular Assist Devices
Authors: McIlvennan Colleen K. , Allen Larry A. , Nowels Carolyn , Brieke Andreas , Cleveland Joseph C. , Matlock Daniel D. 
Published: May 2014

Background—
Destination therapy left ventricular assist devices (DT LVADs) are one of the most invasive medical interventions for end-stage illness. How patients decide whether or not to proceed with device implantation is unknown. We aimed to understand the decision-making processes of patients who either accept or decline DT LVADs.

Methods and Results—
Between October 2012 and September 2013, we conducted semistructured, in-depth interviews to understand patients’ decision-making experiences. Data were analyzed using a mixed inductive and deductive approach. Twenty-two eligible patients were interviewed, 15 with DT LVADs and 7 who declined. We found a strong dichotomy between decision processes with some patients (11 accepters) being automatic and others (3 accepters, 7 decliners) being reflective in their approach to decision making. The automatic group was characterized by a fear of dying and an over-riding desire to live as long as possible: “[LVAD] was the only option I had…that or push up daisies…so I automatically took this.” By contrast, the reflective group went through a reasoned process of weighing risks, benefits, and burdens: “There are worse things than death.” Irrespective of approach, most patients experienced the DT LVAD decision as a highly emotional process and many sought support from their families or spiritually.

Conclusions—
Some patients offered a DT LVAD face the decision by reflecting on a process and reasoning through risks and benefits. For others, the desire to live supersedes such reflective processing. Acknowledging this difference is important when considering how to support patients who are faced with this complex decision.
Drivers of Costs Associated With Reperfusion Therapy in Acute Stroke
Authors: Simpson Kit N. , Simpson Annie N. , Mauldin Patrick D. , Hill Michael D. , Yeatts Sharon D. , Spilker Judith A. , Foster Lydia D. , Khatri Pooja , Martin Renee , Jauch Edward C. , Kleindorfer Dawn , Palesch Yuko Y. , Broderick Joseph P. 
Published: May 2014

Background and Purpose—
The Interventional Management of Stroke (IMS) III study tested the effect of intravenous tissue-type plasminogen activator (tPA) alone when compared with intravenous tPA followed by endovascular therapy and collected cost data to assess the economic implications of the 2 therapies. This report describes the factors affecting the costs of the initial hospitalization for acute stroke subjects from the United States.

Methods—
Prospective cost analysis of the US subjects was treated with intravenous tPA alone or with intravenous tPA followed by endovascular therapy in the IMS III trial. Results were compared with expected Medicare payments.

Results—

The adjusted cost of a stroke admission in the study was $35 130 for subjects treated with endovascular therapy after intravenous tPA treatment and $25 630 for subjects treated with intravenous tPA alone (
P
<0.0001). Significant factors related to costs included treatment group, baseline National Institutes of Health Stroke Scale, time from stroke onset to intravenous tPA, age, stroke location, and comorbid diabetes mellitus. The mean cost for subjects who had routine use of general anesthesia as part of endovascular therapy was $46 444 when compared with $30 350 for those who did not have general anesthesia. The costs of embolectomy for IMS III subjects and patients from the National Inpatient Sample cohort exceeded the Medicare diagnosis-related group payment in ≥75% of patients.

Conclusions—
Minimizing the time to start of intravenous tPA and decreasing the use of routine general anesthesia may improve the cost-effectiveness of medical and endovascular therapy for acute stroke.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00359424.
Postacute Stromal Cell–Derived Factor-1α Expression Promotes Neurovascular Recovery in Ischemic Mice
Authors: Li Yaning , Huang Jun , He Xiaosong , Tang Guanghui , Tang Yao-Hui , Liu Yanqun , Lin Xiaojie , Lu Yifan , Yang Guo-Yuan , Wang Yongting 
Published: May 2014

Background and Purpose—
Acute interventions of stroke are often challenged by a narrow treatment window. In this study, we explore treatments in the postacute phase of stroke with wider windows of opportunity. We investigated the effects of stromal cell–derived factor (SDF-1α) in neurovascular recovery during the postacute phase and downstream signaling pathways, underlying SDF-1α–mediated neurovascular recovery.

Methods—
Adult male Institute of Cancer Research (ICR) mice underwent middle cerebral artery occlusion. One week after middle cerebral artery occlusion, the animals received stereotactic injection of adenoassociated virus (AAV) carrying SDF-1α gene as treatment or AAV-green fluorescent protein as control and were monitored for 5 weeks. Neurobehavioral outcomes were evaluated, and brain atrophy was measured. Neurogenesis and angiogenesis were examined. The proliferation and migration of neural progenitor cells were evaluated. Downstream pathways of SDF-1α were investigated. Inflammatory response was monitored.

Results—

Neurobehavioral outcomes were improved, and brain atrophy was greatly reduced for ≤5 weeks in AAV-SDF-1α groups when compared with the control. SDF-1 receptor CXCR4 was upregulated and colocalized with neural and endothelial progenitor cells. The number of nestin
+
and doublecortin
+
/bromodeoxyuridine
+
cells in the subventricular zone, doublecortin
+
and neuron
+
/bromodeoxyuridine
+
cells in the perifocal region, and cluster of differentiation (CD)31
+
and bromodeoxyuridine
+
/CD31
+
microvessels are also significantly increased in AAV-SDF-1α groups. Administration of CXCR4 antagonist AMD3100 eliminated the beneficial effects of SDF-1α. SDF-1α/CXCR4 interaction activated AKT, extracellular signal-regulated kinases (ERK), and P38 mitogen-activated protein kinase (MAPK) signaling pathways but not the c-Jun N-terminal kinase (JNK) pathway.

Conclusions—
SDF-1α promoted neurogenesis and angiogenesis during the postacute phase of ischemia without eliciting an inflammatory response. AAV-SDF-1α expression represents a promising avenue for ischemic stroke therapy with a wider treatment window.
Vitamin K Antagonists and Risk of Subdural Hematoma
Authors: Connolly Ben J. , Pearce Lesly A. , Hart Robert G. 
Published: May 2014

Background and Purpose—
Subdural hematomas are an important bleeding complication of anticoagulation. We quantify the risk of subdural hematoma associated with anticoagulation with vitamin K antagonists (VKAs) compared with other oral antithrombotic therapies.

Methods—
Randomized trials were identified from the Cochrane Central Register of Controlled Trials and were included if published since 1980 and compared oral VKAs with antiplatelet therapy or with direct-acting oral anticoagulants. Two reviewers independently extracted data with differences resolved by joint review.

Results—
Nineteen randomized trials were included that involved 92 156 patients and 275 subdural hematomas. By meta-analysis, VKAs were associated with a significantly increased risk of subdural hematoma (odds ratios, 3.0; 95% confidence interval, 1.5–6.1) compared with antiplatelet therapy (9 trials, 11 603 participants). The risk of subdural hematoma was also significantly higher with VKAs versus factor Xa inhibitors (meta-analysis odds ratios, 2.9; 95% confidence interval, 2.1–4.1; 5 trials, 49 687 patients) and direct thrombin inhibitors (meta-analysis odds ratios, 1.8; 95% confidence interval, 1.2–2.7; 5 trials, 30 866 patients) versus VKAs. The absolute rate of subdural hematoma among 24 485 patients with atrial fibrillation treated with VKAs pooled from 6 trials testing direct-acting oral anticoagulants was 2.9 (95% confidence interval, 2.5–3.5) per 1000 patient-years.

Conclusions—
VKA use significantly increases the risk of subdural hematoma by ≈3-fold relative to antiplatelet therapy. Direct-acting oral anticoagulants are associated with a significantly reduced risk of subdural hematomas versus VKAs. Based on indirect comparisons to VKAs, the risks of subdural hematoma are similar with antiplatelet monotherapies and factor Xa inhibitors.
A Cytokine‐Delivering Polymer Is Effective in Reducing Tumor Burden in a Head and Neck Squamous Cell Carcinoma Murine Model
Authors: Lin Yuan , Luo Jie , Zhu Weichao Eric , Srivastava Minu , Schaue Dorthe , Elashoff David A. , Dubinett Steven M. , Sharma Sherven , Wu Benjamin , St. John Maie A. 
Published: May 2014

ObjectiveThis study aimed to evaluate the therapeutic efficacy of a novel polymer platform delivering cisplatin and cytokines in the treatment of head and neck squamous cell carcinoma (HNSCC).Study DesignIn vivo study.SettingAcademic research laboratory.Subjects and MethodsMice were randomized to receive implantation of (1) no polymer, (2) plain polymer, (3) plain polymer with local cisplatin injection, or (4) cisplatin polymer. The 2 groups of mice implanted with cisplatin polymer or no polymer were further randomized to receive (1) 4 Grays external beam radiation for 4 days or (2) no radiation. For cytokine studies, mice were grouped into (1) no polymer, (2) plain polymer, (3) plain polymer with intratumoral injection of recombinant CCL21 twice a week, (4) polymer containing parental dendritic cells, or (5) polymer containing dendritic cells secreting CCL21 (DC‐CCL21).ResultsThe cisplatin‐secreting polymer effectively reduced tumors in the mice by more than 16‐fold (P <. 01). We also observed a statistically significant lower tumor weight among mice treated with cisplatin polymer and concomitant radiation compared to control groups. The DC‐CCL21 polymer reduced SCCVII/SF tumors in the C3H/HeJ mice by more than 41% (P <. 01).ConclusionHerein, we demonstrate the efficacy of a novel polymer platform in delivering cisplatin and cytokines. We also demonstrate that we can effectively grow dendritic cells in the polymer that can actively secrete CCL21 for a minimum of 5 days. This polymer may represent a new therapeutic modality for patients with HNSCC. Once this polymer platform is optimized, we will plan to pursue prospective trials in patients with HNSCC.
Multidisciplinary Critical Care and Intensivist Staffing
Authors: Yoo Erika J. , Edwards Jeffrey D. , Dean Mitzi L. , Dudley R. Adams 
Published: May 2014

Purpose: The role of multidisciplinary teams in improving the care of intensive care unit (ICU) patients is not well defined, and it is unknown whether the use of such teams helps to explain prior research suggesting improved mortality with intensivist staffing. We sought to investigate the association between multidisciplinary team care and survival of medical and surgical patients in nonspecialty ICUs. Materials and Methods: We conducted a community-based, retrospective cohort study of data from 60 330 patients in 181 hospitals participating in a statewide public reporting initiative, the California Hospital Assessment and Reporting Taskforce (CHART). Patient-level data were linked with ICU organizational data collected from a survey of CHART hospital ICUs between December 2010 and June 2011. Clustered logistic regression was used to evaluate the independent effect of multidisciplinary care on the in-hospital mortality of medical and surgical ICU patients. Interactions between multidisciplinary care and intensity of physician staffing were examined to explore whether team care accounted for differences in patient outcomes. Results: After adjustment for patient characteristics and interactions, there was no association between team care and mortality for medical patients. Among surgical patients, multidisciplinary care was associated with a survival benefit (odds ratio 0.79; 95% confidence interval (CI), 0.62-1.00; P = .05). When stratifying by intensity of physician staffing, although the lowest odds of death were observed for surgical patients cared for in ICUs with multidisciplinary teams and high-intensity staffing (odds ratio, 0.77; 95% CI, 0.55-1.09; P = .15), followed by ICUs with multidisciplinary teams and low-intensity staffing (odds ratio 0.84, 95% CI 0.65-1.09, p = 0.19), these differences were not statistically significant. Conclusions: Our results suggest that multidisciplinary team care may improve outcomes for critically ill surgical patients. However, no relationship was observed between intensity of physician staffing and mortality.
The influence of sol–gel-derived silica coatings functionalized with betamethasone on adipose-derived stem cells (ASCs)
Authors: Donesz-Sikorska Anna , Grzesiak Jakub , Śmieszeka Agnieszk , Krzak Justyna , Marycz Krzysztof 
Published: May 2014

Silica-based sol–gel coatings have gained attention in bone therapies and orthopedic applications, due to the biocompatibility and bioactivity, including a high potential for the controlled release both in vitro and in vivo. Bioactive materials are created to facilitate the biocompatibility of orthopedic implants. One of the promising alternatives is biomaterials with immobilized drugs. In this study we demonstrated for the first time novel sol–gel-derived silica coatings with active amino groups (SiO2(NH2)) functionalized with a steroid drug—betamethasone, applied to a substrate 316 L using dip coating technique. The presence of betamethasone in functionalized coatings was directly confirmed by Raman spectroscopy and energy-dispersive X-ray spectroscopic analysis. The wettability was evaluated by the sessile drop method, while the surface free energy was estimated based on the contact angles measured. Our results showed a shift in surface properties from hydrophobic to hydrophilic after application of the coatings. We have investigated the morphology, proliferation factor, and the population doubling time of adipose-derived stem cells for biological purposes. Moreover, the analysis of the distribution and localization of cellular microvesicles was performed to evaluate the influence of functionalized surfaces on cellular cytophysiological activity. Increased proliferation and activation of cells, determined by the observations of microvesicles shedding processes, provided evidence of the availability of the drug. Therefore, we conclude that the sol–gel synthesis proposed here allows to improve the metal substrates and can be successfully used for immobilization of betamethasone. This in turn enables the direct delivery of the drug with implanted material into the wound site, and to stimulate the activity of cells to enhance tissue regeneration.
Design and Implementation of a Web-Based Reporting and Benchmarking Center for Inpatient Glucometrics
Authors: Maynard Greg , Schnipper Jeffrey Lawrence , Messler Jordan , Ramos Pedro , Kulasa Kristen , Nolan Ann , Rogers Kendall 
Published: May 2014

Background: Insulin is a top source of adverse drug events in the hospital, and glycemic control is a focus of improvement efforts across the country. Yet, the majority of hospitals have no data to gauge their performance on glycemic control, hypoglycemia rates, or hypoglycemic management. Current tools to outsource glucometrics reports are limited in availability or function. Methods: Society of Hospital Medicine (SHM) faculty designed and implemented a web-based data and reporting center that calculates glucometrics on blood glucose data files securely uploaded by users. Unit labels, care type (critical care, non–critical care), and unit type (eg, medical, surgical, mixed, pediatrics) are defined on upload allowing for robust, flexible reporting. Reports for any date range, care type, unit type, or any combination of units are available on demand for review or downloading into a variety of file formats. Four reports with supporting graphics depict glycemic control, hypoglycemia, and hypoglycemia management by patient day or patient stay. Benchmarking and performance ranking reports are generated periodically for all hospitals in the database. Results: In all, 76 hospitals have uploaded at least 12 months of data for non–critical care areas and 67 sites have uploaded critical care data. Critical care benchmarking reveals wide variability in performance. Some hospitals achieve top quartile performance in both glycemic control and hypoglycemia parameters. Conclusions: This new web-based glucometrics data and reporting tool allows hospitals to track their performance with a flexible reporting system, and provides them with external benchmarking. Tools like this help to establish standardized glucometrics and performance standards.
Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 upregulation in leukemic cells
Authors: Nakahara Fumio , Kitaura Jiro , Uchida Tomoyuki , Nishida Chiemi , Togami Katsuhiro , Inoue Daichi , Matsukawa Toshihiro , Kagiyama Yuki , Enomoto Yutaka , Kawabata Kimihito C. , Chen-Yi Lai , Komeno Yukiko , Izawa Kumi , Oki Toshihiko , Nagae Genta , Harada Yuka , Harada Hironori , Otsu Makoto , Aburatani Hiroyuki , Heissig Beate , Hattori Koichi , Kitamura Toshio 
Published: May 2014

Key Points
Analysis of 20 samples from CML-BC patients showed that MMP-9 was highly expressed in three, with two exhibiting high levels of HES1. MMP-9 is upregulated by Hes1, and MMP-9 deficiency impaired the development of CML-BC–like disease induced by BCR-ABL and Hes1 in mouse BMT.
Mouse xenograft modeling of human adult acute lymphoblastic leukemia provides mechanistic insights into adult LIC biology
Authors: Patel Bella , Dey Aditi , Castleton Anna Z. , Schwab Claire , Samuel Edward , Sivakumaran Janani , Beaton Brendan , Zareian Nahid , Zhang Christie Yu , Rai Lena , Enver Tariq , Moorman Anthony V. , Fielding Adele K. 
Published: May 2014

Key Points
Efforts to understand mechanisms of disease initiation in human adult pre-B ALL are hampered by lack of appropriate animal models. Optimized xenotransplant assays show that niche-based SDF-1/CXCR4 interaction is crucial for adult non-t(4;11) pre-B ALL leukemia initiation.