bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular density‐dependent down‐regulation of EP4 prostanoid receptors via the up‐regulation of hypoxia‐inducible factor‐1α in HCA‐7 human colon cancer cells
Authors: Otake Sho , Yoshida Kenji , Seira Naofumi , Sanchez Christopher M. , Regan John W. , Fujino Hiromichi , Murayama Toshihiko 
Published: December 2014

AbstractIncreases in prostaglandin E2 (PGE2) and cyclooxygenase‐2 (COX‐2) levels are features of colon cancer. Among the different E‐type prostanoid receptor subtypes, EP4 receptors are considered to play a crucial role in carcinogenesis by, for example, inducing COX‐2 when stimulated with PGE2. However, EP4 receptor levels and PGE2‐induced cellular responses are inconsistent among the cellular conditions. Therefore, the connections responsible for the expression of EP4 receptors were investigated in the present study by focusing on cell density‐induced hypoxia‐inducible factor‐1α (HIF‐1α). The expression of EP4 receptors was examined using immunoblot analysis, quantitative polymerase chain reaction, and reporter gene assays in HCA‐7 human colon cancer cells with different cellular densities. The involvement of HIF‐1α and its signaling pathways were also examined by immunoblot analysis, reporter gene assays, and with siRNA. We here demonstrated that EP4 receptors as well as EP4 receptor‐mediated COX‐2 expression levels decreased with an increase in cellular density. In contrast, HIF‐1α levels increased in a cellular density‐dependent manner. The knockdown of HIF‐1α by siRNA restored the expression of EP4 receptors and EP4 receptor‐mediated COX‐2 in cells at a high density. Thus, the cellular density‐dependent increase observed in HIF‐1α expression levels reduced the expression of COX‐2 by decreasing EP4 receptor levels. This novel regulation mechanism for the expression of EP4 receptors by HIF‐1α may provide an explanation for the inconsistent actions of PGE2. The expression levels of EP4 receptors may vary depending on cellular density, which may lead to the differential activation of their signaling pathways by PGE2. Thus, cellular density‐dependent PGE2‐mediated signaling may determine the fate/stage of cancer cells, i.e., the surrounding environments could define the fate/stage of malignancies associated with colon cancer.
Characterization of the 5‐HT2C receptor agonist lorcaserin on efficacy and safety measures in a rat model of diet‐induced obesity
Authors: Higgins Guy A. , Desnoyer Jill , Van Niekerk Annalise , Silenieks Leo B. , Lau Winnie , Thevarkunnel Sandy , Izhakova Julia , DeLannoy Ines A.M. , Fletcher Paul J. , DeLay Josepha , Dobson Howard 
Published: December 2014

AbstractThe 5‐HT2C receptor agonist lorcaserin (Belviq®) has been Food and Drug Administration (FDA) approved for the treatment of obesity. The present study is a back translational investigation into the effect of 28‐day lorcaserin treatment in a diet‐induced obesity (DIO) model using male, Sprague–Dawley rats. An assessment of drug effect on efficacy and multiple safety endpoints including cardiac function was undertaken. Lorcaserin (1–2 mg/kg SC b.i.d.) significantly reduced percentage body weight gain compared to vehicle‐treated controls (VEH: 10.6 ± 0.4%; LOR 1: 7.6 ± 1.2%; LOR 2: 5.4 ± 0.6%). Measurement of body composition using quantitative magnetic resonance (QMR) imaging indicated this change was due to the selective reduction in body fat mass. Modest effects on food intake were recorded. At the completion of the treatment phase, echocardiography revealed no evidence for valvulopathy, that is, no aortic or mitral valve regurgitation. The pharmacokinetics of the present treatment regimen was determined over a 7‐day treatment period; plasma Cmin and Cmax were in the range 13–160 ng/mL (1 mg/kg b.i.d.) and 34–264 ng/mL (2 mg/kg b.i.d.) with no evidence for drug accumulation. In sum, these studies show an effect of lorcaserin in the DIO model, that in the context of the primary endpoint measure of % body weight change was similar to that reported clinically (i.e., 3.0–5.2% vs. 3.2%). The present studies highlight the translational value of obesity models such as DIO, and suggest that assuming consideration is paid to nonspecific drug effects such as malaise, the DIO model has reasonable forward translational value to help predict clinical outcomes of a new chemical entity.
p‐Cresyl sulfate, a uremic toxin, causes vascular endothelial and smooth muscle cell damages by inducing oxidative stress
Authors: Watanabe Hiroshi , Miyamoto Yohei , Enoki Yuki , Ishima Yu , Kadowaki Daisuke , Kotani Shunsuke , Nakajima Makoto , Tanaka Motoko , Matsushita Kazutaka , Mori Yoshitaka , Kakuta Takatoshi , Fukagawa Masafumi , Otagiri Masaki , Maruyama Toru 
Published: December 2014

AbstractThe major cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease. Here, p‐Cresyl sulfate (PCS), a uremic toxin, is considered to be a risk factor for cardiovascular disease in CKD. However, our understanding of the vascular toxicity induced by PCS and its mechanism is incomplete. The purpose of this study was to determine whether PCS enhances the production of reactive oxygen species (ROS) in vascular endothelial and smooth muscle cells, resulting in cytotoxicity. PCS exhibited pro‐oxidant properties in human umbilical vein endothelial cells (HUVEC) and aortic smooth muscle cells (HASMC) by enhancing NADPH oxidase expression. PCS also up‐regulates the mRNA levels and the protein secretion of monocyte chemotactic protein‐1 (MCP‐1) in HUVEC. In HASMC, PCS increased the mRNA levels of alkaline phosphatase (ALP), osteopontin (OPN), core‐binding factor alpha 1, and ALP activity. The knockdown of Nox4, a subunit of NADPH oxidase, suppressed the cell toxicity induced by PCS. The vascular damage induced by PCS was largely suppressed in the presence of probenecid, an inhibitor of organic anion transporters (OAT). In PCS‐overloaded 5/6‐nephrectomized rats, plasma MCP‐1 levels, OPN expression, and ALP activity of the aortic arch were increased, accompanied by the induction of Nox4 expression. Collectively, the vascular toxicity of PCS can be attributed to its intracellular accumulation via OAT, which results in an enhanced NADPH oxidase expression and increased ROS production. In conclusion, we found for the first time that PCS could play an important role in the development of cardiovascular disease by inducing vascular toxicity in the CKD condition.
Common misconceptions about data analysis and statistics
Authors: Motulsky Harvey J. 
Published: December 2014

AbstractIdeally, any experienced investigator with the right tools should be able to reproduce a finding published in a peer‐reviewed biomedical science journal. In fact, the reproducibility of a large percentage of published findings has been questioned. Undoubtedly, there are many reasons for this, but one reason may be that investigators fool themselves due to a poor understanding of statistical concepts. In particular, investigators often make these mistakes: (1) P‐Hacking. This is when you reanalyze a data set in many different ways, or perhaps reanalyze with additional replicates, until you get the result you want. (2) Overemphasis on P values rather than on the actual size of the observed effect. (3) Overuse of statistical hypothesis testing, and being seduced by the word “significant”. (4) Overreliance on standard errors, which are often misunderstood.
Efficient coupling of nanosecond laser pulses with the cluster medium: Generation of hydrogen‐like [C]5+ atomic ions
Authors: Sharma Pramod , Das Soumitra , Vatsa Rajesh K. 
Published: December 2014

RATIONALEClusters exhibit diverse photochemical behavior as a function of laser parameters, i.e. wavelength, pulse duration and intensity. One such aspect of cluster photochemistry is the generation of energetic multiply charged atomic ions, upon efficient interaction of clusters with intense laser pulses. In the present work, mass spectrometric investigations have been carried out on clusters of tetrahydrofuran (THF, C4H8O) – a saturated cyclic ether – subjected to nanosecond laser pulse (spanning from UV to IR wavelength range) with the aim of shedding light on the complex mechanism of laser‐cluster interactions, which is still ambiguous.METHODSTHF clusters, generated via supersonic expansion of room‐temperature THF vapours seeded in argon, were subjected to gigawatt intensity laser pulses (355, 532 and 1064 nm) obtained from a nanosecond Nd:YAG laser. The ions generated upon laser‐cluster interaction were characterized using a time‐of‐flight mass spectrometer.RESULTSAt 355 nm, THF clusters exhibit the usual multiphoton dissociation/ionization behavior while, at 532 nm, observation of multiply charged atomic ions of carbon (up to [C]4+) and oxygen (up to [O]3+) was ascribed to Coulomb explosion of THF clusters. For studies carried out at 1064 nm, multiply charged atomic ions of carbon up to [C]5+ having an ionization energy of ~392 eV were observed, at a laser intensity of 1010 W/cm2.CONCLUSIONSThe observation of [C]5+ atomic ions signifies efficient coupling of the laser energy with the cluster medium, using a nanosecond laser pulse. The results have been rationalized on the basis of a three‐stage cluster ionization mechanism, suggesting the crucial role of the threshold laser intensity for initiating ionization within the cluster and generation of optimum charge centers for efficient extraction of energy from the laser pulse. Copyright © 2014 John Wiley & Sons, Ltd.
Comparison of peak‐picking workflows for untargeted liquid chromatography/high‐resolution mass spectrometry metabolomics data analysis
Authors: Rafiei Atefeh , Sleno Lekha 
Published: December 2014

RATIONALEData analysis is a key step in mass spectrometry based untargeted metabolomics, starting with the generation of generic peak lists from raw liquid chromatography/mass spectrometry (LC/MS) data. Due to the use of various algorithms by different workflows, the results of different peak‐picking strategies often differ widely.METHODSRaw LC/HRMS data from two types of biological samples (bile and urine), as well as a standard mixture of 84 metabolites, were processed with four peak‐picking softwares: Peakview®, Markerview™, MetabolitePilot™ and XCMS Online. The overlaps between the results of each peak‐generating method were then investigated. To gauge the relevance of peak lists, a database search using the METLIN online database was performed to determine which features had accurate masses matching known metabolites as well as a secondary filtering based on MS/MS spectral matching.RESULTSIn this study, only a small proportion of all peaks (less than 10%) were common to all four software programs. Comparison of database searching results showed peaks found uniquely by one workflow have less chance of being found in the METLIN metabolomics database and are even less likely to be confirmed by MS/MS.CONCLUSIONSIt was shown that the performance of peak‐generating workflows has a direct impact on untargeted metabolomics results. As it was demonstrated that the peaks found in more than one peak detection workflow have higher potential to be identified by accurate mass as well as MS/MS spectrum matching, it is suggested to use the overlap of different peak‐picking workflows as preliminary peak lists for more rugged statistical analysis in global metabolomics investigations. Copyright © 2014 John Wiley & Sons, Ltd.
Is It Worth Continuing Sexual Rehabilitation after Radical Prostatectomy with Intracavernous Injection of Alprostadil for More than 1 Year?
Authors: Yiou René , Bütow Zentia , Parisot Juliette , Binhas Michele , Lingombet Odile , Augustin Deborah , de la Taille Alexandre , Audureau Etienne 
Published: December 2014

Abstract

Introduction
Intracavernous alprostadil injection (IAI) is a widely used treatment for sexual rehabilitation (SR) after radical prostatectomy (RP). It is unknown whether the continuation of IAI beyond 1 year continues to improve erectile function.

Aims
To assess evolution of sexual function in patients using IAI who are nonresponsive to phosphodiesterase type 5 inhibitors (PDE5i) between 12 (M12) and 24 (M24) months after RP.

Methods
We retrospectively studied 75 men with a nerve-sparing laparoscopic RP, who had normal preoperative erectile function, and who regularly used IAI for SR for at least 24 months. At M12, no patients had responded to PDE5i.

Main Outcome Measures
At 12 and 24 months, sexual function was assessed with the UCLA Prostate Cancer Index (UCLA-PCI), International Index of Erectile Function (IIEF)-15, and erection hardness score (EHS) with and without IAI. We also assessed the satisfaction rate with IAI, injection-related penile pain, and satisfaction of treatment. Statistical analysis was performed by using t-tests for paired data and Spearman's rho correlation coefficients to assess the relationships between scores at M12 and M24.

Results
Improvement of nocturnal erection was noted (UCLA-PCI, question 25); however, no significant difference was found for IIEF-erectile function with (19.60 ± 9.80 vs. 18.07 ± 10.44) and without IAI (4.63 ± 2.93 vs. 4.92 ± 4.15), UCLA-PCI-sexual bother (37.14 ± 21.45 vs. 37.54 ± 19.67), nor the EHS score with (2.97 ± 1.30 vs. 2.57 ± 1.30) and without IAI (0.67 ± 1.11 vs. 0.76 ± 0.10). The rate of satisfaction with treatment decreased over time (66.6% vs. 46.7%, P = 0.013). Improved response to IAI at M12 was not correlated to improvement in spontaneous erections at M24.

Conclusion
The response to IAI remained stable after 2 years of treatment, and no significant improvement of spontaneous erections during intercourse attempts was found between M12 and M24. Patients should be informed of the limited effect of IAI on natural erections after 1 year.
Expanding Stakeholder Participation in Upfront System Engineering through Storytelling in Virtual Worlds
Authors: Madni* Azad M. 
Published: December 2014

ABSTRACTOver the last decade, systems engineers have successfully created system modeling languages to communicate with other systems engineers. However, the ability to communicate an evolving system concept and design with stakeholders who are nonengineers remains an elusive goal. In large part, this inability stems from the latter having to understand complex diagrams and equations, and learn new notations employed by systems modeling languages. The problem is further exacerbated by the fact that systems today have to frequently adapt to changing operational and regulatory requirements. Thus, to effectively communicate concepts of operation (CONOPS) and evolving system design to those outside the engineering discipline requires a different approach. This paper presents an innovative approach that employs technical storytelling methods to contextualize and map systems engineering (SE) artifacts represented in SysML to virtual worlds within which various storylines can play out. This capability is intended to improve comprehensibility and transparency of CONOPS and system designs when it comes to communicating with the broader stakeholder community. At the heart of this approach is a virtual world enabled by a 3D game engine, and a mapping capability that allows translation of SE artifacts and interdependencies to virtual world entities and interactions. The key idea behind this integrated capability is to allow the broader stakeholder community to collaborate effectively on key decisions during upfront SE. The benefits of this approach are greater stakeholder satisfaction, avoidance of rework, and more responsive system design.
Operative Procedures in the Elderly in Low‐Resource Settings: A Review of Médecins Sans Frontières Facilities
Authors: Wong Evan G. , Trelles Miguel , Dominguez Lynette , Mupenda Mwania Jerome , Kasonga Tshibangu Cheride , Haq Saqeb Sanaul , Hazrati Khalil U. R. , Gupta Shailvi , Burnham Gilbert , Kushner Adam L. 
Published: December 2014

AbstractBackgroundAs the demographic transition occurs across developing countries, an increasing number of elderly individuals are affected by disasters and conflicts. This study aimed to evaluate the elderly population that underwent an operative procedure at MSF facilities.MethodsA retrospective review of prospectively collected operative cases performed at MSF‐Operational Centre Brussels (MSF‐OCB) facilities between June 2008 and December 2012 was completed. Baseline demographic data, American Society of Anesthesiologists (ASA) physical status and surgical indications were collected for each patient. For each procedure, the degree of urgency, anesthesia type, and intra‐operative mortality were noted. All patients aged 50 and over at the time of the procedure were considered elderly, as proposed by the World Health Organization (WHO). Comparisons were made with the 18–49 age group in order to elucidate differences between older and younger individuals.ResultsWe reviewed a total of 93,385 procedures performed on 83,911 patients in 21 different countries. Patients aged 50 and over comprised 11.5 % (9,628/83,911) of all patients. While most procedures (57.6 %) in the comparison group were urgent, this proportion decreased substantially in the elderly. Intra‐operative mortality was considerably lower in the 50–59 group (0.12 %) but increased with each age stratum. The most commonly performed surgical procedures in the elderly included herniorrhaphies, simple and extensive wound debridements, abscess incision and drainages, minor tumorectomies, and urological procedures.ConclusionsIn light of the increasing elderly population in developing countries, efforts should be made to better quantify and address their surgical needs.
Emphysematous Gastritis and Gastric Emphysema: Similar Radiographic Findings, Distinct Clinical Entities
Authors: Matsushima Kazuhide , Won Eugene J. , Tangel Matthew R. , Enomoto Laura M. , Avella Diego M. , Soybel David I. 
Published: December 2014

AbstractIntroductionDespite similar appearances on imaging studies, emphysematous gastritis (EG) and gastric emphysema (GE) are rare clinical entities encountered in surgical practices. The purpose of this review is to clarify the presentation, natural history, and optimal treatment strategies for these two disorders.MethodsWe conducted a comprehensive literature review for reported adult cases of EG and GE in MEDLINE. Two cases from our institution were also included. Patient with demographics, diagnostic and therapeutic data, and outcomes were compared between patients with EG and GE.ResultsA total of 75 cases were included for our review. The finding of intramural air in the stomach was often associated with portal vein gas, pneumatosis intestinalis, or pneumoperitoneum in both groups. Surgical removal of the stomach was performed in 23.1 % of EG patients, but only one patient in the GE group. In the EG group, overall mortality (55 %) appeared to be driven by sepsis and its complications, whereas in the GE group, mortality (29 %) was attributable to comorbid conditions and the underlying illness.ConclusionsPrompt surgical intervention is more commonly indicated for severe EG and is directed at removal of the septic organ, while the primary indication for surgical intervention in GE is the uncertainty of the diagnosis.
Positron Emission Tomography–Computed Tomography in Oesophageal Cancer Staging: A Tailored Approach
Authors: Bunting David M. , Lai Wesley W. , Berrisford Richard G. , Wheatley Tim J. , Drake Brent , Sanders Grant 
Published: December 2014

AbstractBackgroundPositron emission tomography–computed tomography (PET–CT) scanning is used routinely in the staging of oesophageal cancer to identify occult metastases not apparent on CT and changes the management in typically 3–18 % patients. The authors aim to re‐evaluate its role in the management of oesophageal cancer, investigating whether it is possible to identify a group of patients that will not benefit and can safely be spared from this investigation.MethodsConsecutive patients with oesophageal cancer undergoing PET–CT staging between 2010 and 2013 were identified from a specialist modern multidisciplinary team database. Without knowledge of the PET–CT result, patients were stratified into low‐risk or high‐risk groups according to the likelihood of identifying metastatic disease on PET–CT based on specified criteria routinely available from endoscopy and CT reports. Clinical outcomes in the two groups were investigated.ResultsIn 383 undergoing PET–CT, metastatic disease was identified in 52 (13.6 %) patients. Eighty‐three patients were stratified as low risk and 300 as high risk. None of the low‐risk patients went on to have metastatic disease identified on PET–CT. Of the high‐risk patients, 17 % had metastatic disease identified on PET–CT.ConclusionsIn one of the largest studies to date investigating the influence of staging PET–CT on management of patients with oesophageal cancer, the authors report a classification based on endoscopy/CT criteria is able to accurately stratify patients according to the risk of having metastatic disease. This could be used to avoid unnecessary PET–CT 22 % of patients, saving cost, inconvenience and reducing potential delay to definitive treatment in this group.
Radiofrequency Ablation of Benign Symptomatic Thyroid Nodules: Prospective Safety and Efficacy Study
Authors: Ugurlu M. Umit , Uprak Kivilcim , Akpinar Ihsan N. , Attaallah Wafi , Yegen Cumhur , Gulluoglu Bahadir M. 
Published: December 2014

AbstractBackgroundRadiofrequency ablation (RFA) is a relatively novel procedure in the management of benign nodular goiter. This study was conducted to evaluate the safety and efficacy of ultrasound (US)‐guided percutaneous RFA for benign symptomatic thyroid nodules as an alternative to surgery.MethodsThe study involved patients for whom a fine needle aspiration biopsy had proved a diagnosis of benign nodular goiter and had nodule‐related symptoms such as dysphagia, cosmetic problems, sensation of foreign body in the neck, hyperthyroidism due to autonomous nodules or fear of malignancy. Percutaneous RFA was performed as an outpatient procedure under local anesthesia. The primary outcome was an evaluation of the changes in symptom scores (0–10) for pain, dysphagia and foreign body sensation at the 1st, 3rd, and 6th months after the RFA procedure. Secondary outcomes were assessing volume changes in nodules, complication rates, and changes in thyroid function status.ResultsA total of 33 patients (24 % female, 76 % male) and a total of 65 nodules were included into the study. More than one nodule was treated in 63.6 % of the patients. We found a statistically significant improvement from baseline to values at the 1st, 3rd, and 6th months, respectively, as follows: pain scores (2.9 ± 2.7, 2.3 ± 2.01, 1.8 ± 1.7, and 1.5 ± 1.2, p 0.005), dysphagia scores (3.9 ± 2.7, 2.6 ± 1.9; 1.7 ± 1.6, and 1.1 ± 0.3, p 0.032), and foreign body sensation scores 3.6 ± 3, 2.5 ± 2.2; 1.6 ± 1.5, and 1.1 ± 0.4, p 0.002).The mean pre‐treatment nodule volume was 7.3 ± 8.3 mL. There was a statistically significant size reduction in the nodules at the 1st, 3rd, and 6th months after RFA (3.5 ± 3.8, 2.7 ± 3.4, and 1.2 ± 1.7 mL, p 0.002). The volume reduction was found to be 74 % at 6th months following the RFA (p 0.005). 8 patients had autonomously functioning nodules in the pre‐treatment period, 50 % (n: 4) became euthyroid at the 6th month after RFA. There were no complaints other than pain (12 %).ConclusionRFA can be an alternative treatment modality in the management of benign symptomatic thyroid nodules. The results showed that it is a safe and effective procedure.