bluuebunny/crossref_metadata_2025_split huggingface dataset:
GPER-Targeted, 99mTc-Labeled, Nonsteroidal Ligands Demonstrate Selective Tumor Imaging and In Vivo Estrogen Binding
Authors: Nayak Tapan K. , Ramesh Chinnasamy , Hathaway Helen J. , Norenberg Jeffrey P. , Arterburn Jeffrey B. , Prossnitz Eric R. 
Published: July 2014

Abstract
Our understanding of estrogen (17β-estradiol, E2) receptor biology has evolved in recent years with the discovery and characterization of a 7-transmembrane-spanning G protein–coupled estrogen receptor (GPER/GPR30) and the development of GPER-selective functional chemical probes. GPER is highly expressed in certain breast, endometrial, and ovarian cancers, establishing the importance of noninvasive methods to evaluate GPER expression in vivo. Here, we developed 99mTc-labeled GPER ligands to demonstrate the in vivo status of GPER as an estrogen receptor (ER) and for GPER visualization in whole animals. A series of 99mTc(I)-labeled nonsteroidal tetrahydro-3H-cyclopenta[c]quinolone derivatives was synthesized utilizing pyridin-2-yl hydrazine and picolylamine chelates. Radioligand receptor binding studies revealed binding affinities in the 10 to 30 nmol/L range. Cell signaling assays previously demonstrated that derivatives retaining a ketone functionality displayed agonist properties, whereas those lacking such a hydrogen bond acceptor were antagonists. In vivo biodistribution and imaging studies performed on mice bearing human endometrial and breast cancer cell xenografts yielded significant tumor uptake (0.4–1.1%ID/g). Blocking studies revealed specific uptake in multiple organs (adrenals, uterus, and mammary tissue), as well as tumor uptake with similar levels of competition by E2 and G-1, a GPER-selective agonist. In conclusion, we synthesized and evaluated a series of first-generation 99mTc-labeled GPER-specific radioligands, demonstrating GPER as an estrogen-binding receptor for the first time in vivo using competitive binding principles, and establishing the utility of such ligands as tumor imaging agents. These results warrant further investigation into the role of GPER in estrogen-mediated carcinogenesis and as a target for diagnostic/therapeutic/image-guided drug delivery.
Implications: These studies provide a molecular basis to evaluate GPER expression and function as an ER through in vivo imaging. Mol Cancer Res; 12(11); 1635–43. ©2014 AACR.
Novel peptides that inhibit heparanase activation of the coagulation system
Authors: Axelman Elena , Henig Israel , Crispel Yonatan , Attias Judith , Li Jin-Ping , Brenner Benjamin , Vlodavsky Israel , Nadir Yona 
Published: July 2014

SummaryHeparanase is implicated in cell invasion, tumour metastasis and angiogenesis. It forms a complex and enhances the activity of the blood coagulation initiator – tissue factor (TF). We describe new peptides derived from the solvent accessible surface of TF pathway inhibitor 2 (TFPI-2) that inhibit the heparanase procoagulant activity. Peptides were evaluated in vitro by measuring activated coagulation factor X levels and co-immunoprecipitation. Heparanase protein and/or lipopolysaccharide (LPS) were injected intra-peritoneally and inhibitory peptides were injected subcutaneously in mouse models. Plasma was analysed by ELISA for thrombin-antithrombin complex (TAT), D-dimer as markers of coagulation activation, and interleukin 6 as marker of sepsis severity. Peptides 5, 6, 7, 21 and 22, at the length of 11–14 amino acids, inhibited heparanase procoagulant activity but did not affect TF activity. Injection of newly identified peptides 5, 6 and 7 significantly decreased or abolished TAT plasma levels when heparanase or LPS were pre-injected, and inhibited clot formation in an inferior vena cava thrombosis model. To conclude, the solvent accessible surface of TFPI-2 first Kunitz domain is involved in TF/heparanase complex inhibition. The newly identified peptides potentially attenuate activation of the coagulation system induced by heparanase or LPS without predisposing to significant bleeding tendency.
Antibody-based prevention of von Willebrand factor degradation mediated by circulatory assist devices
Authors: Rauch Antoine , Legendre Paulette , Christophe Olivier , Goudemand Jenny , Belle Eric van , Vincentelli André , Denis Cécile , Susen Sophie , Lenting Peter 
Published: July 2014

SummaryHaemorrhagic episodes in patients carrying circulatory assist devices represent a severe life-threatening clinical complication. These bleeding episodes may originate from a reduced functionality of von Willebrand factor (VWF), a multimeric protein pertinent to the formation of a haemostatic plug. It has been reported that the reduced functionality is due to increased proteolytic degradation by the enzyme ADAMTS13, a phenomenon that is facilitated by device-induced increases in shear stress to which VWF is exposed. Here, we have tested a series of VWF-derived protein fragments and monoclonal murine anti-VWF antibodies for their capacity to reduce shear stress-dependent degradation of VWF. Via direct binding experiments, we identified an anti-VWF antibody that partially blocked VWF-ADAMTS13 interactions (46 ± 14%). Epitope mapping experiments revealed that the antibody, designated mAb508, is directed against the distal portion of the VWF D4-domain (residues 2134–2301) and recognises a synthetic peptide encompassing residues 2158–2169. Consistent with its partial inhibition of VWF-ADAMTS13 interactions in binding assays, mAb508 reduced ADAMTS13-mediated VWF degradation in a vortex-based degradation assay by 48 ± 10%. In a HeartMateII-based whole bloodperfusion system, mAb508 was able to reduce degradation of highmolecular- weight (HMW)-VWF-multimers dose-dependently, with a maximal inhibition (83 ± 8%) being reached at concentrations of 10 μg/ml or higher. In conclusion, we report that partial inhibition of VWF-ADAMTS13 interactions using an anti-VWF antibody can prevent excessive degradation of HMW-VWF multimers. This strategy may be used for the development of therapeutic options to treat bleeding episodes due to shear stress-dependent VWF degradation, for instance in patients carrying circulatory assist devices.
Sarcomere Mutation-Specific Expression Patterns in Human Hypertrophic Cardiomyopathy
Authors: Helms Adam S. , Davis Frank M. , Coleman David , Bartolone Sarah N. , Glazier Amelia A. , Pagani Francis , Yob Jaime M. , Sadayappan Sakthivel , Pedersen Ellen , Lyons Robert , Westfall Margaret V. , Jones Richard , Russell Mark W. , Day Sharlene M. 
Published: July 2014

Background—
Heterozygous mutations in sarcomere genes in hypertrophic cardiomyopathy (HCM) are proposed to exert their effect through gain of function for missense mutations or loss of function for truncating mutations. However, allelic expression from individual mutations has not been sufficiently characterized to support this exclusive distinction in human HCM.

Methods and Results—

Sarcomere transcript and protein levels were analyzed in septal myectomy and transplant specimens from 46 genotyped HCM patients with or without sarcomere gene mutations and 10 control hearts. For truncating mutations in
MYBPC3
, the average ratio of mutant:wild-type transcripts was ≈1:5, in contrast to ≈1:1 for all sarcomere missense mutations, confirming that nonsense transcripts are uniquely unstable. However, total
MYBPC3
mRNA was significantly increased by 9-fold in HCM samples with
MYBPC3
mutations compared with control hearts and with HCM samples without sarcomere gene mutations. Full-length MYBPC3 protein content was not different between
MYBPC3
mutant HCM and control samples, and no truncated proteins were detected. By absolute quantification of abundance with multiple reaction monitoring, stoichiometric ratios of mutant sarcomere proteins relative to wild type were strikingly variable in a mutation-specific manner, with the fraction of mutant protein ranging from 30% to 84%.

Conclusions—

These results challenge the concept that haploinsufficiency is a unifying mechanism for HCM caused by
MYBPC3
truncating mutations. The range of allelic imbalance for several missense sarcomere mutations suggests that certain mutant proteins may be more or less stable or incorporate more or less efficiently into the sarcomere than wild-type proteins. These mutation-specific properties may distinctly influence disease phenotypes.
Socioeconomic Position and Incidence of Ischemic Stroke in Denmark 2003–2012. A Nationwide Hospital‐Based Study
Authors: Andersen Klaus Kaae , Steding‐Jessen Marianne , Dalton Susanne Oksbjerg , Olsen Tom Skyhøj 
Published: July 2014

Background
A greater burden of stroke risk factors in general is associated with a higher risk for stroke among people of lower than those of higher socioeconomic position. The relative impact of individual stroke risk factors is still unclear.

Methods and Results
We studied the relations between socioeconomic position, measured as household income and length of education, and all hospital admissions for a first ischemic stroke among 54 048 people over the age of 40 years in Denmark in 2003–2012 in comparison with the general Danish population (23.5 million person‐years). We also studied the cardiovascular risk factor profile associated with socioeconomic position in stroke patients. Relative risks for stroke were estimated in log‐linear Poisson regression models. The risk for hospitalization for a first ischemic stroke was almost doubled for people in the lowest income group, and the risk of those of working age (<65 years) was increased by 36% among people with the shortest education. Diabetes, obesity, smoking, and high alcohol consumption in particular and, to a lesser extent, previous myocardial infarction or intermittent arterial claudication were significantly overrepresented among stroke patients with lower socioeconomic position. Atrial fibrillation and hypertension were not.

Conclusions
In Denmark, there is a strong relation between low socioeconomic position and risk for hospitalization for stroke. Lifestyle, as indicated by smoking, obesity, and alcohol consumption, and diabetes appears to increase the risk for stroke in people with lower socioeconomic position.
Melanotic Neuroectodermal Tumor of Infancy
Authors: Davis Joel M. , DeBenedictis Marianna , Frank Douglas K. , Lessin Michael E. 
Published: July 2014

Introduction: The melanotic neuroectodermal tumor of infancy (MNTI) is an exceptionally rare neoplasm. Despite their potential for local invasion, MNTI are considered benign neoplasms. Sporadic cases have been reported of MNTI acting in a malignant fashion; however, the majority of these tumors were of extragnathic origin. Methods: A 2-month-old male presented with a rapidly expanding maxillary mass. The patient underwent excisional biopsy of the mass and a diagnosis of MNTI was returned. Tumor recurrence was appreciated postoperatively. Neoadjuvant chemotherapy was initiated to render it more amenable to surgical resection. Chemotherapy was suspended prematurely and the patient returned to the operating room for hemimaxillectomy. The postchemotherapy surgical pathology report demonstrated a unique mixed chemotherapy response. Discussion: This report highlights the aggressive nature of gnathic MNTI, the importance of early diagnosis and definitive intervention, and the mixed clinical and histologic response of the lesion to neoadjuvant chemotherapy.
Predictors of mental health-related acute service utilisation and treatment costs in the 12 months following an acute psychiatric admission
Authors: Siskind Dan , Harris Meredith , Diminic Sandra , Carstensen Georgia , Robinson Gail , Whiteford Harvey 
Published: July 2014

Objective: A key step in informing mental health resource allocation is to identify the predictors of service utilisation and costs. This project aims to identify the predictors of mental health-related acute service utilisation and treatment costs in the year following an acute public psychiatric hospital admission. Method: A dataset containing administrative and routinely measured outcome data for 1 year before and after an acute psychiatric admission for 1757 public mental health patients was analysed. Multivariate regression models were developed to identify patient- and treatment-related predictors of four measures of service utilisation or cost: (a) duration of index admission; and, in the year after discharge from the index admission (b) acute psychiatric inpatient bed-days; (c) emergency department (ED) presentations; and (d) total acute mental health service costs. Split-sample cross-validation was used. Results: A diagnosis of psychosis, problems with living conditions and prior acute psychiatric inpatient bed-days predicted a longer duration of index admission, while prior ED presentations and self-harm predicted a shorter duration. A greater number of acute psychiatric inpatient bed-days in the year post-discharge were predicted by psychosis diagnosis, problems with living conditions and prior acute psychiatric inpatient admissions. The number of future ED presentations was predicted by past ED presentations. For total acute care costs, diagnosis of psychosis was the strongest predictor. Illness acuity and prior acute psychiatric inpatient admission also predicted higher costs, while self-harm predicted lower costs. Discussion: The development of effective models for predicting acute mental health treatment costs using existing administrative data is an essential step towards a workable activity-based funding model for mental health. Future studies would benefit from the inclusion of a wider range of variables, including ethnicity, clinical complexity, cognition, mental health legal status, electroconvulsive therapy, problems with activities of daily living and community contacts.
Out of the box
Authors: James Roger 
Published: July 2014

In this series of articles for Business Information Review, I have discussed the dramatic impact of technology and digitization on the world of information. At times, these articles have addressed the need for new skills and competencies from the Information Scientist; they have also introduced the impact of big data in science and society. In this article, I use my recent experience in academic research to explain how the essential disciplines of good records management (RM) are a necessary foundation for big data research. Like the quality movement of the 1990s, embedding good RM in big data research will avoid costly rework, illuminating erroneous conclusions and advancing research. There is more that the Information Scientist can bring to big data – managing the unpublishing process and guiding the integration of documents via structured data. Areas in which Information Scientists have the necessary background, discipline and experience.
Horror films and psychiatry
Authors: Friedman Susan Hatters , Forcen Fernando Espi , Shand John Preston 
Published: July 2014

Objectives: Horror films have been popular for generations. The purpose of this article is to illustrate psychiatric conditions, themes and practice seen in horror films. Conclusions: Horror films often either include psychiatrists as characters or depict (Hollywood’s dangerous version of) serious mental illness. Demonic possession, zombies, and ‘slasher’ killers are described, as well as the horror genre’s characterizations of psychiatrists.
Featured Article: Selective blockade of the OGF–OGFr pathway by naltrexone accelerates fibroblast proliferation and wound healing
Authors: Immonen Jessica A , Zagon Ian S , McLaughlin Patricia J 
Published: July 2014

Naltrexone (NTX) is an opioid receptor antagonist that acts at classical and non-classical opioid receptors including the opioid growth factor receptor (OGFr). Animal models of type 1 and type 2 diabetes, as well as normal rodents, have shown that topical NTX enhances the healing rates of corneal epithelium and full-thickness cutaneous wounds. The mechanism of this general opioid antagonist on growth, and in particular the specific receptor pathway involved, is not understood. Tissue culture studies using NIH 3T3 fibroblasts and primary rat auricular fibroblasts were established to evaluate growth following opioid receptor antagonist treatment. Treatment of cells with CTOP, naltrindole, or nalmefene, selective antagonists for mu, delta, and kappa opioid receptors, respectively, did not accelerate cell replication. Addition of the classical opioid receptor peptides DAMGO, DPDPE, or EKC did not alter cell growth, suggesting that the classical opioid receptors were not involved in cutaneous wound healing. However, NTX (10−6 M) increased the growth of NIH 3T3 fibroblasts in culture over a 96-h period, and the specific ligand OGF decreased cell growth, supporting that the OGF-OGFr axis is tonically active and constitutively expressed in fibroblasts, the primary cell type in granulation tissue of the skin. Transfection of NIH 3T3 cells with OGFr siRNA reduced receptor protein; subsequent treatment with NTX did not accelerate cell proliferation. These data indicate that blockade of the OGFr pathway enhances proliferation of fibroblasts in vitro, and in a primary culture of auricular fibroblasts, suggesting that the effect of NTX on growth is mediated through the OGF-OGFr axis. Finally, antagonists for classical opioid receptors as well as NTX were topically applied to cutaneous wounds in type 1 diabetic rats; only NTX accelerated wound closure. These studies indicate that the mechanistic pathway underlying the effects of NTX to enhance cutaneous wound closure in diabetic and nondiabetic subjects is specific blockade of the OGF–OGFr regulatory axis.
Role of Glucagon-Like Peptide-1 Analogue Versus Amylin as an Adjuvant Therapy in Type 1 Diabetes in a Closed Loop Setting With ePID Algorithm
Authors: Renukuntla Venkat Sasidhar , Ramchandani Neesha , Trast Jeniece , Cantwell Martin , Heptulla Rubina A. 
Published: July 2014

Aims/Hypothesis: Postprandial hyperglycemia due to paradoxical hyperglucagonemia is a major challenge of diabetes treatment despite the use of the artificial pancreas. We postulated that adjunctive therapy with pramlintide or exenatide would attenuate hyperglycemia in the postprandial phase through glucagon suppression, thereby optimizing the functioning of the closed-loop (CL) system. Methods: Subjects with type 1 diabetes (T1DM) on insulin pump therapy were recruited to participate in a 27-hour hospitalized admission on 3 occasions (2-4 weeks apart) and placed on the insulin delivery via CL system in random order to receive (1) insulin alone (control), (2) exenatide 2.5 µg + insulin, (3) pramlintide 30 µg + insulin. Medications were given prior to lunch and dinner, which was a standardized meal of 60 grams of carbohydrates. Insulin delivery was as per the ePID algorithm via the Medtronic CL system and continuous subcutaneous glucose monitoring via Medtronic Sof-sensors. Ten subjects age 23 ± 1 years with a HbA1c of 7.29 ± 0.3% (56 ± 1 mmol/mol) and duration of T1DM 10.6 ± 2.0 years participated in the 3-part study. Results: Exenatide was found to be significantly better in attenuating postprandial hyperglycemia as compared to insulin monotherapy ( P < .03) and pramlintide ( P > .05). Glucagon suppression was statistically significant with exenatide ( P < .03) as compared to pramlintide. Insulin requirements were lower with adjunctive therapy, but statistically insignificant. Conclusions/Interpretations: Insulin monotherapy results in postprandial hyperglycemia in T1DM in the CL setting and adjunctive therapy with exenatide reduces postprandial hyperglycemia effectively and should be considered as adjunctive therapy in T1DM.
Clinical Impact of Indirect Markers of Renal Function in Elderly Patients With Hip Fracture
Authors: López-Martínez Coral , Tovar-Rivera Emanuel , Becerra-Laparra Ivonne K. , Chávez-Tapia Norberto C. 
Published: July 2014

Introduction: There are risk factors associated with mortality in patients older than 70 years with hip fracture, including kidney function. However, indirect formulas to calculate glomerular filtration rate are not validated in patients older than 70 years. We analyzed whether the formula hematocrit, urea, and gender (HUGE) can be used as a prognostic factor. Material and Methods: A retrospective cohort study of 88 patients older than 70 years with a diagnosis of hip fracture. At admission, clinical and biochemical parameters were measured and glomerular filtration rate by Cockcroft-Gault, Modification Of Diet In Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and HUGE value. Accuracy to assess long-term mortality was analyzed with receiver–operating curve analysis. Cox regression analysis was performed to identify risk factor for mortality. Results: Sample included 88 patients; overall mortality was 13.63%, 17.85%, 28.57%, and 75.85% at 6 months, 1, 2, and 3 years, respectively. There was no significant difference in glomerular filtration rate by different formulas, contrary to HUGE, with higher values in the mortality group (1.83 ± 6.38 vs −2.61 ± 2.70, P = .0001). Survival was lower in patients with higher HUGE values (22.7 months, 95% confidence interval [CI] 16.1-29.5 vs 32.9 months, 95% CI 30.2-35.7; P ≤ .001). In the Cox regression analysis, a negative HUGE value is associated with lower mortality (hazards ratio = 0.238; 95% CI 0.568-0.099). Conclusion: The HUGE formula is an independent risk factor for mortality in elderly patients with hip fracture, but not the glomerular filtration rate determined by Cockcroft-Gault, MDRD, and CKD-EPI.
Characteristics affecting oral anticoagulant therapy choice among patients with non-valvular atrial fibrillation: a retrospective claims analysis
Authors: AbuDagga Azza , Stephenson Judith J , Fu An-Chen , Kwong Winghan Jacqueline , Tan Hiangkiat , Weintraub William S 
Published: July 2014

Abstract

Background
Dabigatran is one of the three newer oral anticoagulants (OACs) recently approved in the United States for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. The objective of this study was to identify patient, healthcare provider, and health plan factors associated with dabigatran versus warfarin use among NVAF patients.

Methods
Administrative claims data from patients with ≥2 NVAF medical claims in the HealthCore Integrated Research Database between 10/1/2009 and 10/31/2011 were analyzed. During the study intake period (10/1/2010 - 10/31/2011), dabigatran patients had ≥2 dabigatran prescriptions, warfarin patients had ≥2 warfarin and no dabigatran prescriptions, and the first oral anticoagulant (OAC) prescription date was the index date. Continuous enrollment for 12 months preceding (“pre-index”) and ≥ 6 months following the index date was required. Patients without pre-index warfarin use were assigned to the ‘OAC-naïve’ subgroup. Separate analyses were performed for ‘all-patient’ and ‘OAC-naïve’ cohorts. Multivariable logistic regression (LR) identified factors associated with dabigatran versus warfarin use.

Results
Of 20,320 patients (3,019 dabigatran and 17,301 warfarin) who met study criteria, 27% of dabigatran and 13% of warfarin patients were OAC-naïve. Among all-patients, dabigatran patients were younger (mean 67 versus 73 years, p < 0.001), predominantly male (71% versus 61%, p < 0.001), and more frequently had a cardiologist prescriber (51% versus 30%, p < 0.001) than warfarin patients. Warfarin patients had higher pre-index Elixhauser Comorbidity Index (mean: 4.3 versus 4.0, p < 0.001) and higher ATRIA bleeding risk score (mean: 3.0 versus 2.3, p < 0.001). LR results were generally consistent between all- and OAC-naïve patients. Among OAC-naïve patients, strongest factors associated with dabigatran use were prescriber specialty (OR = 3.59, 95% CI 2.68-4.81 for cardiologist; OR = 2.22, 95% CI 1.65-2.97 for other specialist), health plan type (OR = 1.47 95% CI 1.10-1.96 for preferred provider organization), and prior ischemic stroke (OR = 1.42, 95% CI 1.06-1.90). Older age decreased the probability of dabigatran use.

Conclusions
Beside patient characteristics, cardiology specialty of the prescribing physician and health plan type were the strongest factors associated with dabigatran use.