tbuckley/cabot-search huggingface dataset:
The role of microsomal epoxide hydrolase, Na+‐taurocholate cotransporting polypeptide, and organic anion transporting polypeptide in hepatic sodium‐dependent bile acid transport
Authors: Daniel Levy
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: Recent studies1 reported in Hepatology concerning the hepatic uptake of conjugated bile acids using organic anion transporting polypeptide (OATP) knockout mice lacking Slco1a/1b isoforms demonstrate that OATP as well as Na+‐taurocholate cotransporting polypeptide (NTCP) are required because only 32% of the NTCP knockout mice exhibited elevated serum bile acid levels (reference 8 in Slijepcevic et al.1). This report, however, does not establish that NTCP and OATP are the major bile acid transporters in all systems and do not reference studies described below that demonstrate the existence of alternate pathways. Numerous studies have established that microsomal epoxide hydrolase (mEH) plays a significant role in the hepatic transport of conjugated bile acids, including the identification of two heterozygous mutations in the human mEH gene (EPHX1) resulting in a 95% decrease in mEH expression.2 The patient in this latter study exhibited a 100‐fold increase in serum bile acids in the absence of liver damage, suggesting a defect in transport while NTCP mRNA and protein expression levels were normal. In addition, we recently reported3 the presence of the same EPHX1 intron‐1 heterozygous polymorphism previously described in Shu et al.2 in a high percentage of the Lancaster County Old Order Amish population that present numerous hypercholanemic subjects without liver injury, suggesting the loss of transport capacity. No mutations have been detected in the NTCP gene from this population. In contrast, NTCP and OATP‐1 were undetectable in the fch/fch mouse, which exhibits normal levels of mEH, where a high percentage of intravenously administered taurocholate was rapidly detected in the liver (reference 42 in Peng et al.3). Similar results were observed in mice treated with ciprofibrate where NTCP, OATP‐1, and BSEP were greatly reduced or undetectable while serum bile acid concentrations and biliary bile acid secretion rates were unaffected (reference 43 in Peng et al.3). In addition, there is a significant discord between the ontogenic expression of bile acid transport function and NTCP expression (references 48‐51 in Peng et al.3) while mEH expression parallels transport capacity during development (reference 7 in Peng et al.3). These studies suggest that the mEH intron‐1 polymorphism results in a genetic predisposition for hypercholanemia and further supports the significant role of mEH in mediating hepatic sodium‐dependent bile acid transport in concert with other transport mechanisms.
Transparency about the outcomes of mental health services (IAPT approach): an analysis of public data
Authors: David M Clark, Lauren Canvin, John Green, Richard Layard, Stephen Pilling, Magdalena Janecka
Journal: The Lancet (2017)

Internationally, the clinical outcomes of routine mental health services are rarely recorded or reported; however, an exception is the English Improving Access to Psychological Therapies (IAPT) service, which delivers psychological therapies recommended by the National Institute for Health and Care Excellence for depression and anxiety disorders to more than 537 000 patients in the UK each year. A session-by-session outcome monitoring system ensures that IAPT obtains symptom scores before and after treatment for 98% of patients. Service outcomes can then be reported, along with contextual information, on public websites.
Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma
Authors: Arvind M. Venkatesan, Rajesh Vyas, Alec K. Gramann, Karen Dresser, Sharvari Gujja, Sanchita Bhatnagar, Sagar Chhangawala, Camilla Borges Ferreira Gomes, Hualin Simon Xi, Christine G. Lian, Yariv Houvras, Yvonne J. K. Edwards, April Deng, Michael Green, Craig J. Ceol
Journal: Journal of Clinical Investigation (2017)

Oncogenomic studies indicate that copy number variation (CNV) alters genes involved in tumor progression; however, identification of specific driver genes affected by CNV has been difficult, as these rearrangements are often contained in large chromosomal intervals among several bystander genes. Here, we addressed this problem and identified a CNV-targeted oncogene by performing comparative oncogenomics of human and zebrafish melanomas. We determined that the gene encoding growth differentiation factor 6 (GDF6), which is the ligand for the BMP family, is recurrently amplified and transcriptionally upregulated in melanoma. GDF6-induced BMP signaling maintained a trunk neural crest gene signature in melanomas. Additionally, GDF6 repressed the melanocyte differentiation gene MITF and the proapoptotic factor SOX9, thereby preventing differentiation, inhibiting cell death, and promoting tumor growth. GDF6 was specifically expressed in melanomas but not melanocytes. Moreover, GDF6 expression levels in melanomas were inversely correlated with patient survival. Our study has identified a fundamental role for GDF6 and BMP signaling in governing an embryonic cell gene signature to promote melanoma progression, thus providing potential opportunities for targeted therapy to treat GDF6-positive cancers.
Effects of DLC1 Deficiency on Endothelial Cell Contact Growth Inhibition and Angiosarcoma Progression
Authors: David Sánchez-Martín, Atsushi Otsuka, Kenji Kabashima, Taekyu Ha, Dunrui Wang, Xiaolan Qian, Douglas R Lowy, Giovanna Tosato
Journal: JNCI Journal of the National Cancer Institute (2017)

Deleted in Liver Cancer 1 (DLC1) is a tumor suppressor gene frequently deleted in cancer. However, DLC1 is not known to be deleted in angiosarcoma, an aggressive malignancy of endothelial cell derivation. Additionally, the physiologic functions of DLC1 protein in endothelial cells are poorly defined.We investigated the effects of shRNA-induced DLC1 depletion in endothelial cells. Cell growth was measured by 3H thymidine incorporation, IncuCyte imaging, and population doublings; cell death by cell cycle analysis; gene expression by Affimetrix arrays and quantitative polymerase chain reaction; NF-κB activity by reporter assays; and protein levels by immunoblotting and immunofluorescence staining. We tested Tanespimycin/17-AAG and Fasudil treatment in groups of nine to 10 mice bearing ISOS-1 angiosarcoma. All statistical tests were two-sided.We discovered that DLC1 is a critical regulator of cell contact inhibition of proliferation in endothelial cells, promoting statistically significant (P < .001) cell death when cells are confluent (mean [SD] % viability: control DLC1 = 15.6 [19.3]; shDLC1 = 73.4 [13.1]). This prosurvival phenotype of DLC1-depleted confluent endothelial cells is attributable to a statistically significant and sustained increase of NF-κB activity (day 5, P = .001; day 8, P = .03) associated with increased tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) signaling. Consistently, we found that DLC1 is statistically significantly reduced (P < .001 in 5 of 6) and TNFAIP3/A20 is statistically significantly increased (P < .001 in 2 of 3 and P = 0.02 in 1 of 3) in human angiosarcoma compared with normal adjacent endothelium. Treatment with the NF-κB inhibitor Tanespimycin/17-AAG statistically significantly reduced angiosarcoma tumor growth in mice (treatment tumor weight vs control, 0.50 [0.19] g vs 0.91 [0.21] g, P = .001 experiment 1; 0.66 [0.26] g vs 1.10 [0.31] g, P = .01 experiment 2).These results identify DLC1 as a previously unrecognized regulator of endothelial cell contact inhibition of proliferation that is depleted in angiosarcoma and support NF-κB targeting for the treatment of angiosarcoma where DLC1 is lost.
Effects of vitamin and mineral supplementation on total and cancer mortality (Linxian General Population Randomised Nutrition Intervention Trial): results from the 25-year post-trial follow-up
Authors: Shao-Ming Wang, Philip R Taylor, Jin-Hu Fan, Ruth Pfeiffer, Mitchell H Gail, He Liang, Gwen A Murphy, Sanford M Dawsey, You-Lin Qiao, Christian C Abnet
Journal: The Lancet (2017)
Prostate Cancer Death After Radiotherapy or Radical Prostatectomy: A Nationwide Population-based Observational Study
Authors: David Robinson, Hans Garmo, Ingela Franck Lissbrant, Anders Widmark, Andreas Pettersson, Adalsteinn Gunnlaugsson, Jan Adolfsson, Ola Bratt, Per Nilsson, Pär Stattin
Journal: European Urology (2017)

There are no conclusive results from randomized trials on radiotherapy (RT) versus radical prostatectomy (RP) for prostate cancer. Numerous observational studies have suggested that RP is associated with a lower risk of prostate cancer death, but whether results have been biased due to limited adjustments for confounding factors is unknown.To compare the risk of prostate cancer death after RT versus RP.Nationwide population-based observational study of men in the Prostate Cancer data Base Sweden 3.0 who had undergone RT or RP between 1998 and 2012.Prostate cancer deaths were compared. Hazard ratios (HRs) were calculated in Cox regression models, including clinical T stage, M stage, Gleason grade group, serum levels of prostate-specific antigen, proportion of biopsy cores with cancer, mode of detection, comorbidity, age, educational level, and civil status. Period analysis with left truncation was performed.Primary treatment was RT or RP for 41 503 men. Treatment effect was associated with disease severity. In univariate analysis of RT versus RP, risk of prostate cancer death was higher after RT-low- and intermediate-risk cancer, HR 1.82 (95% confidence interval [CI]: 1.53-2.16), and high-risk cancer, HR 1.57 (95% CI: 1.33-1.85). After full adjustment in period analysis, this difference between the treatments was attenuated-low- and intermediate-risk cancer, HR 1.24 (95% CI: 0.97-1.58), and high-risk cancer, HR 1.03 (95% CI: 0.81-1.31). Confounding remained due to nonrandom allocation to treatment.In comparison with previous studies, the difference in prostate cancer mortality after RT and RP was much smaller.The difference in prostate cancer mortality after contemporary radiotherapy and radical prostatectomy was small in contrast to previous studies, indicating that potential side effects should be more emphasized when selecting treatment.
Gingival crevicular fluid and its immune mediators in the proteomic era
Authors: Nagihan Bostanci, Georgios N. Belibasakis
Journal: Periodontology 2000 (2017)

Abstract The discovery of biomarkers for periodontal disease requires an in‐depth understanding of the molecular basis of the initiation and progression of the disease. The gingival crevicular fluid is a biological medium suitable for identifying and measuring such biomarkers because it can be easily and noninvasively sampled from the immediate vicinity of the affected tissues. An ever‐expanding pool of gingival crevicular fluid proteins associated with periodontal health or disease has been catalogued over the years, particularly with the recent implementation of proteomic technologies. ‘Proteomics’ refers to the large‐scale study of entire arrays of proteins expressed by a genome and present in a cell, tissue, biological fluid or organism. Hence, such technologies provide a broad qualitative and quantitative insight of the proteins present in gingival crevicular fluid. Pertinent studies have amassed on the information gathered to date on protein signatures in periodontal health and disease, and have confirmed the nature of the immunological host response. This review discusses the application of proteomic technologies in characterizing the molecular networks present in gingival crevicular fluid, their potential for discovery of biomarkers that are meaningful for clinical practice, and the associated technical challenges.
Abstract 15047: Evaluation of the Incidence of Major Bleeding in a Heterogeneous Population of 51,842 Rivaroxaban Users With Nonvalvular Atrial Fibrillation
Authors: Sally Tamayo, Manesh Patel, Zhong Yuan, Nicholas Sicignano, Kathleen Hopf, Frank Peacock
Journal: Circulation (2016)

Introduction: Rivaroxaban, a direct factor Xa inhibitor, reduces the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). The central risk associated with o...
GMC says that it should regulate physician associates
Authors: Abi Rimmer
Journal: BMJ (2017)

The General Medical Council has said that it should regulate medical associate professions, including physician associates, as long as this didn’t increase doctors’ fees.

In response to a government consultation on the regulation of medical associate professions (MAPs) the GMC said it would be well placed to accept regulatory responsibility for this staff group.1

Physician associates, physicians’ assistants in anaesthesia, surgical care practitioners, and advanced critical care practitioners are all classed as MAPs.

The GMC said that it could take on MAP regulation as long as the government provides …
External Validation of Generic and Cancer-Specific Risk Stratification Tools in Patients With Pulmonary Embolism and Active Cancer
Authors: Erin R. Weeda, Jonathan T. Caranfa, Simon B. Zeichner, Craig I. Coleman, Elaine Nguyen, Christine G. Kohn
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: Numerous risk stratification tools exist to predict early post-pulmonary embolism (PE) mortality; however, few were specifically designed for use in patients with cancer. This study sought to evaluate the performance of 3 cancer-specific (RIETE, POMPE-C, and Font criteria) and 3 generic (Hestia, Pulmonary Embolism Severity Index [PESI], and Geneva prognostic score [GPS]) risk stratification tools for predicting 30-day post-PE mortality in patients with active cancer. Methods: We identified consecutive, adult, objectively confirmed patients with PE and active cancer presenting to our institution from November 2010 to January 2014. We calculated the proportion of patients categorized as low or high risk by each of the 6 risk stratification tools and determined each tools' accuracy for predicting 30-day all-cause mortality. Results: A total of 124 patients with PE and active cancer were included (mean age, 66.2 years; 46.0% with concurrent deep vein thrombosis; 49.2% with metastatic disease; and 46.8%, 16.9%, and 11.3% receiving chemotherapy, radiation, or both, respectively). Mortality at 30 days occurred in 25 patients (20.2%). The cancer-specific tools (POMPE-C, RIETE, and Font criteria) categorized between 32% and 43% of patients as low risk and displayed sensitivities and specificities of 88.0% to 96.0% and 38.4% to 52.5%, respectively. The generic PESI and Hestia tools had sensitivities >96.0%, but classified <19% of patients as low risk; specificity of these tools were low (PESI, 6.1%; Hestia, 23.2%). Although the final noncancer tool, GPS, classified 43.5% of patients as low risk, it did so with a sensitivity of 52.0% and specificity of 42.4%. Conclusions: When risk-stratifying PE in patients with active cancer, cancer-specific tools appeared to exhibit better prognostic accuracy than their generic counterparts. POMPE-C, RIETE, and the Font criteria identified a substantially greater proportion of patients with PE likely to survive to 30 days with comparable sensitivity to the generic tools.
Expression of the ELAV-like protein HuR in human colon cancer - association with cyclooxygenase-2 (COX-2)
Authors: Carsten Denkert, Ines Koch, Nora Von Keyserlingk, Aurelia Noske, Silvia Niesporek, Manfred Dietel, Steffen Hauptmann, Wilko Weichert
Journal: Cancer Research (2005)

1265   The human family of ELAV-like proteins consists of four members that are highly homologous to the drosophila nuclear protein embryonic-lethal abnormal vision (ELAV). One of these proteins, HuR, has been suggested to serve as a shuttling protein between the nucleus and the cytoplasm. In-vitro studies have shown that HuR is involved in regulation of mRNA stability of cyclooxygenase-2 (COX-2). In this study we investigated expression as well as cellular localization of HuR in a cohort of 87 primary colorectal adenocarcinomas as well as in three colon cancer cell lines (HRT-18, HT-29, CX-2). In addition, we investigated the expression of cyclooxygenase-2 in the primary colorectal carcinomas. Expression of the immunohistochemical markers was correlated with clinico-pathological parameters as well as with patient outcome. All cell lines showed an expression of HuR mRNA and protein by PCR and Western Blot. In the immunohistochemical study, we observed two different staining patterns of HuR in tumor tissue of colon carcinomas: A nuclear expression in 97% of cases as well as an additional cytoplasmic expression in 53% of cases. COX-2 was expressed in 63% of carcinomas. Cytoplasmic expression of HuR was significantly associated with increased COX-2 expression as well as with high tumor stage. In univariate Kaplan-Meier analysis, grading, tumor stage and nodal status but not HuR or COX-2 expression were prognostic factors for overall survival. Our results suggest that cytoplasmic overexpression of HuR in tissue of colorectal adenocarcinomas may regulate COX-2 protein levels. Thus, HuR may be part of a regulatory pathway that controls the mRNA stability of COX-2. Based on our results, further studies are necessary to investigate whether HuR might be a potential target for a molecular tumor therapy.
Abstract 17443: 3D Printing for Precision Drug Therapy: An Initial Proof of Concept Study
Authors: Kevin Yuang, Shirley Pu, Min Pu
Journal: Circulation (2015)

Personalized medicine is an emerging approach for disease management. Individuals can vary dramatically in their response to cardiovascular drugs. Personalization of medication dosing is necessary for increasing efficacy and reduction of side-effects based on the patient's race, weight, renal function, liver function or other relevant factors. However, adjustments for oral medications are not easily made due to limited formulations by pharmaceutical companies. We hypothesized it is feasible to produce personalized pills tailored to each individual patient’s clinical and biological characteristics through automated 3D-printing. Methods: A prototype computer algorithm was developed in our laboratory. The software includes two databases: 3D volume and dosage-adjustment factors. After inputting clinical and biological factors specific to the patients (age, race, weight, GFR, etc.), the software automatically calculates a personalized dose. Once the appropriate dose is determined, 3 volume datasets are generated and transferred to a STL file of a 4x4 pill board for 3D-printing to test the accuracy and variability of 3D-printed “pills”. Five different doses (80 pills) were created with dosing increments of 25%. Results: All pills were successfully printed using a 3D-printer (Figure). Doses of printed pills ranged from 124 mg to 373 mg. There was high reproducibility with standard deviations ranging from 3-5 mg. There were differences of 0.5-6% between the printed pills and computer-generated volumes in 5 different dose ranges indicating pills can be replicated accurately using a volume-concentration equation by the software. Conclusion: The study demonstrates that personalized pills based on each individual's clinical and biological characteristics can be produced with high precision through 3D-printing. Further studies are needed to develop 1) a standard adjustment formula for each individual drugs 2) cost-effective 3D drug printing techniques.
Abstract 20317: Stress-Induced Ischemia Does Not Risk Stratify Patients Prior to Vascular Surgery and is Not Associated With Elevated Post Operative Troponin
Authors: Alejandra Gutierrez, Paul Cremer, Grant Reed, Laura Young, Clevenger Joshua, Umair Malik, Jaber Wael, Venugopal Menon
Journal: Circulation (2016)

Introduction:  Imaging-based stress testing is used to risk stratify patients undergoing vascular surgery, though the evidence is limited. We aim to assess whether ischemia provides prognostic value for post-operative events and is associated with elevated troponin.   Methods:  Consecutive patients with imaging stress tests prior to vascular surgery were included. Clinical risk was determined by the revised cardiac risk index (RCRI). The primary outcome was post-operative myocardial infarction, heart failure, arrhythmia, or death within 30 days. The secondary outcome was elevated troponin.   Results:  Among 688 patients, 7.6% had exercise radionuclide imaging, 14.4% exercise echocardiography, 19.3% dobutamine echocardiography, and 58.7% vasodilator radionuclide imaging. Overall, 21.8% had ischemia. Patients with ischemia were more likely to be male, have CAD, heart failure, and diabetes (Table 1). The primary outcome occurred in 17.2%, and 6.7% had an elevated troponin. Ischemia was not associated with the primary (20.7% v. 16.2%, p=0.22) or secondary outcome (8.7% v. 6.1%, p=0.27). On multivariable analysis, a higher RCRI score and an inability to exercise were associated with the primary outcome while only RCRI was associated with the secondary outcome (Figure 1).   Conclusions:  In patients undergoing vascular surgery, stress-induced ischemia did not provide risk stratification for cardiac events. Ischemia was also not associated with elevated troponin, supporting the hypothesis that post-operative troponinemia is often not mediated by severe epicardial stenosis. Table 1. Baseline Characteristics Figure 1. Multivariable logistic regression models