tbuckley/cabot-search huggingface dataset:
GMC begins High Court appeal over suspension of paediatrician convicted of manslaughter
Authors: Clare Dyer
Journal: BMJ (2017)

A medical practitioners tribunal erred in deciding only to suspend a doctor convicted of gross negligence manslaughter from the UK medical register rather than strike her off, the General Medical Council has said in the High Court.1

Ivan Hare QC, for the GMC, said that the tribunal impermissibly went behind the findings of the Crown Court jury that in November 2015 found Hadiza Bawa-Garba guilty of the manslaughter of 6 year old Jack Adcock.2

The tribunal took account of “multiple systemic failures” at Leicester Royal Infirmary on the day in February 2011 when Jack, who had Down’s syndrome, was admitted with shallow breathing and dehydration caused by vomiting and diarrhoea. But Hare said the court also had information about these failures and yet the jury was left in no doubt as to the trainee …
Emerging Roles of Electrospun Nanofibers in Cancer Research
Authors: Shixuan Chen, Sunil Kumar Boda, Surinder K. Batra, Xiaoran Li, Jingwei Xie
Journal: Advanced Healthcare Materials (2017)

Abstract This article reviews the recent progress of electrospun nanofibers in cancer research. It begins with a brief introduction to the emerging potential of electrospun nanofibers in cancer research. Next, a number of recent advances on the important features of electrospun nanofibers critical for cancer research are discussed including the incorporation of drugs, control of release kinetics, orientation and alignment of nanofibers, and the fabrication of 3D nanofiber scaffolds. This article further highlights the applications of electrospun nanofibers in several areas of cancer research including local chemotherapy, combinatorial therapy, cancer detection, cancer cell capture, regulation of cancer cell behavior, construction of in vitro 3D cancer model, and engineering of bone microenvironment for cancer metastasis. This progress report concludes with remarks on the challenges and future directions for design, fabrication, and application of electrospun nanofibers in cancer diagnostics and therapeutics.
Abstract 14934: Heart Failure, Left Ventricular Remodeling, and Circulating Nitric Oxide Metabolites
Authors: Julio A Chirinos, Scott R Akers, Lien Trieu, Harry Ischiropoulos, Paschalis-Thomas Doulias, Ali Tariq, Izzah Vassim, Maheswara R Koppula, Amer Ahmed Syed, Haideliza Soto-Calderon, Raymond R Townsend, Thomas P Cappola, Kenneth B Margulies, Payman Zamani
Journal: Circulation (2016)

Stable plasma nitric oxide (NO) metabolites (NO M ), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NO M  levels integrate the influence of NO-synthase-derived NO production/metabolism, dietary intake of inorganic nitrate/nitrite, and clearance of NO M . Furthermore, nitrate and nitrate, the most abundant NO M,  can be reduced to NO via the nitrate-nitrite-NO pathway. We compared serum NO M  between subjects without heart failure ( n =126), subjects with heart failure and preserved ejection fraction (HFpEF;  n =43) and subjects with heart failure and reduced ejection fraction (HFrEF;  n =32). LV mass and extracellular volume fraction were measured with cardiac MRI. Plasma NO M  levels were measured after reduction to NO via the reaction with vanadium(III)/hydrochloric acid. Subjects with HFpEF demonstrated significantly lower levels of NO M  (8.0; μM; 95%CI=6.2-10.4 μM; ANOVA  P =0.013) than subjects without HF (12.0; μM; 95%CI=10.4-13.9 μM;  P =0.025) or those with HFrEF (13.5; μM; 95%CI=9.7-18.9 μM;  P =0.03). There were no significant differences in NO M  between subjects with HFrEF and subjects without HF ( P =1.00). In a multivariable model that adjusted for age, sex, race, diabetes mellitus, body mass index, current smoking, systolic blood pressure and glomerular filtration rate, HFpEF remained an independent predictor of lower NO M  (β=-0.43;  P =0.013). NO M  did not correlate with LV mass, or LV diffuse fibrosis. In conclusion. HFpEF, but not HFrEF, is associated with reduced plasma NO M , suggesting greater endothelial dysfunction, enhanced clearance, or deficient dietary ingestion of inorganic nitrate. Our findings may underlie the salutary effects of inorganic nitrate supplementation demonstrated in recent clinical trials in HFpEF.
Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis
Authors: Susanna C Larsson, Matthew Traylor, Rainer Malik, Martin Dichgans, Stephen Burgess, Hugh S Markus
Journal: BMJ (2017)

<h3>Abstract</h3> <h3>Objective</h3> To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer’s disease. <h3>Design</h3> Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables. <h3>Setting</h3> International Genomics of Alzheimer’s Project. <h3>Participants</h3> 17 008 cases of Alzheimer’s disease and 37 154 controls. <h3>Main outcome measures</h3> Odds ratio of Alzheimer’s per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis. <h3>Results</h3> This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P&lt;0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer’s. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10<sup>−6</sup>) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10<sup>−5</sup>) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer’s (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer’s and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer’s. Genetically predicted alcohol consumption, serum folate, serum vitamin B<sub>12</sub>, homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer’s disease. <h3>Conclusion</h3> These results provide support that higher educational attainment is associated with a reduced risk of Alzheimer’s disease.
Abstract 18757: Adenylate Cyclase Type 9 (Adcy9) Regulates Vasomotor Tone in Mice
Authors: Yohann Rautureau, Pierre-Marc Williams, Marie-Ève Higgins, Éric Thorin, Éric Rhéaume, Jean-Claude Tardif
Journal: Circulation (2016)

Single nucleotide polymorphisms located in the adenylate cyclase type 9 (ADCY9) gene determine cardiovascular outcomes of patients treated with dalcetrapib, a cholesteryl ester transfer protein inhibitor (Tardif et al, Circ Cardiovasc Genetics 2015). The roles of the different subtypes of adenylate cyclases responsible for vasodilatation (VD) are ill-defined. We aimed at evaluating the role of Adcy9 expression in the control of vascular tone by using isolated vessels from Adcy9-inactivated (Adcy9Gt) and wild-type (WT) mice. Vasomotor tone was studied by recording the isometric tension developed by aorta rings and the diameter of pressurized isolated femoral arteries from mice aged 8 to 13 weeks. We studied VD in response to adenylate cyclase activators, isoproterenol (Iso), a β-adrenergic receptor (β-AR) agonist and iloprost, a prostaglandin I2 receptor agonist, as well as endothelial-dependent vasodilatation (EDV) in response to acetylcholine (Ach). EDV and β-AR-induced VD in the aorta were similar in WT and Adcy9Gt mice. In femoral arteries, Adcy9 inactivation decreased Iso-induced VD (Emax, WT: 48.3+/-4.7%, n=7; Adcy9Gt: 24.1+/-4.7%, n=11; P
Dendron‐Grafted Polylysine‐Based Dual‐Modal Nanoprobe for Ultra‐Early Diagnosis of Pancreatic Precancerosis via Targeting a Urokinase‐Type Plasminogen Activator Receptor
Authors: Hui Li, Ping Wang, Wenyu Gong, Qi Wang, Jia Zhou, Wei‐Hong Zhu, Yingsheng Cheng
Journal: Advanced Healthcare Materials (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. Early detection of precancerous pancreatic intraepithelial neoplasia (PanIN) tissues is an urgent challenge to improve the PDAC prognosis. Here, a urokinase‐type plasminogen activator receptor (uPAR)‐targeted magnetic resonance (MR)/near‐infrared fluorescence (NIRF) dual‐modal nanoprobe dendron‐grafted polylysine (DGL)‐U11 for ultra‐early detection of pancreatic precancerosis is reported. Because of its good biocompatibility and biodegradability, globular architecture, and well‐defined reactive groups, the DGL is chosen as the platform to load with a pancreatic tumor‐targeting peptide U11, a magnetic resonance contrast agent Gd 3+ ‐diethylene triamine pentaacetic acid, and a near‐infrared fluorescent cyanine dye Cy5.5. The nanoprobe DGL‐U11 has several preferable characteristics, such as active peptide targeting to activator receptor, good biocompatibility, dual‐modal imaging diagnosis, and well controlled diameter in a range of 15–25 nm. Upon incorporation of the active U11 peptide target to the overexpressed activator receptor uPAR, the targeted nanoprobe DGL‐U11 can increase to the earlier PanIN‐II stage through in vivo NIRF imaging. Labeled with both MR and NIRF bioimaging reporters, the uPAR‐targeted dual‐modal nanoprobe is very effective in the targeted imaging of precancerous PanINs and PDAC lesions with high sensitivity and spatial resolution, providing a promising platform to the ultra‐early detection of PDAC.
Abstract 21: Grading dysphagia as a toxicity of head and neck cancer: Differences in severity classification based on MBS DIGEST and clinical CTCAE grades
Authors: Ryan P. Goepfert, Jan S. Lewin, Martha P. Barrow, Carla L. Warneke, Clifton D. Fuller, Stephen Y. Lai, Randal S. Weber, Katherine A. Hutcheson
Journal: Clinical Cancer Research (2017)

Abstract Background: Clinician-reported toxicity grading through Common Terminology Criteria for Adverse Events (CTCAE) stages dysphagia based on symptoms, diet, and tube dependence. The new Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) tool offers a similarly scaled 5-point ordinal summary grade of pharyngeal swallowing as determined through results of a modified barium swallow (MBS) study. This study aims to inform clinicians on the similarities and differences between dysphagia severity according to clinical CTCAE and MBS-derived DIGEST grading. Methods: A cross-sectional sample of 95 MBS studies was randomly selected from a prospectively-acquired MBS database among patients treated with organ preservation strategies for head and neck cancer. MBS DIGEST and clinical CTCAE dysphagia grades were compared. Results: DIGEST and CTCAE dysphagia grades had “fair” agreement per weighted k of 0.358 (95% CI .231-.485). Using a threshold of DIGEST ≥3 as reference, CTCAE had an overall sensitivity of 0.50, specificity of 0.84, and area under the curve (AUC) of 0.67 to identify severe MBS-detected dysphagia. At less than 6 months, sensitivity was 0.72, specificity was 0.76, and AUC was 0.75 while at greater than 6 months, sensitivity was 0.22, specificity was 0.90, and AUC was 0.56 for CTCAE to detect dysphagia as determined by DIGEST. Conclusions: Classification of pharyngeal dysphagia on MBS using DIGEST augments our understanding of dysphagia severity according to the clinically derived CTCAE while maintaining the simplicity of an ordinal scale. DIGEST likely complements CTCAE toxicity grading through improved specificity for physiologic dysphagia in the acute-phase and improved sensitivity for dysphagia in the late-phase. Citation Format: Ryan P. Goepfert, Jan S. Lewin, Martha P. Barrow, Carla L. Warneke, Clifton D. Fuller, Stephen Y. Lai, Randal S. Weber, Katherine A. Hutcheson. Grading dysphagia as a toxicity of head and neck cancer: Differences in severity classification based on MBS DIGEST and clinical CTCAE grades [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 21.
Pharmacokinetics of samarium-153-EDTMP (153Sm) prior to and following zoledronic acid (ZA) in prostate cancer (PC) patients with bone metastases (BM).
Authors: Kenneth S Bauer, Fatemeh Tavakkoli, Mouhamad Bazzi, Olga Molchanova-Cook, Wengen Chen, Arif Hussain
Journal: Journal of Clinical Oncology (2012)

e13075 Background: 153Sm and ZA are often employed to manage complications related to BM. Although 153Sm and ZA bind to overlapping sites within the bone, there is a paucity of information on potential pharmacokinetic (PK) and pharmacodynamic interactions between the two. In this study we report the pharmacokinetics of 153Sm when administered in combination with ZA. Methods: The study was carried out as two independent phase I trials assessing the effects of escalating dose 153Sm (0.5, 0.75, 1.0, and 1.25 µCi/kg) administered prior to or immediately after intravenous ZA 4 mg. Study 1 recruited 12 ZA-naive PC pts, while Study 2 enrolled 10 PC pts who had received at least 3 months of ZA prior to trial entry. On study, pts received 2 doses of 153Sm given 3 months apart and 6 doses of ZA given monthly. In Cycle 1 of both trials, 153Sm was administered on day1 and ZA on day 2. In Cycle 2, ZA was administered 1 hour prior to 153Sm on the same day. Blood samples for radioactive analysis were obtained at 5 min, and 0.5, 1, 2, 4, and 24 h post 153Sm dosing. PK analysis was performed by both model independent and PK modeling methods using WinNonlin. Results: The PK parameters of 153 Sm were highly variable between patients. The coefficient of variation of the Cmax/Dose was greater than 50% in all subgroups. A dose related increase in exposure to 153Sm was observed with high variability as well. The estimated terminal half-life (t 1/2 ) was similar across all dose levels within each study. The t 1/2 for Cycle 1 was 4.73 ± 1.27 for Study 1 and 6.73 ± 3.92 h for Study 2. The dose normalized Cmax (Cmax/Dose) was 0.068 ± 0.036 and 0.061 ± 0.043 µCi/mL for Study 1 and Study 2, respectively. Pharmacokinetic parameters for Cycle 2 were similar to those calculated for Cycle 1 within each study. Conclusions: The Cmax and t 1/2 reported here are similar to previous studies of 153Sm with doses ranging from 1.0 to 3.0 µCi/kg in ZA-untreated pts. Although not statistically significant, the subtle differences in the pharmacokinetics of 153Sm merit further investigation.
Activation of ACE2/angiotensin (1–7) attenuates pancreatic β cell dedifferentiation in a high-fat-diet mouse model
Authors: Xiuping Xuan, Fei Gao, Xiaoyi Ma, Chenghu Huang, Ying Wang, Hongjun Deng, Shiqi Wang, Wencun Li, Li Yuan
Journal: Metabolism (2017)
Defining the role of NDRG1 in prostate cancer
Authors: Sushant Kachhap, Dennis Faith, David Qian, Shabana Shabbeer, Nathan Galloway, Samuel Denmeade, Angelo DeMarzo, Michael Carducci
Journal: Cancer Research (2007)

4934  Progression of cancer from a localized disease to an advanced, invasive stage involves interplay of various molecules involved in cell adhesion, cell motility and cell cohesion. One such molecule that is involved with metastasis of prostate and breast cancer is the N-myc downregulated gene1 (NDRG1). The NDRG1 gene encodes a cytoplasmic 43-kDa protein. NDRG1 gene expression is silenced by native chromatin modulators and promoter methylation in prostate and breast cancer. Its expression is induced by various chemical agents like HDAC inhibitors, DNA methyl transferase inhibitors. Induction of NDRG1 leads to differentiation of cells and decreases metastasis. The exact function of how NDRG1 decreases metastasis is unknown. In an attempt to understand the function we carried out knockdown studies of NDRG1 in prostate cancer cell lines. Knockdown of NDRG1 in DU-145 prostate cancer cells led to knockdown of the cell adhesion molecule E-cadherin without changing the expression of other molecules in the E-cadherin complex. Reduced expression of E-cadherin correlates with metastasis of cancer including prostate cancer. Tissue array data of matched normal and tumor tissue from 42 patients using NDRG1 and E-cadherin antibodies indicated a highly significant correlation between NDRG1 and E-cadherin expression. A decrease in NDRG1 expression also correlated with the increase in grade of the tumor. We investigated the physical localization of NDRG1 after calcium chelation. Our immunofluorescent data revealed that NDRG1 strongly localizes with E-cadherin during the recovery/recycling phase. Ultracentrifugation experiments suggested that NDRG1 does strongly localize to an organelle after calcium chelation that cofractionates with markers of early/recycling and late endosome. Immunoprecipitation with flag tagged-NDRG1 showed NDRG1 physically interacts with Rab4GTpase. Pull-down assays using recombinant Rab4GTpase and NDRG1 revealed NDRG1 specifically interacts with Rab4 loaded with GTPγS indicating that the proteins interact on surface of endosomes. Live cell imaging using spinning disk confocal microscopy of HEK293 cells stably expressing NDRG1DsRed2 protein reveal NDRG1 localizes to discrete vesicles in the perinuclear region and interacts with both late and early endosomes and can recycle Alexa flour labeled- transferrin. In vitro reconstitution studies using purified endosome, in vitro translated NDRG1 and recombinant Rab4GTPase showed NDRG1 localizes to endosomes independent of Rab4GTPase. A lipid overlay analysis using recombinant NDRG1 revealed that the protein specifically binds to phosphatidylionositol 4- phosphate a lipid that defines microdomains in the trans-Golgi network and is involved with protein trafficking. Our data indicate that NDRG1 is involved in recycling of E-cadherin by endosomes and loss of NDRG1 may result in decrease in surface E-cadherin levels potentially resulting in an increase in metastasis.
Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting
Authors: Jun Luo, Gerhardt Attard, Steven P. Balk, Charlotte Bevan, Kerry Burnstein, Laura Cato, Artem Cherkasov, Johann S. De Bono, Yan Dong, Allen C. Gao, Martin Gleave, Hannelore Heemers, Mayuko Kanayama, Ralf Kittler, Joshua M. Lang, Richard J. Lee, Christopher J. Logothetis, Robert Matusik, Stephen Plymate, Charles L. Sawyers, Luke A. Selth, Howard Soule, Wayne Tilley, Nancy L. Weigel, Amina Zoubeidi, Scott M. Dehm, Ganesh V. Raj
Journal: European Urology (2017)
Abstract 17894: Clinical and Electrocardiographic Predictors of Occlusive and Obstructive Coronary Artery Disease Following Out-of-Hospital Cardiac Arrest
Authors: Christopher C Cheung, Darryl Wan, Brian Grunau, Carolyn M Taylor, Marc W Deyell, Kendeep Kaila, Jim Christenson, Michael E Farkouh, Christopher B Fordyce, Krishnan Ramanathan
Journal: Circulation (2017)

Background:  Following an out-of-hospital cardiac arrest (OHCA), there are no clear recommendations for early coronary angiography (CA) in patients without ST elevation (STE).   Purpose:  To examine the association between baseline characteristics, arrest rhythm, post-resuscitation electrocardiogram (ECG) and coronary artery disease (CAD) on CA.   Methods:  We performed a retrospective analysis of consecutive OHCA patients in the Metro Vancouver area from 2009-2015, using the Resuscitation Outcomes Consortium Cardiac Arrest Registry. Patients who did not survive to admission, or had a non-cardiac cause for OHCA were excluded. ECGs were reviewed for ST-segment change (≥0.1mV in 2 contiguous leads). Presence of CAD was defined as obstructive (any artery ≥70% or left main ≥50% stenosis) or occlusive CAD (any artery 99-100% stenosis). Patients with uninterpretable ECGs or left bundle branch block were excluded.   Results:  Baseline characteristics, ECG, and CA results for n=604 OHCA patients are reported (Table 1). After multivariate adjustment, the strongest predictor for occlusive CAD was STE (OR 6.38, 95% CI 3.47-11.7). Among non-STE OHCA patients with CA (n=116), male sex, VT/VF, and prior acute coronary syndrome (ACS) were independently associated with occlusive and obstructive CAD, while ST depression was not predictive (Table 2).   Conclusions:  Male sex, VT/VF, and prior ACS were the strongest predictors of occlusive and obstructive CAD on CA in OHCA patients without STE. In contrast, ST depression on the post-resuscitation ECG had limited value. These results help identify OHCA patients without STE with significant CAD burden, including those who may benefit from early CA.
Abstract 20155: Molecular and Functional Characterization of a Novel RYR2 Mutation Linked to Long QT Syndrome
Authors: Carmen R Valdivia, Erika Antunez-Arguelles, Jonathan Hernandez, Todd Herron, Teresa Villarreal, Pedro Iturralde, Argelia Medeiros-Domingo, Héctor H Valdivia
Journal: Circulation (2016)

Background:  Long QT (LQT) syndrome is characterized by prolongation of the QT interval in the ECG, syncope and sudden death. Mutations in 16 genes that encode ion channels or associated proteins account for ~80% of all cases, however, 20% of the cases still remain genetically unknown. Further, mutations in the cardiac ryanodine receptor gene ( RYR2 ) have been implicated in arrhythmia syndromes such as cathecolaminergic polymorphic ventricular tachycardia (CPVT).   Results:  We identified a novel mutation in  RYR2  (R2920Q), in a patient with family history of sudden death, syncope and prolongation of the QT interval (QTc, 525 ms). 80 cardiogenes were simultaneously sequenced using Haloplex design on a MiSeq device. All novel or low frequency variants predicted to be damaging were confirmed by Sanger sequencing. To elucidate the mechanisms by which R2920Q might cause RyR2 channel dysfunction and lead to LQT instead of CPVT, we engineered the R2920Q mutation in the murine  Ryr2  (mRyR2) and expressed it in HEK293 cells and in human iPS-derived cardiomyocytes (hIPS-CM) from a healthy control. Recombinant RyR2-R2920Q channels displayed increased Ca 2+  sensitivity compared to RyR2-WT in [ 3 H]ryanodine binding experiments (K d  for Ca 2+  activation = 323 and 707 nM, respectively, n=10), with no difference in protein expression. Monolayers of purified  h iPS-CM expressing mRyR2-R2920Q, mRyR2-WT or non-transfected (control) were loaded with a voltage sensitive dye and subjected to optical recordings of action potentials (AP) at 1 Hz pacing. hIPS-CM expressing mRYR2-R2920Q showed an APD90 of 267±13 compared to 197±13 and 185±29 ms in hIPS-CM expressing mRyR2-WT and non-transfected, respectively p   Conclusion:  The novel RyR2-R2920Q mutation confers to RyR2 channels a gain of function that may be linked to the LQT syndrome in this patient. Abnormal intracellular Ca 2+  handling has recently emerged as an important mechanism for arrhythmia generation in animal models of LQT. Spontaneous Ca 2+  release by hyperactive RyR2 channels may give rise to LQT instead of CPVT if the release occurs during the systolic phase of the AP, a mechanism we are currently investigating.