tbuckley/cabot-search huggingface dataset:
Abstract 10466: Post-myocardial Infarction Treatment With Edetate Disodium was Safe in the Trial to Assess Chelation Therapy
Authors: Jeanne Drisko, Karen P Alexander, Rhonda S Roberts, L. Terry Chappell, Kerry L Lee, Robin Boineau, Daniel B Mark, Richard L Nahin, Christine Goertz, Yves Rosenberg, Gervasio A Lamas
Journal: Circulation (2015)

Introduction: Treatment with edetate disodium has been in use for nearly 60 years for cardiovascular disease despite safety concerns, including deaths from hypocalcemia. No careful prospective evaluation of safety had been reported prior to the NIH-sponsored Trial to Assess Chelation Therapy (TACT). Methods: In TACT, 1,708 post-MI patients age ≥ 50 and creatinine ≤ 2.0 mg/dL were randomized doule blind to edetate-based chelation (n=839) or placebo (n=869). TACT implemented extensive site education prior to site activation. During the infusion period, there was close monitoring of vitals and labs, particularly creatinine and calcium, special lab-based (creatinine, calcium, and platelets) algorithms to delay infusions or reduce infusion rate when abnormal criteria were met, and early intervention to respond to safety concerns. Electronic and in-person monitoring took place to ensure adherence to TACT infusion protocols. Results: There were 100 (12%) serious adverse events (SAEs) in the edetate group and 127 (15%) in the placebo group (p=0.1009). Two deaths were possibly or definitely attributed, by the blinded safety monitor, to study therapy, 1 in the chelation group and 1 in the placebo group. Heart failure was reported in 57 edetate patients (7%) and 71 placebo patients (8%) (p=.28). Physical exams were identical over the course of the study, except for more tachycardia (heart rate &gt;100) in the placebo arm (0.1% vs 1.3% p=0.006). There was more infusion site discomfort (1.5% vs. 0.6%, p=0.049) with chelation and more abdominal cramping with placebo (1.7% v. 3.3%, p= 0.029) Reductions in calcium (&lt;8.5mg/dL) occurred in 52 chelation patients (6.2%) and 30 placebo patients (3.5%) during the infusion phase (p=.008). Calcium at last blood draw was not different between groups (mean calcium 9.3 vs 9.3, p=0.15). There was no adverse effect on renal function from edetate disodium (mean creatinine 1.04 (edetate) vs 1.07 (placebo), p=0.03) Conclusions: The experience with 55,222 infusions of edetate disodium or placebo in TACT shows that this therapy is extremely safe when used according to the TACT safe infusion protocol. This finding will be pivotal in informing the design of the TACT2 confirmatory study.
Trusts spend 25 times more on locum fees than on recruiting for permanent posts
Authors: Abi Rimmer
Journal: BMJ (2016)

NHS acute trusts in England are each spending nearly 25 times as much on locum agency fees as they spend on recruiting doctors to permanent positions, figures obtained by BMJ Careers show.

Information obtained through freedom of information requests showed that, on average in 2015, trusts spent £1.4 million on locum agency fees and £55 000 on recruiting doctors to permanent positions. The data also showed that each trust spent an average of £5.8m on employing locum doctors.

BMJ Careers sent freedom of information requests to the 154 acute trusts in England …
Molecular epidemiology of junctional epidermolysis bullosa: discovery of novel and frequent <i>LAMB3</i> mutations in Chilean patients with diagnostic significance
Authors: I. Fuentes, M. Campos, G. Repetto, P. Morandé, M.J. Yubero, S. Gonzalez, A. Klausegger, P. Schnitzhofer, G. Pohla-Gubo, J. Bauer, F. Palisson
Journal: British Journal of Dermatology (2016)

Epidermolysis bullosa (EB) is an inherited disease encompassing a group of clinically and genetically heterogeneous disorders, characterized by mechanical fragility of epithelial tissue with blistering formation following minor trauma, most notably on the skin1. The junctional form of EB (JEB, OMIM #226650 and #226700) is a monogenic autosomal recessive disorder characterized by blistering within the lamina lucida. JEB, among all EB types, can have the most severe clinical manifestations and the highest risk of infant mortality 2. To date, hundreds of mutations in six different genes have been described to cause JEB, provoking a limitation for an assertive molecular diagnosis.

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CBFβ-SMMHC creates aberrant megakaryocyte-erythroid progenitors prone to leukemia initiation in mice
Authors: Qi Cai, Robin Jeannet, Wei-Kai Hua, Guerry J. Cook, Bin Zhang, Jing Qi, Hongjun Liu, Ling Li, Ching-Cheng Chen, Guido Marcucci, Ya-Huei Kuo
Journal: Blood (2016)
Impact of Decrease of Serum Haptoglobin in Patients with Acquired Bone Marrow Failure Syndromes
Authors: Hideyoshi Noji, Kazuhiko Ikeda, Naoto Takahashi, Junichi Kameoka, Katsushi Tajima, Kazunori Murai, Yoshiko Tamai, Toyomi Kamesaki, Yasuchika Takeishi, Ken-Ichi Sawada, Tsutomu Shichishima
Journal: Blood (2008)
Respiratory Muscle Strength as a Predictive Biomarker for Survival in Amyotrophic Lateral Sclerosis
Authors: Michael I. Polkey, Rebecca A. Lyall, Ke Yang, Erin Johnson, P. Nigel Leigh, John Moxham
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Biomarkers for survival in amyotrophic lateral sclerosis (ALS) would facilitate the development of novel drugs. Although respiratory muscle weakness is a known predictor of poor prognosis, a comprehensive comparison of different tests is lacking.Objectives: To compare the predictive power of invasive and noninvasive respiratory muscle strength assessments for survival or ventilator-free survival, up to 3 years.Methods: From a previously published report respiratory muscle strength measurements were available for 78 patients with ALS. Time to death and/or ventilation were ascertained. Receiver operating characteristic analysis was used to determine the cutoff point of each parameter.Measurements and Main Results: Each respiratory muscle strength assessment individually achieved statistical significance for prediction of survival or ventilator-free survival. In multivariate analysis sniff trans-diaphragmatic and esophageal pressure, twitch trans-diaphragmatic pressure (Tw Pdi), age, and maximal static expiratory mouth pressure were significant predictors of ventilation-free survival and Tw Pdi and maximal static expiratory mouth pressure for absolute survival. Although all measures had good specificity, there were differing sensitivities. All cutoff points for the VC were greater than 80% of normal, except for prediction of 3-month outcomes. Sequential data showed a linear decline for direct measures of respiratory muscle strength, whereas VC showed little to no decline until 12 months before death/ventilation.Conclusions: The most powerful biomarker for mortality stratification was Tw Pdi, but the predictive power of sniff nasal inspiratory pressure was also excellent. A VC within normal range suggested a good prognosis at 3 months but was of little other value.
Abstract 1961: Characterization of MicroRNA Expression during the Development of Resistance to a mTOR-Inhibitor in renal cell carcinoma
Authors: Joana Heinzelmann, Franziska Bauer, Gerhard Unteregger, Darja Schendel, Anne Weiland, Michael Stöckle, Kerstin Junker
Journal: Cancer Research (2016)

Abstract Introduction: Second line therapy of metastatic renal cell carcinoma (RCC) using the mTOR inhibitor RAD001 (everolimus) is hampered by the appearance of drug resistance. The cellular mechanisms leading to drug resistance are not yet clarified. Although the influence of miRNAs is proven for other systemic treatments, their impact on mTOR inhibitors is not investigated. Therefore, we analyzed miRNA alterations in correlation to development of resistance to RAD001 in RCC cell culture models. Material and Methods: The RCC cell line 786-O was treated with 1μM RAD001 for up to 20 passages after developing sunitinib resistance. TotalRNA was isolated at defined intervals. Resistance-development as well as drug efficacy during the treatment was monitored by proliferation assays. MiRNA Microarrays (Agilent Technologies) were performed using RAD001 sensitive and RAD001 resistant cells to identify differently expressed miRNAs. Results were validated by qRT PCR. Functional analyses are performed after transfection of RAD001 sensitive cells with miRNA candidates. Results: The Microarray analyses revealed a miRNA signature including 9 differently expressed miRNAs in RAD001 resistant cells compared to sensitive cells. QRT-PCR results showed that especially miR-302e was strongly up-regulated by the factor of four. At present, functional analyses of miR-302e are ongoing. Conclusion: To our knowledge this is the first study analyzing miRNA alterations during the development of resistance to mTOR inhibitors. We have shown that miR-302e expression is associated with RAD001 resistance in RCC cells. Since miR-302e is a known tumor suppressor modulating radio sensitivity and drug sensitivity in several tumors we are proving now if miR-302e can regulate the mTOR inhibitor resistance of RCC. Citation Format: Joana Heinzelmann, Franziska Bauer, Gerhard Unteregger, Darja Schendel, Anne Weiland, Michael Stöckle, Kerstin Junker. Characterization of MicroRNA Expression during the Development of Resistance to a mTOR-Inhibitor in renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1961.
P1100 : Scoring systems proposed for acute-on-chronic liver failure accurately predict short-term mortality in patients with alcoholic hepatitis
Authors: H.Y. Kim, T.Y. Kim, C.W. Kim, D.S. Song, D.H. Sinn, E.L. Yoon, H.J. Lee, Y.K. Jung, Y.S. Kim, S.G. Kim, K.T. Suk, D.J. Kim
Journal: Journal of Hepatology (2015)
Abstract 2744: Synthetic lethal killing of RAD54B-deficient cancer cells by PARP1 silencing and inhibition
Authors: Erin N. McAndrew, Chloe C. Lepage, Kirk J. McManus
Journal: Cancer Research (2016)

Abstract Colorectal Cancer (CRC) is the second leading cause of cancer-related deaths in North America. Currently, many chemotherapeutics are non-specific and preferentially kill cancer cells based on their high proliferation rate. However, due to the lack of tumor specificity, many treatments have unwanted side effects. Accordingly, identifying novel therapeutic strategies and drug targets that better target and combat cancer are needed. To address this need, synthetic lethal (SL) approaches are now being explored in many cancer contexts. Synthetic lethality refers to the lethal combination of two independently viable mutations and functions by exploiting the aberrant genetics contained within cancer cells. RAD54B is an excellent candidate to exploit using a SL paradigm as it normally functions in homologous recombination repair (HRR) and hypomorphic expression and/or function are implicated in tumorigenesis in a wide array of cancers. We predict that RAD54B and PARP1 are SL, as BRCA1 and BRCA2, which also encode functions within HRR, are SL with PARP1. To identify PARP1 as a novel SL interactor of RAD54B, we employed an established RNAi-based screening approach along with a RAD54B isogenic CRC model. Conceptually, following PARP1 silencing, a SL interaction will result in fewer cells within the RAD54B-deficient cells relative to RAD54B-proficient controls. Accordingly, we sought to determine whether PARP1 silencing or inhibition (Olaparib or BMN673) would induce selective killing within RAD54B-deficient HCT116 cells relative to controls. As predicted, PARP1 silencing with either individual or pooled siRNA duplexes and inhibition with both Olaparib and BMN673 was associated with statistically significant decreases in the number of RAD54B-deficient cells relative to controls. To confirm the SL interaction did not occur due to de novo mutations within the RAD54B-deficient cells, dual silencing of RAD54B and PARP1 was performed within the parental line and confirmed the above findings. Finally, real-time cellular analyses were conducted and revealed the decrease in cell numbers was due to cellular cytotoxicity rather than cell cycle arrest. Collectively, these data show that RAD54B and PARP1 are SL, and identify PARP1 is a candidate lead target in CRCs harboring RAD54B defects. Citation Format: Erin N. McAndrew, Chloe C. Lepage, Kirk J. McManus. Synthetic lethal killing of RAD54B-deficient cancer cells by PARP1 silencing and inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2744.
Abstract 4225: Dynamic control of tumor vasculature with direct observation using intravital microscopy
Authors: Emmanuel M. Gabriel, Daniel Fisher, Minhyung Kim, Colin Powers, Anthony Visioni, Jason Muhitch, Joseph Skitzki
Journal: Cancer Research (2016)

Abstract Introduction Intravital microscopy (IVM) provides in vivo real-time imaging of tumor-associated vasculature. Our group was the first to use IVM successfully in human subjects to image melanoma associated vessels. In this preclinical study, we hypothesized that intravenous (IV) nicardipine increases observable blood flow to tumor through vasodilatation and therefore may facilitate drug delivery. Methods Standard window chambers for IVM were implanted into female BALB/c mice. The murine colon cancer cell line CT26HA was inoculated in the skin within the chamber. Fluorescein isothiocyanate dextran (FITC-dex) was injected IV to enhance vessel observation prior to nicardipine (8 μg/mouse). Observations were performed at 100x magnification using a modified Olympus microscope for 10 minutes. Naïve mice were used for control observations. Mice bearing CT26HA were observed on post-inoculation day 5, 12 and 20. Vessel architecture and vessel diameter in response to nicardipine were compared. Results In non-CT26HA bearing mice, nicardipine resulted in a greater than 10% increase in skin vessel diameters directly measured using IVM (pre-nicardipine diameter 82.4 ± 3.6 μm versus post-nicardipine diameter 93.0 ± 3.9 μm. In CT26HA bearing mice, abnormal vessels were observed as early as day 7 even in the absence of a solid tumor mass. Vessel abnormalities included haphazard areas of increased vessel density, aberrant vessel branching patterns, nonfunctional vessels, and altered flow rates. Following nicardipine injection, the diameter of larger tumor-associated vessels did not increase and remained constant (pre: 111.2 ± 2.7 μm vs post: 109.1 ± 3.3 μm). Paradoxically, for smaller vessels (&amp;lt; 20 μm), tumor-associated vessels vasoconstricted following nicardipine injection and returned to baseline diameter after approximately five minutes. Blood flow in these small vessels decreased or stopped during this observation. Conclusions Observation of dynamic vessel changes from vasoactive agents is feasible using IVM. For tumor-associated vessels, nicardipine was not shown to increase vessel diameter and counterintuitively decreased diameters of smaller vessels. Implication on drug delivery from vasoactive agents will lead to further pre-clinical study of applications for human IVM. Citation Format: Emmanuel M. Gabriel, Daniel Fisher, Minhyung Kim, Colin Powers, Anthony Visioni, Jason Muhitch, Joseph Skitzki. Dynamic control of tumor vasculature with direct observation using intravital microscopy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4225.
Recovery from pneumonia requires efferocytosis which is impaired in smokers and those with low body mass index and enhanced by statins
Authors: Daniel G Wootton, Peter J Diggle, Joanne Court, Odiri Eneje, Lynne Keogan, Laura Macfarlane, Sarah Wilks, Mark Woodhead, Stephen B Gordon
Journal: Thorax (2016)

Efferocytosis (the phagocytosis of apoptotic self cells) is a key mechanism in the resolution of inflammatory processes such as community-acquired pneumonia (CAP). Efferocytosis therefore represents a modifiable target for therapy aimed at enhancing intrinsic recovery mechanisms. It is currently not known which patients recovering from CAP would mostly benefit from a strategy aimed at enhancing efferocytosis.We recruited a cohort of patients with CAP admitted to a hospital in Liverpool. One month into recovery, subjects were invited for research bronchoscopy and bronchoalveolar lavage. An ex vivo efferocytosis assay was performed by challenging alveolar macrophages with autologous, apoptotic neutrophils. The percentage of alveolar macrophages that had undergone efferocytosis was determined by flow cytometry. We conducted a multivariable regression using a linear mixed effects model to determine which clinical parameters were most closely associated with efferocytosis.We observed high rates of comorbidity among this CAP cohort. Efferocytosis was measured in 22 subjects. We assessed multiple combinations of clinical parameters for association with efferocytosis and found the best-fitting model included an interaction between smoking status and prior statin use-smoking being associated with decreased efferocytosis and statin use with increased efferocytosis. These effects were modified by an association between efferocytosis and body mass index (BMI), such that as BMI increased so did efferocytosis.This is the first study to measure efferocytosis in patients recovering from CAP. The results suggest that smokers with low BMI have impaired efferocytosis and may benefit from a statin to boost recovery.
Genomic landscape of urothelial cancer (UC), chemotherapy (CTX) response, and outcome based on smoking status.
Authors: Monali K. Vasekar, Hamid Emamekhoo, Petros Grivas, JoAnn Hsu, Sierra Min Li, Junjia Zhu, Arnab Basu, Joseph J. Drabick, Sheldon L. Holder, Joshua Warrick, Matthew Kaag, Garrett Michael Frampton, Siraj Mahamed Ali, Vincent A. Miller, Jeffrey S. Ross, Sumanta K. Pal, Monika Joshi
Journal: Journal of Clinical Oncology (2016)

e16030 Background: Smoking has a strong association with UC but never-smokers can also get UC. We studied the genomic alterations in pts with UC along with their clinicopathological features and outcome in relation to their smoking status. Methods: Retrospective clinicopathologic and outcome data from 83 UC pts at 3 academic institutions were collected along with details of CTX and next generation sequencing of tumor DNA (315 genes; FoundationOne). Pts were divided into 3 cohorts based upon smoking status: CS (current-smokers), ES (ex-smokers who quit smoking at-least 1 month before dateof diagnosis) and NS (never-smokers). Heatmaps were plotted using the threshold of minimum frequency difference of 0.1 or 0.075 to select genes with difference among the 3 cohorts Results: M:F ratio was 3:1; median age 65; CS (23%) vs. ES (55%) vs. NS (22%); stage IV 95%; 73% had tumor analysis prior to any CTX. With a median follow up of 14.4 m (0-51.6) the ORR (CR+PR) to first-line CTX given for advanced disease (N=79): CS 37.5%, ES 47%, NS 19% (p 0.15).The median overall survival was significantly higher in the NS+ES 51.6 m vs. 15.6 m in CS (p=0.04). Of 315 genes tested, genomic alterations differed amongst NS, ES and CS cohorts, however only alterations of NSD1 and TGFBR2 genes were significantly different (table 1). The average numbers of genomic alterations were NS 18.39, ES 20.91 and CS 17.28. Conclusions: NSD1 mutations were absent in NS, ATR mutations were absent in CS whereas BRCA1 was absent in both NS and CS. Trial of demethylating agents in CS may be of interest given the exclusive presence of NSD1 gene alteration. Response to CTX in NS appeared lower compared to ES and CS, and the genomic landscape appeared to differ by smoking status; both findings merit further evaluation. Potential correlation between mutational load, smoking status, CTX response and outcome is pursued. Frequency of selected genes by smoking status. Gene Never-smokers (%) Ex-smokers (%) Current smokers (%) P-value ATR 4 (21) 3 (7) 0 (0) 0.07 BRCA1 0 (0) 7 (15) 0 (0) 0.06 MET 0 (0) 4 (9) 3 (17) 0.14 NOTCH3 0 (0) 9 (20) 2 (11) 0.09 NSD1 0 (0) 3 (7) 7 (39) <0.001 TGFBR2 2 (11) 0 (0) 2 (11) 0.04
What the USPSTF “Insufficient” Skin Cancer Screening Recommendation Means for Primary Care Clinicians and Dermatologists
Authors: Susan M. Swetter, Alan C. Geller, Allan C. Halpern
Journal: JAMA Dermatology (2016)

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Inhibition of Jak1/Jak2 Is More Effective Than Inhibition of Jak3 in Protecting Mice From Acute Graft-Versus-Host Disease (aGvHD) by Significantly Decreasing Alloreactive CD4+ T-Cells.
Authors: Cristiana Carniti, Silvia Gimondi, Raffaella Vaccaroli, Antonio Vendramin, Anisa Bermema, Enrico Radaelli, Jacopo Mariotti, Paolo Corradini
Journal: Blood (2012)
MPTH-01ESTABLISHMENT OF A RAPID AND EFFICIENT GENETIC ANALYSIS SYSTEM OF GLIOMAS
Authors: Jun-ichi Adachi, Kozue Watanabe, Kyoko Totake, Tomonari Suzuki, Kazuhiko Mishima, Joji Ishida, Takamitsu Fujimaki, Ryo Nishikawa
Journal: Neuro-Oncology (2015)

Of the genetic mutations seen in gliomas, IDH1/2 mutations, chromosome 1p/19q loss, MGMT promoter methylation, and genetic alterations of TERT promoter, BRAF, and H3F3A, have become increasingly important as
Lung Function in African Infants in the Drakenstein Child Health Study. Impact of Lower Respiratory Tract Illness
Authors: Diane M. Gray, Lidija Turkovic, Lauren Willemse, Ane Visagie, Aneesa Vanker, Dan J. Stein, Peter D. Sly, Graham L. Hall, Heather J. Zar
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Lower respiratory tract illness is a major cause of childhood morbidity and mortality. It is unknown whether infants are predisposed to illness because of impaired lung function or whether respiratory illness reduces lung function.