tbuckley/cabot-search huggingface dataset:
Alcohol and Seizures: A Review
Authors: F N Brennan, J A Lyttle
Journal: Journal of the Royal Society of Medicine (1987)

A relationship between alcohol and seizures has been recognized for many centuries, and in the last century Echevarria 1 described 45% of an alcoholic population as having seizures at some stage. The exact relationship, however, between alcohol and seizures has remained uncertain. Advice with regard to the management of these patients, particularly as regards drug therapy and advice on fitness to drive, remains equally imprecise.
GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis
Authors: Saori Katayama, Mikiko Suzuki, Ayaka Yamaoka, Nadine Keleku-Lukwete, Fumiki Katsuoka, Akihito Otsuki, Shigeo Kure, James Douglas Engel, Masayuki Yamamoto
Journal: Blood (2017)
Erratum: Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia
Authors: A Hochhaus, S G O'Brien, F Guilhot, B J Druker, S Branford, L Foroni, J M Goldman, M C Müller, J P Radich, M Rudoltz, M Mone, I Gathmann, T P Hughes, R A Larson
Journal: Leukemia (2010)
Hospitalization for Recently Diagnosed Versus Worsening Chronic Heart Failure
Authors: Stephen J. Greene, Adrian F. Hernandez, Allison Dunning, Andrew P. Ambrosy, Paul W. Armstrong, Javed Butler, Lukasz P. Cerbin, Adrian Coles, Justin A. Ezekowitz, Marco Metra, Randall C. Starling, John R. Teerlink, Adriaan A. Voors, Christopher M. O’Connor, Robert J. Mentz
Journal: Journal of the American College of Cardiology (2017)
Exploring trends in mutation distribution of MGPT based on ethnicity.
Authors: Laura Panos, Jill S Dolinsky, Shuwei Li, Patrick Reineke, Rachel E. McFarland, Melissa Pronold
Journal: Journal of Clinical Oncology (2016)

e13112 Background: As the uptake of genetic testing continues to increase, clinicians have questions regarding ethnic-specific mutation rates. Founder mutations explain some variability between ethnic groups, such as the Ashkenazi Jewish BRCA1 and BRCA2 founders. We aim to define any differences in mutation frequencies across ethnic groups and identify potential reasons for these differences in a cohort undergoing multi-gene panel testing (MGPT) for hereditary cancer. Methods: Results from 104,875 patients were reviewed. Ethnicity was self-reported on requisitions or attached pedigrees: Caucasian (n = 68,929), Ashkenazi Jewish (n = 6,454), African American/Black (n = 6,218), Hispanic (n = 5,867), Asian (n = 4,108), Middle Eastern (n = 598), and Native American (n = 119). Individuals with mixed, other, or unknown ethnicity were excluded (n = 12,582). Fisher’s exact test was used to estimate associations between ethnicity and frequency of mutations detected. Results: Interesting findings in this large cohort appeared in several genes. SDHD mutations were significantly more frequent in Caucasians (OR 7.995, P = 1.638e-4), with p.P81L accounting for 66.7% of SDHD mutations. Mutations in RAD51D were most frequent in Asians, with c.270_271dupTA being unique to and accounting for 71.4% of RAD51D mutations in this population. Some genes showed ethnic-specific trends without a major recurrent mutation. BMPR1A mutations were most frequent in African Americans (OR 4.267, p = 0.011) and BRIP1 mutations were most frequentin Caucasians (OR 2.288, P = 3.170e-5). As expected, known founder mutations, such as APC p.I1307K in Ashkenazi Jewish patients and CDKN2A p.I49P in Hispanics, showed significant differences (P < 1.053e-6) in mutation frequencies by ethnicity. Conclusions: Our results demonstrate that mutation rates vary between ethnic groups in some genes, not all due to ethnic-specific founder effects. Possible founder mutations were identified in genes in which data is still emerging, such as a potential Asian founder mutation in RAD51D. This data underscores the need for large cohorts to draw conclusions regarding founder effects and ethnic variation, particularly for genes in which mutations are exceedingly rare, even among affected individuals.
Integrin Stimulation Favors Uptake of Macromolecules by Cardiomyocytes In Vitro
Authors: Arnoud Van der Laarse, Zhongyan Li, Soban Umar, Elizabeth Van der Valk, Wilhelmina Bax, Cindy Schutte, Douwe Atsma, Martin Schalij, Ernst Van der Wall
Journal: Circulation (2010)
Abstract 5251: Defective Inter-domain Interaction May Cause Spontaneous Ca <sup>2+</sup> Release Via Reduced Affinity of Calmodulin Binding to RyR2 in Failing Hearts
Authors: Makoto Ono, Masafumi Yano, Takeshi Suetomi, Xiaojuan Xu, Hitoshi Uchinoumi, Hiroki Tateishi, Shinichi Okuda, Shigeki Kobayashi, Takeshi Yamamoto, Yasuhiro Ikeda, Tomoko Ohkusa, Masunori Matsuzaki
Journal: Circulation (2008)

We previously reported that interaction between N-terminal 1–600 and central domains 2000–2500 of ryanodine receptor (RyR2), harboring many mutation sites in CPVT, is defective (i.e. domain unzipping) in failing hearts. Here, we investigated the pathogenic role of calmodulin (CaM), one of the accessory proteins in RyR2, on Ca 2+ release in failing hearts. Sarcoplasmic reticulum (SR) vesicles were isolated from dog LV muscles {normal (N), n=6; 4-weeks rapid RV pacing (HF: n=6). To assess CaM binding to RyR2, SR was mixed with CaM-SANPAH conjugate (16nM-1μM), followed by UV photolysis. Then, the RyR2-bound CaM was detected by Western blotting using anti-CaM antibody. The affinity of CaM binding to RyR2 was lower in failing SR than normal SR (Kd: 47nM in HF: 19nM in N , p&lt;0.01). To assess the possible relationship between domain unzipping and CaM dissociation from RyR2, RyR2 was also fluorescently labeled with methylcoumarin acetamido (MCA) using DP 2460–2495 (DPc10), which harbors a mutation site in CPVT; R2474S, as a site-directing carrier. In failing SR, domain unzipping was already taken place, as evidenced by an increased accessibility of the bound MCA to a large-size fluorescence quencher. Interestingly, addition of FK506 (10 μM), which was found to dissociate FKBP12.6 from RyR2 and to induce domain unzipping mimicking failing SR, to normal SR indeed reduced the CaM binding affinity to RyR2. In saponin-permeabilized, failing cardiomyocytes ([Ca 2+ ]=buffered at 75 nM), the frequency of Ca 2+ sparks was markedly increased (SpF; s −1 ·100μm −1 : 13.9±0.63 in HF; 7.3±0.6 in N, p&lt;0.01). Addition of CaM (1 μM) in the presence of KN-93 (CaMKII inhibitor) inhibited the increase in SpF (7.9 ±0.41 , p&lt;0.01). This CaM’s effect was, however, markedly inhibited by co-addition of CaM-binding domain peptide within RyR2 (3583–3603) (10.4±0.65, p=ns), strongly suggesting that the re-binding of CaM to RyR2 corrects the abnormal Ca 2+ release in failing cardiomyocytes. In conclusion, the defective inter-domain interaction between N-terminal and central domains within RyR2 seems to increase spontaneous Ca 2+ release events in failing SR, via the reduced CaM-binding to RyR2. Fixing CaM binding to RyR2 may be protective against the diastolic Ca 2+ release in failing hearts.
Detection of Epidermal Growth Factor Receptor Mutations in Serum DNA Using the Scorpion ARMS in Patients with Advanced Non-Small-Cell Lung Cancer
Authors: Isamu Okamoto, Hideharu Kimura, Kazuo Kasahara, Kazuto Nishio
Journal: Clinical Cancer Research (2007)

PL01-03  There is a growing interest in strategies that target the epidermal growth factor receptor (EGFR) for treatment of various cancers. The discovery of somatic mutations in the tyrosine kinase domain of EGFR and of the association of such mutations with a high response rate to EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib or elrotinib has had a profound impact on the treatment of advanced non-small cell lung cancer (NSCLC). The two most common NSCLC-associated EGFR mutations are the 15-bp nucleotide in-frame deletion in exon 19 (E746_A750del) and the point mutation replacing leucine with arginine at codon 858 in exon 21 (L858R). We and other groups have reported prospective phase II studies of EGFR-TKIs in advanced-stage NSCLC, which were designed to take account of the patients9 EGFR mutations. These studies reported a high response rate (75-90%) and extended progression-free survival (7.7-9.7 months) compared to historical controls. Most tumor-based diagnostic tests for EGFR mutations currently use direct nucleotide sequencing that is a relatively insensitive technique, particularly for heterozygous mutations. Consequently, EGFR testing by this method is generally restricted to patients with adequate tumor tissue. Limited availability of tumor specimens for molecular analyses, however, has seriously hampered genotype-directed clinical trials to date. Thus, it is necessary to establish a highly sensitive method to detect mutant EGFR, especially the two major mutations, from other more readily accessible patient samples. We employed Scorpion Amplified Refractory Mutation System (Scorpion ARMS) technology and found that the EGFR Scorpion ARMS method is superior to the direct sequencing method for the detection of two major mutations of EGFR, E746_A750del and L858R, in tumor tissues. We next examined whether the EGFR mutations were detectable in serum DNA with the EGFR Scorpion ARMS from patients with advanced NSCLC. In pairs of tumor and serum samples obtained from patients, the EGFR mutation status in the tumors and serum samples was consistent in more than 70% of the pairs. Furthermore, we present that patients with EGFR mutations in serum DNA have better outcomes with EGFR-TKI treatment, in terms of progression-free survival, overall survival, and response, than those patients without EGFR mutations. These observations indicate that the detection of EGFR mutations in serum DNA may provide a noninvasive and repeatable source of genotypic information. Individualizing therapy according to EGFR mutation status in serum may maximize the effect of EGFR-TKIs.
Trends and Outcomes of Off-label Use of Transcatheter Aortic Valve Replacement
Authors: Ravi S. Hira, Sreekanth Vemulapalli, Zhuokai Li, James M. McCabe, John S. Rumsfeld, Samir R. Kapadia, Mahboob Alam, Hani Jneid, Creighton Don, Mark Reisman, Salim S. Virani, Neal S. Kleiman
Journal: JAMA Cardiology (2017)

<h3>Importance</h3> Transcatheter aortic valve replacement (TAVR) was approved by the US Food and Drug Administration for severe aortic stenosis in patients who cannot undergo surgery and for patients at high operative risk. Use of TAVR for off-label indications has not been previously reported. <h3>Objective</h3> To evaluate patterns and adverse outcomes of off-label use of TAVR in US clinical practice. <h3>Design, Setting and Participants</h3> Patients receiving commercially funded TAVR in the United States are included in the Transcatheter Valve Therapy Registry. A total of 23 847 patients from 328 sites performing TAVR between November 9, 2011, and September 30, 2014, were assessed for this study. Off-label TAVR was defined as TAVR in patients with known bicuspid valve, moderate aortic stenosis, severe mitral regurgitation, severe aortic regurgitation, or subaortic stenosis. Data were linked with the Centers for Medicare &amp; Medicaid Services for 15 397 patients to evaluate 30-day and 1-year outcomes. <h3>Exposure</h3> Off-label use of TAVR. <h3>Main Outcomes and Measures</h3> Frequency of off-label TAVR use and the association with in-hospital, 30-day, and 1-year adverse outcomes. <h3>Results</h3> Among the 23 847 patients in the study (11 876 women and 11 971 men; median age, 84 years [interquartile range, 78-88 years]), off-label TAVR was used in 2272 patients (9.5%). In-hospital mortality was higher among patients receiving off-label TAVR than those receiving on-label TAVR (6.3% vs 4.7%;<i>P</i> &lt; .001), as was 30-day mortality (8.5% vs 6.1%;<i>P</i> &lt; .001) and 1-year mortality (25.6% vs 22.1%;<i>P</i> = .001). Adjusted 30-day mortality was higher in the off-label group (hazard ratio, 1.27; 95% CI, 1.04-1.55;<i>P</i> = .02), while adjusted 1-year mortality was similar in the 2 groups (hazard ratio, 1.11; 95% CI, 0.98-1.25;<i>P</i> = .11). The median rate of off-label TAVR use per hospital was 6.8% (range, 0%-34.7%; interquartile range, 3.4%-12.1%), with hospitals in the highest tertile of off-label use associated with increased 30-day adverse cardiovascular events compared with the lowest tertile. However, this difference was not observed in adjusted 30-day or 1-year outcomes. <h3>Conclusions and Relevance</h3> Approximately 1 in 10 patients in the United States have received TAVR for an off-label indication. After adjustment, 1-year mortality was similar in these patients to that in patients who received TAVR for an on-label indication. These results reinforce the need for additional research on the efficacy of off-label TAVR use.
Allo- HSCT for Advanced Myelodysplastic Syndrome:MSKCC Vs MDACC
Authors: Roni Tamari, Betul Oran, Patrick Hilden, Esperanza B Papadopoulos, Piyanuch Kongtim, Gabriela Rondon, Ann A. Jakubowski, Borje S Andersson, Sean M. Devlin, Sairah Ahmed, James W. Young, Uday R. Popat, Julianne Chen, Marcos de Lima, Richard J O'Reilly, Sergio Giralt, Richard E. Champlin, Hugo Castro-Malaspina
Journal: Blood (2014)
The online concussion awareness training tool (catt)
Authors: Shelina Babul, Ian Pike
Journal: British Journal of Sports Medicine (2017)

Objective To support standardise concussion recognition, diagnosis, treatment and management through an evaluated online resource based upon the Zurich Consensus Statement on Concussion in Sport and other evidence-based resources. The online Concussion Awareness Training Tool (CATT–www.cattonline.com) includes three free toolkits providing training for: Medical Professionals–MP; Parents, Players and Coaches–PPC; School Professionals–SP. Design Pre-post intervention survey with sample size of at least 33 for power to detect a large effect size of 0.5. Setting British Columbia, Canada. Participants MP: 42 physicians and 33 nurses practising in BC; PPC: 35 parents in BC with a child registered in organised sport; SP: 43 K-12 teachers working in BC. Intervention CATT MP aims to standardise practice in a clinical setting with a focus on the paediatric patient. CATT PPC speaks to concussion identification and management, with Smartphone accessible resources: Concussion Response Tool and Questions to Ask Your Doctor . CATT SP includes Return-to-Learn protocol and resources for teachers, administrators, counsellors and others in the school setting. Outcome measures Change in knowledge, attitudes and practices. Results CATT MP was launched April 2013. Physicians demonstrated significant positive change in concussion practices (p=0.001), and significant change in knowledge by those treating more than 10 concussions per year (p=0.039). Nurses had significant positive change in practices (p=0.005) and attitudes (p=0.035). CATT PPC was launched June 2014. Parents demonstrated significant positive change in concussion knowledge (p=0.002). CATT SP was launched February 2016; evaluation in process. Conclusions CATT increases concussion knowledge and awareness among target audiences. Competing interests None.
FRI0748-HPR Cross-cultural validation of the portuguese “rheumatoid arthritis impact of disease” score: cross-sectional study
Authors: RJO Ferreira, L Gossec, S Hewlett, C Duarte, JK Nicklin, JAP da Silva, M Ndosi
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The Rheumatoid Arthritis Impact of Disease (RAID) score<sup>1</sup> assesses 7 impact domains of interest for people with rheumatoid arthritis (RA). Its use in research and clinical practice has been growing, and it is already translated into over 70 languages<sup>2</sup> but the cross-cultural validity of the Portuguese RAID has not been well established. <h3>Objectives</h3> To validate the Portuguese RAID for use in Portugal. <h3>Methods</h3> This was a single centre, cross-sectional validation study involving 2 phases: (i) cognitive debriefing with 38 patients to determine comprehension of the existing<sup>2</sup> Portuguese RAID (ii) cross-cultural validation using data from adult patients who were willing and able to complete the Portuguese RAID unaided. Analyses included fit to the Rasch model (implying construct validity, reliability and statistical sufficiency), tests for unidimensionality and invariance across different patient subgroups i.e. age, gender, education background, disease duration, function and culture. To test invariance to culture, the Portugal dataset was compared with datasets from France (n=195) and the UK (n=205).<sup>3</sup> RUMM2030 software was used in all analyses. <h3>Results</h3> Phase I led to minor changes in phrasing 3 items to enhance understanding and conceptual equivalence between the original RAID and the Portuguese version. In Phase II, 288 patients were included: mean (SD) age=60 (12) years, 82% females, 76% with disease duration ≥5 years, 30% on biologics. The Portuguese RAID was shown to have adequate fit to the Rasch model and high internal consistency (Table 1). Unidimensionality and invariance to age, gender, disease duration and function were confirmed (data not shown). The scale was well targeted for patients with different levels of disease impact (Figure 1). Pooling the datasets from Portugal, France and the UK revealed no cultural response bias (Table 1). RAID was then calibrated into logit-based scores to enable parametric analyses and bias-free cross-cultural comparisons if desired (data not shown). <h3>Conclusions</h3> This study confirms the Portuguese RAID as a robust unidimensional tool for use in Portugal. The raw scores of the 7-item RAID can be used with confidence in clinical practice. Conversion charts are available to enable accurate cross-cultural comparisons across Portugal, France and the UK. <h3>References</h3> Gossec L, et al. Ann Rheum Dis, 2011;70:935–42. EULAR RAID and PsAID Questionnaires. Available from http://www.eular.org/tools_products_.cfm Accessed 25th Jan. 2017. Hewlett S, et al. Ann Rheum Dis, 2015;74:Suppl 2:559. <h3>Disclosure of Interest</h3> None declared
Erratum: Characterization of a recurrent translocation t(2;3)(p15–22;q26) occurring in acute myeloid leukemia
Authors: M Trubia, F Albano, F Cavazzini, G R Cambrin, G Quarta, F Fabbiano, F Ciambelli, D Magro, J M Hernandez, M Mancini, D Diverio, P G Pelicci, F L Coco, C Mecucci, G Specchia, M Rocchi, V Liso, G Castoldi, A Cuneo
Journal: Leukemia (2006)
Functional characterization of non-V600 BRAF mutations and their response to Trametinib (Tram).
Authors: Ryan J. Sullivan, Zohar Barbash, Oded Edelheit, Michael Vidne, Jeffrey Alan Sosman, Keith Flaherty, Michael A. Davies, Douglas Buckner Johnson, Gabi Tarcic
Journal: Journal of Clinical Oncology (2016)

9537 Background: In metastatic melanoma (MM), non-V600 BRAF mutations are less understood than BRAF-V600 mutations. We functionally characterized non-V600 BRAF mutations and their response to Tram within the scope of a phase II trial of Tram in patients (pts) with BRAF non-V600 mutant MM. We utilized the NovellusDx Precision Cancer Analysis system (PCAS), which monitors the activity of signaling pathways by means of a transfected cell-based assay. As a functional platform, PCAS reveals activated pathways regardless of the type of mutation, i.e. whether it is a known mutation or a variant of unknown significance Methods: On trial, pts are eligible for inclusion if a non-V600 BRAF mutation or fusion is identified on NGS and receive Tram 2 mg daily continuously until disease progression (PD) or intolerable toxicities. NGS data served as the basis for analysis of the potentially actionable genes. These genes were then mapped to their major signaling pathways, and the reporters that best account for their activation were selected. Using the PCAS platform, we compared signaling pathway activity level of these genes and their response to Tram with the observed initial clinical response in 3 pts by cross-sectional imaging Results: In the first pt only one potentially actionable mutation, BRAF, was identified and found active and sensitive to Tram in PCAS. The pts clinical response validated this prediction. In the second pt, 4 potentially actionable mutations (BRAF fusion, ERBB4, PTEN and AR) were found. The BRAF fusion was tested and found active and sensitive. However, integration of BRAF fusion and ERBB4 mutation predicted ineffectiveness of Tram. In line, the patient had PD on Tram. In the third pt, two potentially actionable mutations with unknown function were found (BRAF and cKIT). PCAS analysis found a low activity BRAF mutant, as well as a highly active cKIT mutation. The combined measurement of both mutations predicted no response, due to the presence of the oncogenic cKIT mutation, and the pt had PD on Tram Conclusions: This proof of concept analysis shows that detailed functional mutational profiling of the non-V600 BRAF mutant mm pts enrolled to a clinical trial of Tram enabled prediction of response to therapy
Proliferation-based prediction for overall survival in locally advanced HER2(+) breast cancer.
Authors: Manuel Pedregal, Federico Rojo, Cristina Carames Sanchez, Francisco Lobo, Yann Izarzugaza, Ion Cristobal, Sandra Zazo, Irene Moreno, Victor Zenzola, Andrea Correa, Imanol Martinez, Roberto Hernández, Jesus Garcia-Foncillas
Journal: Journal of Clinical Oncology (2017)

e12007 Background: Breast cancer prognosis is influenced by several factors including Ki67 expression which may have a predictive role in luminal breast cancer patients. The aim of this study was to assess the value of Ki67 in breast cancers with positive hormonal receptors and HER2 overexpressed and to evaluate its impact on survival. Methods: Seventy eight consecutive patients diagnosed with locally advanced HER2 positive breast cancer who were treated with adjuvant therapy based on HER2 treatment were selected for this study (2004-2014). The adjuvant chemotherapy schemes were 44% TCH, 16% FEC, 11% AC/T and 29% other therapies. The median of followup was 68 months. Tumor proliferation was assessed immunohistochemically by Ki67 expression and calculated as percentage of stained tumor cells from this cohort previous to adjuvant chemotherapy administration and the results obtained were correlated with disease status and outcome. Results: High proliferation defined as a percentage &gt; 15 of tumor cells was observed in 69% of the breast cancer patients cases. High proliferation significantly predicted longer overall survival (OS) (Log rank 0,012). At 10 years of follow-up, 93% of the patients with KI67 high expression were alive versus 43% of patients without overexpression. Multivariate analysis confirmed the clinical significance of Ki67 predicting OS for luminal HER2 breast cancer patients (p 0,04 y HR 9,6). Conclusions: High proliferation identifies a setting of luminal-B HER2+ subtype breast cancer patients with a significantly longer overall survival.