tbuckley/cabot-search huggingface dataset:
Exercise-Induced ST-Segment Elevation. Role of Left Ventricular Wall Motion Abnormalities and Coronary Artery Narrowing.
Authors: Hiroyuki Miyakoda, Masahiko Kato, Noriyasu Noguchi, Hiroki Omodani, Shuichi Osaki, Tatsuhiko Matsumoto, Toru Kinugawa, Akira Hoshio, Hiroshi Kotake, Hiroto Mashiba
Journal: Circulation (1995)

We studied the causes of exercise-induced ST-segment elevation. Group I consisted of 15 patients with anterior myocardial infarction in the absence of a coronary artery luminal narrowing of 75% or more. Group II consisted of 36 patients with predominantly exertional angina and a luminal narrowing of 90% or more in the left anterior descending coronary artery in the absence of previous myocardial infarction. In group I, exercise-induced ST-segment elevation occurred frequently during treadmill exercise (15/15, 100%). None of the patients showed 201Tl redistribution. The standard deviation of the phase in radionuclide ventriculography increased during bicycle exercise. Of group II patients, only those with 99% narrowing and poor collaterals showed exercise-induced ST-segment elevation (13/14, 93%), whereas none of those with complete occlusion or 99% narrowing and good collaterals, or 90% narrowing showed ST-segment elevation. In group II, patients with exercise-induced ST-segment elevation showed lower 201Tl uptake during exercise and washout in the territory of the diseased vessel than those without exercise-induced ST-segment elevation. In conclusion, wall motion abnormalities may cause exercise-induced ST-segment elevation independently of myocardial ischemia. In patients with predominantly exertinal angina, exercise-induced ST-segment elevation may be a marker for 99% narrowing with poor collaterals and severe myocardial ischemia.
NGTS-02CHARACTERISTICS OF GLIOMAS IN PATIENTS WITH ENCHONDROMATOSIS
Authors: Charlotte Bonnet, Laure Thomas-Maisonneuve, Dimitri Psimaras, Elodie Vauleon, Hugues Loiseau, Stephanie Cartalat-Carel, Jerome Honnorat, Marc Sanson, Francois Ducray
Journal: Neuro-Oncology (2015)

BACKGROUND: Enchondromatosis (Ollier disease and Maffucci syndrome) are rare non-hereditary skeletal disorders which were recently shown to be due to somatic mosaic mutations of IDH1 or IDH2. Enchondromatosis patients are at increased risk of developing gliomas. The aim of the present study was to describe the characteristics of gliomas occurring in these patients in comparison to the characteristics of sporadic IDH mutated gliomas. METHODS: The clinical, histological and radiological characteristics of 39 enchondromatosis patients with gliomas (present series n = 7, previously reported cases n = 32) were analyzed and compared to the characteristics of 159 patients with sporadic IDH mutated gliomas. RESULTS: Gliomas occurring in patients with enchondromatosis were diffuse low-grade (73%) or anaplastic gliomas (21%). They were, most frequently located in the frontal lobe (53%) or in the brainstem (23%). An IDH mutation was present in 7 out of the 8 patients in whom it was assessed. Median age at diagnosis was 28 years [range 6-46]. Twelve patients (30.8%) had multicentric gliomas and 2 patients a gliomatosis cerebri. Compared to sporadic IDH mutated gliomas, enchondromatosis gliomas were diagnosed at an earlier age (28 versus 44 years, p < 0.001), were more frequently multicentric (30.8% versus 1.3%, p < 0.001) and were more frequently located within the brainstem (22.5% versus 0.6%, p < 0.001). CONCLUSION: The histological and molecular characteristics of gliomas observed in patients with enchondromatosis as well as their high rate of multicentricity are in agreement with the hypothesis of an underlying mosaicism of the IDH mutation. The differences between the characteristics of enchondromatosis and sporadic IDH mutated gliomas (earlier age at diagnosis, more frequent brainstem involvement) suggest that the characteristics of IDH related gliomagenesis could vary according to the age at which the mutation is acquired.
130. Gene Editing of the AAVS1 Locus with CRISPR/Cas9
Authors: Mathieu Vieira, Ana Buj Bello, Florence G. Le Roy
Journal: Molecular Therapy (2015)

One strategy for gene therapy is gene editing with engineered nucleases such as Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs) or the CRISPR/Cas9 system. The latter uses the Cas9 endonuclease and a small guide RNA (sgRNA) to direct specific DNA double-stranded breaks at the chosen target site. Once the DNA breaks have occurred, they are repaired by the natural process of homologous recombination (HR). The introduction in the cell of a HR donor template allows replacement of a defective gene with a normal allele at its natural location. In order to improve the Cas9 nuclease activity and specificity for a target sequence, we altered the structure of the sgRNA by shortening the sequence complementary to the target site and lengthening the binding sequence of Cas9. We tested the efficacy of these modified sgRNAs on the adeno-associated virus integration site 1 (AAVS1) in human cells transduced by lentiviral vectors. We used an Integration-deficient Lentiviral vector (IDLV) carrying both cassettes of Cas9 and a modified sgRNA targeting AAVS1, together with another IDLV carrying a GFP donor cassette integrating at AAVS1 site after HR. We observed similar level of Cas9 nuclease activity with sgRNAs bearing shorter complementary sequence, compared to the non-modified sgRNAs, at the AAVS1 site. Moreover, by increasing the length of the scaffold RNA part of the sgRNA, we significantly increased the rate of homologous recombination at the AAVS1 site. The improvement of the sgRNA structure tested on the AAVS1 locus can benefit to the targeting of other genome sequences by the CRISPR/Cas9 system.
Adjuvant hysterectomy following unsuccessful intracavitary brachytherapy in cervical carcinoma
Authors: A. L. Chue, N. Walji, L. J. Rogers, S. A. Hussain, K. K. Chan, K. Singh, I. N. Fernando
Journal: Journal of Clinical Oncology (2009)

e16543 Background: In cervical carcinoma unsuccessful intracavitary brachytherapy (ICBT) treatment results in sub-optimal chemoradiation (CRT) thus increasing risk of recurrence. Optimal management following unsuccessful ICBT remains undefined. Methods: Retrospective analysis of all women with cervical carcinoma treated from January 2000-July 2007 where ICBT insertion was unsuccessful following initial pelvic external beam radiotherapy (EBRT). Data collected and analysed included histology, stage of disease, response to initial CRT, cause for unsuccessful ICBT insertion and subsequent treatment received, morbidity, and recurrence and survival rates. Results: ICBT insertion was unsuccessful in 18 out of 207 (8.7%) women. Causes of failure included: unable to dilate cervix (3); uterine perforation (2); vesicovaginal fistula (2); patient refusal (3); other problems, e.g., pyometrium (4); consultant choice- no obvious reason (4). 13/18 women (72%) received further pelvic EBRT alone. The remaining 5 women (28%) underwent adjuvant hysterectomy, all within 21 days of completing EBRT. 12/18 women (66%) remain alive and recurrence-free at a median follow-up of 6 years. 6/13 women (46%) in the EBRT alone group have died of disease recurrence of which only 1 patient did not develop pelvic relapse. 3/6 patients had potentially resectable disease at examination under anaesthesia (EUA) prior to attempted ICBT insertion with subsequent MRI scanning demonstrating an apparent near complete initial radiological response. Another patient with initial FIGO stage 2A cervical carcinoma absconded from treatment and potentially had resectable disease following initial CRT. The remaining 2 patients had unresectable disease at EUA. All 5 women in the adjuvant hysterectomy group remain alive and recurrence-free with no patient developing any significant late toxicity such as bowel stenosis or fistula. Conclusions: Adjuvant hysterectomy following unsuccessful ICBT does not appear to increase late toxicity and reduces risk of pelvic recurrence. This may be considered as a treatment option for any woman having sub-optimal CRT where the residual tumour remains operable after initial EBRT. No significant financial relationships to disclose.
Abstract 1969: Regulation of cell cycle progression in BRAFV600E inhibitor-resistant human melanoma by histone deacetylase inhibitor
Authors: Antoni X. Toresss-Collado, Ramin Nazarian, Ali R. Jazirehi
Journal: Cancer Research (2015)

Abstract The BRAFV600E specific inhibitor vemurafenib blocks MAPK pathway and induces cell cycle arrest at the G0/G1 phase leading to apoptosis of melanomas. To gain an understanding of the dynamics of cell cycle regulation during vemurafenib therapy, we established several vemurafenib-resistant (VemR) human melanoma sublines from BRAFV600E vemurafenib-sensitive parental lines. Vemurafenib provoked G0/G1 phase arrest in parental but not in VemR sublines. We hypothesized that the refractoriness of VemR sublines to vemurafenib-mediated cell cycle inhibition can be partially rescued by the chromatin modifier SAHA. SAHA promoted G2/M arrest at expense of the S phase irrespective of vemurafenib sensitivity. In parental lines, combination of SAHA and vemurafenib induced both G0/G1 arrest and apoptosis, whereas in VemR sublines combination induced G0/G1 as well as G2/M arrest resulting in dramatic cytostasis. VemR sublines preferentially exhibited ERK1/2 and AKT hyperphosphorylation. Gene expression profiling revealed MAPK hyperactivation and deregulations of cyclins and cyclin-dependent kinases (CDK) in VemR sublines, all of which were reversed by SAHA; changes that may explain the cytostatic effects of SAHA. These results suggest that unresponsiveness of VemR sublines to the biological effects of vemurafenib may be amenable by SAHA. These in vitro results, while require further investigation may provide rational biological basis for combination therapy in the management of VemR melanoma. Citation Format: Antoni X. Toresss-Collado, Ramin Nazarian, Ali R. Jazirehi. Regulation of cell cycle progression in BRAFV600E inhibitor-resistant human melanoma by histone deacetylase inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1969. doi:10.1158/1538-7445.AM2015-1969
Methodological aspects of assessing hand eczema: comparison of two tools and three different categories of evaluators
Authors: A. Josefson, M. Berg, A. Gånemo, A. Hallander, M. Hindsén-Stenström, B. Meding, Å. Svensson, M. Lindberg
Journal: British Journal of Dermatology (2016)

Methodological aspects of assessing hand eczema : comparison of two tools and three different categories of evaluators
Abstract 991: Role of autophagy as potential molecular mechanism in trastuzumab-induced cardiotoxicity
Authors: Nishant Mohan, Yi Shen, Wen Jin Wu
Journal: Cancer Research (2015)

Abstract Autophagy is basic catabolic cellular process which is essential for maintaining cellular homeostasis during nutrient starved and stress conditions. Even though autophagy is altered in various cardiovascular diseases including cardiomyopathy and heart failure, its precise role in heart conditions remains ambiguous. Trastuzumab is a humanized monoclonal antibody approved for treatment of HER2-positive breast cancer. Trastuzumab treatment has been shown to induce considerable cardiotoxicity. Molecular mechanism for trastuzumab-induced cardiotoxicity remains largely unclear. In this study, we investigated the role of autophagy as potential molecular mechanism in trastuzumab-induced cardiotoxicity. We treated human primary cardiomyocytes with trastuzumab at different time points, and then examined the expression of prominent autophagic markers such as LC3A/B, Beclin 1 and Bcl-2 by western blotting. Results divulged that expression levels of LC3A/B were markedly decreased in cardiomyocytes after 24 and 48 h of trastuzumab treatment. Beclin 1 protein levels also significantly decreased, although Bcl-2 expression was increased. These results indicate that downregulation of Beclin 1 and upregulation of Bcl-2 after trastuzumab treatment could potentially impede the formation of autophagosomes resulting in inhibition of autophagy. Collectively, these data indicate that autophagy plays a beneficial role in normal cardiac tissues by preventing the accumulation of abnormal proteins or damaged organelles. However, trastuzumab treatment may inhibit the autophagy, resulting in cardiomyopathy. Citation Format: Nishant Mohan, Yi Shen, Wen Jin Wu. Role of autophagy as potential molecular mechanism in trastuzumab-induced cardiotoxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 991. doi:10.1158/1538-7445.AM2015-991
Towards the reduction of injury and illness in athletes: defining our research priorities
Authors: Caroline F Finch, Roald Bahr, Jonathan A Drezner, Jiri Dvorak, Lars Engebretsen, Timothy Hewett, Astrid Junge, Karim M Khan, Domhnall MacAuley, Gordon O Matheson, Paul McCrory, Evert Verhagen
Journal: British Journal of Sports Medicine (2016)

A decade ago, Blair1 pondered the future of physical activity research, much of which has since come to pass. More recently, a BJSM Blog2 invited readers to consider how their future research would look. Given the increased international focus on reducing injury/illness in athletes, it is timely to consider what research needs to be undertaken and acted on to achieve feasible reductions over the next 10 years.

‘Future Studies’3 or ‘Thought Leadership’ happens when a defined group of experts calls attention to what they think will be important for their field in the future. This is common in social science disciplines (eg, finance) and in scientific areas with major implications for policy development (eg, in climate control/environmental science). It has been less commonly applied in medicine, though it has underpinned discussion in areas like cancer research4 and academic medicine.5

Thought leadership involves big picture thinking and can lead to new ideas for major developments over time. There is evidence that such exercises can significantly shape research agenda and priority setting. This novel approach was applied to Sports and Exercise Medicine through asking a select group of international experts to contribute their priority research directions for the next 10 years. This is intended as a starting point only, to stimulate discussion with, and elicit responses from, the broader community interested in the prevention of injury and illness in athletes.

International experts were invited to participate if they had delivered ≥1 keynote addresses at the International Olympic Committee (IOC) World Conferences of Prevention of Injury and Illness in Sport in 2011, 2014 or their precursor conferences organised by the Oslo Sports Trauma Research Centre in 2005 and 2008. Of 21 keynote speakers, 12 contributed their views to this paper. The experts covered a range of disciplines, including clinical sports …
Herbert Percival Cooper Harrison
Authors: Michelle Harrison
Journal: BMJ (2016)

Herbert Percival Cooper Harrison (“Perry”) was born in Guilford with his identical twin brother Ronnie during the first world war, before his father’s work as a chief engineer brought them to Glasgow. He dedicated most of his 100 years to medicine, serving during the second world war and working in numerous different specialties before finding his true passion in general practice. A founding member of the Royal College of General Practitioners and designer of the college’s coat of arms, he made important contributions in this specialty, as well as in undergraduate teaching.

After graduating from Glasgow University in 1940, Perry Harrison worked at Glasgow Royal Infirmary, the Southern General Hospital, Shieldhall Fever Hospital, Lennox Castle Hospital, and the Royal Cornwall Infirmary, gaining experience in ear, nose, and throat medicine; dermatology; plastics; radiotherapy; orthopaedics; and anaesthetics. This experience was to prove valuable when he found himself travelling the world as a ship’s surgeon during the second world war, first in the Merchant Navy and then the Royal Navy. His war time had some …
Use of Romiplostim to Facilitate Platelet Engraftment in Allogeneic Hematopoietic Transplantation
Authors: Emilio Ojeda, Jose A. Garcia-Marco, Belen Navarro, Almudena DelaIglesia, Rafael Fores, Guiomar Bautista, Isabel Krsnik, Amelia Sanchez-Guerrero, Isabel SanJuan, Carmen Regidor, Santiago Gil, Rosa Gonzalo-Daganzo, Trinidad Martin-Donaire, Rocio Sanchez, Gracia Bravo, Nuria Claros, Martin Cabero, Pilar Beltran, Jose Rafael Cabrera
Journal: Blood (2011)
Glycoprotein Ibα Clustering Induces Macrophage-Mediated Platelet Clearance in the Liver
Authors: Rong Yan, Mengxing Chen, Na Ma, Lili Zhao, Lijuan Cao, Yiwen Zhang, Jie Zhang, Ziqiang Yu, Zhaoyue Wang, Lijun Xia, Changgeng Ruan, Kesheng Dai
Journal: Blood (2014)
542. Novel Barcode-Based In Vivo Screening Method for Generating De Novo AAV Serotypes for CNS-Directed Gene Therapy
Authors: Marcus Davidsson, Gang Wang, Patrick Aldrin-Kirk, Morgan Hartnor, Tomas Björklund
Journal: Molecular Therapy (2016)

Capsid modification is a useful strategy to create adeno-associated virus (AAV) vectors with subtype specific neuronal targeting and enhanced retrograde transport. Incorporating known cell-specific binding ligands is a rational method, but the creation of vectors without prior knowledge has the potential to reveal novel targets. Directed evolution and phage display are broadly utilized high-throughput methods, but are inefficient due to displaying random peptides wherein the vast majority will be non-functional.Here, we have developed a novel AAV library in which each virus particle display a peptide derived from known neuron-related proteins on the surface of an AAV2 capsid. The packaged viral genome encodes a unique barcode sequence to facilitate capsid identification. 92398 unique oligos encoding 14-amino-acid peptides derived from 135 proteins were synthesized using microarray. Four-fragment Gibson assembly and novel emulsion PCR was then used to generate a plasmid library by inserting oligos into the capsid gene and barcodes between the inverted terminal repeats. This plasmid library was then used to assemble a diverse library of AAV capsids, such that particles were composed of only peptide-modified capsid proteins which package an expression cassette containing RNA expressed barcodes providing post hoc identification of the capsid structure.In parallel, the plasmid library was sequences using Illumina paired-end sequencing to link the RNA expressed barcodes to the de novo capsid structures. The successfully generated AAV library efficiently infected neurons and astrocytes in vitro and displayed a subset of peptides that had efficient retrograde transport ability in neurons in vivo (e.g., transported from striatum to substantia nigra). Functional peptides, which successfully promoted neuronal infectivity or retrograde transport, were identified by Illumina sequencing of RNA expressed barcodes both in vitro and in vivo and efficacy modeled through barcode counting. In conclusion, we developed a high-throughput combinatorial method to generate peptide-modified AAV libraries that are valuable for evaluation of receptor expression of neuronal populations and have the potential to generate novel vectors with unique properties for in vivo gene transfer in the CNS.
Does newborn screening influence the young cystic fibrosis cohort included in national registries?
Authors: Kris De Boeck, Anne Munck, Isabelle de Monestrol, Vincent Gulmans, Lydie Lemonnier, Peter G. Middleton, Simeon Wanyama, Muriel Thomas
Journal: European Respiratory Journal (2016)

Cystic fibrosis newborn screening (NBS), has not yet become a reality in all countries. We therefore compared the demographic and clinical characteristics of young children included in national cystic fibrosis registries from countries with and without NBS. We hypothesised that registries from countries with NBS would contain a higher proportion of milder and equivocal cases. National cystic fibrosis newborn screening programmes lead to changes in the composition of the CF registry cohort <http://ow.ly/12o8304uinU> All patients, cystic fibrosis centre directors and personnel who contribute to national cystic fibrosis registries.
Complete Absence of the Lineage-Determining Transcription Factor C/EBPα Results in Loss of Myeloid Identity in Bcr/abl Induced Malignancy.
Authors: Katharina Wagner, Pu Zhang, Frank Rosenbauer, Bettina Drescher, Susumu Kobayashi, Hanna S. Radomska, Jeffery L. Kutok, Jürgen Krauter, Daniel G. Tenen
Journal: Blood (2005)
Predictive Value of the Pre-Operative CT Scan for Splenectomy in Patients with Primary, and Post Essential Thrombocythemia/Post Polycythemia Vera Myelofibrosis.
Authors: Ruben A. Mesa, Brian Bartholmai, Chin Y. Li, Susan Schwager, Animesh Pardanani, Kebede Hussein, Ayalew Tefferi
Journal: Blood (2007)
A single-arm multicenter proof-of-concept study of denosumab to treat hypercalcemia of malignancy in patients who are refractory to IV bisphosphonates.
Authors: M. I. Hu, R. Gucalp, K. L. Insogna, I. Glezerman, H. G. Bone, A. Jaccard, W. Misiorowski, B. W. Yu, H. Yeh
Journal: Journal of Clinical Oncology (2011)

TPS245 Background: Hypercalcemia of malignancy (HCM) is a serious complication thought to result in large part from tumor-driven increases in bone resorption. IV bisphosphonates (BP) are used for treatment of HCM, but some patients relapse after or become refractory to IV BP treatment. In addition, although severe renal impairment may worsen HCM due to reduced calcium clearance, IV BP are not recommended in these patients. Available alternative agents (eg, calcitonin, mithramycin, gallium nitrate) are now used infrequently due to efficacy and safety limitations. Thus, there is an unmet medical need in patients with HCM for whom BP treatment is ineffective or not recommended. In animal models of humoral HCM, inhibition of RANK ligand (RANKL), the primary effector of bone resorption, reversed established hypercalcemia more effectively than high‐dose BP, suggesting that RANKL inhibition is a rational therapeutic strategy for patients with HCM. Denosumab is a fully human monoclonal antibody against RANKL approved in the US for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Denosumab does not interfere with renal function and does not require renal monitoring. This single-arm study is evaluating denosumab in patients with HCM who have not responded to recent BP treatment. Methods: Patients with confirmed cancer, recent IV BP treatment (between 30 to 7 days prior), and corrected serum calcium (CSC) levels of > 12.5 mg/dL, are eligible. Patients with benign hyperparathyroidism, hyperthyroidism, adrenal insufficiency, or on dialysis are ineligible. Patients receive denosumab 120 mg SC monthly with a loading dose on study days 8 and 15. The primary endpoint is the proportion of patients with a response in CSC (defined as CSC ≤ 11.5 mg/dL by day 10 of treatment. Secondary endpoints include complete response (defined as CSC ≤ 10.8 mg/dL by day 10 of treatment), response by visit, time to response, response duration, and safety. The trial began enrolling patients in November 2009, with a total of 33 patients planned. This trial is sponsored by Amgen Inc. and is registered with the ClinicalTrials.gov identifier: NCT00896454.