tbuckley/cabot-search huggingface dataset:
Abstract 3094: Implantable Cardioverter Defibrillator Therapy for Congenital Long QT Syndrome: a Single Center Experience
Authors: Justin M Horner, Masayoshi Kinoshita, Carla Haglund, Paul Friedman, Michael J Ackerman
Journal: Circulation (2008)

Background: Long QT syndrome (LQTS) is a potentially lethal yet highly treatable channelopathy underscored by marked heterogeneity that necessitates evidence-based and individualized therapeutic approaches. One such therapy is the implantable cardioverter defibrillator (ICD). Here, we sought to determine the percentage of patients (pts) with LQTS that received an ICD in our LQTS clinic and its short term outcomes. Methods: An IRB-approved, retrospective analysis of the electronic medical records of 167 LQT1, 113 LQT2, and 29 LQT3 pts evaluated in our LQTS Clinic with subset analysis of those implanted with an ICD in our institution from January 2000 to June 2007. Results: Forty-eight pts (15% of total, 33 females, 14 LQT1, 20 LQT2, and 14 LQT3) received an ICD. The average age at implant was 30 ± 12 years (range 8 – 52 years). Nearly two-thirds received an ICD as primary prevention. The QTc exceeded 500 ms in 18 (37.5%). With an average follow-up of 42 ± 32 months, 9 (19%) have had an appropriate, VF-terminating therapy including 3 with LQT1 and 6 with LQT2. Notably, 5 of the 6 LQT2 females have already received an appropriate ICD therapy whereas none of the LQT3 pts have received one. Secondary prevention indications (p = 0.006), LQT2 genotype (p = 0.03), QTc &gt; 500 ms (p = 0.001), and surprisingly a negative family history (p = 0.0005) predicted those ICD pts most likely to receive an appropriate therapy. Importantly, none of the non-ICD treated pts (&gt; 250) have died a LQT-related death during the same follow-up. Conversely, 9 pts have experienced an inappropriate shock including 6 with LQT3 and males were more likely to receive inappropriate therapies (p = 0.002). Conclusions: The majority of pts with LQTS can be treated effectively without an ICD. In this study, potentially life-saving therapies have been rendered so far at a 5– 6%/year rate. Inappropriate shocks occurred with similar frequency. Secondary prevention, genotype, and QTc predicted those ICD recipients most likely to receive appropriate therapy. Although LQT3 status is commonly associated with an ICD recommendation, so far none of the LQT3 positive ICD recipients have needed their device. Instead, the greatest “save” rate has occurred among the LQT2 positive females deemed at high risk.
Abstract P3-05-11: Glutamine metabolism promotes survival through the unfolded protein response in endocrine resistant breast cancer
Authors: Ayeasha N Shajahan-Haq, Susan Demo, Robert Clarke
Journal: Cancer Research (2015)

Abstract About 70% of all breast cancers are estrogen receptor alpha positive (ER+). Anti-hormone therapy such as antiestrogens (e.g.,Tamoxifen; TAM) are often used to treat ER+ breast cancer but breast cancer cells can develop resistance to these drugs (endocrine resistance). Unfortunately, ∼50% percent of all antiestrogen treated tumors eventually develop endocrine resistance, and therefore, there is an urgent need to find ways to treat this incurable disease. Endocrine resistant cells survive antiestrogen treatment by initiating a pro-survival pathway mediated by an evolutionary conserved process call the unfolded protein response (UPR) within the endoplasmic reticulum. Cellular stress induced by therapeutics can be initiated by the UPR leading to a pro-survival response in the short-term and a pro-death response in the long-term, depending on the magnitude of the stress signal. Our studies show that antiestrogens can decrease glucose uptake in ER+ breast cancer cells, and in glucose-deprived conditions, presence of glutamine in the media can trigger the UPR through GRP78-IRE1a. Subsequently, a glutamine-dependent pathway can induce cell death via GRP78-IREa-JNK-CHOP and survival in others via GRP78-IRE1a-XBP1. Glutamine metabolites such as glutamate (essential substrate for many vital cellular processes) and proline (substrate for collagen production) are significantly elevated in endocrine resistant cells. Knockdown of glutaminase (GLS1) with siRNA or small molecule inhibitor, CB-839, significantly decreased cell proliferation in endocrine resistant cells compared with sensitive cells within 48 h. Moreover, cell lines derived from endocrine resistant cells that are grown in glucose-free media are significantly more sensitive to CB-839 compared with their respective controls, indicating an increased dependency on glutamine. Glutamine may offer an alternate source of energy and raw materials in periods of glucose deprivation, and in endocrine resistant cells, this adaptive pro-survival cellular metabolic mechanism is up-regulated. Thus, CB-839 may be a potent anti-cancer agent in treating antiestrogen resistant breast cancers. Citation Format: Ayeasha N Shajahan-Haq, Susan Demo, Robert Clarke. Glutamine metabolism promotes survival through the unfolded protein response in endocrine resistant breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-11.
HUMAN ELASTIC FIBRES..
Authors: ARWYN CHARLES
Journal: British Journal of Dermatology (1961)

Journal Article HUMAN ELASTIC FIBRES.: Electron Microscopic Appearancesofthe Elastic Fibres of Human Skin in Thin Section. Get access ARWYN CHARLES, M.Sc., Ph.D. ARWYN CHARLES, M.Sc., Ph.D. Departments of Dermatology and Biomolecular Structure, The University, Leeds Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 73, Issue 2, 1 February 1961, Pages 57–60, https://doi.org/10.1111/j.1365-2133.1961.tb14407.x Published: 01 February 1961
Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy
Authors: Gisèle Bonne, Marina Raffaele Di Barletta, Shaida Varnous, Henri-Marc Bécane, El-Hadi Hammouda, Luciano Merlini, Francesco Muntoni, Cheryl R. Greenberg, Françoise Gary, Jon-Andoni Urtizberea, Denis Duboc, Michel Fardeau, Daniela Toniolo, Ketty Schwartz
Journal: Nature Genetics (1999)
Abstract 12140: Beneficial Effects of Heme Oxygenase-1 Expression and Activity in Experimental Abdominal Aortic Aneurysm
Authors: Junya Azuma, Ronald Wong, Lars Maegdefessel, Hui Zhao, Alicia Deng, David K Stevenson, Philip S Tsao, Flora S Kalish
Journal: Circulation (2010)

The cytoprotective enzyme, heme oxygenase-1 (HO-1) is expressed in several vascular cell types, including macrophages. We hypothesized that HO-1 attenuates macrophage activation and inhibits abdominal aortic aneurysm (AAA) formation. Wild-type (WT, HO-1+/+, n=14) or HO-1 heterozygous (HO-1+/−, n=13) FVB mice were subjected to aortic elastase perfusion to induce experimental AAAs. AAA progression was monitored weekly by ultrasonography. At days 7 and 28 post-AAA induction, mice were euthanized for histological analyses. Expression of inflammatory cytokines and chemokines were assessed by qRT-PCR in thioglycollate-elicited macrophages from WT and HO-1+/− mice (n=5 for each group). The abdominal aortic diameter was significantly increased in HO-1+/− mice compared to WT mice after elastase perfusion (Figure1). HO-1+/− mice also had increased tissue macrophages at day 7 (310.6±4.2 vs 179.5±6.2 cells/high-power field [hpf], p
Bournewood: an indefensible gap in mental health law
Authors: N. Eastman, J. Peay
Journal: BMJ (1998)

In December 1997 the Court of Appeal ruled that it was unlawful to admit an autistic adult to a psychiatric hospital on an informal basis when the patient lacked the capacity to take part in that admission, even if he did not object. In so doing the court determined that any patient who was incapable of consenting to informal admission could only lawfully be admitted under the statutory procedures of the Mental Health Act 1983, thereby enjoying the protections afforded by the act. The judgment has now been overturned by the House of Lords,1 seemingly assuaging the concern of professionals and the Department of Health that having to detain all such patients would have major resource implications (through increasing the average number of detained patients from 13 000 to 35 0001). The House of Lords' judgment turned on a legal technicality, as well as discussing at length whether the patient was “detained” and, if he was, whether such detention could be justified in terms of the common law doctrine of “necessity.” Yet, an ethical and legal gap remains, since, as Lord Steyn argued, “there can …
When I use a word . . .: Allergy and immunity
Authors: J. Aronson
Journal: BMJ (1999)

At a witness seminar, 15 or so key figures are gathered together and allowed to talk freely about historical events in which they took part, supporting or correcting one another as may be. Tilly Tansey has organised more than a dozen of these at the Wellcome Institute for the History of Medicine since 1993 and two volumes of proceedings have been published by the Wellcome Trust (see Med Hist 1998; 42:404-5). In one of these meetings, “Self and Non-Self: a History of Autoimmunity,” held in February 1995, Professor Robin Coombs from Cambridge complained about the word “autoimmunity,” which he described as “misconstrued, absurd, and extremely confusing.” The word we should use, he said, is “autoallergy.”

The …
Abstract 2193: Towards Optimal Therapeutic Angiogenesis for Critical Limb Ischemia-Determining Ideal Release Period of Basic Fibroblast Growth Factor -
Authors: Yoshio Arai, Yuhong Huang, Akira Marui, Keiichi Hirose, Hisashi Sakaguchi, Shyamal C Bir, Jiro Esaki, Tadashi Ikeda, Yasuhiko Tabata, Masashi Komeda
Journal: Circulation (2006)
Reply to “Reactive oxygen species and the segregation of mtDNA sequence variants”
Authors: José A Enriquez, Raquel Moreno-Loshuertos, Rebeca Acín-Pérez, Nieves Movilla, M Esther Gallardo, Santiago Rodriguez de Córdoba, Acisclo Pérez-Martos, Patricio Fernández-Silva
Journal: Nature Genetics (2007)
Abstract 15948: Impact of Age on Safety of Radiofrequency Ablation in Patients With Atrial Fibrillation
Authors: Janet W Elcano, Hui Nam Pak
Journal: Circulation (2014)

Background: The incidence of atrial fibrillation (AF) is increasing in the elderly population, however, there is paucity of data on the safety outcomes of this patient subgroup thus we sought to investigate on the impact of age on the safety of catheter ablation for AF. Methods and Results: We included 1,293 (male 75%) patients enrolled in Yonsei AF Ablation Cohort database in Seoul, South Korea, from March 2009 to November 2013. We divided the patients into 4 groups according to age (Group 1, aged 17-49, N=295 ; Group 2 50-59, N=421; Group 3 60-69 N=408; and Group 4 ≥ 70, N=169) and evaluated the incidence of procedure related complications. No procedure-related death occurred in this study. There was a trend of increasing incidence of procedure related complications with age noted as follows: Group 1= 3.7%; Group 2= 4.0%; Group 3=6.6%; and Group 4 7.1%, (p= 0.15). There were 28 cases (2.2%) of major complications (Group 1=1.7%, Group 2=1.9%, Group 3=2%, Group 4 4.1%), tamponade being the most common. Major complications in group 4 include: tamponade 4 cases, phrenic nerve palsy 1 case, atrioesophaeal fistula 1 and 3rd degree AV block in 1 patient. Multivariate regression analysis shows ablation time (odds ratio (OR) 1.2 confidence interval (CI)1.0-1.017, p=0.017), procedure time (OR 1.008, CI 1.0-1.15, p=0.04), decreasing eGFR (OR 1.013, CI 1.002-1.026 p=0.018), coronary artery disease (CAD) (OR 1.847, CI 1.003-3.524, p0.04) and age (OR 1.028, CI 1.003-1.055, p=0.03) were associated with increased adjusted risk of total complications. Predictors of major complications include age (OR 1.044, CI 1.003-1.086, p0.02) and ablation time (OR 1.009, CI 0.999-1.000, p=0.033). Conclusion: Our data suggest that incidence of procedural complications in RFA of AF increase with age. Ablation time and age are independent predictors of a major complication.
2. Promoter Trapping Reveals Significant Differences in Integration Site Selection between MLV and HIV Vectors
Authors: Brian C. Beard, Kirsten A. Keyser, Julie Morris, Bobbie Thomasson, Hans-Peter Kiem
Journal: Molecular Therapy (2004)

Replication defective retroviral gene transfer vectors have been used as an effective method for transduction of hematopoietic stem cells (HSC). Recent advances allowed for gene transfer levels that made gene therapy applicable to use in clinical trials and successfully cured immunodeficient children. Unfortunately two patients in the trial developed T cell leukemia that was found to be associated with insertional mutagenesis caused by retroviral integration in the LMO2 gene (Hacein-Bey-Abina S., et al., Science, 302: 415). This unexpected result has caused a critical evaluation of retrovirus integration in clinically relevant large animal models to assess the likelihood of malignant transformation occurring in gene therapy trials in patients with different diseases and different transgenes. Here we describe the genomic location of more than 100 viral integrations after transplantation of lentivirally or oncoretrovirally transduced stem cells in non-human primates. CD34-enriched cells from G-CSF/SCF primed marrow or mobilized peripheral blood were transduced with oncoretroviral or lentiviral vectors and transplanted into the animals and peripheral blood DNA was prepared for retroviral integration analysis. Integration sites were cloned out of the bulk genomic DNA background by linear-amplification mediated PCR (LAM-PCR). A valid sequence was only scored as an actual integration site if it contained LTR sequence, linker sequence, and matched with at least 90% identity to the July 2003 assembly of the human genome as scored by the BLAT genome analyzing software. For both oncoretroviral and lentiviral integration sites analyzed, 40% mapped into a coding region for a RefSeq gene and that is approximately two times the frequency that was calculated in a computer simulation (Wu X., et al., Science, 300: 1749). This dramatic shift in distribution of integration sites to RefSeq genes indicates a non-random nature to retroviral insertion. Several sites are of interest in that the RefSeq genes are potential proto-oncogenes: melanoma differentiation associate protein-5 (MDA5), neuroblastoma-amplified protein, and RAB37 a member of RAS oncogene family. A variety of genomic locations have insertions, but no gene or region of the genome has been shown to have retroviral integrations in more than one animal. Importantly, all of these animals have been followed from about one to three years and are healthy with no leukemia or other hematologic abnormalities. This evaluation and other recent evidence (Dave U., et al., Science, 303: 333) suggest that retroviral integration into an oncogene is not sufficient for malignant transformation but requires other additional genetic alterations. This analysis and others like it are critical pre-clinical data to address the inherent risks of gene therapy and the effect that retroviral integration has on hematopoietic development.
Abstract 11113: A Novel ATF4 Dependent ER-Stress Induced Transcriptional Unit Within the CHAC1 Promoter
Authors: Rebecca R Crawford, Eugenia T Prescott, Imran N Mungrue
Journal: Circulation (2014)

A systems genetics screen of transcriptome wide RNA co-expression in a population of human cell cultures can broadly define novel functional gene-gene relationships. Using this method, we predicted a role for the human gene, CHAC1, within the ER-stress pathway functionally linked to ATF4. Targeted cell culture and genetic perturbations refined a role for CHAC1 as an ER-stress gene regulated by ATF4. ATF4 siRNAs blocked induction of CHAC1 mRNA by ER-stress, and ATF4 over-expression induced CHAC1 mRNA expression. ATF4 is an important gene involved in ER-stress and apoptotic signaling, and we demonstrated the pro-apoptotic potential for CHAC1. ATF4 plays important roles in osteoblast development, metabolic disease and atherosclerosis. Herein a direct transcriptional link between ATF4 and the CHAC1 promoter by ATF4 is defined in the setting of ER-stress. We cloned the CHAC1 promoter upstream of luciferase reporter system to define functional elements by deletion analysis. A highly conserved bipartite DNA element dubbed the ATF/CRE and ACM were the major regulators of basal CHAC1 expression, induction by ER-stress agonists or ATF4 co-expression. We compared the CHAC1 promoter -luciferase reporter to well-characterized ATF4 target genes CHOP and ASNS, using parallel luciferase assays. Notably, the CHAC1 promoter-reporter was induced to the highest extent following ATF4 co-expression compared to CHOP and ASNS promoters. Using a novel Immunoblot-EMSA assay we determined binding of ATF4 and ATF3, but not CHOP to CHAC1 ATF/CRE and ACM oligos. We also used the CHip method to query binding of ATF3 and ATF4 at the CHAC1 promoter under control and ER-stress conditions. We noted significant binding of ATF3 to the CHAC1 promoter under control and ER-stress treatment. Interestingly, we noted a dramatic increase in ATF4 occupancy at the CHAC1 promoter accompanying ER-stress. The ATF4 responsive ATF/CRE and ACM of the CHAC1 promoter represent a novel target for ATF4, and may reveal important contributions to disease processes involving ATF4. These data also implicate CHAC1 as an important target gene of ATF4, which may mediate important biological effects in the setting of ER-stress, and might have implications for cardiovascular and metabolic disease.
Abstract 1523: Molecular typing of Chinese gastrointestinal stromal tumors using a multigene next generation sequencing panel
Authors: Zhi Xu, Zhibin Hu, Xinying Huo, Chuanning Tang, Si-Yi Chen, Jinfei Chen
Journal: Cancer Research (2014)

Abstract Identifying mutations in individual tumor is critical to improve the efficacy of cancer therapy by matching targeted drugs to specific mutations. Gastrointestinal stromal tumor (GIST) is a stromal or mesenchymal subepithelial neoplasm affecting the gastrointestinal tract and it frequently contains an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. Although GIST is highly responsive to several selective tyrosine kinase inhibitors, combined use of inhibitors targeting other mutations is needed to further prolong survival. In this study, we aim to screen and identify genetic mutations in GIST for targeted therapy using the new Ion Torrent next-generation sequencing platform. By utilizing the Ion Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes from DNA extracted from formalin-fixed and paraffin-embedded (FFPE) samples of 125 human gastrointestinal stromal tumors, set up stringent parameters for reliable variant calling by filtering out potential raw base calling errors, and identified frequent mutations in PDGFRA, KIT, APC, MLH1, MET, RET, and PIK3CA. Moreover, frequent missense mutations were detected in MLH1 (12%), MET (16.80%), KIT (33.60%), and PIK3CA (41.60%) genes. The mutations in MLH1 gene were frequently detected in the exons 2, while MET gene was frequently mutated in the exon 12. In addition, we identified missense mutations in other genes, including FLT3, KRAS, PDGFRA, and STK11, at lower frequencies. This study demonstrates the utility of using Ion Torrent sequencing to efficiently identify human cancer mutations. With the finding of the frequent mutations in MLH1 and MET genes, in addition to KIT, PDGFRA and PIK3CA, in GISTs, this study provides a molecular basis for clinically developing new drugs targeting these gene mutations for GIST therapy. Citation Format: Zhi Xu, Zhibin Hu, Xinying Huo, Chuanning Tang, Si-Yi Chen, Jinfei Chen. Molecular typing of Chinese gastrointestinal stromal tumors using a multigene next generation sequencing panel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1523. doi:10.1158/1538-7445.AM2014-1523
NHS Executive to research removal of patients from GP lists in England
Authors: John Warden
Journal: BMJ (1999)

Research into why 83 000 patients are removed from GPs' lists in England each year is being initiated by the NHS Executive. The chief executive of the NHS, Sir Alan Langlands, has agreed to look into the problem, which has been highlighted by complaints to the health service ombudsman sincehis jurisdiction was extended to general practice three years ago.

One GP whom the ombudsman criticised for striking off …
Anemia Protein Identified
Authors: Rebecca Voelker
Journal: JAMA (1998)

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Sentinel-Lymph-Node Biopsy for Cutaneous Melanoma
Authors: Vincenzo de Giorgi, Marta Grazzini, Daniela Massi
Journal: New England Journal of Medicine (2011)

Purpose: To assess the importance of sentinel lymph node biopsy in patients with cutaneous melanoma.Methods: Ninety consecutive non-randomized patients with stages I and II melanoma who underwent sentinel lymph node biopsy were followed up prospectively for six years.Results: Patients were followed up for a mean period of 30 months.Their mean age was 53.3 years, ranging from 12 to 83 years.Thirty patients were male (37.5%) and 50, female (62.5%).Sentinel lymph node was positive in 32.5% and negative in 67.5%.It was found that the thicker the tumor, the greater the incidence of positive sentinel lymph nodes.In the group of patients with positive sentinel lymph nodes, recurrence occurred in 43.5%, but in those with negative sentinel lymph nodes, in only 7%, what points out to the association of tumor recurrence and positive sentinel lymph nodes.There were no major postoperative complications.Conclusion: Sentinel lymph node biopsy was demonstrated to be a safe method for selecting patients who need therapeutic lymphadenectomy.
ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis
Authors: Takashi Miki, Birgit Liss, Kohtaro Minami, Tetsuya Shiuchi, Atsunori Saraya, Yasushige Kashima, Masatsugu Horiuchi, Frances Ashcroft, Yasuhiko Minokoshi, Jochen Roeper, Susumu Seino
Journal: Nature Neuroscience (2001)