tbuckley/cabot-search huggingface dataset:
SDHA and SDHB mutations in KIT/PDGFRA WT gastrointestinal stromal tumors.
Authors: Margherita Nannini, Maria A. Pantaleo, Annalisa Astolfi, Milena Urbini, Serena Formica, Valentina Indio, Chiara Gnocchi, Maristella Saponara, Cristian Lolli, Maria Caterina Pallotti, Anna Mandrioli, Lidia Gatto, Alessandra Maleddu, Rita Casadio, Guido Biasco
Journal: Journal of Clinical Oncology (2012)

10087 Background: KIT/PDGFRA wild-type (WT) GISTs harbour mutations on SDHB and SDHC and, more recently, we described mutations on SDHA using massively parallel sequencing approach. We sequenced SDHA and SDHB genes in a larger series in order to validate the data. Methods: SDHA gene (1-15 exons) and SDHB gene (1-8 exons) (even not all exons in all samples) were sequenced on tumor (T) and/or peripheral blood (PB) of WT GIST patients by Sanger Sequencing method. DNA was extracted from tumor specimens by the QIAmp DNA Mini kit (Qiagen, Milan, Italy) and amplified with specific primer pairs designed to amplify exons but not SDHA pseudo-genes located on chromosomes 3 and 5. Then, PCR products were purified with the Qiaquick PCR purification kit (Qiagen, Milan, Italy) and sequenced on both strands using the Big Dye Terminator v1.1 Cycle Sequencing kit (Applied Biosystems). Sanger sequencing was performed on ABI 3730 Genetic Analyzer (Applied Biosystems). Results: SDHA gene exons were sequenced on a total of 27 WT GIST patients, in particular on T, PB and both from 12, 6 and 9 patients respectively. SDHB gene exons were sequenced on a total of 18 out of 27 patients, in particular on T, PB and both from 7, 8 and 3 patients respectively. 8 SDHA mutations were found in 5 samples (18.5%). Besides those previously identified, 5 new SDHA mutations were found in other 3 samples: one sample harboured R171C and R589Q heterozygous missense mutation in exons 5 and 13 respectively. The other one harboured G419R and E564K heterozygous missense mutations in exons 9 and 13 respectively. The third sample harboured a delCAG immediately upstream of exon 5, in heterozygosis on PB and in homozygosis on T. A SDHB heterozygous mutation (301delT) in exon 4 was found on 1 PB sample. Conclusions: the presence of SDHA mutations has been confirmed in a subgroup of WT GIST patients. All subunits of SDH complex should be sequenced on WT GIST patients in order to explore the frequency and any linkage between each other and the pathogenetic and clinical significance.
MiR-661 promotes tumor invasion and metastasis by directly inhibiting RB1 in non small cell lung cancer
Authors: Feiye Liu, Yanjun Cai, Xiaoxiang Rong, Jinzhang Chen, Dayong Zheng, Lu Chen, Junyi Zhang, Rongcheng Luo, Peng Zhao, Jian Ruan
Journal: Molecular Cancer (2017)

Aberrant microRNA expression has been implicated in metastasis of cancers. MiR-661 accelerates proliferation and invasion of breast cancer and ovarian cancer, while impedes that of glioma. Its role in non small cell lung cancer (NSCLC) and underlying mechanism are worthy elucidation. Expression of miR-661 was measured with real-time PCR in both NSCLC tissues and cell lines. The effects of miR-661 on migration, invasion and metastasis capacity of NSCLC were evaluated using wound healing, transwell assay and animal models. Dual reporter luciferase assay and complementary experiments were performed to validate RB1 as a direct target of miR-661 for participation in the progression of NSCLC. MiR-661 was upregulated in NSCLC tissues as compared to paired adjacent tissues and associated with shorter overall survival. Furthermore, miR-661 promoted proliferation, migration and metastasis of NSCLC. Then, we identified RB1 as a direct target of miR-661 through which miR-661 affected EMT process and metastasis of NSCLC. RB1 interacted with E2F1 and both could mediate EMT process in NSCLC. MiR-661 promotes metastasis of NSCLC through RB/E2F1 signaling and EMT events, thus may serves as a negative prognostic factor and possible target for treatment of NSCLC patient.
Fd-895 and Pladienolide B Inhibit mRNA Splicing and Induce Apoptosis in Chronic Lymphocytic Leukemia
Authors: Manoj Kumar Kashyap, Deepak Kumar, Harrison Jones Jones, Maria Schwaederlé, Emanuela M. Ghia, Reymond Villa, James J La Clair, Michael D Burkart, Thomas J. Kipps, Januario E. Castro
Journal: Blood (2012)
Pneumococcal Vaccination Among Medicare Beneficiaries Occurring After the Advisory Committee on Immunization Practices Recommendation for Routine Use Of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults Aged ≥65 Years
Authors: Carla L. Black, Walter W. Williams, Rob Warnock, Tamara Pilishvili, David Kim, Jeffrey A. Kelman
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

On September 19, 2014, CDC published the Advisory Committee on Immunization Practices (ACIP) recommendation for the routine use of 13-valent pneumococcal conjugate vaccine (PCV13) among adults aged ≥65 years, to be used in series with 23-valent pneumococcal polysaccharide vaccine (PPSV23) (1). This replaced the previous recommendation that adults aged ≥65 years should be vaccinated with a single dose of PPSV23. As a proxy for estimating PCV13 and PPSV23 vaccination coverage among adults aged ≥65 years before and after implementation of these revised recommendations, CDC analyzed claims for vaccination submitted for reimbursement to the Centers for Medicare & Medicaid Services (CMS). Claims from any time during a beneficiary's enrollment in Medicare Parts A (hospital insurance) and B (medical insurance) since reaching age 65 years were assessed among beneficiaries continuously enrolled in Medicare Parts A and B during annual periods from September 19, 2009, through September 18, 2016. By September 18, 2016, 43.2% of Medicare beneficiaries aged ≥65 years had claims for at least 1 dose of PPSV23 (regardless of PCV13 status), 31.5% had claims for at least 1 dose of PCV13 (regardless of PPSV23 status), and 18.3% had claims for at least 1 dose each of PCV13 and PPSV23. Claims for either type of pneumococcal vaccine were highest among beneficiaries who were older, white, or with chronic and immunocompromising medical conditions than among healthy adults. Implementation of the National Vaccine Advisory Committee's standards for adult immunization practice to assess vaccination status at every patient encounter, recommend needed vaccines, and administer vaccination or refer to a vaccinating provider might help increase pneumococcal vaccination coverage and reduce the risk for pneumonia and invasive pneumococcal disease among older adults (2).
TP53 Mutations in AML Predict Adverse Outcome in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant
Authors: Bartlomiej M Getta, Arnab Ghosh, Catherine C. Coombs, Sean Devlin, Maria Arcila, Abhinita Mohanty, Ross L. Levine, Martin S. Tallman, Ann A. Jakubowski, Sergio A. Giralt, Alan M Hanash
Journal: Blood (2016)
Rapid onset of action in patients with moderate-to-severe psoriasis treated with brodalumab: A pooled analysis of data from two phase 3 randomized clinical trials (AMAGINE-2 and AMAGINE-3)
Authors: Andrew Blauvelt, Kim A Papp, Mark G Lebwohl, Lawrence J Green, Sylvia Hsu, Varsha Bhatt, Shipra Rastogi, Radhakrishnan Pillai, Robert Israel
Journal: Journal of the American Academy of Dermatology (2017)
Impact of low-dose CT screening on smoking cessation among high-risk participants in the UK Lung Cancer Screening Trial
Authors: Kate Brain, Ben Carter, Kate J Lifford, Olivia Burke, Anand Devaraj, David R Baldwin, Stephen Duffy, John K Field
Journal: Thorax (2017)

<h3>Background</h3> Smoking cessation was examined among high-risk participants in the UK Lung Cancer Screening (UKLS) Pilot Trial of low-dose CT screening. <h3>Methods</h3> High-risk individuals aged 50–75 years who completed baseline questionnaires were randomised to CT screening (intervention) or usual care (no screening control). Smoking habit was determined at baseline using self-report. Smokers were asked whether they had quit smoking since joining UKLS at T<sub>1</sub> (2 weeks after baseline scan results or control assignment) and T<sub>2</sub> (up to 2 years after recruitment). Intention-to-treat (ITT) regression analyses were undertaken, adjusting for baseline lung cancer distress, trial site and sociodemographic variables. <h3>Results</h3> Of a total 4055 individuals randomised to CT screening or control, 1546 were baseline smokers (759 intervention, 787 control). Smoking cessation rates were 8% (control n=36/479) versus 14% (intervention n=75/527) at T<sub>1</sub> and 21% (control n=79/377) versus 24% (intervention n=115/488) at T<sub>2</sub>. ITT analyses indicated that the odds of quitting among screened participants were significantly higher at T<sub>1</sub> (adjusted OR (aOR) 2.38, 95% CI 1.56 to 3.64, p&lt;0.001) and T<sub>2</sub> (aOR 1.60, 95% CI 1.17 to 2.18, p=0.003) compared with control. Intervention participants who needed additional clinical investigation were more likely to quit in the longer term compared with the control group (aOR 2.29, 95% CI 1.62 to 3.22, p=0.007) and those receiving a negative result (aOR 2.43, 95% CI 1.54 to 3.84, p&lt;0.001). <h3>Conclusions</h3> CT lung cancer screening for high-risk participants presents a teachable moment for smoking cessation, especially among those who receive a positive scan result. Further behavioural research is needed to evaluate optimal strategies for integrating smoking cessation intervention with stratified lung cancer screening. <h3>Trial registration number</h3> Results, ISRCTN 78513845
Outcome Analysis of High-Dose Chemotherapy Followed By Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma: A Francophone Society of Bone Marrow Transplantation and Cellular Therapy Study
Authors: Remy Dulery, Oumedaly Reman, Ariane Boumemdil, Reda Bouabdallah, Pauline Brice, Thomas Gastinne, Reza Tabrizi, Philippe Quittet, Anne Huynh, Gilles Salles, Helene Monjanel, Aspasia Stamatoullas, Jean-Henri Bourhis, Caroline Bonmati, Sylvie Francois, Stephanie Nguyen Quoc, Jacques Olivier Bay, Jean-Yves Cahn, Pascal Turlure, Charles Dauriac, Mohamad Mohty, Regis Peffault De Latour, Ibrahim Yakoub-Agha
Journal: Blood (2016)
Oral-Contraceptive Use and the Risk of Breast Cancer
Journal: New England Journal of Medicine (1987)

To the Editor: The study on oral-contraceptive use and the risk of breast cancer from the Centers for Disease Control (CDC) and the National Institute of Child Health and Human Development (Aug. 14 issue)1 seems to be reassuring for oral-contraceptive users. But, as stated in the editorial by Shapiro in the same issue,2 there are some weak points that need further elucidation. We have found a highly increased risk of breast cancer among young (teenage) oral-contraceptive users in southern Sweden.3 From incidence figures for Sweden, an increase in premenopausal breast cancer can be seen to have started in about 1975,…
GP escapes erasure after failures that led to two deaths
Authors: Clare Dyer
Journal: BMJ (2017)

A GP who misled a coroner about his treatment of two patients has been suspended for four months by a medical practitioners tribunal that rejected a request from the General Medical Council to strike him off.

Abubakr Osman, who qualified in Sudan in 2002, was asked by a coroner’s officer in February 2014 to provide records of his last interaction with a patient who had died at home of bleeding from a burst abscess in his groin.

Osman had spoken to the patient while on telephone triage duty three days earlier. After a two minute phone consultation in which the patient mentioned his abscess and said that it was causing pain, Osman had prescribed flucloxacillin. He had not …
Signs of Gas Trapping in Normal Lung Density Regions in Smokers
Authors: Sandeep Bodduluri, Joseph M. Reinhardt, Eric A. Hoffman, John D. Newell, Hrudaya Nath, Mark T. Dransfield, Surya P. Bhatt
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

A substantial proportion of subjects without overt airflow obstruction have significant respiratory morbidity and structural abnormalities as visualized by computed tomography. Whether regions of the lung that appear normal using traditional computed tomography criteria have mild disease is not known.To identify subthreshold structural disease in normal-appearing lung regions in smokers.We analyzed 8,034 subjects with complete inspiratory and expiratory computed tomographic data participating in the COPDGene Study, including 103 lifetime nonsmokers. The ratio of the mean lung density at end expiration (E) to end inspiration (I) was calculated in lung regions with normal density (ND) by traditional thresholds for mild emphysema (-910 Hounsfield units) and gas trapping (-856 Hounsfield units) to derive the ND-E/I ratio. Multivariable regression analysis was used to measure the associations between ND-E/I, lung function, and respiratory morbidity.The ND-E/I ratio was greater in smokers than in nonsmokers, and it progressively increased from mild to severe chronic obstructive pulmonary disease severity. A proportion of 26.3% of smokers without airflow obstruction had ND-E/I greater than the 90th percentile of normal. ND-E/I was independently associated with FEV1 (adjusted β = -0.020; 95% confidence interval [CI], -0.032 to -0.007; P = 0.001), St. George's Respiratory Questionnaire scores (adjusted β = 0.952; 95% CI, 0.529 to 1.374; P < 0.001), 6-minute-walk distance (adjusted β = -10.412; 95% CI, -12.267 to -8.556; P < 0.001), and body mass index, airflow obstruction, dyspnea, and exercise capacity index (adjusted β = 0.169; 95% CI, 0.148 to 0.190; P < 0.001), and also with FEV1 change at follow-up (adjusted β = -3.013; 95% CI, -4.478 to -1.548; P = 0.001).Subthreshold gas trapping representing mild small airway disease is prevalent in normal-appearing lung regions in smokers without airflow obstruction, and it is associated with respiratory morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).
Exposure-response methods and dose approval of new oncology drugs by FDA from 2005 to 2015.
Authors: Kaitlyn Minchella, Hongmei Xu, Nidal Al-Huniti
Journal: Journal of Clinical Oncology (2016)

2530 Background: Exposure-response (E-R) analysis is critical for dose justification throughout drug development. The relationship between dose, exposure, and response is crucial for optimizing a drug's safety and efficacy. We analyzed the E-R methods, the approved dose, and any dose or indication changes of all New Molecular Entities (NMEs) in oncology that were approved by FDA from 2005 to 2015. Methods: E-R analyses information was obtained from the "Clinical Pharmacology & Biopharmaceutics Reviews" of each NME (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). E-R methods from both the FDA and sponsor were included in the analysis. If the same exposure-efficacy (E-E) or exposure-safety (E-S) method was used for multiple response endpoints, it was counted once. Different E-E or E-S methods used for the same NME were all counted. Dosage information was collected from the approved and revised labels. Results: From 2005 to 2015, FDA approved 59 NMEs in oncology. There were 44 small molecule drugs: 17 tyrosine kinase inhibitors (TKIs), 17 non-TKI molecular targeted agents, 9 chemotherapeutic agents, and 1 radioactive agent. Fifteen were large molecule drugs: 11 monoclonal antibodies, 2 anti-body drug conjugates, 1 enzyme, and 1 fusion protein. Methods used for E-E analysis and E-S analysis, respectively, were 25 and 32 logistic plot and regression analyses, 26 and 7 Kaplan Meier (KM) or Cox proportional hazard (Cox PH) analyses, 13 and 18 exploratory plots, 3 and 6 summary statistics, and 4 and 4 other analyses. Logistic regression and Cox PH analyses accounted for the majority of significant E-R relationships (13 and 2 for E-E, and 22 and 2 for E-S, respectively). Twenty-four drugs had a dosage and/or indication change on their label post-approval; in total, there were 13 new indications, 11 modified indications, 1 dose reduction, 1 additional dose option, and 1 dose schedule change. Conclusions: E-R analysis has played an important role in supporting dose labeling for oncology drugs. More opportunities still exist to advance the E-R methodology regarding safety and efficacy optimization and dose justification.
Melt Electrospinning Writing of Poly‐Hydroxymethylglycolide‐<i>co</i>‐ε‐Caprolactone‐Based Scaffolds for Cardiac Tissue Engineering
Authors: Miguel Castilho, Dries Feyen, María Flandes‐Iparraguirre, Gernot Hochleitner, Jürgen Groll, Pieter A. F. Doevendans, Tina Vermonden, Keita Ito, Joost P. G. Sluijter, Jos Malda
Journal: Advanced Healthcare Materials (2017)

Current limitations in cardiac tissue engineering revolve around the inability to fully recapitulate the structural organization and mechanical environment of native cardiac tissue. This study aims at developing organized ultrafine fiber scaffolds with improved biocompatibility and architecture in comparison to the traditional fiber scaffolds obtained by solution electrospinning. This is achieved by combining the additive manufacturing of a hydroxyl-functionalized polyester, (poly(hydroxymethylglycolide-co-ε-caprolactone) (pHMGCL), with melt electrospinning writing (MEW). The use of pHMGCL with MEW vastly improves the cellular response to the mechanical anisotropy. Cardiac progenitor cells (CPCs) are able to align more efficiently along the preferential direction of the melt electrospun pHMGCL fiber scaffolds in comparison to electrospun poly(ε-caprolactone)-based scaffolds. Overall, this study describes for the first time that highly ordered microfiber (4.0-7.0 µm) scaffolds based on pHMGCL can be reproducibly generated with MEW and that these scaffolds can support and guide the growth of CPCs and thereby potentially enhance their therapeutic potential.
Abstract 338: Thioredoxin-Interacting Protein Contributes to Aggravated Myocardial Ischemia/Reperfusion Injury by Hyperglycemia
Authors: Haifeng Zhang, Wenjuan Xing, Lele Ji, Hui Su, Xin Sun, Ru Tie, Xiangyan Liang, Fei Tian, Ling Tao, Feng Gao
Journal: Circulation Research (2013)

Hyperglycemia during acute myocardial infarction is common and associated with increased mortality. Thioredoxin-interacting protein (Txnip) is a modulator of cellular redox state and contributes to cell apoptosis. This study aimed to investigate whether hyperglycemia enhances Txnip expression and consequently exacerbates myocardial ischemia/reperfusion (MI/R) injury. Adult male SD rats were subjected to MI/R (30 min/4 h) and treated with saline or high glucose (HG, 500 g/L, 4 ml/kg/h, intravenously throughout the whole MI/R). In vitro study was performed on cultured neonatal rat cardiomyocytes subjected to simulated ischemia/reperfusion (SI/R) and incubated with HG (25 mM) or normal glucose (5.6 mM) medium. In vivo HG infusion significantly reduced the ± LV d P /dt max by 13.2 and 14.1% respectively (n=8, P &lt;0.05), increased infarct size and myocardial apoptosis ( P &lt;0.05) and increased superoxide accumulation ( P &lt;0.01) compared with those in the saline group. Meanwhile, Txnip expression was enhanced (Ratio of Txnip/β-actin: 1.22 ± 0.16 vs. 0.92 ± 0.05 of MI/R+saline, n=6-8, P &lt;0.05) whereas thioredoxin activity was inhibited (0.50 ± 0.05 vs. 1.41 ± 0.06 μmol/min/mg protein, P &lt;0.01) following HG treatment in MI/R hearts. Additionally, HG significantly activated p38 MAPK and inhibited Akt in I/R hearts ( P &lt;0.05). In cultured cardiomyocytes subjected to SI/R, HG incubation stimulated Txnip expression and reduced thioredoxin activity (n=6, P &lt;0.05). Overexpression of Txnip enhanced HG-induced superoxide generation and aggravated cell apoptosis (n=6, P &lt;0.05), while Txnip RNAi significantly blunted the deleterious effects of HG ( P &lt;0.05). Moreover, inhibition of p38 MAPK or activation of Akt markedly blocked HG-induced Txnip expression in I/R cardiomyocytes. Most importantly, intramyocardial injection of Txnip siRNA markedly decreased Txnip expression and alleviated MI/R injury as evidenced by reduced infarction size (23.7 ± 1.6% vs. 43.1 ± 4.8%, n=6, P &lt;0.05) and caspase 3 activity ( P &lt;0.05) in HG-treated rats. Hyperglycemia enhances myocardial Txnip expression, possibly through reciprocally modulating p38 MAPK and Akt activation, leading to aggravated oxidative stress and subsequent amplification of cardiac injury following MI/R.
The Evolving Nomenclature of Erythema Ab Igne—Redness From Fire
Authors: Deepa P. Patel
Journal: JAMA Dermatology (2017)

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Hoxa9 Suppresses Cellular Senescence and Sustains the Development of Leukemic Stem Cells Induced by Fusion Proteins In the Absence of Bmi1.
Authors: Lan-Lan Smith, Jenny Yeung, Bernd B Zeisig, Ivo Huijbers, Nik Popov, Josephine Barnes, Amanda J Wilson, Sanne Lugthart, Ruud Delwel, Jesus Gil, Maarten van Lohuizen, Chi Wai Eric So
Journal: Blood (2010)
Activity-Dependent Gating of Parvalbumin Interneuron Function by the Perineuronal Net Protein Brevican
Authors: Emilia Favuzzi, André Marques-Smith, Rubén Deogracias, Christian M. Winterflood, Alberto Sánchez-Aguilera, Laura Mantoan, Patricia Maeso, Cathy Fernandes, Helge Ewers, Beatriz Rico
Journal: Neuron (2017)