tbuckley/cabot-search huggingface dataset:
Molecular Pathogenic Basis for<i>GABRG2</i>Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome
Authors: Jing-Qiong Kang, Robert L. Macdonald
Journal: JAMA Neurology (2016)

In this review article, we focus on the molecular pathogenic basis for genetic generalized epilepsies associated with mutations in the inhibitory γ-aminobutyric acid (GABAA) receptor γ2 subunit gene, GABRG2 (OMIM 137164), an established epilepsy gene.The γ-aminobutyric acid (GABAA) receptor γ2 subunit gene, GABRG2, is abundantly expressed in the mammalian brain, and its encoded γ2 subunit is assembled into αβγ2 receptors, which are the major GABAA receptor isoforms in the brain. The γ2 subunits have a critical role in GABAA receptor trafficking and clustering at synapses. They reside inside the endoplasmic reticulum after synthesis, where they oligomerize with other binding partners, such as α and β subunits, and further assemble into pentameric receptors. Only correctly assembled receptors can traffic beyond the endoplasmic reticulum and reach the cell surface and synapses, where they conduct chloride ion current when activated by GABA. Mutations in GABRG2 have been associated with simple febrile seizures and with genetic epilepsy syndromes, including childhood absence epilepsy, generalized epilepsy with febrile seizures plus, and Dravet syndrome or severe myoclonic epilepsy in infancy. The mutations include missense, nonsense, and frameshift mutations, as well as splice-site and deletion mutations. The mutations have been identified in both coding and noncoding sequences like splice sites. In the coding sequence, these mutations are found in multiple locations, including the extracellular N-terminus, transmembrane domains, and transmembrane 3-transmembrane 4 intracellular loop. All of these mutations reduced channel function but to different extents and by diverse mechanisms, including nonsense-mediated messenger RNA decay, endoplasmic reticulum-associated protein degradation, dominant negative suppression of partnering subunits, mutant subunit aggregation causing cell stress and cell death, and gating defects.We conclude that the epilepsy phenotypic heterogeneity associated with GABRG2 mutations may be related to the extent of the reduction of GABAA receptor channel function and the differential dominant negative suppression, as well to toxicity related to the metabolism of mutant subunit proteins resulting from each mutant γ2 subunit, in addition to different genetic backgrounds.
Quantitative Studies on the Latent Period of Tumors Induced with Subcutaneous Injections of the Agent of Chicken Tumor I. II. Estimation of the Latent Period
Authors: Bryan, W. Ray
Journal: JNCI Journal of the National Cancer Institute (1946)

Journal Article Quantitative Studies on the Latent Period of Tumors Induced with Subcutaneous Injections of the Agent of Chicken Tumor I. II. Estimation of the Latent Period Get access W. Ray Bryan W. Ray Bryan senior biologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 6, Issue 6, June 1946, Pages 373–377, https://doi.org/10.1093/jnci/6.6.373 Published: 01 June 1946
Correlation Between Balance of Specific Chromosomes and Expression of Malignancy in Hamster Cells 2
Authors: William F. Benedict, Natalie Rucker, Corey Mark, Richard E. Kouri
Journal: JNCI Journal of the National Cancer Institute (1975)

Four 1-theta-D-arabinofuranosylcytosine (ara-C)-and one dimethylnitrosamine-transformed Syrian hamster cell lines were established. All produced tumors when inoculated into newborn hamsters. Specific chromosome changes were found in these lines consistent with changes observed recently by other investigators. Clones that had either high or low malignant potential were derived from two fibrosarcomas produced by one of the ara-C-transformed cell lines. The expression of malignancy in these clones was associated with an excess of 57 chromosomes over 73 chromosomes.
TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment
Authors: Antonio Pierini, William Strober, Caitlin Moffett, Jeanette Baker, Hidekazu Nishikii, Maite Alvarez, Yuqiong Pan, Dominik Schneidawind, Everett Meyer, Robert S. Negrin
Journal: Blood (2016)
Long-Term Risk of Atherosclerotic Cardiovascular Disease in US Adults With the Familial Hypercholesterolemia Phenotype
Authors: Amanda M. Perak, Hongyan Ning, Sarah D. de Ferranti, Holly C. Gooding, John T. Wilkins, Donald M. Lloyd-Jones
Journal: Circulation (2016)

Background: Heterozygous familial hypercholesterolemia (FH) affects up to 1 in 200 individuals in the United States, but atherosclerotic cardiovascular disease (ASCVD) outcomes of FH in the general US population have not been described. We therefore sought to evaluate long-term coronary heart disease (CHD) and total ASCVD risks in US adults with an FH phenotype. Methods: Using individual pooled data from 6 large US epidemiological cohorts, we stratified participants by low-density lipoprotein cholesterol level at index ages from 20 to 79 years. For the primary analysis, low-density lipoprotein cholesterol levels ≥190 and &lt;130 mg/dL defined the FH phenotype and referent, respectively. Sensitivity analyses evaluated the effects of varying the FH phenotype definition. We used Cox regression models to assess covariate-adjusted associations of the FH phenotype with 30-year hazards for CHD (CHD death or nonfatal myocardial infarction) and total ASCVD (CHD or stroke). Results: We included 68 565 baseline person-examinations; 3850 (5.6%) had the FH phenotype by the primary definition. Follow-up across index ages ranged from 78 985 to 308 378 person-years. After covariate adjustment, the FH phenotype was associated with substantially elevated 30-year CHD risk, with hazard ratios up to 5.0 (95% confidence interval, 1.1–21.7). Across index ages, CHD risk was accelerated in those with the FH phenotype by 10 to 20 years in men and 20 to 30 years in women. Similar patterns of results were found for total ASCVD risk, with hazard ratios up to 4.1 (95% confidence interval, 1.2–13.4). Alternative FH phenotype definitions incorporating family history, more stringent age-based low-density lipoprotein cholesterol thresholds, or alternative lipid fractions decreased the FH phenotype prevalence to as low as 0.2% to 0.4% without materially affecting CHD risk estimates (hazard ratios up to 8.0; 95% confidence interval, 1.0–61.6). Conclusions: In the general US population, the long-term ASCVD burden related to phenotypic FH, defined by low-density lipoprotein cholesterol ≥190 mg/dL, is likely substantial. Our finding of CHD risk acceleration may aid efforts in risk communication.
Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): Results of a North American phase III study (MM-009)
Authors: D. M. Weber, C. Chen, R. Niesvizky, M. Wang, A. Belch, E. Stadtmauer, Z. Yu, M. Olesnyckyj, J. Zeldis, R. Knight
Journal: Journal of Clinical Oncology (2006)

7521 Background: Lenalidomide is a novel, orally administered, immunomodulatory drug (IMiD) that has single-agent activity against MM and additive effects when combined with dexamethasone (Dex). Methods: In this phase 3, multicenter, double-blind trial, 354 patients (pts)with relapsed or refractory MM were treated with Dex 40 mg daily on days 1–4, 9–12, 17–20 every 28 days and were randomized to receive either lenalidomide (Len) 25 mg daily orally on days 1–21 every 28 days or placebo. Beginning with cycle 5, Dex was reduced to 40 mg daily on days 1–4 only, every 28 days. Patients were stratified with respect to B 2 M (≤ 2.5 vs. &gt; 2.5 mg/mL), prior stem cell transplant (none vs. ≥ 1), and number of prior regimens (1 vs &gt; 1). The treatment arms were well balanced for prognostic features. Results: The overall response rate was greater with Len-Dex than with Dex-placebo (59.4% vs. 21.1%; p &lt; 0.001). Complete responses were achieved in 12.9% of pts treated with Len-Dex and 0.6% of pts treated with Dex-placebo. The median time to progression (TTP) for pts treated with Len-Dex was 11.1 months compared to 4.7 months for pts treated with Dex-placebo (p &lt; 0.000001). Median overall survival was higher with Len-Dex (not reached) compared to Dex-placebo (24 months) (hazard ratio 1.76, p = .0125). Grade 3–4 neutropenia was more frequent with combination therapy than with Dex-placebo (24% vs. 3.5%), however ≥ grade 3 infections were similar in both groups. Thromboembolic events occurred in 15% of pts treated with Len-Dex and in 3.5% of pts treated with Dex-placebo. Atrial fibrillation occurred in 8 pts and CHF developed in 4 pts treated with Len-Dex. Conclusions: Considering the ease of oral administration, higher response rate, longer time to progression and overall survival benefit, the combination of lenalidomide-dexamethasone may very well represent the treatment of choice for early refractory or relapsing multiple myeloma. The relatively infrequent side effects should not detract from these improvements, but the use of prophylactic antithrombotic therapy should be considered for patients treated with the combination of lenalidomide and dexamethasone. [Table: see text]
Remarkable Positive Correlation of Blood Monocyte Counts with Blood Plasmacytoid Dendritic Cells and Blood Regulatory T Cells.
Authors: Norihiro Watanabe, Miwako Narita, Anri Saito, Nozomi Tochiki, Miku Satoh, Noriyuki Satoh, Haruka Kanii, Masayoshi Masuko, Tatsuo Furukawa, Ken Toba, Sadao Aoki, Ichiro Fuse, Yoshifusa Aizawa, Masuhiro Takahashi
Journal: Blood (2006)
GiniClust: detecting rare cell types from single-cell gene expression data with Gini index
Authors: Lan Jiang, Huidong Chen, Luca Pinello, Guo-Cheng Yuan
Journal: Genome biology (2016)

High-throughput single-cell technologies have great potential to discover new cell types; however, it remains challenging to detect rare cell types that are distinct from a large population. We present a novel computational method, called GiniClust, to overcome this challenge. Validation against a benchmark dataset indicates that GiniClust achieves high sensitivity and specificity. Application of GiniClust to public single-cell RNA-seq datasets uncovers previously unrecognized rare cell types, including Zscan4-expressing cells within mouse embryonic stem cells and hemoglobin-expressing cells in the mouse cortex and hippocampus. GiniClust also correctly detects a small number of normal cells that are mixed in a cancer cell population.
Radiotherapy in relation to temozolomide: Subgroup analysis of molecular markers of the randomized phase III study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033) in patients with a high risk low-grade glioma.
Authors: Brigitta G. Baumert, Monika E. Hegi, Warren P. Mason, Gail Ryan, Khê Hoang-Xuan, Jacoline E Bromberg, Martin J. Van Den Bent, Mohamed Ben Hassel, Christine Marosi, Alba Ariela Brandes, Jeremy Rees, Andreas von Deimling, Christian Hartmann, Johan M Kros, Denis A. Lacombe, Thierry Gorlia, David Capper, Sebastian Kurscheid, Roger Stupp
Journal: Journal of Clinical Oncology (2015)

2006 Background: A subgroup analysis based on molecular markers of patients randomized between standard radiotherapy (RT) and temozolomide (TMZ) alone in the randomized EORTC22033 trial. Methods: A posthoc analysis of molecular markers was done for 407 patients (of 477 randomized). The IDH status was determined by immunohistochemistry for the most common IDH mutant, complemented by sequencing of IDH1 and 2 for all negative cases. The status of 1p/19q codeletion was evaluated by LOH or FISH, the MGMTpromoter methylation status on the HM450k beadchip (Illumina) and classified by MGMTSTP27. Results: IDH1 and IDH2 mutations were detected in 83% (327/392) and 2.8% (n = 9). Co-deletions of 1p/19q were identified in 33% (n = 117/357). MGMT was methylated in 90% (135/150), of which 86% were IDH mutant (128/140). For 318 patients the status for both IDH1/2 and 1p/19q codel was available: 269 (85%) were IDHmt, 104 (39%) IDHmt/codel and 49 (15%) IDHwt. Mutation of the IDH 1 or 2 (IDHmt) regardless of 1p/19q co-deletion was a positive prognostic factor. Exploratory analysis of these 318 patients showed that patients with IDHmt/non-codel tumors had a shorter PFS after treatment with TMZ than after RT (HR 1.86; 95% CI, 1.21-2.87; logrank p = 0.0043), while no difference was observed between these treatments for patients with IDHwt, and IDHmt/codel tumors. Conclusions: Subgroup analysis suggests that PFS is longer in patients with IDHmut/non-codel tumors when treated in first-line with RT compared to treatment with TMZ. With still only a few events no such difference is visible in 1p/19q co-deleted tumors. However, maturation of survival data is needed to derive more firm conclusions. Clinical trial information: NCT00182819. Treatment Progression-free survival Patients Observed Events HR (95% CI) P-Value Median (95% CI) (Mths) RT-IDHmt/codel 45 17 1.00 0.0000 61.6 (42.3, N) RT-IDHwt 29 25 5.4 (2.9, 10.1) 0.0000 19.1 (11.3, 25.7) RT- IDHmt/non-codel 89 37 1.1 (0.6, 2.0) 0.6655 55.4 (47.9, 65.9) TMZ-IDHmt/codel 59 24 1.1 (0.6, 1.9) 0.8509 55.0 (37.9, N) TMZ-IDHwt 20 15 3.1 (1.6, 6.3) 0.0013 23.7 (5.6, 42.3) TMZ-IDHmt/non-codel 76 47 2.1 (1.2, 3.6) 0.0103 36.0 (28.4, 46.9)
Should Restrictions Be Relaxed for Metformin Use in Chronic Kidney Disease? Yes, They Should Be Relaxed! What’s the Fuss?
Authors: George L. Bakris, Mark E. Molitch
Journal: Diabetes Care (2016)

Metformin is and has been considered as first-line therapy for type 2 diabetes for over a quarter of a century. Like other biguanides, metformin can cause a lactic acidosis that is exceptionally rare but fatal. The likelihood of metformin-associated lactic acidosis is substantially higher in patients with kidney impairment and also among those with seemingly normal kidney function who are at risk of acute kidney injury (AKI). Hence, regulatory agencies in many industrialized nations have maintained strict renal restrictions surrounding metformin. However, there have been millions of people exposed to metformin for many years, many of them with serum creatinine values at or close to 1.5 mg/dL with estimated glomerular filtration rates (eGFRs) much below 60 mL/min/1.73 m2 who have not developed lactic acidosis. Thus, there clearly remains controversy in this area, and there has been heightened pressure to remove the renal restrictions of metformin. To provide a discussion on the pros and cons of relaxing the renal restrictions for metformin use, we provide a Point-Counterpoint. In the preceding point narrative, Drs. Kalantar-Zadeh and Kovesdy provide their argument that although there is little evidence of the potential benefits of metformin in kidney disease, just considering the sheer numbers of metformin users and the high fatality rate of its associated lactic acidosis, the most appropriate practice is to avoid metformin use in people with eGFR &amp;lt;45 mL/min/1.73 m2 or in those who are at high risk of AKI irrespective of underlying eGFR. In the counterpoint narrative below, Drs. Bakris and Molitch argue that the data from a very large analysis demonstrate clearly that serum creatinine should be supplanted with eGFR as the criteria for metformin use and that the incidence of lactic acidosis is only elevated in those with a reduced eGFR who become dehydrated for various reasons or in those exposed to some toxin resulting in AKI. Otherwise the data clearly support the use of metformin under normal circumstances down to eGFR &amp;gt;30 mL/min/1.73 m2. —William T. Cefalu Editor in Chief, Diabetes Care
The scientific basis for offering seasonal influenza immunisation to risk groups in Europe
Authors: A Nicoll, B  C Ciancio, S Tsolova, P R Blank, C Yilmaz
Journal: Eurosurveillance (2008)

This paper summarises the scientific evidence supporting selection of risk groups that would benefit from annual seasonal influenza immunisation in European Union (EU) countries. Risk groups are defined restrictively as persons in Europe at higher than average risk of adverse outcomes should they be infected with seasonal influenza and for whom use of vaccine is demonstrated to be effective in reducing the risk of those outcomes. Existing evidence indicate that older people and those with chronic disease are at higher risk of severe adverse outcome and that immunisation reduces this risk. There is thus good scientific evidence for routinely offering annual immunisation to all older people (at least those aged 65 years and older), and people with certain groups of chronic medical conditions. We estimated that these two groups account for between 19% and 28% of the population of EU countries. Thus in 2006, an estimated 84 million older people aged 65 years and over and 41 million people younger than 65 years of age with chronic conditions were living in these countries. There is also strong evidence for immunising staff caring for patients belonging to these two risk groups in residential (care home) settings in order to protect the patients. There are as yet no strong data on whether or not immunising other healthcare workers and carers protect patients though immunisation of healthcare workers can be justified on occupational health grounds. At present the scientific evidence for immunising other suggested risk groups, notably children and pregnant women is not strong for Europe though equally there is no evidence against immunising these groups.
Safety and Efficacy of the Totally Subcutaneous Implantable Defibrillator
Authors: Martin C. Burke, Michael R. Gold, Bradley P. Knight, Craig S. Barr, Dominic A.M.J. Theuns, Lucas V.A. Boersma, Reinoud E. Knops, Raul Weiss, Angel R. Leon, John M. Herre, Michael Husby, Kenneth M. Stein, Pier D. Lambiase
Journal: Journal of the American College of Cardiology (2015)

The entirely subcutaneous implantable cardioverter-defibrillator (S-ICD) is the first implantable defibrillator that avoids placing electrodes in or around the heart. Two large prospective studies (IDE [S-ICD System IDE Clinical Investigation] and EFFORTLESS [Boston Scientific Post Market S-ICD Registry]) have reported 6-month to 1-year data on the S-ICD. The objective of this study was to evaluate the safety and efficacy of the S-ICD in a large diverse population. Data from the IDE and EFFORTLESS studies were pooled. Shocks were independently adjudicated, and complications were measured with a standardized classification scheme. Enrollment date quartiles were used to assess event rates over time. Eight hundred eighty-two patients who underwent implantation were followed for 651 ± 345 days. Spontaneous ventricular tachyarrhythmia (VT)/ventricular fibrillation (VF) events (n = 111) were treated in 59 patients; 100 (90.1%) events were terminated with 1 shock, and 109 events (98.2%) were terminated within the 5 available shocks. The estimated 3-year inappropriate shock rate was 13.1%. Estimated 3-year, all-cause mortality was 4.7% (95% confidence interval: 0.9% to 8.5%), with 26 deaths (2.9%). Device-related complications occurred in 11.1% of patients at 3 years. There were no electrode failures, and no S-ICD–related endocarditis or bacteremia occurred. Three devices (0.3%) were replaced for right ventricular pacing. The 6-month complication rate decreased by quartile of enrollment (Q1: 8.9%; Q4: 5.5%), and there was a trend toward a reduction in inappropriate shocks (Q1: 6.9% Q4: 4.5%). The S-ICD demonstrated high efficacy for VT/VF. Complications and inappropriate shock rates were reduced consistently with strategic programming and as operator experience increased. These data provide further evidence for the safety and efficacy of the S-ICD. (Boston Scientific Post Market S-ICD Registry [EFFORTLESS]; NCT01085435; S-ICD® System IDE Clinical Study; NCT01064076)
Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells
Authors: Wing Y. Lam, Amy M. Becker, Krista M. Kennerly, Rachel Wong, Jonathan D. Curtis, Elizabeth M. Llufrio, Kyle S. McCommis, Johannes Fahrmann, Hannah A. Pizzato, Ryan M. Nunley, Jieun Lee, Michael J. Wolfgang, Gary J. Patti, Brian N. Finck, Erika L. Pearce, Deepta Bhattacharya
Journal: Immunity (2016)
Adherence and persistence to second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia.
Authors: Digisha Trivedi, Shahla Amin, Ling Zhu, Sam Joo, Hugh Kawabata, Theodore Darkow, Tony Hebden
Journal: Journal of Clinical Oncology (2012)

e17009 Background: Some studies have demonstrated the correlation between adherence and persistence to therapy and the effectiveness of that therapy, thereby reinforcing the need to optimize both as a core treatment strategy. Because available data are limited, we examined real world adherence and persistence to the 2 nd generation tyrosine kinase inhibitors (TKIs) used to treat chronic myeloid leukemia (CML). Methods: An observational retrospective study was conducted using pooled Invision Data Mart and Pharmetrics claims data. Adult CML patients with at least two prescriptions for a 2 nd generation TKI between July 1, 2006 and December 31, 2010 were identified and followed for a maximum of 6 months from their index date (first observed prescription date). Dasatinib and nilotinib patients with prior imatinib use in 6 month pre-index period were classified as second-line and those with no prior use as first-line patients. Adherence to treatment was defined by the medication possession ratio (MPR) and persistence as the proportion of patients refilling prescriptions within 1.5 times the days supply during the follow-up period. Results: Of the 276 CML patients identified, 179 received dasatinib (n=50 first-line; n=129 second-line) and 97 received nilotinib (n=27 first-line; n=70 second-line). Patient characteristics were similar across treatment groups. Proportions with MPR ≥85% were 64% and 75% for first- and second-line dasatinib and 48% and 61% for first- and second-line nilotinib. Persistence rates were 36% and 47% for first- and second-line dasatinib and 26% and 39% for first- and second-line nilotinib. Conclusions: In both first- and second-line use, dasatinib was associated with higher adherence and persistence than the corresponding nilotinib-treated group. The reason for the difference between these TKIs is not known and will require further study.
Intralobar Pulmonary Sequestration
Authors: N S Opanasenko
Journal: JAMA (1963)

For the period of 21 years the intralobar pulmonary sequestration was revealed in 6 patients aging from 11 to 47 years old. In all the observations of the intralobar sequestration the only affection of lower pulmonary lobes was noted. In 4 patients the symptomless course of the disease was present, while in 2 it was manifested by the recurrent pneumonia. The correct diagnosis before the operation was established in one patient only. All the patients were operated on, in 2 two aberrant vessels to the sequestrated pulmonary region were revealed and in all the patients--bronchogenic cyst in the affected region.