tbuckley/cabot-search huggingface dataset:
BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure
Authors: Qiming Duan, Sarah McMahon, Priti Anand, Hirsh Shah, Sean Thomas, Hazel T. Salunga, Yu Huang, Rongli Zhang, Aarathi Sahadevan, Madeleine E. Lemieux, Jonathan D. Brown, Deepak Srivastava, James E. Bradner, Timothy A. McKinsey, Saptarsi M. Haldar
Journal: Science Translational Medicine (2017)

Despite current standard of care, the average 5-year mortality after an initial diagnosis of heart failure (HF) is about 40%, reflecting an urgent need for new therapeutic approaches. Previous studies demonstrated that the epigenetic reader protein bromodomain-containing protein 4 (BRD4), an emerging therapeutic target in cancer, functions as a critical coactivator of pathologic gene transactivation during cardiomyocyte hypertrophy. However, the therapeutic relevance of these findings to human disease remained unknown. We demonstrate that treatment with the BET bromodomain inhibitor JQ1 has therapeutic effects during severe, preestablished HF from prolonged pressure overload, as well as after a massive anterior myocardial infarction in mice. Furthermore, JQ1 potently blocks agonist-induced hypertrophy in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Integrated transcriptomic analyses across animal models and human iPSC-CMs reveal that BET inhibition preferentially blocks transactivation of a common pathologic gene regulatory program that is robustly enriched for NFκB and TGF-β signaling networks, typified by innate inflammatory and profibrotic myocardial genes. As predicted by these specific transcriptional mechanisms, we found that JQ1 does not suppress physiological cardiac hypertrophy in a mouse swimming model. These findings establish that pharmacologically targeting innate inflammatory and profibrotic myocardial signaling networks at the level of chromatin is effective in animal models and human cardiomyocytes, providing the critical rationale for further development of BET inhibitors and other epigenomic medicines for HF.
International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes
Journal: Diabetes Care (2009)

We appreciate the comment by Kilpatrick et al. (1) regarding the International Expert Committee report on the diagnosis of diabetes with the A1C assay (2). The Committee considered all of the limitations of the A1C assay for populations in which it is not available or is currently too expensive, as well as for individuals in whom the assay may be misleading. On the basis of these recognized limitations, the Committee emphasized the use of the currently recommended glucose tests and criteria in such populations or individuals. We did not “breeze over” any of the relative advantages or disadvantages of the A1C assay as a means of diagnosis; rather, the …
Anorexia: A perverse effect of attempting to control the starvation response
Authors: Randolph M. Nesse
Journal: Behavioral and Brain Sciences (2017)

Abstract Starvation arouses evolved protective mechanisms including binge eating and increased metabolic efficiency and fat storage. When aroused by dieting, the experiences of out-of-control eating, increased appetite, and increased fat storage arouse greater fears of obesity, spurring renewed attempts to restrict intake severely. The resulting positive feedback cycle escalates into bulimia for many, and anorexia in a few.
Abstract 265: Assessment Of Oxidative DNA Double Strand Break And Repair In Cardiomyocytes
Authors: Bo Ye, Ning Hou, Lu Xiao, Haodong Xu, Faqian Li
Journal: Circulation Research (2013)

Backgrounds: DNA damage occurs in cardiomyocytes during normal cellular metabolism and is significantly increased under cardiac stresses. How cardiomyocytes repair their DNA damage, especially DNA double strand breaks (DSBs), remains undetermined. We assessed DSBs caused by oxidative stress. More importantly, we investigated the spatiotemporal dynamics of DNA repair protein assembly/disassembly in DNA damage sites. Methods: Cultured neonatal rat cardiomyocytes were treated with different doses of hydrogen peroxide (H2O2) for 30 minutes to assess DNA damage response (DDR). To investigate the dynamics of DDR, cells were treated with 200 uM H2O2 and followed up to 72 hours. DSBs were evaluated by counting DNA damage foci after staining with antibody against histone H2AX phosphorylation at serine 139 (g-H2AX). The dynamics and posttranslational modification of DNA repair proteins were determined by Western blotting, immunolabeling, and confocal microscopy. Result: g-H2AX was proportionally increased to H2O2 dosage. Discrete nuclear g-H2AX foci were seen 30 minutes after hydrogen peroxide treatment with 50 uM, but became pannuclear when H2O2 was above 400 uM. At 200 uM of hydrogen peroxide, g-H2AX started to increase at 15 minutes and reached to highest levels at 60 minutes with up to 70 nuclear foci, started to decline at 2 hours, and returned to basal levels at 24 hours. DDR transducer kinase, ataxia telangiectasia mutated (ATM) was activated at 5 minutes with increased phosphorylation at serine 1981 (pATM) which started to decrease at 24 hours, but remained elevated up to 48 hours. Another DDR transducer kinase, ATM and Rad3-related (ATR) showed a biphasic activation at 30 minutes and 8 hours. ATM and ATR colocalized with g-H2AX. DNA damage mediator proteins such as MRN complex and p53BP1 were also recruited to sites of DNA damage at g-H2AX foci. Conclusions: DSBs and their repair have emerged as a new frontier of stress responses. Newly developed methods for studying g-H2AX and DNA repair protein dynamics can be explored to investigate DDR to oxidative stress in cardiomyocytes.
Global Representations of Goal-Directed Behavior in Distinct Cell Types of Mouse Neocortex
Authors: William E. Allen, Isaac V. Kauvar, Michael Z. Chen, Ethan B. Richman, Samuel J. Yang, Ken Chan, Viviana Gradinaru, Benjamin E. Deverman, Liqun Luo, Karl Deisseroth
Journal: Neuron (2017)

The successful planning and execution of adaptive behaviors in mammals may require long-range coordination of neural networks throughout cerebral cortex. The neuronal implementation of signals that could orchestrate cortex-wide activity remains unclear. Here, we develop and apply methods for cortex-wide Ca2+ imaging in mice performing decision-making behavior and identify a global cortical representation of task engagement encoded in the activity dynamics of both single cells and superficial neuropil distributed across the majority of dorsal cortex. The activity of multiple molecularly defined cell types was found to reflect this representation with type-specific dynamics. Focal optogenetic inhibition tiled across cortex revealed a crucial role for frontal cortex in triggering this cortex-wide phenomenon; local inhibition of this region blocked both the cortex-wide response to task-initiating cues and the voluntary behavior. These findings reveal cell-type-specific processes in cortex for globally representing goal-directed behavior and identify a major cortical node that gates the global broadcast of task-related information.
A Phase I Dose-Escalation Study of the Class 1 Selective Histone Deacetylase Inhibitor CHR-3996 in Combination with Tosedostat for Patients with Relapsed, Refractory Multiple Myeloma: Results of the Muk Three Trial
Authors: Rakesh Popat, Sarah R Brown, Avie-Lee Tillotson, Fiona Collinson, Louise M Flanagan, Cathy D Williams, Kwee L Yong, Gordon Cook, Matthew W Jenner, Martin Kaiser, Jim Cavet, Dima El-Sharkawi, Chin-Hin Ng, Eric Low, Gareth J Morgan, Faith E Davies
Journal: Blood (2016)
Factor V (his 1299 arg) in Turkish patients with venous thromboembolism
Authors: Nejat Akar, Ece Akar, Erkan Yilmaz
Journal: American Journal of Hematology (2000)

To the Editor: Semenzato et al. proposed new criteria for large granular lymphocyte (LGL) leukemia because patients with low levels of GL were similar to those with levels greater than 2,000 GL/l [1].LGL leukemia is a GL proliferative disease often accompanied by pure red cell aplasia (PRCA).T-cell LGL leukemia is a clonal disease, and the phenotype of leukemic cells is CD3 + 4 -8 + .PRCA with thymoma is often associated with peripheral T cell expansion.We previously reported a case of PRCA with thymoma in which the T-cell receptor ␤ of both the thymus and peripheral mononuclear cells was rearranged [2].Thymoma and PRCA may be caused by T-cell clonal expansion, leukemia.We examined four patients with PRCA and thymoma (Table I), one of which was previously reported.Three of the four showed CD3 + 4 -8 + lymphocytosis and two exhibited T-cell receptor ␤ rearrangement of peripheral mononuclear cells.Patient 2 showed low levels of lymphocytes and the mononuclear cell's CD4/8 ratio of patient 3 was greater than 1.Due to the low levels of abnormal cells and low sensitivity of Southern blot analysis, we could not confirm the clonality of these two cases.According to treatment of PRCA with thymoma, the response rate of thymectomy was 12% [3].This limited effectiveness of thymectomy indicated that thymoma did not play a causative role in PRCA.Loughran reported 129 patients with LGL leukemia [4] and Oshimi et al. examined 33 patients [5].Neither study noted a complication of thymoma.PRCA with thymoma had been considered a distinct clinical entity from LGL leukemia.The old diagnostic criteria for LGL leukemia was "greater than 2,000 GL/l."The normal value of GL is 223 ± 99 l [4].Three of the 4 patients with PRCA and thymoma demonstrated levels greater than the mean + 3 SD (Table I).However, it is unknown whether or not a distinction between 'PRCA with thymoma' and 'PRCA with LGL leukemia' exists.Patients with LGL leukemia showed an indolent clinical course, and immunosuppressive therapy with cyclosporin A or low-dose cyclophosphamide was effective for the clinical symptoms.In contrast, patients with PRCA with thymoma were treated with more aggressive therapy such as surgical resection, intensive chemotherapy, or radiation.As the effectiveness of surgical resection for PRCA with thymoma is limited, PRCA with thymoma should be initially treated with immunosuppressive therapy.
Safety and efficacy of AMG 386 in combination with sunitinib in patients with metastatic renal cell carcinoma (mRCC) in an open-label multicenter phase II study.
Authors: Michael B. Atkins, Alain Ravaud, Gwenaelle Gravis, Kazimierz Drosik, Tomasz Demkow, Piotr Tomczak, Karolyn Kracht, Markus Puhlmann, David Michael Weinreich
Journal: Journal of Clinical Oncology (2012)

4606 Background: AMG 386, an investigational peptide-Fc fusion protein, inhibits angiogenesis by disrupting the angiopoietin/Tie2 axis. We evaluated the safety and efficacy of AMG 386 plus sunitinib in patients (pts) with mRCC. Methods: Adults with mRCC who were naïve to angiogenesis inhibitors were sequentially enrolled to 2 cohorts: sunitinib 50 mg PO QD (4 wks on, 2 wks off) plus AMG 386 at 10 mg/kg (A) or 15 mg/kg (B) IV QW. Primary endpoints: adverse events (AEs), dose interruptions/reductions due to AEs in the first 12 wks of treatment; secondary endpoints included: progression-free survival (PFS) and response rate (ORR). Results: 85 pts received ≥1 dose of study medication (A/B, n=43/42). In A/B, 88%/76% were male and 30%/36% were age ≥65; MSKCC risk scores were low (40%/36%) or intermediate (60%/62%). For A/B: median follow-up time was 19.6/12.0 mos; AMG 386 discontinuations due to AEs were 16%/29%; and grade ≥3 treatment-related AEs occurred in 72%/74% with virtually all attributed to sunitinib. Grade 3 AEs occurring with &gt;5% frequency were hypertension, hand foot syndrome, asthenia, fatigue, elevated lipase, diarrhea, mucositis, vomiting, thrombocytopenia, and neutropenia, with no distinction between dose levels. The percentage of pts with sunitinib dose interruptions within the first 12 wks (A/B, 58%/57%) met the prespecified criteria. One pt in B had fatal acute pulmonary edema. No pt developed anti-AMG 386 antibodies. The Kaplan-Meier estimate (95% CI) of PFS was 13.9 (10.4, 19.2) mos in A; PFS in B is not yet mature with only 21% of pts having disease progression. ORR (95% CI) was 58% (42, 73) in A including 1 CR, and 59% (42, 74) in B. Conclusions: In pts with mRCC, AMG 386 at 10 and 15 mg/kg combined with sunitinib appeared to be tolerable. Reported sunitinib dose modifications for the observation period were within the prespecified range. Efficacy results suggest potential benefit for the addition of AMG 386 to sunitinib.
Detection of Calcified and Noncalcified Coronary Atherosclerotic Plaque by Contrast-Enhanced, Submillimeter Multidetector Spiral Computed Tomography
Authors: Stephan Achenbach, Fabian Moselewski, Dieter Ropers, Maros Ferencik, Udo Hoffmann, Briain MacNeill, Karsten Pohle, Ulrich Baum, Katharina Anders, Ik-kyung Jang, Werner G. Daniel, Thomas J. Brady
Journal: Circulation (2003)

Background— We investigated the ability of multidetector spiral computed tomography (MDCT) to detect atherosclerotic plaque in nonstenotic coronary arteries. Methods and Results— In 22 patients without significant coronary stenoses, contrast-enhanced MDCT (0.75-mm collimation, 420-ms rotation) and intravascular ultrasound (IVUS) of one coronary artery were performed. A total of 83 coronary segments were imaged by IVUS (left main, 19; left anterior descending, 51; left circumflex, 4; right coronary, 9). MDCT data sets were evaluated for the presence and volume of plaque in the coronary artery segments. Results were compared with IVUS in a blinded fashion. For the detection of segments with any plaque, MDCT had a sensitivity of 82% (41 of 50) and specificity of 88% (29 of 33). For calcified plaque, sensitivity was 94% (33 of 36) and specificity 94% (45 of 47). Coronary segments containing noncalcified plaque were detected with a sensitivity of 78% (35 of 45) and specificity of 87% (33 of 38), but presence of exclusively noncalcified plaque was detected with only 53% sensitivity (8 of 15). If analysis was limited to the 41 proximal segments (segments 1, 5, 6, and 11 according to American Heart Association classification), sensitivity and specificity were 92% and 88% for any plaque, 95% and 91% for calcified plaque, and 91% and 89% for noncalcified plaque. MDCT substantially underestimated plaque volume per segment as compared with IVUS (24±35 mm 3 versus 43±60 mm 3 , P &lt;0.001). Conclusions— The results indicate the potential of MDCT to detect coronary atherosclerotic plaque in patients without significant coronary stenoses. However, further improvements in image quality will be necessary to achieve reliable assessment, especially of noncalcified plaque throughout the coronary tree.
Increased mumps incidence in the Netherlands: Review on the possible role of vaccine strain and genotype
Authors: P Kaaijk, B A van der Zeijst, M C Boog, C W Hoitink
Journal: Eurosurveillance (2008)

As reported in a recent issue of Eurosurveillance, a mumps outbreak is ongoing in the Netherlands despite high vaccination coverage of 90-95% [1]. The reported mumps cases are restricted to geographic regions with a high percentage of residents who are members of a religious community that rejects vaccination. Consequently, two thirds of the mumps patients were not vaccinated. However, also vaccinated individuals in these regions were affected [1]. Since 1987, the measles-mumps-rubella (MMR) combination vaccine produced by the Netherlands Vaccine Institute (NVI) is part of the Dutch national immunisation programme and administered at the ages of 14 months and nine years.
Does qualitative radiologic assessment of tumor response measure up to traditional quantitative scoring methods?
Authors: R. Gottlieb, A. M. Litwin, T. L. Mashtare, G. Wilding, C. L. Raczyk, J. Taylor, M. G. Fakih, B. Gupta
Journal: Journal of Clinical Oncology (2007)

17034 Background: The Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) radiologic metrics are the standards for tumor response to therapy. However these methods are difficult to use and are limited in their prediction of clinical outcome. We hypothesize a simpler qualitative assessment of tumor response by CT is as reproducible and predictive of clinical outcome as the RECIST and WHO methods. Methods: This was a retrospective evaluation of 23 patients (11 males, 12 females, mean age 56.1 years, range 40–81 years) with biopsy proven metastatic colo-rectal carcinoma treated at our institution between 2002 and 2006 who did not have their primary tumor resected. Only patients with two consecutive CT examinations separated by at least three weeks were included. Two board certified radiologists, blinded to the other's reads, independently interpreted all CT examinations measuring up to five hepatic lesions on both CT examinations using RECIST and WHO criteria and qualitatively assessing all hepatic metastases, categorizing them as increased, decreased, or unchanged between scans. Clinical outcome, using time to progression of disease (TTP), was measured, utilizing a Cox proportional hazards model, to compare the predictive value of all three scoring systems for those patients starting first line chemotherapy (11 patients) at the time of our analysis. Results: Qualitative assessment resulted in agreement in 21/23 patients (91.3%, kappa = 0.78) classifying hepatic metastases as any increase (2 patients), any decrease (17 patients), or no change (2 patients) between scans compared with agreement in 20/23 patients (87.0%) for RECIST (kappa = 0.62) and WHO ( kappa = 0.67) methods placing patients into partial response (2 patients by RECIST and WHO), stable disease (17 patients by RECIST, 16 patients by WHO), and disease progression (1 patient by RECIST, 2 patients by WHO)categories by accepted criteria. No significant difference in prediction of TTP between methods was found. Conclusions: Our pilot data suggests our qualitative scoring system may be at least as reproducible and predictive of patient clinical outcome as the RECIST and WHO methods. No significant financial relationships to disclose.
Allograft steatosis is a feature of progressive familial intrahepatic cholestasis, type 1 (FIC1 disease), treated by orthotopic liver transplantation (OLTX).
Authors: G Bhagat, S J Lobritto, J H Lefkowitch, B Bourke, M McDermott, B C Portmann, S S Strautnieks, R J Thompson, B B Dahms, R Jaffe, S A Kocoshis, L N Bull, A S Knisely
Journal: Hepatology (2001)
Papillary and Follicular Thyroid Carcinoma
Authors: Martin Jean Schlumberger
Journal: New England Journal of Medicine (1998)

Papillary and follicular (differentiated) thyroid carcinomas are among the most curable cancers. However, some patients are at high risk for recurrent disease or even death. Most of these patients can be identified at the time of diagnosis by using well-established prognostic indicators. The extent of the initial treatment and follow-up care should therefore be tailored to the level of risk. Although treatment guidelines have been published,1,2 clinical procedures vary considerably among clinicians.3 EpidemiologyAlthough thyroid nodules are common, differentiated thyroid carcinomas are relatively rare. Clinically detectable thyroid carcinomas constitute less than 1 percent of all human cancers. The annual . . .
Canicola Fever in Man from Contact with Infected Pigs
Authors: J. D. Coghlan, J. Norval
Journal: BMJ (1960)

MEDB'umwJOL 1711Before we had identified the viruses we isolated, Dr. L. A. Galloway, of the Foot and Mouth Research Centre at Pirbright, kindly examined sera from two patients for us, but found no evidence of any antibodies against any of the standard types of foot-and-mouth disease virus.Summary An outbreak of mild infection characterized by vesicular lesions in the mouth and on the hands and feet occurred in Birmingham in the summer of 1959.A few patients also had a maculo-papular rash on the buttocks.Coxsackie group A type 16 virus was isolated from vesicle fluid from the hands of one.The disease was similar to that described by Robinson et al. (1958) as occurring in Toronto in 1957.Our thanks are due to Dr. D. Hobson for the cultures of baboon-kidney cells, and to Dr. J. Hotchin for the prototype coxsackie A 16 virus.The technical work described will form part of a thesis for the F.I.M.L.T. by one of us (J.R. F.).Our thanks are also due to the College of General Practitioners, whose Epidemic Observation Unit enabled us to collect as many cases as we
Leptomeningeal metastases: A rano proposal for response criteria.
Authors: Marc C. Chamberlain, Larry Junck, Dieta Brandsma, Riccardo Soffietti, Jeffrey J. Raizer, Roberta Ruda, Willem Boogerd, Sophie Taillibert, Morris D. Groves, Emilie Le Rhun, Jacoline E Bromberg, Martin J. Van Den Bent, Patrick Y. Wen, Kurt A. Jaeckle
Journal: Journal of Clinical Oncology (2014)

e13019 Background: Leptomeningeal metastasis (LM) currently lacks standardization with respect to response assessment. Methods: Investigators with expertise in LM developed a consensus proposal for evaluating patients treated with LM. Results: Three basic elements in assessing response in LM are proposed; a standardized neurological examination, CSF cytology or parametric flow cytometry and radiographic evaluation. The group recommends that all patients enrolling in clinical trials undergo CSF analysis (cytology in all cancers; flow cytometry in hematologic cancers), complete contrast-enhanced neuraxis MRI and in instances of planned intra-CSF therapy, radioisotope CSF flow studies. In conjunction with the Response Assessment in Neuro-Oncology (RANO) Neurological Assessment Working Group, a standardized instrument was created for assessing the neurological exam in patients with LM. Response based on CSF cytology is considered when CSF converts from positive to negative at all previously positive sites, and with a confirmatory determination after 4 weeks. CSF flow cytometry is a quantitative analysis that also utilizes a binary outcome, i.e. positive or negative. Either CSF cytology (assessed in all patients) or CSF flow cytometry (assessed in patients with hematologic cancers), if unresponsive, constitutes progressive (refractory) disease irrespective of neurological or radiological determination. Considering that most lesions in LM are non-measurable and that assessment of neuroimaging in LM is subjective, neuroimaging is graded as stable, progressive or improved using radiological LM response criteria. Radiographic disease progression in isolation i.e. negative CSF cytology/flow cytometry and stable neurological assessment would be defined as LM disease progression. Conclusions: RANO LM has proposed a method of response evaluation for patients with LM that will require further testing, validation and likely refinement with use.