tbuckley/cabot-search huggingface dataset:
Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer
Authors: Alexander W Wyatt, Fan Mo, Kendric Wang, Brian McConeghy, Sonal Brahmbhatt, Lina Jong, Devon M Mitchell, Rebecca L Johnston, Anne Haegert, Estelle Li, Janet Liew, Jake Yeung, Raunak Shrestha, Anna V Lapuk, Andrew McPherson, Robert Shukin, Robert H Bell, Shawn Anderson, Jennifer Bishop, Antonio Hurtado-Coll, Hong Xiao, Arul M Chinnaiyan, Rohit Mehra, Dong Lin, Yuzhuo Wang, Ladan Fazli, Martin E Gleave, Stanislav V Volik, Colin C Collins
Journal: Genome biology (2014)

Genomic analyses of hundreds of prostate tumors have defined a diverse landscape of mutations and genome rearrangements, but the transcriptomic effect of this complexity is less well understood, particularly at the individual tumor level. We selected a cohort of 25 high-risk prostate tumors, representing the lethal phenotype, and applied deep RNA-sequencing and matched whole genome sequencing, followed by detailed molecular characterization. Ten tumors were exposed to neo-adjuvant hormone therapy and expressed marked evidence of therapy response in all except one extreme case, which demonstrated early resistance via apparent neuroendocrine transdifferentiation. We observe high inter-tumor heterogeneity, including unique sets of outlier transcripts in each tumor. Interestingly, outlier expression converged on druggable cellular pathways associated with cell cycle progression, translational control or immune regulation, suggesting distinct contemporary pathway affinity and a mechanism of tumor stratification. We characterize hundreds of novel fusion transcripts, including a high frequency of ETS fusions associated with complex genome rearrangements and the disruption of tumor suppressors. Remarkably, several tumors express unique but potentially-oncogenic non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression. Finally, one ETS-negative tumor has a striking tandem duplication genotype which appears to be highly aggressive and present at low recurrence in ETS-negative prostate cancer, suggestive of a novel molecular subtype. The multitude of rare genomic and transcriptomic events detected in a high-risk tumor cohort offer novel opportunities for personalized oncology and their convergence on key pathways and functions has broad implications for precision medicine.
The influence of lung volume reduction surgery on exercise in patients with COPD
Authors: T.E. Dolmage, T.K. Waddell, F. Maltais, G.H. Guyatt, T.R.J. Todd, S. Keshavjee, S. van Rooy, B. Krip, P. LeBlanc, R.S. Goldstein
Journal: European Respiratory Journal (2003)

Although the influence of lung volume reduction surgery (LVRS) on incremental- and constant-power exercise is important in the evaluation of this procedure for patients with chronic obstructive pulmonary disease (COPD), it is rarely reported even in large randomised controlled trials. This report describes 39 patients with severe COPD ((mean +/- SE) forced expiratory volume in one second 32 +/- 2% pred, functional residual capacity 195 +/- 6% pred) who participated in a randomised controlled trial of LVRS and who completed incremental exercise tests at 6 months as well as endurance tests (constant power of 25 +/- 1 W) at 3, 9 and 12 months. Peak oxygen uptake (V'O2,pk) was similar between the treatment (n = 19) and control groups (n = 20) at baseline. After LVRS, the treatment group had a significantly greater V'O2,pk (mean difference (95% CI) 1.28 (0.07-2.50) mL x kg x min(-1)) and power (13 (6-20) W). The treatment group achieved a significantly greater minute ventilation (7.1 (2.9-11.3) L x min(-1)) with a greater tidal volume (0.16 (0.04-0.28) L). Baseline endurance was similar between groups. After surgery, there were significant between-group differences in endurance time, which were maintained at 12 months (7.3 (3.9-10.8) min). Lung volume reduction surgery is associated with an increase in exercise capacity and endurance, as compared with conventional medical treatment.
Racial Differences in Advanced Colorectal Cancer Outcomes and Pharmacogenetics: A Subgroup Analysis of a Large Randomized Clinical Trial
Authors: Hanna K. Sanoff, Daniel J. Sargent, Erin M. Green, Howard L. McLeod, Richard M. Goldberg
Journal: Journal of Clinical Oncology (2009)

Purpose Racial disparities in colorectal cancer (CRC) survival are documented, but there are few data on comparative response to chemotherapy. A subgroup analysis of a multisite National Cancer Institute–sponsored trial (N9741) was performed comparing outcomes of black and white patients with metastatic CRC receiving uniform treatment. Patients and Methods Adverse events (AEs), response rate (RR), time to progression (TTP), overall survival (OS), and dose-intensity were examined as a function of self-reported race in 1,412 patients treated with irinotecan/fluorouracil, fluorouracil/oxaliplatin, or irinotecan/oxaliplatin. Pharmacogenetic analysis was performed on 486 patients with blood available for germline DNA analysis. Results OS was 1.5 months shorter and TTP was 0.6 months shorter in black than white patients (OS: hazard ratio [HR] = 1.13; 95% CI, 0.90 to 1.42; TTP: HR = 0.91, 95% CI, 0.73 to 1.13); neither difference was statistically significant. RR was significantly higher in whites (41%) than blacks (28%; P = .008). Grade 3 or greater AEs were also higher in whites (48%) than blacks (34%; P = .004). These relationships were maintained in multivariate models adjusting for arm, age, sex, and performance status. There was no difference in dose-intensity of delivered therapy. Significant racial differences in prevalence of pharmacogenetic variants were observed, although small sample size precluded investigating the relationship between treatment, race, and genotype. Conclusion OS and TTP are similar in black and white patients treated per protocol with standardized therapy for metastatic CRC. However, RR and AEs vary considerably by race. The marked racial differences in relevant pharmacogenetics, a potential explanation for differing RR and AEs, are worthy of future study.
Infection of human immunodeficiency virus 1 transgenic mice with Toxoplasma gondii stimulates proviral transcription in macrophages in vivo.
Authors: R T Gazzinelli, A Sher, A Cheever, S Gerstberger, M A Martin, P Dickie
Journal: The Journal of Experimental Medicine (1996)

Human immunodeficiency virus (HIV) 1 transgenic mice expressing low or undetectable levels of viral mRNA in lymphoid tissue were infected with the intracellular protozoan Toxoplasma gondii. Exposure to this parasite resulted in an increase in HIV-1 transcript in lymph nodes, spleens, and lungs during the acute phase of infection and in the central nervous system during the chronic stage of disease. In vivo and ex vivo experiments identified macrophages as a major source of the induced HIV-1 transcripts. In contrast, T. gondii infection failed to stimulate HIV-1 transcription in tissues of two HIV-1 transgenic mouse strains harboring a HIV-1 proviral DNA in which the nuclear factor (NF) kappa B binding motifs from the viral long terminal repeats had been replaced with a duplicated Moloney murine leukemia virus core enhancer. A role for NF-kappaB in the activation of the HIV-1 by T. gondii was also suggested by the simultaneous induction of NF-kappaB binding activity and tumor necrosis factor alpha synthesis in transgenic mouse macrophages stimulated by exposure to parasite extracts. These results demonstrate the potential of an opportunistic pathogen to induce HIV-1 transcription in vivo and suggest a mechanism for the in vivo dissemination of HIV-1 by macrophages.
How early in the course of rheumatoid arthritis does the excess cardiovascular risk appear?
Authors: Anne M Kerola, Markku J Kauppi, Tuomas Kerola, Tuomo V M Nieminen
Journal: Annals of the Rheumatic Diseases (2012)

Rheumatoid arthritis (RA) is a chronic inflammatory disease which is associated with an increased cardiovascular (CV) burden. Whether the risk is already present at the time of RA diagnosis remains a key area of debate. The aim of this review was to evaluate the existence of both subclinical CV changes, including endothelial dysfunction and atherosclerosis, CV risk factors, as well as CV disease manifestations such as coronary heart disease, myocardial infarction, congestive heart failure and CV death prior to RA diagnosis and during the first few years of the disease. The state of the endothelial function remains controversial in patients with newly diagnosed RA. Studies with impaired brachial artery vasodilatory responses at baseline showed a reversal of the dysfunction after 6–12 months of anti-inflammatory therapy. Morphological evidence of arterial wall atherosclerosis, measured by carotid artery intima-media thickness or the prevalence of carotid plaques, was already present during the first year following RA diagnosis. The risk of coronary heart disease and myocardial infarction is increased even prior to and, at the latest, within 1 year of the clinical onset of RA. The prevalence of hypertension was similar among patients with RA and controls. CV mortality may not increase within the first years of RA diagnosis. In conclusion, the CV risk seems to increase sooner after the RA diagnosis than previously thought. In addition to systematic CV risk assessment, patients with early RA might benefit from being targeted with stricter than conventional CV risk prevention and intervention.
Plasma Adiponectin as a Marker of Insulin Receptor Dysfunction
Authors: Robert K. Semple, Elaine K. Cochran, Maria A. Soos, Keith A. Burling, David B. Savage, Phillip Gorden, Stephen O'Rahilly
Journal: Diabetes Care (2008)

Severe insulin resistance is associated with high morbidity. Identification of severely insulin-resistant patients who have genetic or acquired insulin receptor dysfunction may aid therapeutic decision making; however, onerous diagnostic tests allied to a low frequency of insulin receptor dysfunction often preclude formal diagnosis. Our previous observation of paradoxical hyperadiponectinemia in insulin receptoropathy provides a possible basis for a simpler and cheaper screening test.
Differential effect of IFN alpha-2b and ribavirin on the HCV-RNA level in primary cultures of human hepatocytes derived from chronic HCV carriers and of human hepatocytes infected in vitro
Authors: C. Clarysse, F. Nevens, J. Pirenne, R. Aerts, A. Soumillion, N. Roberts, S.H. Yap
Journal: Journal of Hepatology (1998)
Clinical characteristics and course of chronic lymphocytic leukemia patients with the combination favorable and unfavorable cytogenetics
Authors: R. R. Harting, P. Venugopal, W. Hsu, R. Catchatourian, O. Ogundipe
Journal: Journal of Clinical Oncology (2007)

8086 Background: Patients with CLL have a highly variable clinical course. Genomic aberrations detected by FISH have been shown to correlate with survival and treatment free interval (TFI). Patients with the presence of 17p or 11q deletions (del) either alone or in combination with other cytogenetic abnormalities have the worst prognosis while patients with 13q del as a sole abnormality have the best prognosis. Our objective was to further investigate poor prognosis CLL patients with either del 17p or 11q to determine if the addition of the favorable 13q del influences the predicted clinical course and survival. Methods: We performed a retrospective chart review on 22 patients (pts) who had been identified by FISH as having either the combination of del 17p and 13q or del 11q and 13q. Results: 128 CLL FISH panels were performed from April of 2003 through October of 2006. Twenty-two pts (17%) had either del 17p and 13q (9%) or del 11q and 13q (9%). Historical data notes a frequency of 7% and 8% for deletions 17p and 11q, respectively, and 55% for 13q as a sole aberration. The median age was 66 yrs, the majority of whom were male (73%). Two of 22 pts (9%) presented with advanced stage disease. Splenomegaly was seen more often in the 17p/13q pts (36%) vs 11q/13q pts (9%). With a median follow up of 46 months since diagnosis, the median TFI for all patients (20 known) was 56 months. TFI was 13 months for patients with 17p/13q del; whereas TFI was not reached for patients with 11q/13q. Historical data noted a TFI for patients with deletions 17p, 11q, and 13q (as a sole aberration) as 9, 13, and 92 months respectively. The median survival from diagnosis was not reached for the group overall or for either combination of genetic abnormalities. Historical data noted, with 70 months follow up, a median survival of 108 months overall and 32, 79, and 133 months for 17p, 11q, and 13q (as a sole aberration) respectively. Conclusions: The addition of favorable cytogenetics, del 13q, in a CLL patient with an unfavorable cytogenetic pattern (either del 17p or del 11q) appears to improve the predicted clinical outcome and survival. Additional follow up and prospective studies are needed to further define which genetic subgroups help to prognosticate CLL patients. No significant financial relationships to disclose.
Delayed myocardial ischemia induced by anger.
Authors: R L Verrier, E L Hagestad, B Lown
Journal: Circulation (1987)

The objectives of this study were to develop a reproducible behavioral model that simulates the anger state and to characterize its influence on myocardial blood flow in both the normal and compromised coronary circulations. Fourteen mongrel dogs of both sexes were studied. The animals were instrumented for the recording of electrocardiogram, arterial blood pressure, and left circumflex coronary arterial blood flow. A critical level of coronary stenosis was achieved with an adjustable occluder placed just distal to the flow probe. Anger was induced in the instrumented animals by having another dog challenge their access to food. In the absence of coronary artery stenosis, provocation of anger increased heart rate from 107 +/- 6 to 215 +/- 15 beats/min, arterial blood pressure from 95 +/- 4 to 142 +/- 5 mm Hg, and coronary blood flow from 31 +/- 5 to 72 +/- 9 ml/min. These variables returned to the preanger levels within 2 to 4 min. Induction of anger was repeated after a critical stenosis was applied to the left circumflex coronary artery. Anger increased heart rate from 112 +/- 6 to 210 +/- 16 beats/min, arterial blood pressure from 99 +/- 3 to 142 +/- 6 mm Hg, and coronary arterial flow from 23 +/- 5 to 35 +/- 7 ml/min. Within 2 to 4 min after the bout of anger, all dogs exhibited significant reductions in coronary arterial flow (35% of baseline; p less than .001), increases in coronary vascular resistance (557% of baseline; p less than .002), and ischemic ST segment changes in leads II, III, and aVF.(ABSTRACT TRUNCATED AT 250 WORDS)
Beneficial Effects of a 4-Week Exercise Program on Plasma Concentrations of Adhesion Molecules
Authors: Anke Tönjes, Markus Scholz, Mathias Fasshauer, Jürgen Kratzsch, Fauci Rassoul, Michael Stumvoll, Matthias Blüher
Journal: Diabetes Care (2007)

Plasma concentrations of adhesion molecules are elevated in patients with endothelial dysfunction and atherosclerosis (1), as well as in patients with impaired glucose tolerance (IGT) or type 2 diabetes—even those without angiographic evidence for atherosclerosis (2). Physical activity is associated with reduced risk of cardiovascular disease and total mortality in men with type 2 diabetes (3). The beneficial effects of physical activity could be mediated by improved markers of endothelial dysfunction, including adhesion molecules. We therefore tested the hypothesis that an intensive 4-week physical training program leads to improved plasma concentrations of intracellular …
Possible missed diagnosis of syllogomania
Authors: J. Keeley, V. Keeley, J. Keeley
Journal: BMJ (1996)

been treated for depression in the past.3Which treatment, if any, would be the most effective in such cases has not been established as most trials have been conducted in more severely depressed patients.Randomised trials are needed to establish which is the best treatment for mild depression in primary care.Maybe when general practitioners have clearer evidence of the benefits of treating mild depression, disclosure of the diagnosis will make a difference to outcome.
Identification of Intragenic Methylation in the Tusc1 Gene As a Novel Prognostic Marker of Hepatocellular Carcinoma
Authors: D. Shimizu, M. Kanda, H. Sugimoto, H. Oya, H. Takami, S. Hibino, R. Hashimoto, Y. Okamura, S. Yamada, T. Fujii, G. Nakayama, M. Koike, S. Nomoto, M. Fujiwara, Y. Kodera
Journal: Annals of Oncology (2014)
BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources
Authors: Chunlei Wu, Camilo Orozco, Jason Boyer, Marc Leglise, James Goodale, Serge Batalov, Christopher L Hodge, James Haase, Jeff Janes, Jon W Huss, Andrew I Su
Journal: Genome biology (2009)

Online gene annotation resources are indispensable for analysis of genomics data. However, the landscape of these online resources is highly fragmented, and scientists often visit dozens of these sites for each gene in a candidate gene list. Here, we introduce BioGPS http://biogps.gnf.org, a centralized gene portal for aggregating distributed gene annotation resources. Moreover, BioGPS embraces the principle of community intelligence, enabling any user to easily and directly contribute to the BioGPS platform.
MAPK phosphatase–3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice
Authors: Zhidan Wu, Ping Jiao, Xueming Huang, Bin Feng, Yajun Feng, Shengyong Yang, Phillip Hwang, Jing Du, Yaohui Nie, Guozhi Xiao, Haiyan Xu
Journal: Journal of Clinical Investigation (2010)

Insulin resistance results in dysregulated hepatic gluconeogenesis that contributes to obesity-related hyperglycemia and progression of type 2 diabetes mellitus (T2DM). Recent studies show that MAPK phosphatase-3 (MKP-3) promotes gluconeogenic gene transcription in hepatoma cells, but little is known about the physiological role of MKP-3 in vivo. Here, we have shown that expression of MKP-3 is markedly increased in the liver of diet-induced obese mice. Consistent with this, adenovirus-mediated MKP-3 overexpression in lean mice promoted gluconeogenesis and increased fasting blood glucose levels. Conversely, shRNA knockdown of MKP-3 in both lean and obese mice resulted in decreased fasting blood glucose levels. In vitro experiments identified forkhead box O1 (FOXO1) as a substrate for MKP-3. MKP-3-mediated dephosphorylation of FOXO1 at Ser256 promoted its nuclear translocation and subsequent recruitment to the promoters of key gluconeogenic genes. In addition, we showed that PPARγ coactivator-1α (PGC-1α) acted downstream of FOXO1 to mediate MKP-3-induced gluconeogenesis. These data indicate that MKP-3 is an important regulator of hepatic gluconeogenesis in vivo and suggest that inhibition of MKP-3 activity may provide new therapies for T2DM.
Insulin Resistance and Hyperinsulinemia Are Related to Plasma Aldosterone Levels in Hypertensive Patients
Authors: GianLuca Colussi, Cristiana Catena, Roberta Lapenna, Elisa Nadalini, Alessandra Chiuch, Leonardo A. Sechi
Journal: Diabetes Care (2007)

An association between aldosterone and insulin resistance has been demonstrated in obesity and primary aldosteronism and in blacks with the metabolic syndrome. The aim of this study was to evaluate the relationship of plasma aldosterone with insulin sensitivity in white subjects.In 356 patients with essential hypertension and 102 normotensive control subjects of comparable age and BMI, we measured, after discontinuation of treatment, plasma active renin, aldosterone, cortisol, glucose, insulin, and C-peptide levels and calculated markers of insulin sensitivity. Direct assessment of insulin sensitivity was obtained in a subset of 64 hypertensive patients by a hyperinsulinemic clamp.Hypertensive patients had significantly greater fasting plasma insulin and C-peptide concentrations and homeostasis model assessment (HOMA) indexes than normotensive control subjects. A positive association with increasing plasma aldosterone concentrations was demonstrated for plasma glucose, insulin, C-peptides, and HOMA. Assessment of insulin sensitivity by clamp showed a significant decrease of the metabolic clearance rate of glucose with increasing aldosterone levels. Significant correlations were found between plasma aldosterone, plasma insulin, and C-peptide levels, HOMA, and glucose metabolic clearance rate. Blood pressure and plasma potassium, plasma cortisol, and renin levels, but not BMI, were also directly correlated with plasma aldosterone. Multiple regression analysis showed that HOMA, together with plasma potassium, cortisol, and renin levels, was independently correlated with plasma aldosterone.This study demonstrates a direct relationship between aldosterone, insulin resistance, and hyperinsulinemia in white subjects. In patients with hypertension, this relationship might contribute to maintenance of high blood pressure and increased cardiovascular risk.
Particulate air pollution and the blood
Authors: A. Seaton, A. Soutar, V. Crawford, R. Elton, S. McNerlan, J. Cherrie, M. Watt, R. Agius, R. Stout
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Particulate air pollution has been associated with excess deaths from, and increases in hospital admissions for, cardiovascular disease among older people. A study was undertaken to determine whether this may be a consequence of alterations in the blood, secondary to pulmonary inflammation caused by the action of fine particles on alveolar cells, by repeatedly measuring haematological factors in older people and relating them to measurements of exposure to airborne particles. <h3>METHODS</h3> One hundred and twelve individuals aged 60+ years in two UK cities provided repeated blood samples over 18 months, 108 providing the maximum of 12 samples. Estimates of individual exposure to particles of less than 10 μm diameter (PM<sub>10</sub>), derived from a mathematical model based on activity diaries and comparative measurements of PM<sub>10</sub> at multiple sites and during a variety of activities, were made for each three day period prior to blood sampling. The relationships between blood values and estimates of both personal exposure and city centre measurements of PM<sub>10</sub> were investigated by analysis of covariance, adjusting for city, season, temperature, and repeated individual measurements. <h3>RESULTS</h3> Estimated personal exposure to PM<sub>10</sub> over the previous three days showed negative correlations with haemoglobin concentration, packed cell volume (PCV), and red blood cell count (p&lt;0.001), and with platelets and factor VII levels (p&lt;0.05). The changes in red cell indices persisted after adjustment for plasma albumin in a sample of 60 of the subjects. City centre PM<sub>10</sub> measurements over three days also showed negative correlations with haemoglobin and red cell count (p&lt;0.001) and with PCV and fibrinogen (p&lt;0.05), the relationship with haemoglobin persisting after adjustment for albumin. C reactive protein levels showed a positive association with city centre measurements of PM<sub>10</sub> (p&lt;0.01). Based on a linear relationship, the estimated change in haemoglobin associated with an alteration in particle concentration of 100 μg/m<sup>3</sup> is estimated to have been 0.44 g/dl (95% CI 0.62 to 0.26) for personal PM<sub>10</sub> and 0.73 g/dl (95% CI 1.11 to 0.36) for city centre PM<sub>10</sub> measurements. <h3>CONCLUSIONS</h3> This investigation is the first to estimate personal exposures to PM<sub>10</sub> and to demonstrate associations between haematological indices and air pollution. The changes in haemoglobin adjusted for albumin suggest that inhalation of some component of PM<sub>10</sub>may cause sequestration of red cells in the circulation. We propose that an action of such particles either on lung endothelial cells or on erythrocytes themselves may be responsible for changing red cell adhesiveness. Peripheral sequestration of red cells offers an explanation for the observed cardiovascular effects of particulate air pollution.