tbuckley/cabot-search huggingface dataset:
Absolute Assignment of Breast Cancer Intrinsic Molecular Subtype
Authors: Eric R. Paquet, Michael T. Hallett
Journal: JNCI Journal of the National Cancer Institute (2014)

Massively parallel gene expression profiling has provided a more objective, molecular-level characterization of breast cancer subtypes. Several bioinformatics tools are available to infer patient subtype from a gene expression profile including the well-studied PAM50. The specific algorithmic methods used in these tools require access to a broad patient dataset. The choice of subtype for an individual is determined relative to all other patients across the panel, making subtypes heavily dependent on the composition of the dataset. Our aim was to develop a bioinformatics approach assigning absolute breast cancer subtypes, independent of dataset composition. Using a dataset of 4924 breast cancer patients, we defined a new bioinformatics approach: Absolute Intrinsic Molecular Subtyping (AIMS) that assigns subtype from a gene expression profile for an individual sample without the need for a large, diverse, and normalized dataset. We evaluated the agreement of AIMS with PAM50 and compared subtype assignment and prognostic value of the subtypes. We assessed AIMS' robustness using a benchmark set of tests including subtype reproducibility between technologies, gene removal, and normal gene expression contamination, and compared it with PAM50. All statistical tests, except where noted, were two-sided. AIMS vastly agreed with PAM50, with 76% and 77% agreement for cross validation and the test set, respectively, and the prognostic capacity of the intrinsic subtypes was preserved. AIMS is fully stable, and its absolute nature enables its use on a wide range of datasets and technologies, including RNA-seq. The instability of a breast cancer subtyping scheme like PAM50 could have important consequences in clinical management of patients. AIMS is a fully stable and robust subtyping scheme that recapitulates PAM50.
Metformin and Colorectal Cancer Risk in Diabetic Patients
Authors: George N. Ioannou, Edward J. Boyko
Journal: Diabetes Care (2011)

There has been substantial interest in investigating whether the long-term administration of metformin to diabetic patients leads to a reduction in the incidence of malignancies in general or more specifically colorectal cancer. A number of studies have been published on this field with mixed results (1,2). In this issue of Diabetes Care , Zhang et al. (3) report the results of a meta-analysis of five observational studies including 108,161 patients with type 2 diabetes. As compared with other antidiabetic treatments combined, use of metformin was associated with a lower risk of colorectal cancer (relative risk 0.63 [95% CI 0.47–0.84]). There was no evidence of significant heterogeneity among the included studies or statistical evidence of publication bias.

Metformin is the first drug of choice for the management of type 2 diabetes (4,5). It has two main antidiabetic mechanisms of action, both of which have also been implicated as anticarcinogenic mechanisms. Firstly, metformin inhibits hepatic glucose production through an LKB1/AMP-activated protein kinase–mediated mechanism. Metformin-induced initiation of an LKB1-mediated AMP-activated protein kinase–dependent energy stress response has been shown to adversely affect the survival of cancer cell lines (6,7). Secondly, metformin improves insulin sensitivity in peripheral tissues reducing hyperinsulinemia. Insulin resistance and hyperinsulinemia have been associated with increased risk of several types of neoplasm (8,9) and specifically with colorectal cancer (10). These mechanistic pathways provide sufficient rationale for investigating the hypothesis that use of metformin is associated with reduced risk of selected malignancies.

It is worth emphasizing that the study by Zhang et al. is a meta-analysis of observational studies and not a meta-analysis of randomized controlled trials. Thus, all the limitations inherent in the original observational studies included in the meta-analysis …
Immunotherapy in patients allergic to cat and dog dander
Authors: L. Haugaard, R. Dahl
Journal: Allergy (1992)

Twenty‐four asthmatics allergic to cat and/or dog dander were included in a study to examine the efficacy and safety of immunotherapy (IT) with partially purified, standardized extracts of cat or dog dander. In the first placebo controlled, double‐blind part of the study, 10 patients were treated with extracts of both eat and dog, 12 with cat extracts and 2 with dog extracts. Fifteen patients received active IT and 9 placebo injections. Patients treated with both extracts received active extracts only, or placebo only. Bronchial allergen challenge after 5 months demonstrated a significant fall in sensitivity to eat (P = 0.04) in patients treated with cat extracts. No significant changes were found in sensitivity to dog after treatment with dog dander extract or in the placebo groups. During this period, bronchial sensitivity to histamine did not change significantly in any of the groups. To examine the effect of more prolonged IT, 19 patients allergic to cat (17) and/or dog (9) were treated for 12 months. Bronchial sensitivity to cat decreased further (P = 0.003), while no significant change was found in dog extract‐treated patients. In cat extract‐treated patients a significant decrease in bronchial histamine sensitivity developed (P = 0.02). Systemic side effects were few, but in some eases, local side effects were a dose‐limiting factor. This study demonstrated that IT with cat extract may benefit cat‐allergic asthmatics, whereas no influence of IT with dog extract was detected in dog‐sensitive asthmatics.
S152 Dexamethasone reverses established monocrotaline-induced pulmonary hypertension in rats and increases pulmonary BMPR2 expression
Authors: L. C. Price, S. J. Wort, D. Montani, C. Tcherakian, P. Dorfmuller, R. Souza, D. Shao, G. Simonneau, L. S. Howard, I. Adcock, M. Humbert, F. Perros
Journal: Thorax (2010)

<h3>Background</h3> Pulmonary arterial hypertension (PAH) is associated with pulmonary vascular inflammation and dysregulated bone morphogenetic protein receptor type 2 (BMPR2) signalling in both human and experimental PAH. We evaluated the effects of dexamethasone on established monocrotaline-induced PAH in rats for potential reversal of PAH, at time points when pulmonary vascular remodelling has already developed (from day 14 after a single injection of monocrotaline at day 0), and for the effects on pulmonary IL6 and BMPR2 expression. <h3>Methods</h3> Saline-treated controls, monocrotaline-exposed, monocrotaline-exposed and dexamethasone-treated rats (5 mg/kg/day, 1.25 mg/kg and 2.5 mg/kg/48 h given from day 14–28 and day 21–35) were evaluated at day 28 and day 35 following monocrotaline for pulmonary vascular haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, whole lung <i>IL-6</i> and <i>BMPR2</i> expression by quantitative real-time PCR (qRT-PCR). <h3>Results</h3> Dexamethasone significantly improved pulmonary haemodynamics and morphometric indices of pulmonary vascular remodelling, reversing PAH when given at day 14–28, day 21–35 following monocrotaline, as well as improving survival in monocrotaline-exposed rats compared to controls (log rank p&lt;0.0001). Dexamethasone reduced both monocrotaline-induced whole lung <i>IL-6</i> overexpression (p&lt;0.05), as well as reducing IL-6-expressing adventitial inflammatory cell infiltration as assessed by immunohistochemistry. This was associated with pulmonary <i>BMPR2</i> down-regulation (p&lt;0.01) following monocrotaline, which was significantly increased following day 14–28 dexamethasone treatment in whole lung (p&lt;0.05) (Abstract S152 Figure 1). Cellular <i>BMPR2</i> was also increased following <i>in vitro</i> treatment of control pulmonary artery smooth muscle cells (PASMC) with ×10<sup>−8</sup> molar dexamethasone (p&lt;0.05), but not in PASMC isolated from pulmonary hypertensive rats. Dexamethasone (×10<sup>−8</sup> and 10<sup>−7</sup> molar) also reduced proliferation of PASMC isolated from both control and pulmonary hypertensive rats (p&lt;0.05 for both doses). <h3>Conclusion</h3> PAH in this well-characterised experimental model can be reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, reduced proliferation of vascular smooth muscle cells, and restoration of pulmonary <i>BMPR2</i> expression may be important.
Alcohol and ADH2 in Israel: Ashkenazis, Sephardics, and Recent Russian Immigrants
Authors: Deborah Hasin, Efrat Aharonovich, Xinhua Liu, Ziona Mamman, Karen Matseoane, Lucinda Carr, Ting-Kai Li
Journal: American Journal of Psychiatry (2002)

Jews drink less than other Caucasians and have a higher prevalence of ADH2*2, an allele of an alcohol dehydrogenase gene that protects against heavy drinking. The relationship of ADH2 polymorphisms to lifetime maximum number of drinks per occasion was investigated in recent Russian immigrants to Israel (exposed to heavier drinking in their country of origin), other Israeli Ashkenazis, and Sephardics.Seventy-five randomly sampled Israelis participated in a structured interview. ADH2 was genotyped for 68 subjects.ADH2*2 predicted less drinking; however, associations between ADH2 and drinking appeared to differ across the groups, consistent with differences in environmental exposure to heavy drinking.The findings support a protective effect for ADH2*2 against heavy drinking in Jewish samples but also suggest the importance of environment. Future work should investigate interactions between genes and the environment in larger samples.
Epstein-Barr virus-specific cytotoxic T lymphocytes as probes of HLA polymorphism. Heterogeneity of T cell-restricting determinants associated with the serologically defined HLA-A2 antigen.
Authors: J S Gaston, A B Rickinson, M A Epstein
Journal: The Journal of Experimental Medicine (1983)

Epstein-Barr (EB) virus-specific effector T cell lines were established from nine virus-immune donors positive for the serologically defined HLA-A2 antigen; of these, four lines contained a demonstrable A2-restricted cytotoxic component. When these four effector populations were each tested on the same panel of EB virus-transformed lines from 20 HLA-A2-positive individuals, 16 of the target cell lines were consistently killed at levels above 25% of the relevant autologous cell lysis. Cytotoxicity appeared to be mediated through a restricting determinant associated with the 'common A2' antigen that these lines shared; indeed the lysis could be specifically blocked by high concentrations of an HLA-A2-specific monoclonal antibody. In contrast, 4 out of 20 target cell lines were not killed by HLA-A2-restricted effector cells, even though they did express the serologically defined A2 antigen and were found in other tests to be susceptible to EB virus-specific cytolysis restricted through other HLA-A or -B antigens on their surface. These results suggest that EB virus-specific cytotoxic T cells can distinguish between serologically identical HLA-A2 molecules via the heterogeneity of their T cell-restricting determinants. Data from one of the effector cell populations further suggested that a serologically defined cross-reaction between the otherwise distinct HLA-A2 and -Bw57 antigens might also be reflected in a cross-reactivity of T cell-restricting determinants.
Effect of pacing-induced ischemia on left ventricular diastolic pressure-volume relations in dogs with coronary stenoses.
Authors: T Serizawa, B A Carabello, W Grossman
Journal: Circulation Research (1980)

Mechanisms involved in altering left ventricular (LV) diastolic properties during angina were studied in 10 chloralose-anesthetized dogs with chest and pericardium open.Proximal coronary artery stenoses of >90% were created in both left anterior descending and circumflex coronary arteries to abolish reactive hyperemia, and the heart was paced at nearly twice its resting rate (115 ± 4 to 200 ± 5 beats/min).After pacing, increases occurred in LV end-diastolic pressure (EDP, 10 ± 2 to 21 ± 2 mm Hg, P< 0.001), LV minimum diastolic pressure (5 ± 1 to 13 ± 2 mm Hg, P< 0.001), LV end-diastolic volume (55 ± 3 to 60 ± 2 ml, P < 0.001), LV end-systolic volume (28 ± 2 to 33 ± 2 ml, P < 0.001), right ventricular (RV) systolic pressure (RVP, 27 ± 2 to 32 ± 2 mm Hg, P < 0.01), RVEDP (5 ± 1 to 6 ± 1 mm Hg, P < 0.05), and time constant (T) of LV pressure fall in diastole (35 ± 4 to 53 ±4 msec, P < 0.001).Decreases occurred in LV peak systolic pressure (121 ± 5 to 102 ± 5 mm Hg, P< 0.001), LV maximum negative dp/dt (2300 ± 158 to 1319 ± 154 mm Hg/sec, P< 0.001), and LV ejection fraction (0.49 ± 0.02 to 0.44 ± 0.03, NS), whereas heart rate was not significantly different.LV diastolic pressure-volume curves were shifted upward for each dog; at any diastolic volume, pressure was higher than control.In four dogs, the pulmonary artery was abruptly constricted, and saline was infused to produce an acute increase in RV loading (RVP, 29 ± 1/6 ± 1 to 67 ± 5/11 ± 1 mm Hg, P < 0.001/P< 0.001), and the effect on the LV diastolic pressure-volume relation was examined.Only minor changes in this relation could be detected in contrast to the changes with pacing-induced ischemia.Since the upward shift in the LV diastolic pressure-volume curve in our ischemia model occurred in the absence of the pericardium and was associated with only small changes in RVEDP, we conclude that altered myocardial diastolic properties play an important role in this phenomenon.
Activation of Human Neutrophil by Cytokine-Activated Endothelial Cells
Authors: Tatsuji Takahashi, Fumihiko Hato, Takahisa Yamane, Hiroshi Fukumasu, Kenichi Suzuki, Sachio Ogita, Yoshiki Nishizawa, Seiichi Kitagawa
Journal: Circulation Research (2001)

Abstract —Cytokine activation of vascular endothelial cells renders the hyperadhesiveness for neutrophils. During the processes of inflammation and atherosclerosis, the production of reactive oxygen species by neutrophils contributes to endothelial cell (EC) damage and injury. However, the precise mechanisms for neutrophil activation by ECs remain unknown. Thus, we investigated what kinds of pathophysiological factors synthesized by inflammatory cytokine-activated ECs potentiated the activity of neutrophil functions. The magnitude of O 2 − release from neutrophils, which is one of pivotal neutrophil functions, was measured as an indicator potentiated by activated ECs. Neutrophils release massive amounts of O 2 − on coculture with activated ECs. Anti–granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody (Ab) or specific platelet-activating factor (PAF)-receptor antagonist suppressed the O 2 − release from neutrophils on coculture with the activated ECs by 50% to 70%. The supernatants from activated ECs also induced O 2 − release by neutrophils. This stimulatory effect of activated EC supernatants on O 2 − release by neutrophils was abolished by anti–GM-CSF Ab or by PAF-receptor antagonist. As we previously reported, we demonstrated the expression of GM-CSF mRNA by Northern blotting and protein synthesis of GM-CSF by ELISA on tumor necrosis factor as well as interleukin-1–activated ECs. Although phosphorylation of mitogen-activated protein kinases was observed in ECs stimulated by tumor necrosis factor and interleukin-1, treatment of ECs with PD98059 (MEK1 inhibitor) and SB203580 (p38 mitogen–activated protein kinase inhibitor) in the presence of the cytokine failed to attenuate the stimulatory effect of activated ECs on neutrophil activation. We found that activated ECs regulated neutrophil function on coculture. We show here for the first time, to our knowledge, that the collaboration between GM-CSF and PAF synthesized by activated ECs markedly potentiated neutrophil activation.
Characterization of a potentially reversible increase in beta-adrenergic receptors in isolated, neonatal rat cardiac myocytes with impaired energy metabolism.
Authors: L M Buja, K H Muntz, T Rosenbaum, Z Haghani, D K Buja, A Sen, K R Chien, J T Willerson
Journal: Circulation Research (1985)

Previous studies have reported that the numbers of beta- and alpha-adrenergic receptors increase in ischemic myocardium. In vivo studies have raised questions regarding the mechanisms involved in the adrenergic receptor alterations and the consequences of these alterations. The purpose of this study was to evaluate potential relationships among beta-adrenergic receptor changes, high energy phosphate reduction, and severity of cell injury in cultured neonatal rat myocytes treated with metabolic inhibitors. The potential for reversal of the receptor changes also was addressed. Binding parameters were measured using [125I]iodocyanopindolol. After 4 hours incubation in potassium cyanide and 2-deoxyglucose, there was a 43% increase in beta-adrenergic receptor number, 41% decrease in adenosine triphosphate, and minimal morphological change in myocytes. Twenty-four hours after removal of the inhibitors, myocytes exhibited a return to normal of the receptor number and adenosine triphosphate level. Iodoacetate treatment for up to 3 hours resulted in marked reduction in adenosine triphosphate and increasing severity of cell injury. The number of beta-adrenergic receptors was unchanged at 1.2 hours, increased at 1.5-2 hours, and decreased at 3 hours. Thus: beta-adrenergic receptor density increases during relatively early stages of injury in metabolically impaired myocytes with reduced adenosine triphosphate levels and decreases subsequently, after the myocytes become irreversibly injured; the increased beta-adrenergic receptor density in moderately injured myocytes can be reversed upon removal of the injurious agent and restoration of the cellular adenosine triphosphate level; and changes in catecholamines mediated by an intact nervous system are not required for an increase in beta-adrenergic receptor density in the setting of impaired energy metabolism.
Effects of cromolyn and nedocromil on ion currents in canine tracheal smooth muscle
Authors: LJ Janssen, J Wattie, PA Betti
Journal: European Respiratory Journal (1998)

Cromolyn and nedocromil are often used in the treatment of asthma. Recently, these agents have been shown to block Cl- currents and/or Ca2+ currents in a variety of cell preparations. Ca2+ and Cl- currents play central roles in excitation-contraction coupling in airway smooth muscle. This study therefore aimed to investigate the effects of these agents on membrane currents, elevations of [Ca2+] and contractions evoked by depolarization and/or acetylcholine in airway smooth muscle. Patch-clamp, fura-2 fluorimetric and muscle-bath techniques were used to monitor ion currents, [Ca2+] and contractions, respectively, in canine tracheal smooth muscle in the presence and absence of the chromones. Cromolyn and nedocromil eliminated voltage-dependent Ca2+ currents, leading to a reduction in depolarization-evoked K+ currents. Both chromones had little or no effect on either acetylcholine-evoked release of internal Ca2+ or the subsequent contraction; however, cromolyn (but not nedocromil) at high concentrations suppressed Ca2+-dependent Cl- currents triggered by acetylcholine. In conclusion, cromolyn and nedocromil abolished voltage-dependent Ca2+ currents and cromolyn also suppressed Ca2+-dependent Cl- currents in airway smooth muscle; neither chromone greatly altered either the release of internally sequestered Ca2+ or the resultant contractions. Further investigation is needed to determine whether the local concentrations obtained by inhaled chromones within the airway wall allow these cellular effects to occur in patients in vivo.
Genetic association between methyl-CpG binding protein 2 (MECP2) and primary Sjogren's syndrome
Authors: B. L. Cobb, Y. Fei, R. Jonsson, A. I. Bolstad, J. G. Brun, M. Rischmueller, S. E. Lester, T. Witte, G. Illei, M. Brennan, S. Bowman, K. L. Moser, J. B. Harley, A. H. Sawalha
Journal: Annals of the Rheumatic Diseases (2010)

Primary Sjogren's syndrome (pSS) is a complex autoimmune disease that is incompletely understood. The principal manifestations of pSS are dry eyes and dry mouth due to lymphocytic infiltration of the salivary and lacrimal glands. Like lupus, women are affected by pSS over nine times more than with men. The association of human leucocyte antigen loci with pSS and other autoimmune diseases is well documented.1,–,3

A genetic association of the methyl-CpG binding protein 2 ( MECP2 ) gene with lupus has been reported and confirmed in multiple independent cohorts.4 5 Herein, we examine the genetic association between MECP2 and pSS in a large cohort of pSS patients and healthy controls.

We studied a cohort of 460 European-derived independent pSS patients (423 women and 37 men) and 1828 ethnically matched normal healthy controls (1279 women and 549 men). All patients fulfiled the American–European Consensus Group classification criteria for pSS.6 Our study protocols were …
Double‐blind, placebo‐controlled evaluation of sublingual immunotherapy with standardized olive pollen extract in pediatric patients with allergic rhinoconjunctivitis and mild asthma due to olive pollen sensitization
Authors: D. Vourdas, E. Syrigou, P. Potamianou, F. Carat, T. Batard, C. André, P. S. Papageorgiou
Journal: Allergy (1998)

For evaluation of the efficacy and the safety of specific sublingual immunotherapy with high allergen dose, 66 children with seasonal asthma, rhinitis, and conjunctivitis due to sensitization to olive pollen were enrolled in a double‐blind, randomized, placebo‐controlled study between October 1994 and October 1996 in Greece. Thirty‐four patients were randomly allocated to the active group, and 32 received placebo. Immunotherapy consisted of olive‐allergen extracts (Stallergenes SA) administered sublingually pre‐ and coseasonally from January to July for 2 consecutive years. Serial concentrations from 1 to 300 IR were used up to the maintenance dose of 20 drops of 300 IR daily. The cumulative dose for each patient was 300 times higher than in parenteral immunotherapy, and the cumulative dose of the major allergen Ole e 1 was 8.1 mg/2 years. The patients were assessed by clinical parameters (symptom and medication scores from patients' daily diaries) and immunologic measurements (specific IgE. lgG4. eosinophil cationic protein [ECP]) were performed. The actively treated patients had a significantly lower score for dyspnea (P&lt;0.04 during the first season; P&lt;0.03 during the second season). At the poUinic peak during the second year, a lower score of conjunctivitis was recorded (P&lt;0.05) in the actively treated patients. The analysis of intragroup evolution showed that the total score of rhinitis increased significantly during the pollinic peak in the group under placebo, whereas there was no symptomatic peak for the same period in the group under active treatment. However, the difference between the groups was not significant. The medication score did not differ significantly between the groups. Oral steroids were the only variables with a P value near the significance level (P=0.06) in favor of the actively treated group. A significant decrease in skin reactivity was recorded in the active group after 2 years of treatment. No significant variation in specific IgE and IgG4 was detected. A significantly lower level of serum ECP was observed at the pollinic peak in the actively treated patients during the first pollen season (P=0.01), but this was not confirmed the second year when the ECP levels doubled in both groups without correlation to the clinical findings. Tolerance was excellent with only a few minor side‐effects reported. In conclusion, high‐dose specific sublingual immunotherapy appears to be safe and effective in improving mild seasonal asthma and conjunctivitis linked to olive‐pollen sensitization.