tbuckley/cabot-search huggingface dataset:
Androgen Receptor-Independent Function of FoxA1 in Prostate Cancer Metastasis
Authors: Hong-Jian Jin, Jonathan C. Zhao, Irene Ogden, Raymond C. Bergan, Jindan Yu
Journal: Cancer Research (2013)

Abstract FoxA1 (FOXA1) is a pioneering transcription factor of the androgen receptor (AR) that is indispensible for the lineage-specific gene expression of the prostate. To date, there have been conflicting reports on the role of FoxA1 in prostate cancer progression and prognosis. With recent discoveries of recurrent FoxA1 mutations in human prostate tumors, comprehensive understanding of FoxA1 function has become very important. Here, through genomic analysis, we reveal that FoxA1 regulates two distinct oncogenic processes via disparate mechanisms. FoxA1 induces cell growth requiring the AR pathway. On the other hand, FoxA1 inhibits cell motility and epithelial-to-mesenchymal transition (EMT) through AR-independent mechanism directly opposing the action of AR signaling. Using orthotopic mouse models, we further show that FoxA1 inhibits prostate tumor metastasis in vivo. Concordant with these contradictory effects on tumor progression, FoxA1 expression is slightly upregulated in localized prostate cancer wherein cell proliferation is the main feature, but is remarkably downregulated when the disease progresses to metastatic stage for which cell motility and EMT are essential. Importantly, recently identified FoxA1 mutants have drastically attenuated ability in suppressing cell motility. Taken together, our findings illustrate an AR-independent function of FoxA1 as a metastasis inhibitor and provide a mechanism by which recurrent FoxA1 mutations contribute to prostate cancer progression. Cancer Res; 73(12); 3725–36. ©2013 AACR.
CD8-positive tumor-infiltrating lymphocytes influence the long-term survival of patients with mycosis fungoides
Authors: Richard T Hoppe, L.Jeffrey Medeiros, Roger A Warnke, Gary S Wood
Journal: Journal of the American Academy of Dermatology (1995)

Background: Nonneoplastic mononuclear cells commonly infiltrate lesions of mycosis fungoides. Objective: We sought to determine the immunophenotypic characteristics of these cells and to determine whether the presence of CD8+ tumor-infiltrating lymphocytes has an impact on prognosis. Methods: Skin biopsy specimens from 78 patients were stained with immunopleroxidase techniques to determine their phenotypic characteristics. The proportion of CD8+ tumor-infiltrating lymphocytes was quantified and compared with stage of disease and survival rate. Results: Patients with more limited T-stage disease tended to have a higher proportion of CD8+ cells in their skin biopsy specimens, compared with patients with more advanced T-stage disease. Within each T-stage patients with a larger proportion of CD8+ cells had a better survival rate than those with fewer CD8+ cells (p < 0.05 for T1 and T3). A multivariate analysis confirmed the importance of T stage (p = 0.0006), overal stage (p = 0.0112), and CD8 positivity (p = 0.0335) in this cohort of patients. Conclusion: CD8+ tumor-infiltrating lymphocytes in mycosis fungoides correlate with improved survival rate and may exert an antitumor effect rather than being mere bystander cells.
The Early Bactericidal Activity of Isoniazid Related to Its Dose Size in Pulmonary Tuberculosis
Authors: PETER R. DONALD, FREDERICK A. SIRGEL, FREDERICK J. BOTHA, HEINER I. SEIFART, DONALD P. PARKIN, MICHEL L. VANDENPLAS, BERNARD W. VAN de WAL, JOHANNES S. MARITZ, DENIS A. MITCHISON
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Collections of sputum from 105 patients with newly diagnosed pulmonary tuberculosis were made before and at 1 and 2 d after the start of chemotherapy with isoniazid (INH) alone given to groups of patients in doses of 600 mg, 300 mg, 150 mg, 75 mg, 37.5 mg, 18.75 mg, and 9 mg daily, as well as from an untreated group. Counts of colony forming units (cfu) of Mycobacterium tuberculosis in the collections were set up on plates of selective 7H10 medium. The early bactericidal activity (EBA) of INH was defined as the decrease in log10 cfu/ml sputum/day during the first 2 d of treatment. A smooth curve relating EBA to log dose was obtained, with 600 mg INH yielding the highest mean EBA of 0.539, and 18.75 mg INH yielding the lowest EBA (0.111) that could be distinguished from the bactericidal activity of the untreated group. The ratio of the usual dose of 300 mg INH to the lowest dose, of 18.75 mg, that produced a detectable EBA, termed the therapeutic margin, was therefore 16, in contrast to the lower therapeutic margin of 4 for rifampin. The EBA was related to the INH acetylator genotype of patients treated with 600 mg or 9 mg INH.
Why religion is better conceived as a complex system than a norm-enforcing institution
Authors: Richard Sosis, Jordan Kiper
Journal: Behavioral and Brain Sciences (2014)

Abstract Although religions, as Smaldino demonstrates, provide informative examples of culturally evolved group-level traits, they are more accurately analyzed as complex adaptive systems than as norm-enforcing institutions. An adaptive systems approach to religion not only avoids various shortcomings of institutional approaches, but also offers additional explanatory advantages regarding the cultural evolution of group-level traits that emerge from religion.
Endothelial G Protein β-Subunits Trigger Nitric Oxide– but not Endothelium-Derived Hyperpolarizing Factor–Dependent Dilation in Rabbit Resistance Arteries
Authors: Philippe Véquaud, Eric Thorin
Journal: Circulation Research (2001)

A single subtype of heterotrimeric G protein–coupled receptor controls both nitric oxide (NO) (sensitive to l -arginine analogues) and endothelium-derived hyperpolarizing factor (EDHF) (sensitive to high-external K + and apamine) production by the vascular endothelium leading to dilation. We hypothesized that α- and βγ-subunits of the G protein serve as distinct intermediates to produce NO and EDHF. In pressurized resistance arteries, selective pinocytotic endothelial incorporation of specific antibodies (Abs) directed against α q/11 -subunits abolished acetylcholine (Ach)-mediated dilation but failed to influence oxymetazoline (Oxy, α 2 -adrenergic receptor agonist)-induced dilation. In contrast, α i1-2 -subunit Abs prevented Oxy- but not Ach-induced dilation. Thus, as expected, endothelial muscarinic and α 2 -adrenoceptors couple to G q protein and G i proteins, respectively. β-subunit Abs reduced both Ach- and Oxy-induced dilation. The β-subunit Abs abolished the nitro- l -arginine (L-NNA)-sensitive component but did not impair the high-external K + -sensitive component of the dilation induced by Ach and Oxy. Thus, G protein β-subunits primarily accounted for NO production. Neutralization of Hsp90 and inhibition of the phospholipase C by U73122 (1 μmol/L) or intracellular Ca 2+ buffering with BAPTA-AM (10 μmol/L) sharply reduced NO-dependent but not K + -sensitive dilation. In conclusion, mobilization of the G protein β-subunit is pivotal to NO-dependent dilation triggered through muscarinic and α 2 -adrenergic receptors. In contrast, receptor-operated EDHF-dependent dilation was insensitive to β-subunit Abs. Although not directly activating the NO pathway, α-subunit activation is an absolute prerequisite for receptor-operated endothelium-dependent dilation of resistance arteries.
Irinotecan Plus Carboplatin Versus Oral Etoposide Plus Carboplatin in Extensive Small-Cell Lung Cancer: A Randomized Phase III Trial
Authors: Andreas Hermes, Bengt Bergman, Roy Bremnes, Lars Ek, Sverre Fluge, Christer Sederholm, Stein Sundstrøm, Lars Thaning, Jan Vilsvik, Ulf Aasebø, Sverre Sörenson
Journal: Journal of Clinical Oncology (2008)

A Japanese randomized trial showed superior survival for patients with extensive-disease (ED) small-cell lung cancer (SCLC) receiving irinotecan plus cisplatin compared with etoposide plus cisplatin. The present trial evaluated the efficacy of irinotecan plus carboplatin (IC) compared with oral etoposide plus carboplatin (EC).Patients with ED SCLC were randomly assigned to receive either IC, which consisted of carboplatin (area under the curve = 4; Chatelut formula) and irinotecan (175 mg/m2) intravenously both on day 1, or EC, which consisted of carboplatin as in IC and etoposide (120 mg/m(2)/d) orally on days 1 through 5. Courses were repeated every 3 weeks with four cycles planned. Doses were reduced by one third in patients with a WHO performance status (PS) of 3 to 4 and/or age older than 70 years. Primary end point was overall survival (OS). Secondary end points were quality of life (QOL) and complete response (CR) rate.Of 220 randomly assigned patients, 209 were eligible for analysis (IC, n = 105; EC, n = 104). Thirty-five percent were older than 70 years, and 47% had a PS of 2 to 4. The groups were well balanced with respect to prognostic factors. OS was inferior in the EC group (hazard ratio = 1.41; 95% CI, 1.06 to 1.87; P = .02). Median survival time was 8.5 months for IC compared with 7.1 months for EC. One-year survival rate was 34% for IC and 24% for EC. CR was seen in 18 IC patients compared with seven EC patients (P = .02). There were no statistically significant differences in hematologic grade 3 or 4 toxicity. Grade 3 or 4 diarrhea was more common in the IC group. QOL differences were small, with a trend toward prolonged palliation with the IC regimen.IC prolongs survival in ED SCLC with slightly better scores for QOL.
Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling
Authors: Hisaaki Shinohara, Akane Inoue, Noriko Toyama-Sorimachi, Yoshinori Nagai, Tomoharu Yasuda, Hiromi Suzuki, Reiko Horai, Yoichiro Iwakura, Tadashi Yamamoto, Hajime Karasuyama, Kensuke Miyake, Yuji Yamanashi
Journal: The Journal of Experimental Medicine (2005)

Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras–Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-κB, resulting in hyperproduction of TNF-α and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-α and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-α production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity.
Increased Regulatory T-Cell Fraction Amidst a Diminished CD4 Compartment Explains Cellular Immune Defects in Patients with Malignant Glioma
Authors: Peter E. Fecci, Duane A. Mitchell, John F. Whitesides, Weihua Xie, Allan H. Friedman, Gary E. Archer, James E. Herndon, Darell D. Bigner, Glenn Dranoff, John H. Sampson
Journal: Cancer Research (2006)

Abstract Immunosuppression is frequently associated with malignancy and is particularly severe in patients with malignant glioma. Anergy and counterproductive shifts toward TH2 cytokine production are long-recognized T-cell defects in these patients whose etiology has remained elusive for &amp;gt;30 years. We show here that absolute counts of both CD4+ T cells and CD4+CD25+FOXP3+CD45RO+ T cells (Tregs) are greatly diminished in patients with malignant glioma, but Tregs frequently represent an increased fraction of the remaining CD4 compartment. This increased Treg fraction, despite reduced counts, correlates with and is sufficient to elicit the characteristic manifestations of impaired patient T-cell responsiveness in vitro. Furthermore, Treg removal eradicates T-cell proliferative defects and reverses TH2 cytokine shifts, allowing T cells from patients with malignant glioma to function in vitro at levels equivalent to those of normal, healthy controls. Such restored immune function may give license to physiologic antiglioma activity, as in vivo, Treg depletion proves permissive for spontaneous tumor rejection in a murine model of established intracranial glioma. These findings dramatically alter our understanding of depressed cellular immune function in patients with malignant glioma and advance a role for Tregs in facilitating tumor immune evasion in the central nervous system. (Cancer Res 2006; 66(6): 3294-302)
c-Jun NH2-Terminal Kinase Signaling Axis Regulates Diallyl Trisulfide–Induced Generation of Reactive Oxygen Species and Cell Cycle Arrest in Human Prostate Cancer Cells
Authors: Jedrzej Antosiewicz, Anna Herman-Antosiewicz, Stanley W. Marynowski, Shivendra V. Singh
Journal: Cancer Research (2006)

Abstract We have shown previously that generation of reactive oxygen species (ROS) is a critical event in G2-M phase cell cycle arrest caused by diallyl trisulfide (DATS), which is a highly promising anticancer constituent of processed garlic. Using DU145 and PC-3 human prostate cancer cells as a model, we now report a novel mechanism involving c-Jun NH2-terminal kinase (JNK) signaling axis, which is known for its role in regulation of cell survival and apoptosis, in DATS-induced ROS production. The DATS-induced ROS generation, G2-M phase cell cycle arrest and degradation, and hyperphosphorylation of Cdc25C were significantly attenuated in the presence of EUK134, a combined mimetic of superoxide dismutase and catalase. Interestingly, the DATS-induced ROS generation and G2-M phase cell cycle arrest were also inhibited significantly in the presence of desferrioxamine, an iron chelator, but this protection was not observed with iron-saturated desferrioxamine. DATS treatment caused a marked increase in the level of labile iron that was accompanied by degradation of light chain of iron storage protein ferritin. Interestingly, DATS-mediated degradation of ferritin, increase in labile iron pool, ROS generation, and/or cell cycle arrest were significantly attenuated by ectopic expression of a catalytically inactive mutant of JNK kinase 2 and RNA interference of stress-activated protein kinase/extracellular signal-regulated kinase 1 (SEK1), upstream kinases in JNK signal transduction pathway. In conclusion, the present study provides experimental evidence to indicate existence of a novel pathway involving JNK signaling axis in regulation of DATS-induced ROS generation. (Cancer Res 2006; 66(10): 5379-86)
The clinical significance of bundle branch block complicating acute myocardial infarction. 2. Indications for temporary and permanent pacemaker insertion.
Authors: M C Hindman, G S Wagner, M JaRo, J M Atkins, M M Scheinman, R W DeSanctis, A H Hutter, L Yeatman, M Rubenfire, C Pujura, M Rubin, J J Morris
Journal: Circulation (1978)

The indication for prophylactic temporary and permanent pacing during acute myocardial infarction (MI) complicated by bundle branch block is high risk of progression via a Type II pattern to second or third degree (high degree) AV block during hospitalization or follow-up. In this study, determinants of high degree AV block during hospitalization and sudden death or recurrent high degree block during the first year of follow-up were examined in 432 patients with MI and bundle branch block. Timing of onset of bundle branch block, the involved fascicles, and the PR interval were examined as determinants of risk of progression to high degree AV block during MI. At highest risk were 186 patients with blocks involving the right bundle and at least one fascicle of the left bundle which were not documented on prior electrocardiograms. Risk was similar with (38%) or without (31%) accompanying first degree AV block. Patients with transient high degree AV block during MI had a 28% incidence of sudden death or recurrent high degree block during the first year of follow-up. Patients not continuously paced had a higher incidence of sudden death or recurrent high degree block than patients continuously paced (65% vs 10%, P less than 0.001). Sudden death during follow-up also occurred in 13% of patients without high degree block during MI. A subgroup with 1) documented prior MI, 2) anterior or indeterminant acute MI, and 3) no symptoms of cardiac failure had a 35% risk of sudden death. The role of permanent pacing in this group is unknown. Thus, patients at high risk of high degree AV block should receive prophylactic temporary pacing. Patients who survive high degree block with MI should receive temporary and then permanent pacing. Patients without high degree AV block during MI who nervertheless have a high risk of sudden death may benefit from permanent pacing.
Non-coding RNAs and respiratory disease
Authors: P. Mestdagh, J. Vandesompele, G. Brusselle, K. Vermaelen
Journal: Thorax (2014)

Recent scientific developments have radically changed the way we look at the vast 'non-coding' part of our genome. It is now clear that this genomic 'dark matter' is transcribed into myriads of RNA species that act behind the scenes to veto, or boost, the production of proteins in our cells. As a consequence, non-coding RNAs (ncRNAs) represent an additional layer of regulation for fundamental biological processes such as organ development, tissue repair and immunity. It also follows that disturbances in ncRNA networks (among which microRNAs and long ncRNAs are the best studied) can give rise to a whole range of pathological conditions. Increasing preclinical and translational evidence places ncRNAs as key players in a wide spectrum of diseases affecting the lung. In this concise review, we will provide essential concepts of ncRNA science, with special emphasis on discoveries relevant to the pulmonary physician.
Economic Outcomes of Treatment Strategies for Type 2 Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial
Authors: Mark A. Hlatky, Derek B. Boothroyd, Kathryn A. Melsop, Laurence Kennedy, Charanjit Rihal, William J. Rogers, Lakshmi Venkitachalam, Maria M. Brooks
Journal: Circulation (2009)

The economic outcomes of clinical management strategies are important in assessing their value to patients.Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized patients with type 2 diabetes mellitus and angiographically documented, stable coronary disease to strategies of (1) prompt revascularization versus medical therapy with delayed revascularization as needed to relieve symptoms and (2) insulin sensitization versus insulin provision. Before randomization, the physician declared whether coronary artery bypass grafting or percutaneous coronary intervention would be used if the patient were assigned to revascularization. We followed 2005 patients for medical utilization and costs and assessed the cost-effectiveness of these management strategies. Medical costs were higher for revascularization than medical therapy, with a significant interaction with the intended method of revascularization (P<0.0001). In the coronary artery bypass grafting stratum, 4-year costs were $80 900 for revascularization versus $60 600 for medical therapy (P<0.0001). In the percutaneous coronary intervention stratum, costs were $73 400 for revascularization versus $67 800 for medical therapy (P<0.02). Costs also were higher for insulin sensitization ($71 300) versus insulin provision ($70 200). Other factors that significantly (P<0.05) and independently increased cost included insulin use and dose at baseline, female sex, white race, body mass index > or =30, and albuminuria. Cost-effectiveness based on 4-year data favored the strategy of medical therapy over prompt revascularization and the strategy of insulin provision over insulin sensitization. Lifetime projections of cost-effectiveness showed that medical therapy was cost-effective compared with revascularization in the percutaneous coronary intervention stratum ($600 per life-year added) with high confidence. Lifetime projections suggest that revascularization may be cost-effective in the coronary artery bypass grafting stratum ($47 000 per life-year added) but with lower confidence.Prompt coronary revascularization significantly increases costs among patients with type 2 diabetes mellitus and stable coronary disease. The strategy of medical therapy (with delayed revascularization as needed) appears to be cost-effective compared with the strategy of prompt coronary revascularization among patients identified a priori as suitable for percutaneous coronary intervention.
Relations of the myocardial imaging agents 99mTc-MIBI and 201T1 to myocardial blood flow in a canine model of myocardial ischemic insult.
Authors: R C Canby, S Silber, G M Pohost
Journal: Circulation (1990)

Myocardial imaging with thallium 201 has proven to be an important clinical procedure to assess the severity of the myocardial ischemic insult. Uptake of 201Tl is related to perfusion to and extraction by intact myocardium. Recently, a newer group of agents based on 99mTc alkyl isonitriles has been developed and appears promising for myocardial imaging. Although the distribution of this new agent has been shown to be related to myocardial perfusion, its dependence on myocardial integrity has not been established. This study compared the distribution of 99mTc-2-methoxy-isobutyl-isonitrile (99mTc-MIBI) with that of 201Tl in a clinically relevant canine model of ischemic insult. Fifteen adult dogs underwent 2 hours of occlusion by left anterior descending coronary artery ligation followed by reperfusion. In one group of dogs, 201Tl and 99mTc-MIBI were administered 5 minutes before 35 minutes of reflow (group 1, n = 5). In the other animals, the agents were given 5 minutes after onset of reflow, and dogs were killed after 10 (group 2, n = 5) and 35 minutes of reperfusion (group 3, n = 5). 99mTc-MIBI activity was significantly correlated with 201Tl activity (r = 0.91, 0.77, and 0.92, for groups 1, 2, and 3, respectively). Both 201Tl and 99mTc-MIBI activities were correlated similarly with blood flow in all models. In groups 1 and 2, 201Tl and 99mTc-MIBI activities correlated directly with microsphere-determined blood flow, whereas in group 3, they correlated inversely. The present study shows that in these models of myocardial ischemic insult, 99mTc-MIBI distribution is closely related to that of 201Tl.