tbuckley/cabot-search huggingface dataset:
Integrative Genomic Analysis of Protein Kinase C (PKC) Family Identifies PKCι as a Biomarker and Potential Oncogene in Ovarian Carcinoma
Authors: Lin Zhang, Jia Huang, Nuo Yang, Shun Liang, Andrea Barchetti, Antonis Giannakakis, Mark G. Cadungog, Ann O'Brien-Jenkins, Marco Massobrio, Katherine F. Roby, Dionyssios Katsaros, Phyllis Gimotty, Ralf Butzow, Barbara L. Weber, George Coukos
Journal: Cancer Research (2006)

Abstract The protein kinase C (PKC) family plays a key regulatory role in a wide range of cellular functions as well as in various cancer-associated signal transduction pathways. Here, we investigated the genomic alteration and gene expression of most known PKC family members in human ovarian cancer. The DNA copy number of PKC family genes was screened by a high-resolution array-based comparative genomic hybridization in 89 human ovarian cancer specimens. Five PKC genes exhibited significant DNA copy number gains, including PKCι (43.8%), PKCβ1 (37.1%), PKCγ (27.6%), PKCζ (22.5%), and PKC𝛉 (21.3%). None of the PKC genes exhibited copy number loss. The mRNA expression level of PKC genes was analyzed by microarray retrieval approach. Two of the amplified PKC genes, PKCι and PKC𝛉, were significantly up-regulated in ovarian cancer compared with normal ovary. Increased PKCι expression correlated with tumor stage or grade, and PKCι overexpression was seen mostly in ovarian carcinoma but not in other solid tumors. The above results were further validated by real-time reverse transcription-PCR with 54 ovarian cancer specimens and 24 cell lines; overexpression of PKCι protein was also confirmed by tissue array and Western blot. Interestingly, overexpressed PKCι did not affect ovarian cancer cell proliferation or apoptosis in vitro. However, decreased PKCι expression significantly reduced anchorage-independent growth of ovarian cancer cells, whereas overexpression of PKCι contributed to murine ovarian surface epithelium transformation in cooperation with mutant Ras. We propose that PKCι may serve as an oncogene and a biomarker of aggressive disease in human ovarian cancer. (Cancer Res 2006; 66(9): 4627-35)
Estrogen-Related Receptor α in Human Breast Carcinoma as a Potent Prognostic Factor
Authors: Takashi Suzuki, Yasuhiro Miki, Takuya Moriya, Norihiro Shimada, Takanori Ishida, Hisashi Hirakawa, Noriaki Ohuchi, Hironobu Sasano
Journal: Cancer Research (2004)

Abstract Estrogen-related receptor α (ERRα) was identified as a gene related to estrogen receptor α (ERα) and belongs to a class of nuclear orphan receptors. ERRα binds to estrogen responsive element(s) (ERE) and is considered to be involved in modulation of estrogenic actions. However, biological significance of ERRα remains largely unknown. Therefore, we examined the expression of ERRα in human breast carcinoma tissues using immunohistochemistry (n = 102) and real-time reverse transcription-PCR (n = 30). ERRα immunoreactivity was detected in the nuclei of carcinoma cells in 55% of breast cancers examined, and relative immunoreactivity of ERRα was significantly (P = 0.0041) associated with the mRNA level. Significant associations were detected between ERα and ERE-containing estrogen-responsive genes, such as pS2 (P &amp;lt; 0.0001) and EBAG9/RCAS1 (P = 0.0214), in breast carcinoma tissues. However, no significant association was detected between ERα and pS2 (P = 0.1415) in the ERRα-positive cases (n = 56) or between ERα and EBAG9/RCAS1 (P = 0.8271) in the ERRα-negative group (n = 46). ERRα immunoreactivity was significantly associated with an increased risk of recurrence and adverse clinical outcome by both uni- (P = 0.0097 and P = 0.0053, respectively) and multi- (P = 0.0215 and P = 0.0118, respectively) variate analyses. A similar tendency was also detected in the group of breast cancer patients who received tamoxifen therapy after surgery. Results from our study suggest that ERRα possibly modulates the expression of ERE-containing estrogen-responsive genes, and ERRα immunoreactivity is a potent prognostic factor in human breast carcinoma.
ICUD-EAU International Consultation on Bladder Cancer 2012: Urinary Diversion
Authors: Richard E. Hautmann, Hassan Abol-Enein, Thomas Davidsson, Sigurdur Gudjonsson, Stefan H. Hautmann, Henriette V. Holm, Cheryl T. Lee, Frederik Liedberg, Stephan Madersbacher, Murugesan Manoharan, Wiking Mansson, Robert D. Mills, David F. Penson, Eila C. Skinner, Raimund Stein, Urs E. Studer, Joachim W. Thueroff, William H. Turner, Bjoern G. Volkmer, Abai Xu
Journal: European Urology (2012)
Treatment with infliximab (Remicade) when etanercept (Enbrel) has failed or vice versa: data from the STURE registry showing that switching tumour necrosis factor blockers can make sense
Authors: R van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> When one TNFα blocker (etanercept or infliximab) has failed, to determine whether it makes sense to treat patients with the other. <b>Patients and methods:</b> Since 1999 patients treated with etanercept or infliximab have been systematically followed up at our institution in the STURE database. We identified 31 patients who had received both agents. <b>Results:</b> Eighteen patients received etanercept first; discontinuation was mostly due to lack of efficacy. DAS28 values had improved only slightly with etanercept, with a mean (SEM) best DAS28 value of 4.8 (0.6). After switching to infliximab, the mean best DAS28 was 3.6 (0.6)—significantly better than the previous result (p&lt;0.05). Similarly, the mean best ACR-N during etanercept treatment was 17.2 (6.65) and during subsequent infliximab treatment 40.4 (10.6) (p = 0.08). Thirteen patients received infliximab first; discontinuation was mainly due to adverse events. The best DAS28 value achieved during etanercept was 3.6 (0.4) compared with 4.1 (0.4) for infliximab (p&lt;0.05), but the change in DAS28 was not different and ACR-N were similar for infliximab and etanercept in this group. <b>Conclusion:</b> For patients with insufficient efficacy from etanercept, treatment with infliximab provided better results, suggesting that a trial of infliximab is reasonable for such patients. For patients who discontinued infliximab owing to adverse events, treatment with etanercept gave at least similar clinical efficacy. Taken together, these data provide support for a trial of the reciprocal TNFα blocker in patients when one such agent has failed.
QUANTITATIVE STUDIES OF THE ADOPTIVE IMMUNOLOGICAL MEMORY IN MICE
Authors: Franco Celada
Journal: The Journal of Experimental Medicine (1967)

A calibrated cell transfer system allows detection of the anamnestic response to albumin without interference from the host's immune machinery; it was used to study the immunological memory of mouse spleen cell populations. The secondary antibody-forming capacity of the transferred cells was measured by challenging them at periods up to 6 months after transfer. The peak levels attained show a declining pattern in two phases: during the first month with a half-life of 15 days; thereafter, with a half-life of 100 days. The corresponding half-lives of the cellular memory are 26 and 190 days. In the light of these and of radioinactivation data, immunological memory is defined as the persistence of a specifically determined stem cell line, along which the information necessary to give rise to an antibody-forming cell population is transmitted from mother to daughter cells.
Phase I and Pharmacokinetic Study of Flavopiridol followed by 1-β-<scp>d</scp>-Arabinofuranosylcytosine and Mitoxantrone in Relapsed and Refractory Adult Acute Leukemias
Authors: Judith E. Karp, Antonino Passaniti, Ivana Gojo, Scott Kaufmann, Keith Bible, Tushar S. Garimella, Jacqueline Greer, Janet Briel, B. Douglas Smith, Steven D. Gore, Michael L. Tidwell, Douglas D. Ross, John J. Wright, A. Dimitrios Colevas, Kenneth S. Bauer
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The serine/threonine kinase inhibitor flavopiridol targets multiple cyclin-dependent kinases, induces checkpoint arrest, and interrupts transcriptional elongation. We designed a phase I clinical trial using a timed sequential therapy approach where flavopiridol was given for the dual purpose of initial cytoreduction and enhancing cell cycle progression of the remaining leukemia cell cohort followed by cycle-dependent drugs 1-β-d-arabinofuranosylcytosine (ara-C) and mitoxantrone. Experimental Design: Flavopiridol was given by 1-hour infusion daily for 3 days beginning day 1 followed by 2 g/m2/72 h ara-C beginning day 6 and 40 mg/m2 mitoxantrone beginning day 9. In vivo correlates included pharmacokinetics, modulation of blast cycle regulators, and serum and marrow supernatant vascular endothelial growth factor levels. Results: Of 34 adults receiving induction therapy, 16 (47%) evinced direct leukemia cytotoxicity with ≥50% drop in peripheral blast counts and tumor lysis in 9 (26%). Four (12%) died during therapy (two fungal infections and two sudden death). Dose-limiting toxicity occurred at 60 mg/m2/d with profound neutropenia &amp;gt;40 days duration, and maximal tolerated dose was 50 mg/m2/d. Overall response rate was 31% in 26 acute myelogenous leukemia and 12.5% in acute lymphoblastic leukemia. Pharmacokinetics showed that a linear two-compartment model with first-order elimination provided the best fit of the observed concentration versus time data. Flavopiridol down-regulated one or more target proteins in marrow blasts in vivo. Vascular endothelial growth factor was detected in sera and marrow supernatant pretreatment, and sera obtained on day 3 inhibited bovine aortic endothelial cell proliferation by a mean of 32% (range, 10-80%). Conclusions: Our data suggest that flavopiridol is cytotoxic to leukemic cells and, when followed by ara-C and mitoxantrone, exerts biological and clinical effects in patients with relapsed and refractory acute leukemias. These findings warrant continuing development of flavopiridol at 50 mg/m2/d × 3 days in combination with cytotoxic and biological agents for acute leukemias.
Activated Pregnenolone X-Receptor Is a Target for Ketoconazole and Its Analogs
Authors: Hongwei Wang, Haiyan Huang, Hao Li, Denise G. Teotico, Michael Sinz, Sharyn D. Baker, Jeffrey Staudinger, Ganjam Kalpana, Matthew R. Redinbo, Sridhar Mani
Journal: Clinical Cancer Research (2007)

Variations in biotransformation and elimination of microtubule-binding drugs are a major cause of unpredictable side effects during cancer therapy. Because the orphan receptor, pregnenolone X-receptor (PXR), coordinately regulates the expression of paclitaxel metabolizing and transport enzymes, controlling this process could improve therapeutic outcome.In vitro RNA-, protein-, and transcription-based assays in multiple cell lines derived from hepatocytes and PXR wild-type and null mouse studies were employed to show the effects of ketoconazole and its analogues on ligand-activated PXR-mediated gene transcription and translation.The transcriptional activation of genes regulating biotransformation and transport by the liganded human nuclear xenobiotic receptor, PXR, was inhibited by the commonly used antifungal ketoconazole and related azole analogs. Mutations at the AF-2 surface of the human PXR ligand-binding domain indicate that ketoconazole may interact with specific residues outside the ligand-binding pocket. Furthermore, in contrast to that observed in PXR (+/+) mice, genetic loss of PXR results in increased (preserved) blood levels of paclitaxel.These studies show that some azole compounds repress the coordinated activation of genes involved in drug metabolism by blocking PXR activation. Because loss of PXR maintains blood levels of paclitaxel upon chronic dosing, ketoconazole analogues may also serve to preserve paclitaxel blood levels on chronic dosing of drugs. Our observations may facilitate new strategies to improve the clinical efficacy of drugs and to reduce therapeutic side effects.
Smoking and Smoking Cessation in Relation to Mortality in Women
Authors: Stacey A. Kenfield
Journal: JAMA (2008)

<h3>Context</h3>Smoking is associated with an increased risk of total and cause-specific death, but the rate of mortality risk reduction after quitting compared with continuing to smoke is uncertain. There is inadequate or insufficient evidence to infer the presence or absence of a causal relationship between smoking and ovarian cancer and colorectal cancer.<h3>Objective</h3>To assess the relationship between cigarette smoking and smoking cessation on total and cause-specific mortality in women.<h3>Design, Setting, and Participants</h3>Prospective observational study of 104 519 female participants in the Nurses' Health Study with follow-up from 1980 to 2004.<h3>Main Outcome Measure</h3>Hazard ratios (HRs) for total mortality, further categorized into vascular and respiratory diseases, lung cancer, other cancers, and other causes.<h3>Results</h3>A total of 12 483 deaths occurred in this cohort, 4485 (35.9%) among never smokers, 3602 (28.9%) among current smokers, and 4396 (35.2%) among past smokers. Compared with never smokers, current smokers had an increased risk of total mortality (HR, 2.81; 95% confidence interval [CI], 2.68-2.95) and all major cause-specific mortality. The HR for cancers classified by the 2004 surgeon general's report to be smoking-related was 7.25 (95% CI, 6.43-8.18) and 1.58 (95% CI, 1.45-1.73) for other cancers. Compared with never smokers, the HR for colorectal cancer was 1.63 (95% CI, 1.29-2.05) for current smokers and 1.23 (95% CI, 1.02-1.49) for former smokers. A significant association was not observed for ovarian cancer. Significant trends were observed for earlier age at initiation of smoking for total mortality (P = .003), respiratory disease mortality (P = .001), and all smoking-related cancer mortality (P = .001). The excess risk for all-cause mortality decreases to the level of a never smoker 20 years after quitting, with different time frames for risk reduction observed across outcomes. Approximately 64% of deaths among current smokers and 28% of deaths among former smokers were attributable to cigarette smoking.<h3>Conclusions</h3>Most of the excess risk of vascular mortality due to smoking in women may be eliminated rapidly upon cessation and within 20 years for lung diseases. Postponing the age of smoking initiation reduces the risk of respiratory disease, lung cancer, and other smoking-related cancer deaths but has little effect on other cause-specific mortality. These data suggest that smoking is associated with an increased risk of colorectal cancer mortality but not ovarian cancer mortality.
Biostatistics: how to detect, correct and prevent errors in the medical literature.
Authors: S A Glantz
Journal: Circulation (1980)

Approximately half the articles published in medical journals that use statistical methods use them incorrectly. These errors are so widespread that the present system of peer review has not been able to control them. This article presents a few rules of thumb to help readers identify questionable statistical analysis and estimate what the authors would have concluded had they used appropriate statistical methods. To prevent such errors from appearing, journals should secure review by someone knowledgeable in statistics before accepting a manuscript. In addition, human research committees should insist that an investigator define an appropriate strategy for data analysis before approving a protocol. Such policies should quickly and effectively increase the reliability of the clinical and scientific literature.
The Earliest Record of Sudden Death Possibly Due to Atherosclerotic Coronary Occlusion
Authors: WALTER L. BRUETSCH
Journal: Circulation (1959)

The sudden death of an Egyptian nobleman is portrayed in the relief of a tomb from the Sixth Dynasty (2625-2475 B.C.). Since there is indisputable evidence from the dissections of Egyptian mummies that atherosclerosis was prevalent in ancient Egypt, it was conjectured that the sudden death might have been due to atheroselerotic occlusion of the coronary arteries.
Granulocyte-macrophage colony-stimulating factor and IL-5 activate mitogen-activated protein kinase through Jak2 kinase and phosphatidylinositol 3-kinase inhuman eosinophils
Authors: Kazuhiro Hiraguri, Satoshi Miike, Hideki Sano, Kazuhiro Kurasawa, Yasushi Saito, Itsuo Iwamoto
Journal: Journal of Allergy and Clinical Immunology (1997)
Mechanisms of Endocrine Dysfunction in Patients With Testicular Cancer
Authors: D. W. Morrish, P. M. Venner, O. Siy, G. Barron, D. Bhardwaj, D. Outhet
Journal: JNCI Journal of the National Cancer Institute (1990)

To determine mechanisms of endocrine dysfunction in patients with testicular cancer, we performed static and dynamic testing of the hypothalamic-pitu-itary-testicular axis and testicular exo-crine function in 13 patients and 11 normal control subjects, as well as in vitro studies of tumor tissue and remaining adjacent "normal" testicular tissue in the 13 patients. In tumor tissue, we demonstrated ( a ) elevated concentrations of total serum estradiol and serum estradiol not bound to sex hormone-binding globulin, ( b ) impaired spermatogenesis and sperm motility, and ( c ) blocking of multiple enzymes necessary for steroidogenesis. The data were consistent with a paracrine-endo-crine mechanism in which tumor-produced human chorionic gonadotropin stimulates production of estradiol by "normal" testicular tissue but not tumor tissue, and the high estradiol levels then result in impaired spermatogenesis. [J Natl Cancer Inst 82: 412–418, 1990]
Experimental Assessment of Technique for Measurement of Valvular Regurgitation by Constant Infusion of Indicator
Authors: LUCEIN I. ARDITI, CHARLES W. PEARCE, A. LEE WINSTON, DANIEL S. LUKAS
Journal: Circulation Research (1961)

The continuous infusion of indicator into the left ventricle at a constant rate, with comparison of indicator concentration in aortic and left atrial blood at equilibrium prior to recirculation, is theoretically a valid method for measurement of mitral regurgitation. When assessed in dogs with constantly metered left ventricular-atrial regurgitation, however, the method failed to measure regurgitation accurately and yielded values which, in general, were well below the true ones. The failure of the method appeared to be due to incomplete dispersion of dye in the ventricle and limited distribution of regurgitated blood within the atrium. Despite differences between the animal preparation and naturally occurring mitral regurgitation, the study casts doubt on the quantitative reliability of data on valvular regurgitation in man obtained by indicator methods utilizing left ventricular injection and left atrial sampling.
Effects of Low-Dose Prednisolone on Hepatic and Peripheral Insulin Sensitivity, Insulin Secretion, and Abdominal Adiposity in Patients With Inflammatory Rheumatologic Disease
Authors: Carolyn J. Petersons, Brenda L. Mangelsdorf, Arthur B. Jenkins, Anne Poljak, Malcolm D. Smith, Jerry R. Greenfield, Campbell H. Thompson, Morton G. Burt
Journal: Diabetes Care (2013)

OBJECTIVE The metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations. RESEARCH DESIGN AND METHODS Subjects with inflammatory rheumatologic disease without diabetes mellitus were recruited. Nine subjects (age, 59 ± 11 years) not using oral glucocorticoids were studied before and after a 7- to 10-day course of oral prednisolone 6 mg daily. Baseline data were compared with 12 subjects (age, 61 ± 8 years) using continuous long-term prednisolone (6.3 ± 2.2 mg/day). Basal endogenous glucose production (EGP) was estimated by 6,6-2H2 glucose infusion, insulin sensitivity was estimated by two-step hyperinsulinemic-euglycemic clamp, insulin secretion was estimated by intravenous glucose tolerance test, and adipose tissue areas were estimated by computed tomography. RESULTS Prednisolone acutely increased basal EGP (2.44 ± 0.46 to 2.65 ± 0.35 mg/min/kg; P = 0.05) and reduced insulin suppression of EGP (79 ± 7 to 67 ± 14%; P = 0.03), peripheral glucose disposal (8.2 ± 2.4 to 7.0 ± 1.6 mg/kg/min; P = 0.01), and first-phase (5.9 ± 2.0 to 3.9 ± 1.6 mU/mmol; P = 0.01) and second-phase (4.6 ± 1.7 to 3.6 ± 1.4 mU/mmol; P = 0.02) insulin secretion. Long-term prednisolone users had attenuated insulin suppression of EGP (66 ± 14 vs. 79 ± 7%; P = 0.03) and nonoxidative glucose disposal (44 ± 24 vs. 62 ± 8%; P = 0.02) compared with nonglucocorticoid users, whereas basal EGP, insulin secretion, and adipose tissue areas were not significantly different. CONCLUSIONS Low-dose prednisolone acutely perturbs all aspects of carbohydrate metabolism. Long-term low-dose prednisolone induces hepatic insulin resistance and reduces peripheral nonoxidative glucose disposal. We conclude that hepatic and peripheral insulin sensitivity should be targeted by glucose-lowering therapy for glucocorticoid-induced diabetes.
Endothelin has biological actions at pathophysiological concentrations.
Authors: A Lerman, F L Hildebrand, L L Aarhus, J C Burnett
Journal: Circulation (1991)

BACKGROUND Endothelin is an endothelium-derived peptide that produces sustained contraction of arterial and venous smooth muscle in vitro. Several studies have established endothelin as a systemic, renal, and coronary vasoconstrictor in vivo at pharmacological concentrations. Such concentrations of endothelin were antinatriuretic in association with activation of the renin-angiotensin-aldosterone system. Recent studies have demonstrated that endothelin is present in the plasma and that its plasma concentrations are increased in various pathological states associated with systemic and renal vasoconstriction. To date, it remains unclear if such increases in circulating endothelin are associated with biological activity. Thus, the objective of this study was to determine the biological action of endothelin on cardiorenal and endocrine function through administration of exogenous endothelin, which achieves plasma concentrations that have been reported in various pathophysiological conditions. METHODS AND RESULTS Experiments were conducted in two groups of anesthetized dogs. In group 1, endothelin-1 was infused intravenously at 2.5 ng/kg/ml (n = 6), which produced a doubling of circulating concentrations. Group 2 (n = 8) received saline vehicle to serve as a time control. The current studies demonstrate that a twofold increase in plasma endothelin concentrations did not affect mean blood pressure or coronary blood flow. Heart rate and cardiac output decreased in association with increased renal and systemic vascular resistances and antinatriuresis. CONCLUSIONS The present studies demonstrate that endothelin at pathophysiological plasma concentrations produced by exogenous endothelin has biological action. These studies support a functional role for endogenous endothelin as a potentially pathophysiological vasoconstrictor peptide hormone in the regulation of cardiovascular, renal, and endocrine function.