tbuckley/cabot-search huggingface dataset:
Performance of Common Genetic Variants in Breast-Cancer Risk Models
Authors: Sholom Wacholder, Patricia Hartge, Ross Prentice, Montserrat Garcia-Closas, Heather Spencer Feigelson, W. Ryan Diver, Michael J. Thun, David G. Cox, Susan E. Hankinson, Peter Kraft, Bernard Rosner, Christine D. Berg, Louise A. Brinton, Jolanta Lissowska, Mark E. Sherman, Rowan Chlebowski, Charles Kooperberg, Rebecca D. Jackson, Dennis W. Buckman, Peter Hui, Ruth Pfeiffer, Kevin B. Jacobs, Gilles D. Thomas, Robert N. Hoover, Mitchell H. Gail, Stephen J. Chanock, David J. Hunter
Journal: New England Journal of Medicine (2010)

Genomewide association studies have identified multiple genetic variants associated with breast cancer. The extent to which these variants add to existing risk-assessment models is unknown.
Emerging Concepts in the Immunopathogenesis of AIDS
Authors: Daniel C. Douek, Mario Roederer, Richard A. Koup
Journal: Annual Review of Medicine (2008)

There is an intense interplay between HIV and the immune system, and the literature is replete with studies describing various immunological phenomena associated with HIV infection. Many of these phenomena seem too broad in scope to be attributable either to HIV-infected cells or to the HIV-specific immune response. Recently, a more fundamental understanding of how HIV affects various T cells and T cell compartments has emerged. This review covers the role of immune activation in HIV immunopathogenesis, how that activation could be mediated directly by HIV replicating within and damaging the gut mucosal barrier, how HIV affects multiple T cell functions and phenotypes, and how chronic HIV replication induces immune modulatory pathways to negatively regulate certain functions in HIV-specific T cells.
Transcription Factor Stat5 Synergizes with Androgen Receptor in Prostate Cancer Cells
Authors: Shyh-Han Tan, Ayush Dagvadorj, Feng Shen, Lei Gu, Zhiyong Liao, Junaid Abdulghani, Ying Zhang, Edward P. Gelmann, Tobias Zellweger, Zoran Culig, Tapio Visakorpi, Lukas Bubendorf, Robert A. Kirken, James Karras, Marja T. Nevalainen
Journal: Cancer Research (2008)

Abstract The molecular mechanisms underlying progression of prostate cancer to the hormone-independent state are poorly understood. Signal transducer and activator of transcription 5a and 5b (Stat5a/b) is critical for the viability of human prostate cancer cells. We have previously shown that Stat5a/b is constitutively active in high-grade human prostate cancer, but not in normal prostate epithelium. Furthermore, activation of Stat5a/b in primary human prostate cancer predicted early disease recurrence. We show here that transcription factor Stat5a/b is active in 95% of clinical hormone-refractory human prostate cancers. We show for the first time that Stat5a/b synergizes with androgen receptor (AR) in prostate cancer cells. Specifically, active Stat5a/b increases transcriptional activity of AR, and AR, in turn, increases transcriptional activity of Stat5a/b. Liganded AR and active Stat5a/b physically interact in prostate cancer cells and, importantly, enhance nuclear localization of each other. The work presented here provides the first evidence of synergy between AR and the prolactin signaling protein Stat5a/b in human prostate cancer cells. [Cancer Res 2008;68(1):236–48]
Electrospray Ionization-Tandem Mass Spectrometry and 32P-Postlabeling Analyses of Tamoxifen-DNA Adducts in Humans
Authors: F. A. Beland, M. I. Churchwell, D. R. Doerge, D. R. Parkin, D. Malejka-Giganti, A. Hewer, D. H. Phillips, P. L. Carmichael, G. Gamboa da Costa, M. M. Marques
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Although the nonsteroidal antiestrogen tamoxifen is used as an adjuvant chemotherapeutic agent to treat hormone-dependent breast cancer and as a chemopreventive agent in women with elevated risk of breast cancer, it has also been reported to increase the risk of endometrial cancer. Reports of low levels of tamoxifen–DNA adducts in human endometrial tissue have suggested that tamoxifen induces endometrial cancer by a genotoxic mechanism. However, these findings have been controversial. We used electrospray ionization–tandem mass spectrometry (ES-MS/MS) and 32 P-postlabeling analyses to investigate the presence of tamoxifen–DNA adducts in human endometrial tissue. Methods: Endometrial DNA from eight tamoxifen-treated women and eight untreated women was hydrolyzed to nucleosides and assayed for ( E )-α-(deoxyguanosin- N2 -yl)-tamoxifen (dG-Tam) and ( E )-α-(deoxyguanosin- N2 -yl)- N -desmethyltamoxifen (dG-desMeTam), the two major tamoxifen–DNA adducts that have been reported to be present in humans and/or experimental animals treated with tamoxifen, using on-line sample preparation coupled with high-performance liquid chromatography (HPLC) and ES-MS/MS. The same DNA samples were assayed for the presence of dG-Tam and dG-desMeTam by 32 P-postlabeling methodology, using two different DNA digestion and labeling protocols, followed by both thin-layer chromatography and HPLC. Results: We did not detect either tamoxifen–DNA adduct by HPLC–ES-MS/MS analyses (limits of detection for dG-Tam and dG-desMeTam were two adducts per 10 9 nucleotides and two adducts per 10 8 nucleotides, respectively) or by 32 P-postlabeling analyses (limit of detection for both adducts was one adduct per 10 9 nucleotides) in any of the endometrial DNA samples. Conclusion: The initiation of endometrial cancer by tamoxifen is probably not due to a genotoxic mechanism involving the formation of dG-Tam or dG-desMeTam.
Reconstruction of the immunogenic peptide RNase(43-56) by identification and transfer of the critical residues into an unrelated peptide backbone.
Authors: R G Lorenz, A N Tyler, P M Allen
Journal: The Journal of Experimental Medicine (1989)

The involvement of each of the amino acid residues of the I-Ak-restricted T cell determinant RNase(43-56) was examined in detail using a series of peptides containing single amino acid substitutions. Four positions were identified as being essential for the formation of the determinant, Phe-46, Val-47, His-48, and Leu-51. When these four residues were substituted into the backbone of the unrelated peptide HA(130-144), a nonstimulatory peptide was obtained. The inclusion of an additional residue, Val-54, resulted in a chimeric peptide, RN/HA2, which was nearly as active as the native molecule. The peptide RN/HA2 was able to prime in vivo for RNase reactivity, confirming that these five residues contained all of the specificity of the RNase(43-56) determinant. The role of three of these critical residues was examined using both a functional competition assay and an in vivo priming assay. It was ascertained that the Phe-46 was directly involved in contacting the TCR, while the His-48 and Leu-51 were either involved in binding to the I-Ak molecule or in determining the conformation of the peptide. Thus, by critically evaluating the contribution of each of the amino acid residues in a T cell determinant, we were able to generate a chimeric peptide only containing 5 of 15 residues from the RNase(43-56) sequence that was functionally identical to the native RNase(43-56) molecule both in vitro and in vivo.
Plasma cyclic AMP levels during a secretin-caerulein pancreatic function test in liver and pancreatic disease.
Authors: M Adler, P Robberecht, M G Poitevin, J Christophe
Journal: Gut (1978)

Plasma cyclic AMP levels were determined during a 40 minute secretin infusion (1 Cl.U kg-1h-1) followed by a 40 minute combined secretin (1 Cl.U kg-1h-1) caerulein (75 ng kg-1h-1) infusion. In nine healthy subjects, both secretin alone and secretin in combination with caerulein did not affect plasma cyclic AMP levels. The same was observed in six patients with chronic pancreatitis. By contrast, in patients suffering from liver disease (nine cases) or extrahepatic cholestasis (six cases), secretin elicited large increases in plasma cyclic AMP concentration; the mean values attained being, respectively, seven and four times higher than before the infusion. On the other hand, increases in plasma cyclic AMP 10 minutes after a bolus injection of glucagon (1 mg) were four times lower in the liver disease group as compared to the controls. The results reported here suggest that the liver plays a major role in the degradation of plasma cyclic AMP produced by target tissues responding to secretin, and in the release of cyclic AMP under glucagon. Liver disease reduce the capacity of the liver to clear cyclic AMP from the blood. The pancreas does not contribute significantly to the cyclic AMP in the blood.
Exosomes and Cardiac Repair After Myocardial Infarction
Authors: Susmita Sahoo, Douglas W. Losordo
Journal: Circulation Research (2014)

Myocardial infarction is a leading cause of death among all cardiovascular diseases. The analysis of molecular mechanisms by which the ischemic myocardium initiates repair and remodeling indicates that secreted soluble factors are key players in communication to local and distant tissues, such as bone marrow. Recently, actively secreted membrane vesicles, including exosomes, are being recognized as new candidates with important roles in intercellular and tissue-level communication. In this review, we critically examine the emerging role of exosomes in local and distant microcommunication mechanisms after myocardial infarction. A comprehensive understanding of the role of exosomes in cardiac repair after myocardial infarction could bridge a major gap in knowledge of the repair mechanism after myocardial injury.
Chylothorax complicating a thoracic aortic aneurysm
Authors: V Gil-Suay, E Martinez-Moragon, A de Diego, J Sanchis
Journal: European Respiratory Journal (1997)

Chylothorax is an uncommon condition, usually associated with advanced malignant disease or trauma to the thoracic duct. Idiopathic chylothorax and other diverse causes have been anecdotally reported. We describe a rare case of chylothorax, developing as a result of damage to the thoracic duct by a thoracic aortic aneurysm. Tetracycline pleurodesis was successful in controlling the chylous effusion.
Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib
Authors: Tammy F Chu, Maria A Rupnick, Risto Kerkela, Susan M Dallabrida, David Zurakowski, Lisa Nguyen, Kathleen Woulfe, Elke Pravda, Flavia Cassiola, Jayesh Desai, Suzanne George, David M Harris, Nesreen S Ismail, Jey-Hsin Chen, Frederick J Schoen, Annick D Van den Abbeele, George D Demetri, Thomas Force, Ming Hui Chen, Jeffrey A Morgan
Journal: The Lancet (2007)
Local microbleeding facilitates IL-6– and IL-17–dependent arthritis in the absence of tissue antigen recognition by activated T cells
Authors: Masaaki Murakami, Yuko Okuyama, Hideki Ogura, Shogo Asano, Yasunobu Arima, Mineko Tsuruoka, Masaya Harada, Minoru Kanamoto, Yukihisa Sawa, Yoichiro Iwakura, Kiyoshi Takatsu, Daisuke Kamimura, Toshio Hirano
Journal: The Journal of Experimental Medicine (2011)

Cognate antigen recognition by CD4+ T cells is thought to contribute to the tissue specificity of various autoimmune diseases, particularly those associated with class II MHC alleles. However, we show that localized class II MHC–dependent arthritis in F759 mice depends on local events that result in the accumulation of activated CD4+ T cells in the absence of cognate antigen recognition. In this model, transfer of in vitro polarized Th17 cells combined with the induction of experimental microbleeding resulted in CCL20 production, the accumulation of T cells in the joints, and local production of IL-6. Disease induction required IL-17A production by transferred T cells, IL-6 and CCL20 expression, and STAT3 signaling in type I collagen–expressing cells. Our data suggest a model in which the development of autoimmune disease in F759 mice depends on four events: CD4+ T cell activation regardless of antigen specificity, local events that induce T cell accumulation, enhanced sensitivity to T cell–derived cytokines in the tissue, and activation of IL-6 signaling in the tissue. This model provides a possible explanation for why tissue-specific antigens recognized by activated CD4+ T cells have not been identified in many autoimmune diseases, especially those associated with class II MHC molecules.
Rifaximin Treatment in Hepatic Encephalopathy
Authors: Nathan M. Bass, Kevin D. Mullen, Arun Sanyal, Fred Poordad, Guy Neff, Carroll B. Leevy, Samuel Sigal, Muhammad Y. Sheikh, Kimberly Beavers, Todd Frederick, Lewis Teperman, Donald Hillebrand, Shirley Huang, Kunal Merchant, Audrey Shaw, Enoch Bortey, William P. Forbes
Journal: New England Journal of Medicine (2010)

Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established.In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy.Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events.Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)
Portal Venous–Esophageal Luminal Pressure Gradient in Cirrhosis
Authors: Pierre Reding, Daniel Urbain, André Grivegnee, Daniel Frere
Journal: Hepatology (1986)

The portal venous-esophageal luminal pressure gradient may be more important than the absolute portal venous pressure in explaining hemorrhages caused by esophageal varices. A continuous recording of portal venous pressure and the esophageal luminal pressure enabled the authors to study the gradient between these pressures in 12 cirrhotic patients with varices of different size and under different circumstances, in particular inspiration, expiration, coughing and a Valsalva maneuver. A significant increase of portal venous pressure occurred during inspiration (+15%), coughing (+77%) and Valsalva maneuver (+157%). The value of portal venous-esophageal luminal pressure gradient increased during inspiration (+38%), coughing (+90%) and Valsalva maneuver (+69%) while it decreased during expiration (-14%).
Requirement for IFN-γ, CD8+ T Lymphocytes, and NKT Cells in Talactoferrin-Induced Inhibition of neu+ Tumors
Authors: Michela Spadaro, Claudia Curcio, Atul Varadhachary, Federica Cavallo, Jose Engelmayer, Paul Blezinger, Federica Pericle, Guido Forni
Journal: Cancer Research (2007)

Abstract We have previously shown that talactoferrin-alfa (TLF), a recombinant human lactoferrin, is an immunomodulatory protein that is active against implanted tumors, both as a single agent and in combination with chemotherapy. In this study, we show that talactoferrin is active against autochthonous tumors in a transgenic mouse line, which is more analogous to human cancers, and identify key mechanistic steps involved in the anticancer activity of oral TLF. BALB/c mice transgenic for the rat neu (ErbB2) oncogene (BALB-neuT) treated with oral TLF showed a significant delay in carcinogenesis, with 60% tumor protection relative to vehicle-treated mice at week 21. Oral TLF also showed tumor growth inhibition in wild-type BALB/c mice implanted with neu+ mammary adenocarcinoma, with one third displaying a long-lasting or complete response. Oral TLF induces an increase in intestinal mucosal IFN-γ production and an increase in Peyer's patch cellularity, including expansion of CD8+ T lymphocytes and NKT cells, and the enhancement of CD8+ T-cell cytotoxicity. In IFN-γ knockout mice, there is an absence of the TLF-induced Peyer's patch cellularity, no expansion of CD8+ T lymphocytes and NKT cells, and loss of TLF anticancer activity. TLF antitumor activity is also lost in mice depleted of CD8+ T cells and in CD1 knockout mice, which lack NKT activity. Thus, the inhibition of distant tumors by oral TLF seems to be mediated by an IFN-γ–dependent enhancement of CD8+ T- and NKT cell activity initiated within the intestinal mucosa. [Cancer Res 2007;67(13):6425–32]
THE ENCYSTMENT OF DYSENTERY AMEBÆ IN VITRO
Authors: Kazuyoshi Yoshida
Journal: The Journal of Experimental Medicine (1918)

Dysentery amebæ may live for 72 hours in vitro. The transition of the large vegetative forms into the cyst may be observed in vitro. The large vegetative ameba always passes into an intermediate stage before assuming the small vegetative form. The atypical forms are dysentery amebas with abnormal nuclei and cytoplasm. When circumstances are unfavorable encystment takes place. Under favorable conditions, on the other hand, they may again change into typical forms. The majority of the "degenerative" forms of Hartmann cannot be so classed. According to our observation, they represent forms which have been described here. Hartmann's Entamœba histolytica is really a typical transitional form of Entamœba tetragena. The origin and significance of the central vacuole have been elucidated. Nuclear division of the dysentery ameba proceeds in three ways. The typical forms divide on the whole mitotically, and the atypical a mitotically or in a primitively mitotic manner.
TGF- : Duality of Function Between Tumor Prevention and Carcinogenesis
Authors: D. R. Principe, J. A. Doll, J. Bauer, B. Jung, H. G. Munshi, L. Bartholin, B. Pasche, C. Lee, P. J. Grippo
Journal: JNCI Journal of the National Cancer Institute (2014)

Several mechanisms underlying tumor progression have remained elusive, particularly in relation to transforming growth factor beta (TGF-β). Although TGF-β initially inhibits epithelial growth, it appears to promote the progression of advanced tumors. Defects in normal TGF-β pathways partially explain this paradox, which can lead to a cascade of downstream events that drive multiple oncogenic pathways, manifesting as several key features of tumorigenesis (uncontrolled proliferation, loss of apoptosis, epithelial-to-mesenchymal transition, sustained angiogenesis, evasion of immune surveillance, and metastasis). Understanding the mechanisms of TGF-β dysregulation will likely reveal novel points of convergence between TGF-β and other pathways that can be specifically targeted for therapy.
Prevention of postischaemic lipid peroxidation and liver cell injury by iron chelation.
Authors: R Omar, I Nomikos, G Piccorelli, J Savino, N Agarwal
Journal: Gut (1989)

Liver ischaemia was induced by cross clamping the hilar pedicle for 30 minutes in groups of rats with or without treatment with the iron chelating agent desferrioxamine (deferoxamine, DFR). The groups included eight animals each and were divided into the following treatment categories: control; ischaemia alone; ischaemia with subsequent reperfusion; ischaemia preceded by DFR, 60 mg/kg body weight; and reperfusion preceded by 20, 40, or 60 mg/kg DFR. The drug was given intravenously five minutes before either ischaemia or reperfusion. Malondialdehyde (MDA), a product of lipid peroxidation, and histopathological changes of liver tissue samples were used as indicators of hepatocellular injury. Lipid peroxidation (MDA concentration in mumol/kg liver tissue) was highest (4.76 (1.19] after ischaemia without reperfusion and less pronounced (2.87 (0.34] after reperfusion. Both concentrations, however, were significantly (p less than 0.05) higher than basal (control) values (1.78 (0.27]. At 60 mg/kg body weight, DFR treatment reduced MDA to basal or even lower concentrations in both situations (1.98 (0.08) and 1.26 (0.06), respectively) with a corresponding improvement in liver histopathology. Lower DFR doses were less protective. The data suggest that liver ischaemia is associated with free radical initiated, and apparently iron catalysed lipid peroxidation, which can be significantly decreased by iron chelation.
Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK)
Authors: K L Neuhaus, R von Essen, U Tebbe, A Jessel, H Heinrichs, W Mäurer, W Döring, D Harmjanz, V Kötter, E Kalhammer
Journal: Circulation (1994)

BACKGROUND Adjunctive therapy for thrombolysis in acute myocardial infarction consists of platelet inhibition with aspirin and thrombin inhibition with heparin. Thrombin inhibition may be improved by the use of hirudin as indicated by experimental and phase II clinical studies. The randomized, double-blind phase III r-Hirudin for Improvement of Thrombolysis study (HIT III) compared a recombinant hirudin (HBW 023) with heparin. The primary end point was the incidence of death or reinfarction. METHODS AND RESULTS Seven thousand patients with acute myocardial infarction and a duration of symptoms of less than 6 hours were to be randomized to receive intravenous heparin (70 IU/kg body wt bolus and 15 IU.kg-1.h-1) or hirudin (0.4 mg/kg body wt bolus and 0.15 mg.kg-1.h-1) infused over 48 to 72 hours and adjusted to an activated partial thromboplastin time of 2 to 3.5 times baseline values. In a pilot phase, 1000 patients receiving front-loaded alteplase for thrombolysis were to be recruited by 93 German centers. After enrollment of 302 patients, the trial was stopped after an increased rate of intracranial bleeding was observed in the hirudin group (5 of 148, 3.4%) compared with the heparin group (0 of 154). The overall stroke rate was 3.4% in the hirudin group and 1.3% in the heparin group. Other major bleeding occurred in five versus three patients and ventricular rupture occurred in three versus one patient in the hirudin and heparin groups, respectively. There were 19 in-hospital deaths, with 13 of them from the hirudin group. CONCLUSIONS Although the number of patients was too small for a definite benefit-risk assessment, at the dosage tested, hirudin in combination with front-loaded alteplase and aspirin may be associated with an increased rate of intracranial hemorrhage. Our findings are consistent with the observations of the GUSTO-II and TIMI-9 trials, where higher doses of another recombinant hirudin were used. Therefore, the therapeutic range of hirudin as an adjunct to thrombolysis may be smaller than previously thought, and reappraisal of dose finding should be considered.