tbuckley/cabot-search huggingface dataset:
Mechanisms of Renal Apoptosis in Health and Disease
Authors: Ana Belen Sanz, Beatriz Santamari[Combining Acute Accent]a, Marta Ruiz-Ortega, Jesus Egido, Alberto Ortiz
Journal: Journal of the American Society of Nephrology (2008)

Apoptotic cell death is usually a response to the cell microenvironment. Apoptosis requires the activation of lethal molecules and the inactivation of prosurvival ones. Both are potential therapeutic targets. Apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury. Apoptotic pathways that are active in glomerular and tubular epithelium include death induced by survival factor deprivation, death receptor activation, mitochondrial injury, endoplasmic reticulum stress, lysosomal destabilization, and caspase cascade activation. These pathways are not mutually exclusive, and stimulus-specific differences in the recruitment of apoptotic pathways have been observed. In some cases, the activation of a certain death pathway is redundant, and its inhibition does not prevent eventual cell death. This review summarizes recent advances in the field and discusses the rational basis to choose from the available tools to target apoptosis therapeutically.
Reversible induction of right ventricular atriopeptin synthesis in hypertrophy due to hypoxia.
Authors: P T Stockmann, D H Will, S D Sides, S R Brunnert, G D Wilner, K M Leahy, R C Wiegand, P Needleman
Journal: Circulation Research (1988)

Right ventricular hypertrophy produced in rats exposed to 10% oxygen for 3 weeks resulted in a ninefold increase in atriopeptin immunoreactivity (APir) and a 160-fold increase in atriopeptin messenger RNA (AP mRNA) in the right ventricular myocardium. A small but significant increase in left ventricular APir and AP mRNA was also present, probably representing the interventricular septum. Right atrial APir was decreased by 50%, but left atrial APir was not different from normoxic controls. Purification of ventricular tissue extracts by high-performance liquid chromatography revealed primarily the high molecular weight prohormone. The development of right ventricular hypertrophy and right ventricular APir content followed a similar time course, each evident at 7 days of hypoxia and reaching a plateau at 14 days. Hypoxia followed by normoxia caused right ventricular APir to fall to control levels within 3 days, despite persistent right ventricular hypertrophy. This data demonstrates that hypoxia can reversibly induce extra-atrial expression of atriopeptin synthesis in the cardiac ventricle.
Itraconazole Inhibits Angiogenesis and Tumor Growth in Non–Small Cell Lung Cancer
Authors: Blake T. Aftab, Irina Dobromilskaya, Jun O. Liu, Charles M. Rudin
Journal: Cancer Research (2011)

Abstract The antiangiogenic agent bevacizumab has been approved for the treatment of non–small cell lung cancer (NSCLC), although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral antifungal drug itraconazole as a novel agent with potential antiangiogenic activity. In this article, we define and characterize the antiangiogenic and anticancer activities of itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently showed potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both VEGF- and basic fibroblast growth factor–mediated angiogenic stimulation. In vivo, using primary xenograft models of human NSCLC, oral itraconazole showed single-agent growth-inhibitory activity associated with induction of tumor hypoxia-inducible factor 1 alpha expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the antitumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations, we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral itraconazole in patients with recurrent metastatic NSCLC. Cancer Res; 71(21); 6764–72. ©2011 AACR.
Loss of Functional Beta2-Microglobulin in Metastatic Melanomas From Five Patients Receiving Immunotherapy
Authors: N. P. Restifo, F. M. Marincola, Y. Kawakami, J. Taubenberger, J. R. Yannelli, S. A. Rosenberg
Journal: JNCI Journal of the National Cancer Institute (1996)

In a subset of patients with metastatic melanoma, T lymphocytes bearing the cell-surface marker CD8 (CD8 + T cells) can cause the regression of even large tumors. These antitumor CD8 + ; T cells recognize peptide antigens presented on the surface of tumor cells by major histocompatibility complex (MHC) class I molecules. The MHC class I molecule is a heterodimer composed of an integral membrane glycoprotein designated the α chain and a non-covalently associated, soluble protein called beta 2 -micro-globulin (β 2 m). Loss of β 2 m generally eliminates antigen recognition by antitumor CD8 + T cells. We studied the loss of β 2 m as a potential means of tumor escape from immune recognition in a cohort of patients receiving immunotherapy. We successfully grew 13 independent tumor cell cultures from tumor specimens obtained from 13 patients in a cohort of 40 consecutive patients undergoing immunotherapy for metastatic melanoma and for whom tumor specimens were available. These cell lines, as well as another melanoma cell line (called 1074mel) that had been derived from tumor obtained from a patient in a cytokine-gene therapy study, were characterized in vitro cytofluorometrically for MHC class I expression and by northern and western blot analyses for messenger RNA (mRNA) and protein expression, respectively, and ex vivo by immunohistochemistry. After one melanoma cell line (1074mel) was found not to express functional β 2 m by cytofluorometric analysis, four (31%) of the 13 newly established melanoma cell lines were found to have an absolute lack of functional MHC class I expression. Northern blot analysis of RNA extracted from the five cell lines exhibiting no functional MHC class I expression showed that these cells contained normal levels of α-chain mRNA but variable levels of β 2 m mRNA. In addition, no immunoreactive β 2 m protein was detected by western blot analysis. When human β 2 m was transiently expressed with the use of a recombinant vaccinia virus, cell-surface MHC class I expression was reconstituted and the ability of these five cell lines to present endogenous antigens was restored. Immunohistochemical staining of tumor sections revealed a lack of immunoreactive MHC class I in vivo, supporting the notion that the in vitro observations were not artifactual. Furthermore, archival tumor sections obtained from patients prior to immunotherapy were available from three patients and were found to be β 2 m positive. This result was consistent with the hypothesis that loss of β 2 m resulted from immunotherapy. These data suggest that the loss of β 2 m may be a mechanism whereby tumor cells can acquire immunoresistance. This study represents the first characterization of a molecular route of escape of tumors from immune recognition in a cohort of patients being treated with immunotherapy. [J Natl Cancer Inst 1996; 88: 100–8]
DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model
Authors: Charles I. Berul, Colin T. Maguire, Mark J. Aronovitz, Jessica Greenwood, Carol Miller, Josef Gehrmann, David Housman, Michael E. Mendelsohn, Sita Reddy
Journal: Journal of Clinical Investigation (1999)

Myotonic dystrophy (DM) is the most common form of muscular dystrophy and is caused by expansion of a CTG trinucleotide repeat on human chromosome 19. Patients with DM develop atrioventricular conduction disturbances, the principal cardiac manifestation of this disease. The etiology of the pathophysiological changes observed in DM has yet to be resolved. Haploinsufficiency of myotonic dystrophy protein kinase (DMPK), DM locus-associated homeodomain protein (DMAHP) and/or titration of RNA-binding proteins by expanded CUG sequences have been hypothesized to underlie the multi-system defects observed in DM. Using an in vivo murine electrophysiology study, we show that cardiac conduction is exquisitely sensitive to DMPK gene dosage. DMPK–/– mice develop cardiac conduction defects which include first-, second-, and third-degree atrioventricular (A–V) block. Our results demonstrate that the A–V node and the His-Purkinje regions of the conduction system are specifically compromised by DMPK loss. Importantly, DMPK+/– mice develop first-degree heart block, a conduction defect strikingly similar to that observed in DM patients. These results demonstrate that DMPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsufficiency of DMPK with cardiac disease in myotonic dystrophy.
Cancer Patients Treated with Sunitinib or Sorafenib Have Sufficient Antibody and Cellular Immune Responses to Warrant Influenza Vaccination
Authors: Sasja F. Mulder, Joannes F.M. Jacobs, Michel A.M. Olde Nordkamp, Joep M.D. Galama, Ingrid M.E. Desar, Ruurd Torensma, Steven Teerenstra, Peter F.A. Mulders, Kris C.P. Vissers, Cornelis J.A. Punt, I. Jolanda M. de Vries, Carla M.L. van Herpen
Journal: Clinical Cancer Research (2011)

The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib.Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines.Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls.We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib.
Prolactin Receptors in Human Breast Tumors&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: L Turcot-Lemay, P A Kelly
Journal: JNCI Journal of the National Cancer Institute (1982)

Prolactin-binding sites were determined in 759 human breast tumor biopsy specimens. Ovine prolactin (oPRL) was used in the binding assay of 569 tumors with 13% of the tumors showing a positive content with more than 1% specific binding. Human prolactin (hPRL) was utilized for 343 tumors with 36% of the tumors binding 1% or greater of the added radioactivity. When human growth hormone (hGH) was used as the labeled ligand in 95 tumors, only 2% of the tumors specifically bound more than 1% of the hGH. A total of 153 tumors were assayed simultaneously with the use of labeled hPRL and oPRL. Whereas 10.4% of the tumors showed the presence of prolactin-binding sites (greater than 1% specific binding) when oPRL was used, an approximately threefold increase (29.4%) in tumors possessing prolactin receptors was revealed when hPRL was used as the labeled ligand. Therefore, hPRL is the preferred ligand for the assessment of prolactin receptor levels in human breast cancer biopsy specimens.
Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice
Authors: Justin R. Henning, Christopher S. Graffeo, Adeel Rehman, Nina C. Fallon, Constantinos P. Zambirinis, Atsuo Ochi, Rocky Barilla, Mohsin Jamal, Michael Deutsch, Stephanie Greco, Melvin Ego-Osuala, Usama Bin-Saeed, Raghavendra S. Rao, Sana Badar, Juan P. Quesada, Devrim Acehan, George Miller
Journal: Hepatology (2013)

Nonalcoholic steatohepatitis (NASH) is the most common etiology of chronic liver dysfunction in the United States and can progress to cirrhosis and liver failure. Inflammatory insult resulting from fatty infiltration of the liver is central to disease pathogenesis. Dendritic cells (DCs) are antigen-presenting cells with an emerging role in hepatic inflammation. We postulated that DCs are important in the progression of NASH. We found that intrahepatic DCs expand and mature in NASH liver and assume an activated immune phenotype. However, rather than mitigating the severity of NASH, DC depletion markedly exacerbated intrahepatic fibroinflammation. Our mechanistic studies support a regulatory role for DCs in NASH by limiting sterile inflammation through their role in the clearance of apoptotic cells and necrotic debris. We found that DCs limit CD8+ T-cell expansion and restrict Toll-like receptor expression and cytokine production in innate immune effector cells in NASH, including Kupffer cells, neutrophils, and inflammatory monocytes. Consistent with their regulatory role in NASH, during the recovery phase of disease, ablation of DC populations results in delayed resolution of intrahepatic inflammation and fibroplasia. Conclusion : Our findings support a role for DCs in modulating NASH. Targeting DC functional properties may hold promise for therapeutic intervention in NASH. (HEPATOLOGY 2013;58:589–602)
Cation depletion by the sodium pump in red cells with pathologic cation leaks. Sickle cells and xerocytes.
Authors: C H Joiner, O S Platt, S E Lux
Journal: Journal of Clinical Investigation (1986)

The mechanism by which sickle cells and xerocytic red cells become depleted of cations in vivo has not been identified previously. Both types of cells exhibit elevated permeabilities to sodium and potassium, in the case of sickle cells, when deoxygenated. The ouabain-insensitive fluxes of sodium and potassium were equivalent, however, in both cell types under these conditions. When incubated 18 hours in vitro, sickle cells lost cations but only when deoxygenated. This cation depletion was blocked by ouabain, removal of external potassium, or pretreatment with 4,4'-diisothiocyanostilbene-2,2'-disulfonate, which blocks the increase in cation permeability induced by deoxygenation. The loss of cation exhibited by oxygenated xerocytes similarly incubated was also blocked by ouabain. These data support the hypothesis that the elevated "passive" cation fluxes of xerocytes and deoxygenated sickle cells are not directly responsible for cation depletion of these cells; rather, these pathologic leaks interact with the sodium pump to produce a net loss of cellular cation.
Epigenetics and Complex Disease: From Etiology to New Therapeutics
Authors: Carolyn Ptak, Arturas Petronis
Journal: The Annual Review of Pharmacology and Toxicology (2007)

Epigenetics is a new development in complex non-Mendelian disease, which may not only uncover etiologic and pathogenic mechanisms but may also provide the basis for the development of medications that would target the primary epigenetic causes of such diseases. Such epigenetic drugs would be novel, potentially possessing substantially higher therapeutic potential and a much lower rate of adverse effects in comparison to current symptomatic treatments. A collection of epigenetic drugs already exist at various stages of development and, although their effectiveness has yet to be maximized, they show great promise in the treatment of cancer, psychiatric disorders, and other complex diseases. Here we present a review of the epigenetic theory of complex disease and an evaluation of current epigenetic therapies, as well as predictions of the future directions in this expanding field.
ATM-deficient thymic lymphoma is associated with aberrant <i>tcrd</i> rearrangement and gene amplification
Authors: Shan Zha, Craig H. Bassing, Takaomi Sanda, James W. Brush, Harin Patel, Peter H. Goff, Michael M. Murphy, Suprawee Tepsuporn, Richard A. Gatti, A. Thomas Look, Frederick W. Alt
Journal: The Journal of Experimental Medicine (2010)

Ataxia telangiectasia mutated (ATM) deficiency predisposes humans and mice to T lineage lymphomas with recurrent chromosome 14 translocations involving the T cell receptor α/δ (Tcra/d) locus. Such translocations have been thought to result from aberrant repair of DNA double-strand breaks (DSBs) during Tcra locus V(D)J recombination, and to require the Tcra enhancer (Eα) for Tcra rearrangement or expression of the translocated oncogene. We now show that, in addition to the known chromosome 14 translocation, ATM-deficient mouse thymic lymphomas routinely contain a centromeric fragment of chromosome 14 that spans up to the 5′ boundary of the Tcra/d locus, at which position a 500-kb or larger region centromeric to Tcra/d is routinely amplified. In addition, they routinely contain a large deletion of the telomeric end of one copy of chromosome 12. In contrast to prior expectations, the recurrent translocations and amplifications involve V(D)J recombination–initiated breaks in the Tcrd locus, as opposed to the Tcra locus, and arise independently of the Eα. Overall, our studies reveal previously unexpected mechanisms that contribute to the oncogenic transformation of ATM-deficient T lineage cells.
Effectiveness of Cholinesterase Inhibitors and Memantine for Treating Dementia: Evidence Review for a Clinical Practice Guideline
Authors: Parminder Raina, Pasqualina Santaguida, Afisi Ismaila, Christopher Patterson, David Cowan, Mitchell Levine, Lynda Booker, Mark Oremus
Journal: Annals of Internal Medicine (2008)

Background: The effectiveness of the 5 U.S. Food and Drug Administration–approved pharmacologic therapies for dementias in achieving clinically relevant improvements is unclear. Purpose: To review the evidence for the effectiveness of cholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) and the neuropeptide-modifying agent memantine in achieving clinically relevant improvements, primarily in cognition, global function, behavior, and quality of life, for patients with dementia. Data Sources: Cochrane Central Register of Controlled Trials, MEDLINE, PREMEDLINE, EMBASE, Allied and Complementary Medicine Database, CINAHL, AgeLine, and PsycINFO from January 1986 through November 2006. Study Selection: English-language randomized, controlled trials were included in the review if they evaluated pharmacologic agents for adults with a diagnosis of dementia, did not use a crossover design, and had a quality score of at least 3 on the Jadad scale. Data Extraction: Data were extracted on study characteristics and outcomes, including adverse events. Effect sizes were calculated and data were combined when appropriate. Data Synthesis: 96 publications representing 59 unique studies were eligible for this review. Both cholinesterase inhibitors and memantine had consistent effects in the domains of cognition and global assessment, but summary estimates showed small effect sizes. Outcomes in the domains of behavior and quality of life were evaluated less frequently and showed less consistent effects. Most studies were of short duration (6 months), which limited their ability to detect delay in onset or progression of dementia. Three studies directly compared different cholinesterase inhibitors and found no differences in cognition and behavior. Limitations: Limitations of available studies included short duration, inclusion of only patients with mild to moderate Alzheimer disease, poor reporting of adverse events, lack of clear definitions for statistical significance, limited evaluation of behavior and quality-of-life outcomes, and limited direct comparison of different treatments. Conclusions: Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia.
Prognostic value of right ventricular ejection fraction in pulmonary arterial hypertension
Authors: Pierre-Yves Courand, Géraldine Pina Jomir, Chahéra Khouatra, Christian Scheiber, Ségolène Turquier, Jean-Charles Glérant, Bénédicte Mastroianni, Béatrice Gentil, Anne-Sophie Blanchet-Legens, Alfred Dib, Geneviève Derumeaux, Marc Humbert, Jean-François Mornex, Jean-François Cordier, Vincent Cottin
Journal: European Respiratory Journal (2014)

Right ventricle ejection fraction (RVEF) evaluated with magnetic resonance imaging is a strong determinant of patient outcomes in pulmonary arterial hypertension. We evaluated the prognostic value of RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change 3–6 months after initiating pulmonary arterial hypertension-specific therapy. In a prospective cohort of newly diagnosed patients with idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension, RVEF was measured at baseline (n=100) and 3–6 months after initiation of therapy (n=78). After a median follow-up of 4.1 years, 41 deaths occurred, including 35 from cardiovascular causes. Patients with a (median) baseline RVEF &gt;25% had better survival than those with a RVEF &lt;25% using Kaplan–Meier analysis (p=0.010). RVEF at baseline was an independent predictor of all-cause and cardiovascular mortality in adjusted Cox regression model (p=0.002 and p=0.007, respectively; HR 0.93 for both). Patients with stable or increased RVEF at 3–6 months had a trend for improved all-cause survival (HR 2.43, p=0.086) and had less cardiovascular mortality (HR 3.25, p=0.034) than those in whom RVEF decreased despite therapy. RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change in RVEF 3–6 months after therapy initiation independently predict outcomes in patients with pulmonary arterial hypertension.