tbuckley/cabot-search huggingface dataset:
Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial.
Authors: C J Logothetis, L D Finn, T Smith, R G Kilbourn, J A Ellerhorst, A A Zukiwski, A Sella, S M Tu, R J Amato
Journal: Journal of Clinical Oncology (1995)

Hematopoietic growth factors have been shown to ameliorate the side effects of chemotherapy. Here we assess the ability of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to increase the dose-intensity and reduce the side effects of escalated methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy.A prospective randomized trial to compare escalated MVAC versus escalated MVAC with rhGM-CSF was conducted. All patients were treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) and had a metastatic or unresectable urothelial tumor. Forty-eight patients were randomized (25 to MVAC with rhGM-CSF and 23 to escalated MVAC alone). The clinical characteristics of the study populations were similar (ie, degree of tumor dissemination and performance status).The dose-intensity in the two arms of the study did not differ significantly. No difference in the frequency of bacteriologically documented infections occurred between the two study arms.The use of the hematopoietic growth factor rhGM-CSF did not result in an increased dose-intensity of escalated MVAC. The inability to increase the dose-intensity of MVAC further was a result of nonhematologic side effects of the chemotherapy. Escalation of treatment delivered at its median-tolerated dose is unlikely to result in additional therapeutic benefit for patients with common solid tumors. Future development of therapy may require the development of new agents or concepts, rather than modification of existing therapies.
Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization
Authors: Katy Rivard, Pierre Paradis, Mona Nemer, Céline Fiset
Journal: Cardiovascular Research (2008)

Mice with cardiac-specific overexpression of human angiotensin II type 1 receptor (AT1R) undergo cardiac remodelling and die prematurely of sudden death. Since excessive QT prolongation is a major risk factor for ventricular arrhythmias and sudden death, we hypothesize that chronic stimulation of AT1R might contribute to sudden death by promoting delayed repolarization and ventricular arrhythmias.In the present study, a detailed analysis of ventricular repolarization parameters was undertaken in AT1R mice.Measurement of K+ currents in ventricular myocytes isolated from 6-8 months AT1R male mice revealed a significant reduction of the Ca2+-independent transient outward (I(to)), the ultra-rapid delayed rectifier (I Kur)), and the inward rectifier (I K1) K+ currents compared with littermate controls (CTL). The expression of the underlying K+ channels was also decreased in AT1R ventricles. Moreover, reactivation of I(to) was slower in AT1R mice. Consistent with these findings, AT1R mice presented a longer action potential duration (APD90, CTL: 19.0 +/- 1.8 ms; AT1R: 39.1 +/- 4.7 ms, P = 0.0001) and QTc interval (CTL: 53.6 +/- 1.5 ms, AT1R: 64.2 +/- 1.4 ms, P = 0.0005). In addition, spontaneous ventricular arrhythmias were reported in the AT1R mice. Importantly, the increased incidence of arrhythmia and the repolarization defects also occurred in much younger AT1R mice that do not present signs of hypertrophy, confirming that these arrhythmogenic changes are not secondary to cardiac remodelling.These results strongly suggest that chronic stimulation of AT1R directly leads to an increased incidence of cardiac arrhythmia associated with delayed repolarization.
The Role of Liver-Derived Insulin-Like Growth Factor-I
Authors: Claes Ohlsson, Subburaman Mohan, Klara Sjögren, Åsa Tivesten, Jörgen Isgaard, Olle Isaksson, John-Olov Jansson, Johan Svensson
Journal: Endocrine Reviews (2009)

IGF-I is expressed in virtually every tissue of the body, but with much higher expression in the liver than in any other tissue. Studies using mice with liver-specific IGF-I knockout have demonstrated that liver-derived IGF-I, constituting a major part of circulating IGF-I, is an important endocrine factor involved in a variety of physiological and pathological processes. Detailed studies comparing the impact of liver-derived IGF-I and local bone-derived IGF-I demonstrate that both sources of IGF-I can stimulate longitudinal bone growth. We propose here that liver-derived circulating IGF-I and local bone-derived IGF-I to some extent have overlapping growth-promoting effects and might have the capacity to replace each other (= redundancy) in the maintenance of normal longitudinal bone growth. Importantly, and in contrast to the regulation of longitudinal bone growth, locally derived IGF-I cannot replace (= lack of redundancy) liver-derived IGF-I for the regulation of a large number of other parameters including GH secretion, cortical bone mass, kidney size, prostate size, peripheral vascular resistance, spatial memory, sodium retention, insulin sensitivity, liver size, sexually dimorphic liver functions, and progression of some tumors. It is clear that a major role of liver-derived IGF-I is to regulate GH secretion and that some, but not all, of the phenotypes in the liver-specific IGF-I knockout mice are indirect, mediated via the elevated GH levels. All of the described multiple endocrine effects of liver-derived IGF-I should be considered in the development of possible novel treatment strategies aimed at increasing or reducing endocrine IGF-I activity.
Small-cell carcinoma of the penile urethra: a case report and a short review of the literature
Authors: S. Altintas, N. Blockx, M.T. Huizing, J. Van den Brande, L. Hoekx, J.P. Bogers, E. Van Marck, J.B. Vermorken
Journal: Annals of Oncology (2006)

The diffuse neuroendocrine-cell system (DNS) consists of a wide variety of cells that are present in the central and peripheral nervous system and in many classic endocrine organs. These cells share the ability to produce many biologically active amines, peptides and other substances (such as neuron-specific enolase, chromogranines, synaptophysin and Leu-7). Cells and neoplasms of the DNS are divided into two groups: those of the neural type and those of the epithelial type which includes neuroendocrine tumors (NETs) from numerous sites.
Diabetes and Risk of Fracture-Related Hospitalization
Authors: Andrea L.C. Schneider, Emma K. Williams, Frederick L. Brancati, Saul Blecker, Josef Coresh, Elizabeth Selvin
Journal: Diabetes Care (2012)

To examine the association between diabetes, glycemic control, and risk of fracture-related hospitalization in the Atherosclerosis Risk in Communities (ARIC) Study.Fracture-related hospitalization was defined using International Classification of Diseases, 9th revision, codes (733.1-733.19, 733.93-733.98, or 800-829). We calculated the incidence rate of fracture-related hospitalization by age and used Cox proportional hazards models to investigate the association of diabetes with risk of fracture after adjustment for demographic, lifestyle, and behavioral risk factors.There were 1,078 incident fracture-related hospitalizations among 15,140 participants during a median of 20 years of follow-up. The overall incidence rate was 4.0 per 1,000 person-years (95% confidence interval [CI], 3.8-4.3). Diagnosed diabetes was significantly and independently associated with an increased risk of fracture (adjusted hazard ratio [HR], 1.74; 95% CI, 1.42-2.14). There also was a significantly increased risk of fracture among persons with diagnosed diabetes who were treated with insulin (HR, 1.87; 95% CI, 1.15-3.05) and among persons with diagnosed diabetes with hemoglobin A1c (HbA1c) ≥8% (1.63; 1.09-2.44) compared with those with HbA1c <8%. Undiagnosed diabetes was not significantly associated with risk of fracture (HR, 1.12; 95% CI, 0.82-1.53).This study supports recommendations from the American Diabetes Association for assessment of fracture risk and implementation of prevention strategies in persons with type 2 diabetes, particularly those persons with poor glucose control.
High GATA2 expression is a poor prognostic marker in pediatric acute myeloid leukemia
Authors: Maaike Luesink, Iris H. I. M. Hollink, Vincent H. J. van der Velden, Ruth H. J. N. Knops, Jan B. M. Boezeman, Valérie de Haas, Jan Trka, Andre Baruchel, Dirk Reinhardt, Bert A. van der Reijden, Marry M. van den Heuvel-Eibrink, C. Michel Zwaan, Joop H. Jansen
Journal: Blood (2012)
Linoleyl hydroperoxide transcriptionally upregulates heme oxygenase-1 gene expression in human renal epithelial and aortic endothelial cells.
Authors: A Agarwal, F Shiraishi, G A Visner, H S Nick
Journal: Journal of the American Society of Nephrology (1998)

Atherogenic lipoproteins such as oxidized LDL are implicated in the pathogenesis of atherosclerosis and renal disease. Fatty acid hydroperoxides and phospholipids such as linoleyl hydroperoxide (LAox or 13-HPODE) and lysophosphatidylcholine (lyso-PC), abundant components of oxidized LDL, mediate the effects of atherogenic lipids. Oxidized LDL has been shown to induce heme oxygenase-1 (HO-1), a microsomal enzyme that is involved in heme detoxification and is a major endogenous source of carbon monoxide. HO-1 is also induced by many other stimuli that shift cellular redox. To identify the constituents and molecular mechanisms of oxidized LDL-mediated HO-1 induction, human renal epithelial cells and aortic endothelial cells were exposed to LAox and lyso-PC. Exposure to LAox (25 microM) showed an approximately 16-fold induction of HO-1 mRNA, whereas exposure to lyso-PC (25 microM) showed only an approximate 2.6-fold increase. Treatment with actinomycin-D (4 microM), a transcriptional inhibitor, as well as nuclear run-on assays, demonstrated that LAox-mediated HO-1 gene induction is dependent on de novo transcription. Cycloheximide did not affect LAox-mediated HO-1 mRNA induction, suggesting that new protein synthesis is not required for transcriptional induction. Transfection of a human HO-1 promoter-reporter gene construct showed that LAox upregulation of HO-1 occurs via mechanisms different from those of known inducers, heme and cadmium. These studies are the first demonstration that LAox induces HO-1 by transcriptional mechanisms and may have implications in the pathogenesis of cell injury in atherosclerosis and progressive renal disease.
Comparison of the Transforming Effect of Benzo[&lt;italic&gt;a&lt;/italic&gt;]pyrene in Mammalian Cell Lines &lt;italic&gt;In Vitro&lt;/italic&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Johng S. Rhim, Han Y. Cho, M. H. Joglekar, R. J. Huebner
Journal: JNCI Journal of the National Cancer Institute (1972)

The transforming effect of benzo[a]pyrene (BP) was compared in 3 cell lines (rat, mouse, and hamster) in vitro. A rat-embryo cell line infected with Rauscher leukemia virus, a Swiss mouse cell line infected with AKR wild-type C-type RNA virus, and an uninfected hamster-embryo cell line when treated with BP were each readily transformed and produced tumors when injected into homologous hosts. The infected mouse cell cultures had transformed foci 9 days after BP treatment. Uninfected rat and mouse cells treated with BP and infected cells untreated with BP remained morphologically unchanged and did not produce tumors in vivo. The mouse cells infected with wild-type murine C-type RNA virus appeared to provide the most sensitive system for chemical transformation. The addition of both virus and chemical was an important determinant of the transformation. As in previous reports, we suggest that the postulated oncogenes of the RNA tumor virus genomes were derepressed by the action of BP which induced the transformation in these cells.
Molecular Heterogeneity of Multiple Myeloma: Pathogenesis, Prognosis, and Therapeutic Implications
Authors: Avet-Loiseau Hervé, Magrangeas Florence, Moreau Philippe, Attal Michel, Facon Thierry, Anderson Kenneth, Harousseau Jean-Luc, Munshi Nikhil, Minvielle Stéphane
Journal: Journal of Clinical Oncology (2011)

Multiple myeloma (MM) is characterized by a significant heterogeneity at the molecular level. The first level is the chromosomal one. Although cytogenetics is difficult to assess in MM, patients can be divided into two categories: hyperdiploidy and non-hyperdiploidy (about half in each group). Using molecular cytogenetic techniques, several subgroups of patients are identified, particularly on the basis of 14q32 translocations. This chromosomal heterogeneity is confirmed by genomic techniques (gene expression profiling or single nucleotide polymorphism/comparative genomic hybridization arrays). Unsupervised analyses of gene expression profiles identified several subgroups of patients, essentially on the basis of chromosomal abnormalities such as hyperdiploidy or 14q32 translocations. However, these analyses failed to separate MM into subentities, which could lead to specific therapeutic approaches, as is the case for non-Hodgkin's lymphomas. Nevertheless, these chromosomal/genomic data can be used for prognostication of patients. Specific chromosomal changes, such as loss of the short arm of chromosome 17, or specific gene expression profiles clearly identify patients with short survival. No molecular change so far has been associated with long survival or even cure, probably because of the short follow-up observed in all studies. So far, it is unclear how to use this massive amount of data to treat patients. Because of the complex and heterogeneous picture of the molecular profiles, it is unexpected that targeted therapies might play a role in MM. The only recognized indication is to propose bortezomib-based approaches for the treatment of patients displaying the translocation t(4;14).
Transduction of Human and Mouse Pancreatic Islet Cells Using a Bicistronic Recombinant Adeno-associated Viral Vector
Authors: Matthias Kapturczak, Sergei Zolotukhin, Jeff Cross, Antonello Pileggi, R. Damaris Molano, Marda Jorgensen, Barry Byrne, Terence R. Flotte, Tamir Ellis, Luca Inverardi, Camillo Ricordi, Harry Nick, Mark Atkinson, Anupam Agarwal
Journal: Molecular Therapy (2002)

Recent reports indicate successful transduction of pancreatic islets using recombinant adeno-associated viral (rAAV) vectors. This advance offers new possibilities in rendering islets resistant to rejection and recurrence of autoimmune destruction in the setting of islet transplantation as treatment of type 1 diabetes. Most gene delivery approaches using islets have thus far involved transduction with a single gene. However, the concomitant delivery of more than one gene encoding cytoprotective and/or immunoregulatory molecules may offer superior clinical utility. Here, we have generated a bicistronic rAAV (serotype 2) vector incorporating a viral internal ribosome entry site (IRES), derived from polio virus type 1, to allow for translation of two coupled cDNAs from a single mRNA transcript. Our study demonstrates the ability of this vector to produce significant expression of two reporter proteins in human and mouse islets in vitro. This expression did not interfere with β-cell function. Transduction was maintained in vivo following transplantation of mouse islets. These data are the first report of efficient islet cell transduction with two genes using a single bicistronic rAAV vector and have direct implications for strategies aimed at enhancing islet transplant survival. Recent reports indicate successful transduction of pancreatic islets using recombinant adeno-associated viral (rAAV) vectors. This advance offers new possibilities in rendering islets resistant to rejection and recurrence of autoimmune destruction in the setting of islet transplantation as treatment of type 1 diabetes. Most gene delivery approaches using islets have thus far involved transduction with a single gene. However, the concomitant delivery of more than one gene encoding cytoprotective and/or immunoregulatory molecules may offer superior clinical utility. Here, we have generated a bicistronic rAAV (serotype 2) vector incorporating a viral internal ribosome entry site (IRES), derived from polio virus type 1, to allow for translation of two coupled cDNAs from a single mRNA transcript. Our study demonstrates the ability of this vector to produce significant expression of two reporter proteins in human and mouse islets in vitro. This expression did not interfere with β-cell function. Transduction was maintained in vivo following transplantation of mouse islets. These data are the first report of efficient islet cell transduction with two genes using a single bicistronic rAAV vector and have direct implications for strategies aimed at enhancing islet transplant survival.
Natural Killer Cell Tolerance in Mice with Mosaic Expression of Major Histocompatibility Complex Class I Transgene
Authors: Maria H. Johansson, Charles Bieberich, Gilbert Jay, Klas Kärre, Petter Höglund
Journal: The Journal of Experimental Medicine (1997)

We have studied natural killer (NK) cell tolerance in a major histocompatibility complex (MHC) class I transgenic line, DL6, in which the transgene product was expressed on only a fraction of blood cells. In contrast with transgenic mice expressing the same transgene in all cells, NK cells from mosaic mice failed to reject transgene-negative bone marrow or lymphoma grafts. However, they retained the capability to reject cells with a total missing-self phenotype, i.e., cells lacking also wild-type MHC class I molecules. Tolerance against transgene-negative cells was demonstrated also in vitro, and could be broken if transgene-positive spleen cells of mosaic mice were separated from negative cells before, or after 4 d of culture in interleukin-2. The results provide support for selective NK cell tolerance to one particular missing-self phenotype but not to another. We suggest that this tolerance is determined by NK cell interactions with multiple cells in the environment, and that it is dominantly controlled by the presence of cells lacking a specific MHC class I ligand. Furthermore, the tolerant NK cells could be reactivated in vitro, which suggests that the tolerance occurs without deletion of the potentially autoreactive NK cell subset(s), and that it may be dependent upon the continuous presence of tolerizing cells.
Characterization of the CD4+ T Cell Response to Epstein-Barr Virus during Primary and Persistent Infection
Authors: Elisabeth Amyes, Chris Hatton, Damien Montamat-Sicotte, Nancy Gudgeon, Alan B. Rickinson, Andrew J. McMichael, Margaret F.C. Callan
Journal: The Journal of Experimental Medicine (2003)

The CD8+ T cell response to Epstein-Barr virus (EBV) is well characterized. Much less is known about the evolution of the CD4+ T cell response. Here we show that EBV stimulates a primary burst of effector CD4+ T cells and this is followed by a period of down-regulation. A small population of EBV-specific effector CD4+ T cells survives during the lifelong persistent phase of infection. The EBV-specific effector CD4+ T cells accumulate within a CD27+ CD28+ differentiation compartment during primary infection and remain enriched within this compartment throughout the persistent phase of infection. Analysis of CD4+ T cell responses to individual epitopes from EBV latent and lytic cycle proteins confirms the observation that the majority of the effector cells express both CD27 and CD28, although CD4+ T cells specific for lytic cycle antigens have a greater tendency to express CD45RA than those specific for the latent antigens. In clear contrast, effector CD4+ T cells specific for cytomegalovirus (CMV) accumulate within the CD27− CD28+ and CD27− CD28− compartments. There are striking parallels in terms of the differentiation of CD8+ T cells specific for EBV and CMV. The results challenge current ideas on the definition of memory subsets.
Schmidt's Syndrome in a Child with Diabetes Mellitus
Authors: Richard P Nelson, Howard S Traisman, Ruth B Deddish, Orville C Green
Journal: Diabetes Care (1978)

Schmidt's syndrome (thyroid and adrenal insufficiency) and concurrent diabetes mellitus represent an intriguing multiple endocrinopathy in children. This report describes an eleven-year-old girl with diabetes of eight years' duration presenting in adrenal crisis. Serum thyroxine was undetectable, and antibodies to both thyroglobulin and adrenal tissue were found in high titer. The child's condition stabilized with hormonal replacement therapy, except for persistent growth failure. Approximately two years later she succumbed during a rapidly fulminant episode of ketoacidosis. The natural history of her illness supports recent speculation based on serologic data that juvenile diabetes mellitus may be an immunologic disorder in some children.
SOMATIC CELL HYBRIDS BETWEEN MOUSE PERITONEAL MACROPHAGES AND SV40-TRANSFORMED HUMAN CELLS
Authors: Carlo M. Croce, Hilary Koprowski
Journal: The Journal of Experimental Medicine (1974)

Fusion of mouse peritoneal macrophages with SV40-transformed human cells, deficient in hypoxanthine guanine phosphoribosyltransferase, resulted in the formation of transformed somatic cell hybrids which contained, without exception, the human chromosome 7 carrying the SV40 genome. It is postulated that the hybridization of mouse nondividing cells with human cancer cells could permit the identification of the human "oncogenic" chromosome(s) present in human cancer cells, since such chromosome(s) should be retained by the totality of the mouse-human hybrid cells.
Development of a Small-Molecule Serum- and Glucocorticoid-Regulated Kinase-1 Antagonist and Its Evaluation as a Prostate Cancer Therapeutic
Authors: Andrea B. Sherk, Daniel E. Frigo, Christine G. Schnackenberg, Jeffrey D. Bray, Nicholas J. Laping, Walter Trizna, Marlys Hammond, Jaclyn R. Patterson, Scott K. Thompson, Dmitri Kazmin, John D. Norris, Donald P. McDonnell
Journal: Cancer Research (2008)

Abstract Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathologic growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential component of the pharmacotherapy of prostate cancer. In this study, we explored the utility of targeting processes downstream of AR as an alternate approach for therapy. Specifically, we show that the serum and glucocorticoid-regulated kinase 1 (SGK1) gene is an androgen-regulated target gene in cellular models of prostate cancer. Furthermore, functional serum- and glucocorticoid-regulated kinase 1 (SGK1) protein, as determined by the phosphorylation of its target Nedd4-2, was also increased with androgen treatment. Importantly, we determined that RNA interference–mediated knockdown of SGK1 expression attenuates the androgen-mediated growth of the prostate cancer cell line LNCaP. Given these findings, we explored the utility of SGK1 as a therapeutic target in prostate cancer by developing and evaluating a small-molecule inhibitor of this enzyme. From these studies emerged GSK650394, a competitive inhibitor that quantitatively blocks the effect of androgens on LNCaP cell growth. Thus, in addition to androgen ablation, inhibition of pathways downstream of AR is likely to have therapeutic utility in prostate cancer. [Cancer Res 2008;68(18):7475–83]