tbuckley/cabot-search huggingface dataset:
The Road to Shangri-La Is Paved with Vitamins
Authors: REUBEN BITENSKY
Journal: American Journal of Psychiatry (1973)

A number of people have adopted a belief that vitamins can prevent disease and restore youth. The author examines the implications of this belief as it was uncovered in group therapy sessions. He discusses the liberalism and activism of these middle-aged group members in their younger years, the anti-establishment values of the vitamin cult, and the denial of aging by seeking eternal youth. The author concludes that their common belief in the powers of vitamins has not been beneficial to the growth and well-being of the group.
THE CARDIAC FIBROBLAST: Therapeutic Target in Myocardial Remodeling and Failure
Authors: R. Dale Brown, S. Kelly Ambler, M. Darren Mitchell, Carlin S. Long
Journal: The Annual Review of Pharmacology and Toxicology (2005)

Cardiac fibroblasts play a central role in the maintenance of extracellular matrix in the normal heart and as mediators of inflammatory and fibrotic myocardial remodeling in the injured and failing heart. In this review, we evaluate the cardiac fibroblast as a therapeutic target in heart disease. Unique features of cardiac fibroblast cell biology are discussed in relation to normal and pathophysiological cardiac function. The contribution of cardiac fibrosis as an independent risk factor in the outcome of heart failure is considered. Candidate drug therapies that derive benefit from actions on cardiac fibroblasts are summarized, including inhibitors of angiotensin-aldosterone systems, endothelin receptor antagonists, statins, anticytokine therapies, matrix metalloproteinase inhibitors, and novel antifibrotic/anti-inflammatory agents. These findings point the way to future challenges in cardiac fibroblast biology and pharmacotherapy.
A10.12 Characterisation of a New mPGES-1 Inhibitor in Human and Murine Models of Inflammation
Authors: Patrick Leclerc, Helena Idborg, Patrick Stenberg, Marina Korotkova, Per-Johan Jakobsson
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition has been suggested as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. This approach could potentially mitigate the gastro-intestinal and cardiovascular side effects associated to traditional non-steroidal anti-inflammatory drugs (NSAIDs) and Coxibs. <h3>Aim</h3> To characterise a selective inhibitor of mPGES-1 and study its impact on the prostanoid profile in various models of inflammation. <h3>Materials and Methods</h3> Potency and selectivity: Compound III was incubated with active enzymes of the prostanoid pathway (mPGES-1, COX-1/2, PGIS, H-PGDS). For potential cross-reactivity towards thromboxane synthase, compound III was tested in a thromboxane release assay in platelets. A549 cells: compound III was assayed in both short and long-term assays. Cells were stimulated with IL-1β/TNF-α or IL-1β alone and incubated in the presence of inhibitors. Whole blood assay/mouse peritoneal macrophages: blood and macrophages were induced with LPS and incubated with compound III for 24 h. Air pouch model: the inflammatory reaction was triggered by a carrageenan injection intra-pouch. Inhibitors were injected i.p. and exudates were collected after 6 h. Prostanoid analysis: Prostanoids were measured by mass spectrometry or enzyme immunoassay. <h3>Results</h3> Compound III has an IC<sub>50</sub> of 0.4 µM and 1 µM in human and murine mPGES-1 respectively. It has no activity on other enzymes of the prostanoid pathway and did not inhibit thromboxane release from human platelets. In cellular assays, it reduced PGE<sub>2</sub> production in A549 cells, mouse peritoneal macrophages and LPS-stimulated whole blood. In mouse peritoneal macrophages, compound III caused a shunt to the prostacyclin pathway. Lastly, we assayed compound III in the air pouch model to verify its impact on the prostanoid profile and compare it to the profile obtained in mPGES-1 k.o. mice. As opposed to mPGES-1 genetic deletion, which attenuated PGE<sub>2</sub> induction and caused a shunt to the thromboxane pathway, mPGES-1 inhibition with compound III reduced PGE<sub>2</sub> production and tended to decrease the levels of other prostanoids. <h3>Conclusions</h3> Compound III is an active and selective inhibitor of mPGES-1. Its impact on the prostanoid profile was assay dependent. However, in the air pouch, contrary to mPGES-1 gene deletion, compound III did not trigger shunting, a scenario more likely to represent the outcome of mPGES-1 inhibition at the inflammatory site.
Function and Localization of Urate Transporter 1 in Mouse Kidney
Authors: Makoto Hosoyamada, Kimiyoshi Ichida, Atsushi Enomoto, Tatsuo Hosoya, Hitoshi Endou
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Mouse renal-specific transporter (RST) cDNA, the amino acid sequence of which has 74% identity with that of human urate transporter 1 (hURAT1), is potentially the mouse homologue of hURAT1, the gene responsible for hereditary renal hypouricemia. The aim of this study is to determine the location and characteristics of RST molecule in mouse kidney and investigate urate transport by RST using the Xenopus oocyte expression system. RST transported 14C-urate in a Michaelis-Menten manner. The Km and the Vmax values of RST-dependent urate transport were 1213 ± 222 μM and 268.8 ± 38.0 pmol/oocyte per hr, respectively (n = 3). RST-dependent urate transport was cis-inhibited significantly by 1 mM probenecid (68.7 ± 9.4%), 50 μM benzbromarone (67.9 ± 6.4%), and 10 mM lactate (50.9 ± 9.5%). However, 1 mM p-aminohippurate (PAH), 1 mM xanthine, and 1 mM oxonate did not inhibit RST-dependent urate transport. Substitution of Cl anion with gluconate in the external solution enhanced RST-dependent urate transport. Pre-injected pyrazinoic acid (PZA) or L-lactate trans-stimulated RST-dependent urate transport. Using immunohistochemistry for mouse kidney, the brush border or intracellular membrane of proximal tubules was stained by an affinity-purified antibody that recognized mouse URAT1 (mURAT1) expressed on Xenopus oocyte. Using Western blotting, anti-mURAT1 antibody detected 70-kD and 62-kD protein bands. The 70-kD protein was N-glycosylated and was identified as a Triton X-100 insoluble brush border membrane protein. RST mRNA and protein levels were higher in male kidneys than female. RST transported urate similar to hURAT1 and, therefore, appears to be mURAT1—the mouse homologue of hURAT1.
Long-term clinical and molecular remissions in patients with follicular lymphoma following high-dose therapy and autologous stem cell transplantation
Authors: B. Metzner, C. Pott, T.H. Müller, W. Gebauer, J. Casper, D. Kraemer, B. Rosien, S. Schumann-Binarsch, R. Thole, C.H. Köhne
Journal: Annals of Oncology (2013)
Rheumatological manifestations of infective endocarditis.
Authors: P Thomas, J Allal, D Bontoux, F Rossi, J Y Poupet, J P Petitalot, B Becq-Giraudon
Journal: Annals of the Rheumatic Diseases (1984)

A retrospective study showed musculoskeletal manifestations in 32 of 108 patients treated for infective endocarditis in several departments at the Poitiers CHU. Such manifestations included articular pain or aseptic arthritis, typically involving the major joints, as well as vertebral osteomyelitis, low back pain (inflammatory or non-inflammatory), and myalgia. Patients showing such signs were generally younger than those without musculoskeletal involvement, diagnosis was made later, and prognosis was worse; streptococcus D was more often involved, and microscopic haematuria was more common. With the exception of vertebral osteomyelitis, the pathogenesis was not clear.
Temozolomide-Mediated DNA Methylation in Human Myeloid Precursor Cells: Differential Involvement of Intrinsic and Extrinsic Apoptotic Pathways
Authors: Haiyan Wang, Shanbao Cai, Aaron Ernstberger, Barbara J. Bailey, Michael Z. Wang, Wenjing Cai, W. Scott Goebel, Magdalena B. Czader, Colin Crean, Attaya Suvannasankha, Inna Shokolenkoc, Glenn L. Wilson, Arthur R. Baluyut, Lindsey D. Mayo, Karen E. Pollok
Journal: Clinical Cancer Research (2013)

Abstract Purpose: An understanding of how hematopoietic cells respond to therapy that causes myelosuppression will help develop approaches to prevent this potentially life-threatening toxicity. The goal of this study was to determine how human myeloid precursor cells respond to temozolomide (TMZ)-induced DNA damage. Experimental Design: We developed an ex vivo primary human myeloid precursor cells model system to investigate the involvement of cell-death pathways using a known myelosuppressive regimen of O6-benzylguanine (6BG) and TMZ. Results: Exposure to 6BG/TMZ led to increases in p53, p21, γ-H2AX, and mitochondrial DNA damage. Increases in mitochondrial membrane depolarization correlated with increased caspase-9 and -3 activities following 6BG/TMZ treatment. These events correlated with decreases in activated AKT, downregulation of the DNA repair protein O6-methylguanine–DNA methyltransferase (MGMT), and increased cell death. During myeloid precursor cell expansion, FAS/CD95/APO1(FAS) expression increased over time and was present on approximately 100% of the cells following exposure to 6BG/TMZ. Although c-flipshort, an endogenous inhibitor of FAS-mediated signaling, was decreased in 6BG/TMZ–treated versus control, 6BG-, or TMZ alone–treated cells, there were no changes in caspase-8 activity. In addition, there were no changes in the extent of cell death in myeloid precursor cells exposed to 6BG/TMZ in the presence of neutralizing or agonistic anti-FAS antibodies, indicating that FAS-mediated signaling was not operative. Conclusions: In human myeloid precursor cells, 6BG/TMZ–initiated apoptosis occurred by intrinsic, mitochondrial-mediated and not extrinsic, FAS-mediated apoptosis. Human myeloid precursor cells represent a clinically relevant model system for gaining insight into how hematopoietic cells respond to chemotherapeutics and offer an approach for selecting effective chemotherapeutic regimens with limited hematopoietic toxicity. Clin Cancer Res; 19(10); 2699–709. ©2013 AACR.
Early Impairment of Renal Hemodynamic Reserve in Patients With Asymptomatic Heart Failure Is Restored by Angiotensin II Antagonism
Authors: Paola Magri, Maria A. E. Rao, Sara Cangianiello, Vincenzo Bellizzi, Rosaria Russo, Alessandro F. Mele, Michele Andreucci, Bruno Memoli, None Luca De Nicola, Massimo Volpe
Journal: Circulation (1998)

The early/asymptomatic stages of heart failure (HF) are characterized by sodium retention secondary to derangement of sodium reabsorption at the proximal nephron level. Because this phenomenon is reversed by ACE inhibition, abnormalities of renal sodium handling may depend on intrarenal changes of angiotensin II (AII)/nitric oxide (NO) levels. Renal hemodynamic reserve (ie, the glomerular vasodilatory response to amino acid infusion) has been proposed as a reliable test to assess in vivo AII/NO balance.In this study, the effects of 6 weeks of treatment with 5 mg/d of enalapril or with 50 mg/d of losartan on systemic hemodynamics and renal function were assessed, at baseline and after amino acid infusion (AA), in patients with mild HF (NYHA class I) and in healthy volunteers. Untreated HF patients showed a basal renal function comparable to that of healthy subjects. After AA, glomerular filtration rate and renal plasma flow significantly increased in healthy subjects (+29.0% and +30.4%, respectively), whereas no vasodilatory response was observed in HF. Although they did not affect basal renal hemodynamics, both enalapril and losartan restored a normal response to AA in HF patients. Blood pressure and heart rate were comparable in HF subjects and healthy subjects at baseline and were not modified by either treatment. Left ventricular ejection fraction was depressed in HF but did not change after either drug. Urinary excretions of cGMP and nitrate (indexes of NO activity in the kidney), comparable in healthy subjects and in HF patients, were unchanged by either enalapril or losartan and did not correlate with renal reserve.(1) Renal functional reserve is absent in patients with early/asymptomatic HF and normal renal function and (2) both enalapril and losartan restore a normal vasodilatory response to AA in these patients without affecting basal systemic and renal hemodynamics. These data suggest a major role of AII in the development of early abnormalities in patients with HF.
Abstract 360: Tumor specific imaging by L-5-F-18-ethoxy-Tryptophan mediated by LAT1 and IDO1
Authors: Sandra Borkowski, Holger Siebeneicher, Volker Gekeler, Thomas Brumby, Ludger Dinkelborg
Journal: Cancer Research (2012)

Abstract Purpose Radiolabeled tryptophan is capable of visualizing the amino acid metabolism of tumor cells. We investigated the indirectly labeled derivative L-5-F-18-ethoxy-Trp for its potential to differentiate tumors from inflammation by Positron-Emission-Tomography (PET) and for its possible intracellular trapping after catabolism by indoleamine-2,3-dioxygenase 1 (IDO1). Methods Human NCI-H460 lung cancer and PC-3 prostate cancer cells were used for in vitro studies. Cellular influx and efflux of L-5-F-18-ethoxy-Trp at 37°C was measured by a gamma-counter and via HPLC. Blocking studies were carried out under similar conditions to examine the transporter family being relevant for Trp uptake. The effect of IDO1 was investigated after stimulation of cells with 100 IU interferon-gamma (IFN-γ). Human plasma stability of 5-F-18-ethoxy-Trp was measured by radio-HPLC. The imaging potential was examined in tumor-bearing rodents and inflammation models. NCI-460 tumors in rats and PC-3 tumors in mice were subcutaneously inoculated. A sterile inflammation was induced by Complete Freund's Adjuvant (CFA) and an infection inflammation was induced by E.coli injection into rats. PET/CT imaging after 1 hour was conducted by an Inveon microPET camera. Results High cellular uptake of L-5-F-18-ethoxy-Trp was found in NCI-H460 and PC-3 cells with 10% of the applied radioactive dose per 100,000 cells and 30% per 100,000 cells, respectively. Uptake could be blocked by an excess of L-Trp, L-Leu and bicycloheptan-carboxylic acid indicating transport by the heterodimeric amino acid transporters of the SLC7 family with predominant transport by LAT-1. Both cellular uptake and retention were increased after stimulation of IDO1 activity by IFN-γ. HPLC of the efflux supernatant showed strict IDO1 dependence of the intracellular Trp catabolism. The tracer was rather instable in human plasma in vitro and degraded already after 15 min incubation. Nevertheless, PET imaging revealed good uptake of L-5-F-18-ethoxy-Trp in NCI-H460 and PC-3 tumors in rodents with low background. No uptake was found in both inflammation models in rats. Conclusion Tryptophan derivatives are promising tracers for cancer imaging utilizing enhanced metabolism by IDO1 which has been shown to be overexpressed in tumors to suppress the immune response of their microenvironment. Differentiation between malignant lesions and inflammation seems to be possible which would give this PET tracer an advantage over the currently used FDG. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 360. doi:1538-7445.AM2012-360
Changes in extracranial arteries in obstructive sleep apnoea
Authors: R. Schulz
Journal: European Respiratory Journal (2005)

Obstructive sleep apnoea (OSA) is linked with increased cardiovascular morbidity and mortality, possibly through an enhancement of atherosclerotic vascular changes. Up to now, however, only a few studies have tried to evaluate the occurrence of atherosclerosis in patients with OSA. In the present study, ultrasonography of the large extracranial vessels was performed in a group of consecutively admitted OSA patients (n = 35) and a control group of non-OSA patients (n = 35). Common carotid artery-intima media thickness (CCA-IMT) was measured at the far wall of both proximal carotid arteries. Furthermore, the presence of plaques and stenoses of the extracranial vessels was determined. All measurements were carried out blinded to the status of the patients. In the OSA group, CCA-IMT was significantly increased when compared with the non-OSA patients and was related to the degree of nocturnal hypoxia. Additionally, the formation of plaques was more pronounced and extracranial vessel stenosis was more common in the OSA patients. In conclusion, these findings are in favour of an independent influence of obstructive sleep apnoea on atherosclerotic changes of the arterial wall, and represent further strong arguments for obstructive sleep apnoea being a risk factor on its own for the emergence of cardiovascular disease.
Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies
Authors: Hans-Peter Gerber, Napoleone Ferrara
Journal: Cancer Research (2005)

Abstract Preclinical models have examined the pharmacologic and pharmacodynamic activities of an anti–vascular endothelial growth factor (VEGF) humanized, monoclonal antibody, bevacizumab, and/or its murine equivalent A4.6.1. These studies found that single-agent therapy with bevacizumab/A4.6.1 resulted in tumor growth inhibition of 20 different human tumor cell lines (13 tumor types) implanted into nude mice irrespective of the route of administration or tumor location. Several of these studies also observed significant inhibition of tumor metastases. Various studies have examined the feasibility of combining anti-VEGF therapy with cytotoxic or biological agents. Combining bevacizumab/A4.6.1 with doxorubicin, topotecan, paclitaxel, docetaxel, or radiotherapy resulted in additive or synergistic tumor growth inhibition. Changes in vascular functions were frequently reported, including decreased vessel diameter, density, and permeability in response to treatment. A reduction in interstitial fluid pressure was also observed. In some studies, these improvements resulted in an increase in intratumoral uptake of chemotherapy, implying that the most effective use of anti-VEGF therapy is in combination with chemotherapy. Alternatively, combination treatment with radiation increased tumor oxygenation and tumor growth inhibition. Interestingly, anti-VEGF therapy has also been reported to reduce the development of ascites in ovarian mouse models. Finally, safety pharmacology studies with bevacizumab in cynomolgus monkeys showed that this agent is generally well tolerated with no unexpected adverse events.
Subgroup-Specific Prognostic Implications of <i>TP53</i> Mutation in Medulloblastoma
Authors: Nataliya Zhukova, Vijay Ramaswamy, Marc Remke, Elke Pfaff, David J.H. Shih, Dianna C. Martin, Pedro Castelo-Branco, Berivan Baskin, Peter N. Ray, Eric Bouffet, André O. von Bueren, David T.W. Jones, Paul A. Northcott, Marcel Kool, Dominik Sturm, Trevor J. Pugh, Scott L. Pomeroy, Yoon-Jae Cho, Torsten Pietsch, Marco Gessi, Stefan Rutkowski, Laszlo Bognar, Almos Klekner, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Charles G. Eberhart, Michelle Fevre-Montange, Maryam Fouladi, Pim J. French, Max Kros, Wieslawa A. Grajkowska, Nalin Gupta, William A. Weiss, Peter Hauser, Nada Jabado, Anne Jouvet, Shin Jung, Toshihiro Kumabe, Boleslaw Lach, Jeffrey R. Leonard, Joshua B. Rubin, Linda M. Liau, Luca Massimi, Ian F. Pollack, Young Shin Ra, Erwin G. Van Meir, Karel Zitterbart, Ulrich Schüller, Rebecca M. Hill, Janet C. Lindsey, Ed C. Schwalbe, Simon Bailey, David W. Ellison, Cynthia Hawkins, David Malkin, Steven C. Clifford, Andrey Korshunov, Stefan Pfister, Michael D. Taylor, Uri Tabori
Journal: Journal of Clinical Oncology (2013)

Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas.TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors.Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.
Cellular and humoral immunity in patients with insulin-dependent diabetes
Authors: AmolakS. Bansal, PhilipB. Wilson, RichardS.H. Pumphrey, AndrewJ.M. Boulton, RayazA. Malik, Simon Hawke, Gillian Harcourt, Nadia Pantic, David Beeson, Nick Willcox, John Newsom-Davis
Journal: The Lancet (1993)
Nesidioblastosis, Islet Cell Hyperplasia, and Adenomatosis in a Case of Metastasizing Insulinoma: Contribution to the Genesis of the Islets of Langerhans
Authors: Anthony S-Y Leong, Anthony H Slavotinek, Bruce A Higgins
Journal: Diabetes Care (1980)

An unusual case of insulinoma is described in a 40-yr-old woman whose resected pancreas showed multiple adenomas with lymph node metastasis, associated hyperplasia of islets, and nesidioblastosis. The association of nesidioblastosis with this continuum of proliferative changes adds further evidence for a ductular origin of islet Cell tumors.
Routine high pressure post-stent dilatation did not influence clinical restenosis in STARS
Authors: R. Mehran, J.J. Popma, D.S. Baim, A.J. Lansky, A.S. Abizaid, J.F. Saucedo, K.M. Kent, L.F. Satler, A.D. Pichard, R.E. Kuntz, K. Ho, M.B. Leon
Journal: Journal of the American College of Cardiology (1998)
Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience
Authors: Uma H. Athale, Bassem I. Razzouk, Susana C. Raimondi, Xin Tong, Frederick G. Behm, David R. Head, Deo K. Srivastava, Jeffrey E. Rubnitz, Laura Bowman, Ching-Hon Pui, Raul C. Ribeiro
Journal: Blood (2001)