tbuckley/cabot-search huggingface dataset:
Racial and Ethnic Differences in Kidney Function Decline among Persons without Chronic Kidney Disease
Authors: Carmen A. Peralta, Ronit Katz, Ian DeBoer, Joachim Ix, Mark Sarnak, Holly Kramer, David Siscovick, Steven Shea, Moyses Szklo, Michael Shlipak
Journal: Journal of the American Society of Nephrology (2011)

Whether the rate of kidney function decline before the onset of CKD differs among racial and ethnic groups remains unclear. Here, we evaluated kidney function decline and incident CKD among white, black, Hispanic, and Chinese participants in the Multi-Ethnic Study of Atherosclerosis (MESA) during 5 years of follow-up. We estimated GFR using both cystatin C (eGFRcys) and creatinine (eGFRcreat). The definition of incident CKD required eGFRcys <60 ml/min per 1.73 m(2) and a decline in eGFRcys ≥1 ml/min per year. Among participants with eGFRcreat >60 ml/min per 1.73 m(2) at baseline, blacks had a significantly higher rate of kidney function decline than whites (0.31 ml/min per 1.73 m(2)/yr faster on average, P=0.001), even after adjusting for multiple potential confounders. Among Hispanics, Dominicans and Puerto Ricans had faster rates of decline than whites (0.55 and 0.47 ml/min per 1.73 m(2)/yr faster, respectively). Mexicans, South Americans, or other Hispanics had similar rates of decline compared to whites. We did not detect significant differences in the rates of kidney function decline among Chinese and white participants. Among those with normal or near-normal kidney function at baseline, blacks and Hispanics had the highest rates of incident CKD during follow-up. Adjustment for comorbidities attenuated some of these differences. In conclusion, the average rate of kidney function decline before the onset of CKD differs among racial and ethnic groups. Traditional risk factors do not explain these differences fully, highlighting the need to explore these disparities.
Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use
Authors: Sebastian J. Padayatty, He Sun, Yaohui Wang, Hugh D. Riordan, Stephen M. Hewitt, Arie Katz, Robert A. Wesley, Mark Levine
Journal: Annals of Internal Medicine (2004)

Background: Vitamin C at high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration. Objective: To determine whether plasma vitamin C concentrations vary substantially with the route of administration. Design: Dose concentration studies and pharmacokinetic modeling. Setting: Academic medical center. Participants: 17 healthy hospitalized volunteers. Measurements: Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g. Results: Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose. Vitamin C at a dose of 1.25 g administered orally produced mean (±sd) peak plasma concentrations of 134.8 ± 20.6 µmol/L compared with 885 ± 201.2 µmol/L for intravenous administration. For the maximum tolerated oral dose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 µmol/L and 13 400 µmol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses. Limitations: Patient data are not available to confirm pharmacokinetic modeling at high doses and in patients with cancer. Conclusions: Oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated.
Effects of methylprednisolone on ventricular arrhythmias during acute myocardial ischaemia
Authors: M. S. YOON, B. G. GOEL, J. HAN
Journal: Cardiovascular Research (1979)

Journal Article Effects of methylprednisolone on ventricular arrhythmias during acute myocardial ischaemia Get access MYUNG S. YOON, MYUNG S. YOON From the Department of Medicine (Cardiology), Albany Medical College of Union University, and the Electrocardiography Laboratory, Albany Medical Center Hospital, Albany, New York Search for other works by this author on: Oxford Academic PubMed Google Scholar BRIJ G. GOEL, BRIJ G. GOEL From the Department of Medicine (Cardiology), Albany Medical College of Union University, and the Electrocardiography Laboratory, Albany Medical Center Hospital, Albany, New York Search for other works by this author on: Oxford Academic PubMed Google Scholar JAOK HAN JAOK HAN 1 From the Department of Medicine (Cardiology), Albany Medical College of Union University, and the Electrocardiography Laboratory, Albany Medical Center Hospital, Albany, New York 1Address for reprints: Jaok Han, M.D., Dept. of Medicine, Albany Medical College, Albany, New York 12208, USA. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 13, Issue 1, January 1979, Pages 58–61, https://doi.org/10.1093/cvr/13.1.58 Published: 01 January 1979
Randomized, Placebo-Controlled Trial of Clodronate in Patients With Primary Operable Breast Cancer
Authors: Trevor Powles, Sandy Paterson, John A. Kanis, Eugene McCloskey, Sue Ashley, Alwynne Tidy, Kirsi Rosenqvist, Ian Smith, Lars Ottestad, Sandra Legault, Marjo Pajunen, Auli Nevantaus, Esa Männistö, Anne Suovuori, Sari Atula, Jaakko Nevalainen, Liisa Pylkkänen
Journal: Journal of Clinical Oncology (2002)

PURPOSE: The development of bone metastases depends on tumor-induced osteoclastic resorption of bone, which may be inhibited by the antiosteolytic bisphosphonate clodronate. Given to patients with primary breast cancer, clodronate might reduce the subsequent incidence of bone metastases. PATIENTS AND METHODS: This double-blind, multicenter trial accrued 1,069 assessable patients with operable breast cancer between 1989 and 1995. All patients received surgery, radiotherapy, chemotherapy, and tamoxifen as required. Patients were randomized to receive oral clodronate 1,600 mg/d or a placebo for 2 years starting within 6 months of primary treatment. The primary end point was relapse in bone, analyzed on an intent-to-treat basis, during the medication period and during the total follow-up period (median follow-up, 2,007 days). Secondary end points were relapse in other sites, mortality, and toxicity. RESULTS: During the total follow-up period, there was a nonsignificant reduction in occurrence of bone metastases (clodronate, n = 63; placebo, n = 80; hazards ratio [HR], 0.77; 95% confidence interval [CI], 0.56 to 1.08; P = .127). During the medication period there was a significant reduction in the occurrence of bone metastases (clodronate, n = 12; placebo, n = 28; HR, 0.44; 95% CI, 0.22 to 0.86; P = .016). The occurrence of nonosseous metastases was similar (clodronate, n = 112; placebo, n = 128; P = .257), but there was a significant reduction in mortality (clodronate, n = 98; placebo, n = 129; P = .047) during the total follow-up period. CONCLUSION: Clodronate, given to patients with primary operable breast cancer, may reduce the occurrence of bone metastases, although this reduction was only significant during this medication period. There was a significant reduction in mortality.
Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization
Authors: Shangyu Hong, Jose M Moreno-Navarrete, Xiaojing Wei, Yusuke Kikukawa, Iphigenia Tzameli, Deepthi Prasad, Yoonjin Lee, John M Asara, Jose Manuel Fernandez-Real, Eleftheria Maratos-Flier, Pavlos Pissios
Journal: Nature Medicine (2015)
Targeting Aurora Kinases with Danusertib (PHA-739358) Inhibits Growth of Liver Metastases from Gastroenteropancreatic Neuroendocrine Tumors in an Orthotopic Xenograft Model
Authors: Katharina Fraedrich, Jörg Schrader, Harald Ittrich, Gunhild Keller, Artur Gontarewicz, Verena Matzat, Arno Kromminga, Andrea Pace, Jürgen Moll, Michael Bläker, Ansgar W. Lohse, Dieter Hörsch, Tim H. Brümmendorf, Daniel Benten
Journal: Clinical Cancer Research (2012)

Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies.Human GEP-NETs were tested for aurora kinase expression. The efficacy of the new aurora kinase inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo.The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed aurora kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1- and QGP-derived liver metastases.These results show that danusertib may impose a new therapeutic strategy for aurora kinase expressing metastasized GEP-NETs.
Reply to D.A. Palma et al and A. Addeo et al
Authors: Rafael Santana-Davila, Kiran Devisetty, Jeffrey Whittle
Journal: Journal of Clinical Oncology (2015)

We thank Palma et al for their insightful comments on our study of carboplatin and paclitaxel (CP) versus etoposide and cisplatin (EP) using the Veterans’ Affairs Central Cancer Registry. In our initial analysis, we did not include International Classification of Diseases, 9th revision, code 508.0 as radiation pneumonitis because it is most often a clinical diagnosis with no definitive diagnostic test. Furthermore, in our clinical experience, it is infrequently coded and largely underreported. We have since performed an analysis using this International Classification of Diseases, 9th revision, code and found that this adverse event did not differ between treatment arms and was infrequent overall. Specifically, it was reported in 6.3% of CP treatments and 6.8% of EP treatments (P .001, Pearson ). We agree with Palma et al that the lack of difference in our study, when compared with the individual patient data meta-analysis and randomized clinical trial (RCT), could be because of the patient populations studied. In response to Addeo and Comins, we agree that in the absence of a large, well-powered, prospective RCT, there will be no definitive answer as to either inferiority or superiority of CP versus EP. However, as is often the case in oncology, we must use the best available evidence to guide clinical decision making. We believe that our work adds to this evidence base. In particular, using multiple approaches (multiple regression, propensity score, and instrumental variables) to analyze rich clinical data can increase the usefulness of observational data analyses. We acknowledge the concerns of Addeo and Comins regarding retrospective analysis of observational data. We believe that our analysis comparing the outcomes of CP versus EP in a relatively uniform patient population, along with the limited availability of informative RCTs, establishes sufficient equipoise to justify the conduct of RCTs to settle this important question. In the meantime, our data suggest that after controlling for important clinical variables, patients treated with these two regimens have equivalent survival.
Evaluation of patient skin breakdown and comfort with a new face mask for non-invasive ventilation: a multi-center study
Authors: Cesare Gregoretti, Marco Confalonieri, Paolo Navalesi, Vincenzo Squadrone, Pamela Frigerio, Fabio Beltrame, Giorgio Carbone, Giorgio Conti, Federica Gamna, Stefano Nava, Edoardo Calderini, Yoanna Skrobik, Massimo Antonelli
Journal: Intensive Care Medicine (2002)
Timing Is Everything in Life
Authors: Glenn I. Fishman
Journal: Circulation Research (1998)

Manipulation of the mouse genome by traditional transgenic approaches has facilitated studies of gene function within the context of the intact organism and allowed for the creation of useful animal models of human disease. However, the timing of gene activation or repression is a critical determinant of phenotype, and the ability to regulate the temporal profile of transgene expression remains an important experimental goal. In this Mini Review, we describe the current status of systems to tightly regulate target gene expression in vivo, focusing on binary systems using chimeric transcription factors. Although experimental difficulties persist, regulated expression systems are beginning to produce conditional phenotypes with exciting experimental implications. We review the experience to date and examine the potential utility of these approaches within the context of cardiovascular medicine.
Efficacy and safety of a patch vaccine containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase 3, randomised, double-blind, placebo-controlled field trial in travellers from Europe to Mexico and Guatemala
Authors: Ronald H Behrens, Jakob P Cramer, Tomas Jelinek, Hilary Shaw, Frank von Sonnenburg, Darren Wilbraham, Thomas Weinke, David J Bell, Edwin Asturias, Hermann L Enkerlin Pauwells, Roberto Maxwell, Mercedes Paredes-Paredes, Gregory M Glenn, Shailesh Dewasthaly, Donald M Stablein, Zhi-Dong Jiang, Herbert L DuPont
Journal: The Lancet Infectious Diseases (2013)
Effect of glibenclamide on extracellular potassium accumulation and the electrophysiological changes during myocardial ischaemia in the arterially perfused interventricular septum of rabbit
Authors: M. N Hicks, S. M Cobbe
Journal: Cardiovascular Research (1991)

Study objective – The aim was to study the effects of glibenclamide on the rate of rise of extracellular potassium concentration ([K+]0) and the electrophysiological changes that occur during myocardial ischaemia.
Performance Status Remained the Most Important Prognostic Factor in Pancreas Cancer Patients, Single Center Experience
Authors: Helvacı Kaan, Türker İbrahim, Üyetürk Ümmügül, Sonmez Ozlem, Budakoğlu Burçin, Yalçıntaş Arslan Ülkü, Alkış Necati, Öksüzoğlu Berna
Journal: Annals of Oncology (2014)
Pilot Study of Iodine-131–Metaiodobenzylguanidine in Combination With Myeloablative Chemotherapy and Autologous Stem-Cell Support for the Treatment of Neuroblastoma
Authors: Gregory A. Yanik, John E. Levine, Katherine K. Matthay, James C. Sisson, Barry L. Shulkin, Brahm Shapiro, David Hubers, Susan Spalding, Tom Braun, James L.M. Ferrara, Raymond J. Hutchinson
Journal: Journal of Clinical Oncology (2002)

PURPOSE: The survival for children with relapsed or metastatic neuroblastoma remains poor. More effective regimens with acceptable toxicity are required to improve prognosis. Iodine-131–metaiodobenzylguanidine ( 131 I-MIBG) selectively targets radiation to catecholamine-producing cells, including neuroblastoma cells. A pilot study was performed to examine the feasibility of a novel regimen combining 131 I-MIBG and myeloablative chemotherapy with autologous stem-cell rescue. PATIENTS AND METHODS: Twelve patients with neuroblastoma were treated after relapse (five patients) or after induction therapy (seven patients). Eight patients had metastatic and four had localized disease at the time of therapy. All patients received 131 I-MIBG 12 mCi/kg on day −21, followed by carboplatin (1,500 mg/m 2 ), etoposide (800 mg/m 2 ), and melphalan (210 mg/m 2 ) administered from day −7 to day −4. Autologous peripheral-blood stem cells or bone marrow were infused on day 0. Engraftment, toxicity, and response rates were evaluated. RESULTS: The 131 I-MIBG infusion and myeloablative chemotherapy were both well tolerated. Grade 2 to 3 oral mucositis was the predominant nonhematopoietic toxicity, occurring in all patients. The median times to neutrophil (≥ 0.5 × 10 3 /μL) and platelet (≥ 20 × 10 3 /μL) engraftment were 10 and 28 days, respectively. For the eight patients treated with metastatic disease, three achieved complete response and two had partial responses by day 100 after transplantation. CONCLUSION: Treatment with 131 I-MIBG in combination with myeloablative chemotherapy and hematopoietic stem-cell rescue is feasible with acceptable toxicity. Future study is warranted to examine the efficacy of this novel therapy.
Strength and weakness of the new TNM classification for lung cancer
Authors: R. Rami-Porta, P. Goldstraw
Journal: European Respiratory Journal (2010)

The article by Strand et al. 1 on the evaluation of the new tumour, node, metastasis (TNM) classification and staging system for lung cancer raises important questions on the validity of the classification and its therapeutic implications in clinical practice. The authors analysed a population-based series of 1,885 patients who underwent operation for lung cancer and who were registered at the Cancer Registry of Norway from 2001 to 2005. They pathologically classified these tumours according to the 6th 2 and 7th 3 editions of the TNM classification to assess their prognostic capacity, and found that the 7th edition did not improve the overall predictive ability of the staging system. Moreover, based on the current indications of therapy, nearly one-fifth of the patients could be offered different treatment options because of the rearrangement of some TNM subsets in different stages. Whether this different treatment will result in an improved prognosis is unknown.

Regarding the prognostic capacity of the 7th edition of the TNM classification, the authors' results contradict those of the International Association for the Study of Lung Cancer (IASLC), whose database of >100,000 patients collected worldwide was used to revise the 6th edition of the classification 4, and those of others whose patient series have validated most of the changes introduced in the 7th edition. Soon after the publication of the recommended changes for the new edition, independent groups validated them based on their own data or on data from registries. Zell et al. 5 and Ou and Zell 6, 7 found that the proposed changes better reflected survival for advanced bronchioloalveolar carcinoma and for small cell lung cancer, and validated the revisions of the T4 and M descriptors, respectively. …
Aldosterone suppression with dopamine infusion in low-renin hypertension.
Authors: O B Holland, C Thomas, H Brown, D Schindewolf, Y Hillier, C Gomez-Sanchez
Journal: Journal of Clinical Investigation (1983)

A dopaminergic mechanism has been proposed to suppress aldosterone secretion. To assess the possibility that a defect in the dopaminergic mechanism might enhance aldosterone secretion in hypertensive patients, we determined basal and adrenocorticotropic hormone (ACTH)-stimulated plasma aldosterone (PA), cortisol, renin activity, and potassium concentrations before and during dopamine receptor stimulation with dopamine infusion and bromocriptine administration and dopamine receptor blockade with metoclopramide. The patient study groups included: (a) seven patients with low-renin hypertension and abnormal aldosterone suppression with sodium loading and presumed bilateral zona glomerulosa hyperplasia (ZGHP); (b) two patients with aldosterone-producing adenoma; (c) five patients with low-renin hypertension but normal aldosterone suppression with sodium loading; and (d) six patients with normal-renin hypertension. Dopamine infusion in patients with ZGHP caused PA to fall (P less than 0.01) into the normal range, but did not block the enhanced (P less than 0.05) aldosterone response to ACTH that is characteristic of these patients. Dopamine infusion in patients with low-renin hypertension but normal aldosterone suppression also suppressed PA (P less than 0.01), whereas it had no effect upon PA in patients with normal-renin hypertension or aldosterone-producing adenoma and did not blunt the PA response to ACTH in either group. Bromocriptine administration had no effect upon basal or ACTH-stimulated PA. Dopamine infusion in patients with ZGHP also enhanced (P less than 0.05) diuresis and natriuresis in comparison with normal-renin patients. Metoclopramide administration increased (P less than 0.01) PA in all patients. Thus, a dopaminergic mechanism appears to be important in the regulation of aldosterone secretion in patients with ZGHP and in other low-renin hypertensives with normal aldosterone suppression with sodium loading. In contrast, this latter group does not exhibit an enhanced aldosterone response to ACTH. Both of these groups differ from normal-renin hypertensives, who have no PA suppression with dopamine infusion.
Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse
Authors: Ayumi Takamura, Yasuhide Okamoto, Takeshi Kawarabayashi, Tatsuki Yokoseki, Masao Shibata, Akihiro Mouri, Toshitaka Nabeshima, Hui Sun, Koji Abe, Tsuneo Urisu, Naoki Yamamoto, Mikio Shoji, Katsuhiko Yanagisawa, Makoto Michikawa, Etsuro Matsubara
Journal: Molecular Neurodegeneration (2011)

Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid β (Aβ) oligomers. However, the pathological relevance of Aβ oligomers (AβOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AβOs remain to be determined.To specifically target toxic AβOs in vivo, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AβOs larger than 35-mers and pentamers on Blue native polyacrylamide gel electrophoresis, respectively. Biophysical and structural analysis by atomic force microscopy (AFM) revealed that neurotoxic 1A9 and 2C3 oligomeric conformers displayed non-fibrilar, relatively spherical structure. Of note, such AβOs were taken up by neuroblastoma (SH-SY5Y) cell, resulted in neuronal death. In humans, immunohistochemical analysis employing 1A9 or 2C3 revealed that 1A9 and 2C3 stain intraneuronal granules accumulated in the perikaryon of pyramidal neurons and some diffuse plaques. Fluoro Jade-B binding assay also revealed 1A9- or 2C3-stained neurons, indicating their impending degeneration. In a long-term low-dose prophylactic trial using active 1A9 or 2C3 antibody, we found that passive immunization protected a mouse model of Alzheimer's disease (AD) from memory deficits, synaptic degeneration, promotion of intraneuronal AβOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AβOs initiate the AD toxic process and intraneuronal AβOs may worsen neuronal degeneration and memory loss.Now, we have evidence that HMW-AβOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.