tbuckley/cabot-search huggingface dataset:
Clofibrate-Induced Antidiuresis
Authors: Arnold M. Moses, Joan Howanitz, Marcia Van Gemert, Myron Miller
Journal: Journal of Clinical Investigation (1973)

Normal subjects and patients with antidiuretic hormone (ADH) deficiency were studied to determine the mechanism of the antidiuretic action of clofibrate. Before clofibrate treatment, the patients' ability to concentrate urine with a standardized dehydration procedure correlated with the amount of ADH which was excreted. During clofibrate administration all six patients with ADH deficiency developed an antidiuresis which was like that of ADH, since there was no change in sodium, potassium, total solute, or creatinine excretion. There was a correlation between the patients' ability to concentrate urine during dehydration and the subsequent response to clofibrate, and the excretion of ADH during dehydration correlated with the excretion of ADH on clofibrate therapy. Clofibrate-induced antidiuresis in these patients was partially overcome by ethanol and by water loading. Clofibrate interfered with the ability of patients and subjects to excrete a water load and prevented the water load from inhibiting ADH excretion in the normal subjects. These studies suggested that clofibrate was acting through endogenous ADH and this thesis was supported by the failure of clofibrate to produce an antidiuresis when injected into rats with total ADH deficiency (Brattleboro strain) although an antidiuresis was produced in water-loaded normal rats. When the drug was injected into Brattleboro rats with exogenous ADH, clofibrate either did not alter or it inhibited the action of the ADH. The data demonstrate that clofibrate has a significant ADH-like action. This action appears to be mediated through the release of endogenous ADH.
Targeting the Spleen Tyrosine Kinase with Fostamatinib as a Strategy against Waldenström Macroglobulinemia
Authors: Isere Kuiatse, Veerabhadran Baladandayuthapani, Heather Y. Lin, Sheeba K. Thomas, Chad C. Bjorklund, Donna M. Weber, Michael Wang, Jatin J. Shah, Xing-Ding Zhang, Richard J. Jones, Stephen M. Ansell, Guang Yang, Steven P. Treon, Robert Z. Orlowski
Journal: Clinical Cancer Research (2015)

Waldenström macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target.We studied the impact of the Syk inhibitor fostamatinib on BCWM.1 and MWCL-1 WMG-derived cell lines both in vitro and in vivo, as well as on primary patient cells.In WMG-derived cell lines, fostamatinib induced a time- and dose-dependent reduction in viability, associated with activation of apoptosis. At the molecular level, fostamatinib reduced activation of Syk and Bruton's tyrosine kinase, and also downstream signaling through MAPK kinase (MEK), p44/42 MAPK, and protein kinase B/Akt. As a single agent, fostamatinib induced tumor growth delay in an in vivo model of WMG, and reduced viability of primary WMG cells, along with inhibition of p44/42 MAPK signaling. Finally, fostamatinib in combination with other agents, including dexamethasone, bortezomib, and rituximab, showed enhanced activity.Taken together, these data support the translation of approaches targeting Syk with fostamatinib to the clinic for patients with relapsed and possibly even newly diagnosed WMG.
Minichromosome maintenance (MCM) proteins may be pre-cancer markers
Authors: M R Alison
Journal: Gut (2002)

Aberrant overexpression of proteins called minichromosome maintenance (Mcm) proteins at the mucosal surface of dysplastic oesophageal squamous epithelium and Barrett's mucosa may indicate proliferation potential

Oesophageal cancer contributes about 3% of the cancer burden in the UK, 5% of cancer mortality, and the five year survival is a dismal 6% (www.crc.org.uk). There are two major types of oesophageal carcinoma, squamous cell carcinoma (SCC) and adenocarcinoma, each with different risk factors and epidemiologies. SCC arises from squamous cells lining the oesophagus and the geographical distribution of the disease shows wide variations, being virtually unknown in North Africa but common, for example, in eastern Turkey, Iraq, Iran, and northern China; high risk areas are generally associated with local food preservation practices that favour the generation of nitroso compounds from mould growing on pickled vegetables. In Western populations, heavy alcohol and cigarette consumption are well known risk factors for oesophageal SCC. Most adenocarcinomas on the other hand appear to arise from within areas of metaplasia known as Barrett's oesophagus, the metaplasia probably being caused by prolonged reflux of gastric acid and digestive enzymes (reflux oesophagitis). With the passage of time the epithelial lining becomes progressively more abnormal as it passes through a series of sequential steps that eventually result in the development of invasive adenocarcinoma. These steps include the development of glandular dysplasia, signalled by an increased nuclear:cytoplasmic ratio and loss of nuclear polarity within the cells lining the metaplastic glands: …
Medico-legal Reflections
Authors: G. Forbes
Journal: BMJ (1964)

ReviewsBRrrITI him sick through goal-directed interview," or " Abdominal viscera are able to function normally regardless of their position, and organ ptosis per se is of no clinical significance," or " Most surgeons are somewhat leery of operating upon ..," and so on.This book falls between the comprehensive work of reference and the more readable volumes on gastro-enterology, of which there are several now available.
Calcium sensitivity of isometric tension in intact papillary muscles and chemically skinned trabeculae in different models of hypertensive hypertrophy
Authors: P. Pedroni, G. N Perez, A. Mattiazzi
Journal: Cardiovascular Research (1990)

Study objective – The aim was to examine the contractile state, the inotropic response to [Ca2+]e and the Ca2+ sensitivity of the contractile proteins in different models of hypertensive hypertrophy in an early stage of evolution (3–4 weeks). Design – Renal hypertension was induced by placing a silver clip around the left renal artery. The contralateral kidney was either removed (1K-1C) or left untouched (2K-1C). Hypertension through sodium overload was produced by administration of deoxycorticosterone and 1% NaCl drinking water. (DOCA rats). Active and passive length-tension curves were performed to evaluate basal contractility at Lmax and passive stiffness of cardiac muscle. The inotropic responsiveness to [Ca2+]e and the Ca2+ sensitivity of the contractile proteins were also evaluated. Experimental material – Papillary muscles and skinned trabeculae from the left ventricle of male Wistar hypertensive and age matched normotensive rats were used. Measurements and results – Cardiac hypertrophy was similar in all hypertensive groups. In 2K-1C and 1K-1C rats, basal contractility was not significantly different from controls. In DOCA rats, developed tension and time to peak tension (TTP) were significantly greater than controls. The inotropic response to [Ca2+]e was depressed in 2K-1C and increased in DOCA rats. In DOCA rats, increasing [Ca2+]e produced an increase in TTP greater than in controls. No differences were detected in muscle passive stiffness or in Ca2+ sensitivity of the contractility proteins among the different groups. Conclusions – In the earlier stages of hypertensive hypertrophy, differences in basal contractile state and/or inotropic responsiveness appear to be more related to the initiating cause of hypertensive hypertrophy than to the degree of hypertrophy itself. These differences cannot be attributed to changes in Ca2+ sensitivity of the contractile system.
Effects of Balloon Injury on Neointimal Hyperplasia in Streptozotocin-Induced Diabetes and in Hyperinsulinemic Nondiabetic Pancreatic Islet–Transplanted Rats
Authors: Ciro Indolfi, Daniele Torella, Luigi Cavuto, Alberto M. Davalli, Carmela Coppola, Giovanni Esposito, Mariolina V. Carriero, Antonio Rapacciuolo, Emilio Di Lorenzo, Eugenio Stabile, Cinzia Perrino, Alaide Chieffo, Francesco Pardo, Massimo Chiariello
Journal: Circulation (2001)

The mechanisms of increased neointimal hyperplasia after coronary interventions in diabetic patients are still unknown.Glucose and insulin effects on in vitro vascular smooth muscle cell (VSMC) proliferation and migration were assessed. The effect of balloon injury on neointimal hyperplasia was studied in streptozotocin-induced diabetic rats with or without adjunct insulin therapy. To study the effect of balloon injury in nondiabetic rats with hyperinsulinemia, pancreatic islets were transplanted under the kidney capsule in normal rats. Glucose did not increase VSMC proliferation and migration in vitro. In contrast, insulin induced a significant increase in VSMC proliferation and migration in cell cultures. Furthermore, in VSMC culture, insulin increased MAPK activation. A reduction in neointimal hyperplasia was consistently documented after vascular injury in hyperglycemic streptozotocin-induced diabetic rats. Insulin therapy significantly increased neointimal hyperplasia in these rats. This effect of hyperinsulinemia was totally abolished by transfection on the arterial wall of the N17H-ras-negative mutant gene. Finally, after experimental balloon angioplasty in hyperinsulinemic nondiabetic islet-transplanted rats, a significant increase in neointimal hyperplasia was observed.In rats with streptozotocin-induced diabetes, balloon injury was not associated with an increase in neointimal formation. Exogenous insulin administration in diabetic rats and islet transplantation in nondiabetic rats increased both blood insulin levels and neointimal hyperplasia after balloon injury. Hyperinsulinemia through activation of the ras/MAPK pathway, rather than hyperglycemia per se, seems to be of crucial importance in determining the exaggerated neointimal hyperplasia after balloon angioplasty in diabetic animals.
TPO‐receptor agonists in ITP: A clinician's navigation between scylla and charybdis
Authors: Francesco Rodeghiero
Journal: American Journal of Hematology (2012)

The introduction of thrombopoietin receptor (TPO-R) agonists, also called TPO mimetics, has offered new treatment possibilities to patients with immune thrombocytopenia (ITP). The European Medicine Agency and the Food and Drug Administration in the U.S. have licensed the first two agents of this class (romiplostim and eltrombopag) with partially overlapping but different indications. These agents have been welcomed by most clinicians as a major improvement in their clinical practice, since platelet count can be raised in patients who are otherwise poorly responsive or not tolerant of other treatments. A recent Cochrane review [1] concluded that currently there is no evidence to support TPO-R agonists that are effective in treating chronic ITP. This statement came as a cold shower to many expectations. In this issue, I. Altomare and colleagues challenge Cochrane's statements by asserting methodological and ethical arguments. Critical to any evidence-based analysis is the competence, independence, and transparency of contributors. Clinicians are often burdened by conflicts of interest that are perceived as obstacles to independent assessment; however, they are the only ones who face real patients and thus can best identify the unmet medical needs. Their voices should not be neglected. In this three-author commentary on the paper by I. Altomare et al., the regulatory perspective is presented by F. Pignatti et al.; D. Arnold discusses the methodological aspects; and finally, M. Ruggeri underlines the medical needs covered by these new agents. Ultimately, as the reader will understand, there is still a long way to go before these new agents find their precise position in the algorithmic treatment of ITP. Adoption of clinically meaningful, standardized criteria for response definition and bleeding assessment will certainly be of major importance.
Tobacco Addiction-Reply
Authors: Walter Ling
Journal: JAMA (1996)

<h3>In Reply.</h3> —Dr Lyman's concern that we did not mention nicotine as an addictive drug was echoed by several of our colleagues. Nicotine is increasingly being viewed as an addictive drug among addiction medicine specialists; however, smoking cessation treatment is often provided separately from treatment of other chemical dependencies and is generally not provided as part of the treatment of alcohol and other drug disorders. Most people who are dependent on alcohol and other drugs smoke cigarettes. A recently published study<sup>1</sup>reported the cumulative mortality from tobaccorelated causes (50.9%) among patients previously treated for alcohol and other drug dependencies exceeded that of alcohol (36.0%). As a practical matter, patients undergoing treatment for alcohol or other drug dependencies are often resistant to stopping smoking while they are undergoing treatment. A common response is, "Yes, I want to stop, but not now." Insurers and managed care organizations generally will not pay extra for
Abstract 5593: A combination of HDAC inhibitor Entinostat (MS-275), All Trans Retinoic Acid (ATRA) and low dose Doxorubicin causes regression of established xenografts of triple negative breast cancer
Authors: Nguyen K. Nguyen, Preethi Korangath, Gauri Sabnis, Angela Brodie, Peter Ordentlich, Vered Stearns, Saraswati Sukumar
Journal: Cancer Research (2010)

Abstract Triple negative breast cancer (TNBC) is a subgroup of breast cancer that rapidly develops resistance to chemotherapy. Currently, TNBC patients are treated with anthracycline and taxane-based regimens. These treatments result in some improvements in the clinical outcomes; however, they are associated with poor prognosis. Also, endocrine therapies are ineffective since the tumors do not express the estrogen receptor. Recent studies have shown that histone deacetylase (HDAC) inhibitors could reverse the epigenetic profile of some genes, including ER, EGFR, and RARβ2. We have recently shown that treatments that combine the HDAC inhibitor, Entinostat (MS-275), with the aromatase inhibitor, Letrozole, result in regression of xenografts of MDA-MB-231 breast cancer cells. Since RARβ2 is re-expressed as well, we reasoned that combining epigenetic therapy using MS-275, with differentiation therapy using a RARβ2 agonist (ATRA) will provide an effective combination of drugs against TNBC. We also examined possible potentiation of anticancer activity of these agents by low nontoxic doses of chemotherapy (doxorubicin). In vitro, human TNBC cell lines, MDA-MB-231, HCC1954, HCC 1143, and BT20 responded significantly better to the triple combination compared to the drugs used singly or in combination with MS-275. Upon treatment, re-expression of the silenced RARβ2 and downstream effectors was observed in the cell lines in vitro and in tumor xenografts of MDA-MB-231 cells. Subcutaneous tumor growth in immunodeficient mice was strongly inhibited (10/14 significant regression) using a combination of MS-275, ATRA and low dose Doxorubicin, compared to the drugs administered singly or in combination with MS-275. No significant weight loss was observed in any of the groups. These results suggest that combination of HDAC inhibitor and RARβ2 agonist with low dose chemotherapy has the potential to be an effective treatment against TNBC. This study provides encouraging new information for a nontoxic, and novel combination of drugs which could be effective against TNBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5593.
Exposure to mercury alters early activation events in fish leukocytes.
Authors: K C MacDougal, M D Johnson, K G Burnett
Journal: Environmental Health Perspectives (1996)

Although fish in natural populations may carry high body burdens of both organic and inorganic mercury, the effects of this divalent metal on such lower vertebrates is poorly understood. In this report, inorganic mercury in the form of mercuric chloride (HgCl2) is shown to produce both high-dose inhibition and low-dose activation of leukocytes in a marine teleost fish, Sciaenops ocellatus. Concentrations of inorganic mercury > or = 10 microM suppressed DNA synthesis and induced rapid influx of radiolabeled calcium, as well as tyrosine phosphorylation of numerous cellular proteins. Lower concentrations (0.1-1 microM) of HgCl2 that activated cell growth also induced a slow sustained rise in intracellular calcium in cells loaded with the calcium indicator dye fura-2, but did not produce detectable tyrosine phosphorylation of leukocyte proteins. These studies support the possibility that subtoxic doses of HgCl2 may inappropriately activate teleost leukocytes, potentially altering the processes that regulate the magnitude and specificity of the fish immune response to environmental pathogens.
Abstract 20997: In Postoperative Conotruncal Anomalies Patients Differential Branch Pulmonary Artery Regurgitant Fraction is a Function of Differential Pulmonary Vascular Resistance and Pulmonary Arterial Properties
Authors: Matthew A Harris, Kevin K Whitehead, Matthew J Gillespie, Timothy I Liu, Michael T Cosulich, David C Shin, Elizabeth Goldmuntz, Paul M Weinberg, Mark A Fogel
Journal: Circulation (2010)

Introduction: Repaired conotruncal anomaly patients frequently have residual branch pulmonary artery (BPA) stenosis or size differences associated with differential BPA regurgitation. Hypothesis: I...
A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis
Authors: Gerald G. Krueger, Kim A. Papp, Dow B. Stough, Keith H. Loven, Wayne P. Gulliver, Charles N. Ellis
Journal: Journal of the American Academy of Dermatology (2002)
Training Program in Medical Oncology
Authors: B. J. KENNEDY
Journal: Annals of Internal Medicine (1973)

Medical oncology has been established as a new subspecialty of internal medicine. To define the scope of training programs in medical oncology, proposals have been made to aid in establishing new programs or to standardize existing programs and to provide young physicians seeking training in this field with guidelines for assessing the contents of a training program. Medical oncology encompasses a broad aspect of medicine and requires a firm foundation in the principles of internal medicine. Certification in medical oncology is a commitment to continuing reassessment of competency. The medical oncologist, as an advocate of the cancer patient, has the opportunity to integrate many scientific skills to control, or even cure, neoplastic diseases.
Erythema Nodosum and Erythema Multiforme as Clinical Manifestations of Histoplasmosis in a Community Outbreak
Authors: Antone A. Medeiros, Sophocles D. Marty, Fred E. Tosh, Tom D. Y. Chin
Journal: New England Journal of Medicine (1966)

DURING the fall of 1962 an epidemic of histoplasmosis occurred in Mason City, Iowa. The source of the infection was a starling roost in the center of town, and the epidemic resulted when heavy equipment was used to remove trees and underbrush from the contaminated area.1 In February, 1964, a second attempt to clear the site was made, resulting in a second epidemic of histoplasmosis in the same city. During the second outbreak acute pulmonary histoplasmosis developed in 87, and erythema multiforme or erythema nodosum in 30 persons.This paper will present evidence that the skin lesions were related to . . .
The spatial correlation of fluctuations of the blood flow in forearm skin
Authors: N.T.S. EVANS, P.F.D. NAYLOR, B.McA. SAYERS
Journal: British Journal of Dermatology (1977)

The oxygen tension at the skin surface, with the atmospheric oxygen supply excluded, may be measured polarographically on the human forearm. Under suitable environmental conditions, spontaneous fluctuations in skin surface oxygen tension can be recorded and these are the result of fluctuating blood flow in the superficial skin vessels. An array of separate cathodes in a single polarographic electrode assembly has been used to measure the fluctuations in blood flow which are occurring simultaneously at seven different points in the skin. Spectral analysis of a long recording of such fluctuations shows that most of the power is concentrated at the lower frequencies but does not reveal any clearly defined dominant frequency. It is clear, however, from inspection of the fluctuation patterns, that recurring bursts of activity occur with quite well-defined periodicities in the range of 30s to 5 min. There is a stronger correlation between the fluctuations occurring at points on the skin surface less than 1 mm apart than between points further apart, although there are clearly some components which are common to points separated by up to 5 mm which was the largest separation of cathodes used in these experiments. These observations are supported by the value of cross correlation coefficients between the channels. These results suggest that the observed fluctuations are the result of at least two factors. The first one is common to all the channels but the effect of this may be overridden by a second and more local one controlling the blood flow.
Abstract 5476: gp130 knockdown by short hairpin RNA synergistic effect of bortezomib induced apoptosis in multiple myeloma cells
Authors: Juwon Park, Chansu Lee, Jeong In Oh, Byung-Su Kim, Jung Hye Kwon, Byoung Kook Kim, Kwang-Sung Ahn, Sung-Soo Yoon
Journal: Cancer Research (2010)

Abstract Although bortezomib, one of targeted anti-cancer drugs, effectively suppresses the growth of multiple myeloma (MM) cells via inactivation of NF-κB, activation of IL-6 mediated cell signaling could be suppressed bortezomib mediated apoptosis. Previously we found that the expression levels of IL-6 and sIL-6R in MM patient's bone marrow serum was higher than control. A set of reports suggested that those levels affect the progression of MM. In addition, bortezomib mediated apoptosis directly associated with the activities of NF-κB in MM cells. However, at present, their precise roles, especially IL-6 mediated cell signaling associating with NF-κB activation, in the progression of MM and therapeutic response to anti-cancer treatment still remain largely unknown. In this study, U266 cells treated with combination of IL-6 and sIL-6R showed the prolongation of the phosphorylation of ERK and STAT3 when compared with IL-6 alone. Transient transfection of gp130 shRNA in MM cells (MM/gp130 shRNA) showed inhibition of IL-6/sIL-6R induced ERK and STAT3 phosphorylation. Next, the effect of IL-6 and sIL-6R in an anti-myeloma agent, bortezomib, was investigated. In cell proliferation assay, U266 and RPMI8226 cells exposed to IL-6 and sIL-6R were decreased induction of apoptosis by bortezomib. In addition, MM/gp130 shRNA cells treated with bortezomib showed significantly inhibited c-Myc and cyclinD1 and increased apoptosis by borteozomib compared with parental cells. In this study indicated that the synergic activation of ERK and STAT3 phosphorylation as the result of IL-6 with sIL-6R could diminished by knockdown of gp130 and its effect could be potentiated the apoptotic efficacy of bortezomib in MM cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5476.