tbuckley/cabot-search huggingface dataset:
Abstract 3839: The role of RhoA in human normal mammary epithelial cell immortalization, stem/progenitor cell self-renew, and differentiation
Authors: Xiangshan Zhao, Hamid Band, Vimla Band
Journal: Cancer Research (2010)

Abstract One of the earliest steps in oncogenic transformation of hMECs involves loss of senescence and continuous proliferation, a process referred to as immortalization. Delineation of biochemical pathways that mediate hMEC immortalization is therefore likely to provide answers to key questions about early breast cancer. RhoA GTPases are central players in many aspects of basic cell biology, There is little knowledge about the role of Rho in early breast cancer. Our recent findings have revealed the potential role of RhoA GTPase in early oncogenic transformation in breast cancer. We demonstrated that overexpression of constitutively-active RhoA, a Rho effector domain mutant, and the wild-type RhoA(WTRhoA), but not a dominant-negative Rho mutant, induces the immortalization of normal hMECs. This is highly significant as in breast and other cancers WTRhoA overexpression is seen but not mutation. Furthermore, we observed immortalization with a RhoA mutant T37A, that fails to interact with well known Rho effectors, Rho kinase, mDia1 and PKN, thus pointing towards a novel pathway that does not involve actin cytoskeleton organization, which may be a late event. In order to identify the molecular mechanism of RhoA-induced immortalization, we performed microarray expression profiling of RhoA-immortalized vs. parental cells and found alterations in expression of several genes (ELF3, ZNF217, S100P were overexpressed; DAB2, CLCA2, TFPI2, ALOX15B were downregulated) previously implicated in immortalization of mammary epithelial cells, and breast cancer progression. Our western blot and RT-PCR results showed that similar to immortal cells, the expression of these genes were altered in breast cancer cell lines. these results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked to cellular transformation and breast cancer. There is increasing evidence that breast cancer originates in and is maintained by cancer stem cell (CSC) Which has stem cell properties, including self-renewal, tumorigenicity and multi-lineage differentiation capacity. A major hurdle in addressing how normal stem cell become CSC is the lack of in vitro human stem/progenitor cells that are immortal and can be deliberately manipulated to ask questions related to origins of CSC. Our current work showed that RhoA immortal cells express luminal, myoepithelial, basal, and stem cell markers (K8/18, E-cadherin, ESA, K5, K6, K14, p63, CD29, CD49f). Indicate that these cells may have stem/progenitor cell properties. It is important to further examine the role of RhoA in normal and cancer mammary stem/progenitor cell self-renewal and differentiation. 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 3839.
Nimodipine, a dihydropyridine-type calcium channel blocker, prevents alcoholic hepatitis caused by chronic intragastric ethanol exposure in the rat
Authors: Y Iimuro, K Ikejima, M L Rose, B U Bradford, R G Thurman
Journal: Hepatology (1996)

It has been shown recently that inactivation of Kupffer cells prevents free radical formation and early alcohol–induced liver injury, and that hypoxia subsequent to a hypermetabolic state caused by activated Kupffer cells is likely involved in the mechanism. Calcium is essential for the activation of Kupffer cells, which contain L–type voltage–dependent Ca2+ channels. Therefore, the purpose of this study was to determine whether a Ca2+ channel blocker, nimodipine, prevents early alcohol–induced liver injury in vivo and to evaluate its effect on intracellular calcium ([Ca2+]i) in Kupffer cells in vitro . Male Wistar rats were exposed to ethanol (10–12 g/kg/d) continuously for up to 4 weeks via intragastric feeding using an enteral model developed by Tsukamoto and French. In this model, ethanol causes steatosis, necrosis, and inflammation in only a few weeks. In the experimental group, nimodipine (10 mg/kg/d) was added to the diet and was shielded from direct light. Nimodipine had no effect on body weight over a 4–week treatment period, nor were mean ethanol concentrations or their cyclic pattern in urine affected. The mean urine ethanol values were 154 ± 11 mg/dL in ethanol–fed and 144 ± 38 mg/dL in ethanol + nimodipine–fed rats. After 4 weeks, serum aspartate transaminase (AST) levels were elevated in ethanol–treated rats to 183 ± 78 U/L. In contrast, values only reached 101 ± 9 U/L in rats given nimodipine + ethanol–values which were significantly lower. Steatosis and necrosis assessed histologically were also reduced significantly by nimodipine. Nimodipine (10 micrograms/kg) also blocked the swift increase in alcohol metabolism and elevated oxygen consumption in perfused livers from rats treated with alcohol in vivo. Further, in cultured Kupffer cells, nimodipine (1 mumol/L) largely prevented the elevation in [Ca2+]i caused by lipopolysaccharide (LPS) (LPS, 200 ± 11 nmol/L; LPS + nimodipine, 94 ± 31 nmol/L; P &lt; .05). These results indicate that nimodipine prevents alcoholic hepatitis, possibly by inhibition of endotoxin–mediated Kupffer cell activation.
Microarray-Based Prediction of Tumor Response to Neoadjuvant Radiochemotherapy of Patients With Locally Advanced Rectal Cancer
Authors: Caroline Rimkus, Jan Friederichs, Anne–laure Boulesteix, Jörg Theisen, Jörg Mages, Karen Becker, Hjalmar Nekarda, Robert Rosenberg, Klaus–Peter Janssen, Jörg Rüdiger Siewert
Journal: Clinical Gastroenterology and Hepatology (2008)
Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
Authors: M Bai, N Janicic, S Trivedi, S J Quinn, D E Cole, E M Brown, G N Hendy
Journal: Journal of Clinical Investigation (1997)

Missense mutations have been identified in the coding region of the extracellular calcium-sensing receptor (CASR) gene and cause human autosomal dominant hypo- and hypercalcemic disorders. The functional effects of several of these mutations have been characterized in either Xenopus laevis oocytes or in human embryonic kidney (HEK293) cells. All of the mutations that have been examined to date, however, cause single putative amino acid substitutions. In this report, we studied a mutant CASR with an Alu-repetitive element inserted at codon 876, which was identified in affected members of families with the hypercalcemic disorders, familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), to understand how this insertion affects CASR function. After cloning of the Alu-repetitive element into the wild-type CASR cDNA, we transiently expressed the mutant receptor in HEK293 cells. Expression of mutant and wild-type receptors was assessed by Western analysis, and the effects of the mutation on extracellular calcium (Ca2+(o)) and gadolinium (Gd3+(o)) elicited increases in the cytosolic calcium concentration (Ca2+(i)) were examined in fura-2-loaded cells using dual wavelength fluorimetry. The insertion resulted in truncated receptor species that had molecular masses some 30 kD less than that of the wild-type CASR and exhibited no Ca2+(i) responses to either Ca2+(o) or Gd3+(o). A similar result was observed with a mutated CASR truncated at residue 876. However, the Alu mutant receptor had no impact on the function of the coexpressed wild-type receptor. Interestingly, the Alu mutant receptor demonstrated decreased cell surface expression relative to the wild-type receptor, whereas the CASR (A877stop) mutant exhibited increased cell surface expression. Thus, like the missense mutations that have been characterized to date in families with FHH, the Alu insertion in this family is a loss-of-function mutation that produces hypercalcemia by reducing the number of normally functional CASRs on the surface of parathyroid and kidney cells. In vitro transcription of exon 7 of the CASR containing the Alu sequence yielded the full-length mutant product and an additional shorter product that was truncated due to stalling of the polymerase at the poly(T) tract. In vitro translation of the mutant transcript yielded three truncated protein products representing termination in all three reading frames at stop codons within the Alu insertion. Thus sequences within the Alu contribute to slippage or frameshift mutagenesis during transcription and/or translation.
Re: Stephan Madersbacher. After Three Randomised Controlled Trials Comparing 120-W High-performance-system Potassium-titanyl-phosphate Laser Vaporisation to Transurethral Resection of the Prostate (TURP), Is This Procedure Finally First-line, Outdated, or Still Not Surpassing TURP? Eur Urol 2012;61:1174–6
Authors: Henry H. Woo, Alexander Bachmann
Journal: European Urology (2012)
Transient Receptor Potential A1 (TRPA1) Activity in the Human Urethra—Evidence for a Functional Role for TRPA1 in the Outflow Region
Authors: Christian Gratzke, Tomi Streng, Eginhard Waldkirch, Katja Sigl, Christian Stief, Karl-Erik Andersson, Petter Hedlund
Journal: European Urology (2008)
Risk of Mortality with a Bloodstream Infection Is Higher in the Less Severely Ill at Admission
Authors: Peter W. Kim, Trish M. Perl, Eithne F. Keelaghan, Patricia Langenberg, Eli N. Perencevich, Anthony D. Harris, Xiaoyan Song, Mary-Claire Roghmann
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Health care–associated bloodstream infections are common in critically ill patients; however, investigators have had difficulty in quantifying the clinical impact of these infections given the high expected mortality among these patients. Objective: To estimate the impact of health care–associated bloodstream infections on in-hospital mortality after adjusting for severity of illness at critical care admission. Method: A cohort of medical and surgical intensive care unit patients. Measurements: Severity of illness at admission, bloodstream infection, and in-hospital mortality. Main Results: Among the 2,783 adult patients, 269 developed unit-associated bloodstream infections. After adjusting for severity of illness, patients with a lower initial severity of illness who developed an infection had a greater than twofold higher risk for in-hospital mortality (hazard ratio [HR] = 2.42, 95% confidence interval [CI] 1.70, 3.44) when compared with patients without infection and with a similar initial severity of illness. In contrast, patients with a higher initial severity of illness who subsequently developed an infection did not have an increased risk for in-hospital mortality (HR = 0.96, 95%CI 0.76, 1.23) when compared with patients without infection but with a similar initial severity of illness. Conclusions: These results suggest that these infections in less ill patients have a higher attributable impact on subsequent mortality than in more severely ill patients. Focusing interventions to prevent bloodstream infections in less severely ill patients would be expected to have a greater benefit in terms of mortality reduction.
Sectioning of patients with visual difficulties.
Authors: R Seymour, D Millar-Jones
Journal: BMJ (1990)

Wielding the propaganda weapon SIR,-Scrutator is concerned with examples of disinformation, and one of the subjects he considers is the hours of work of junior doctors.'He may be spreading disinformation himself.He quotes, with seeming approval, from a letter written by a junior doctor who suggests a way to force hospitals to cut overtime.The
1170 THE CYCLOPHILIN INHIBITOR SCY-635 RESTORES THE INNATE RECOGNITION OF HCV BY PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM HCV POSITIVE SUBJECTS
Authors: P. Probst, S. Mosier, B. Scorneaux, A. Sluder, D. Heuman, K. Borroto-Esoda
Journal: Journal of Hepatology (2013)
Depressive Symptoms and Risks of Coronary Heart Disease and Mortality in Elderly Americans
Authors: Abraham A. Ariyo, Mary Haan, Catherine M. Tangen, John C. Rutledge, Mary Cushman, Adrian Dobs, Curt D. Furberg
Journal: Circulation (2000)

Background —Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort. Methods and Results —In a prospective cohort of 5888 elderly Americans (≥65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 ( P =0.006); the ratio for all-cause mortality was 1.29 ( P &lt;0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 ( P =0.006) and that for all-cause mortality was 1.16 ( P =0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores. Conclusions —Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.
Ameliorating the Developmental Neurotoxicity of Chlorpyrifos: A Mechanisms-Based Approach in PC12 Cells
Authors: Theodore A. Slotkin, Emiko A. MacKillop, Ian T. Ryde, Frederic J. Seidler
Journal: Environmental Health Perspectives (2007)

Organophosphate developmental neurotoxicity involves multiple mechanisms converging on neural cell replication and differentiation.We evaluated mechanisms contributing to the adverse effects of chlorpyrifos (CPF) on DNA synthesis, cell number and size, and cell signaling mediated by adenylyl cyclase (AC) in PC12 cells, a neuronotypic cell line that recapitulates the essential features of developing mammalian neurons.In undifferentiated cells, cholinergic receptor antagonists had little or no protective effect against the antimitotic actions of CPF; however, when nerve growth factor was used to evoke differentiation, the antagonists showed partial protection against deficits in cell loss and alteration in cell size elicited by CPF, but were ineffective in preventing the deterioration of AC signaling. Nicotine, which stimulates nicotinic acetylcholine receptors but also possesses a mixture of prooxidant/antioxidant activity, had adverse effects by itself but also protected undifferentiated cells from the actions of CPF and had mixed additive/protective effects on cell number in differentiating cells. The antioxidant vitamin E also protected both undifferentiated and differentiating cells from many of the adverse effects of CPF but worsened the impact on AC signaling. Theophylline, which prevents the breakdown of cyclic AMP, was the only agent that restored AC signaling to normal or supranormal levels but did so at further cost to cell replication.Our results show definitive contributions of cholinergic hyperstimulation, oxidative stress, and interference with AC signaling in the developmental neurotoxicity of CPF and point to the potential use of this information to design treatments to ameliorate these adverse effects.
Degradation of parathyroid hormone and fragment production by the isolated perfused dog kidney. The effect of glomerular filtration rate and perfusate CA++ concentrations.
Authors: K A Hruska, K Martin, P Mennes, A Greenwalt, C Anderson, S Klahr, E Slatopolsky
Journal: Journal of Clinical Investigation (1977)

The renal degradation of intact bovine parathyroid hormone (b-PTH 1-84) was studied with the isolated perfused dog kidney. Disappearance of b-PTH 1-84 from the perfusate occurred concomitantly with the appearance of smaller molecular weight forms of immunoreactive parathyroid hormone (PTH). These smaller molecular weight PTH fragments included both carboxyl and amino terminal regions of the PTH peptide. Perfusate from kidneys with lower glomerular filtration rates (GFR) contained b-PTH 1-84 for longer periods of time than kidneys with higher GFRs, and perfusate from kidneys with lower GFRs demonstrated greater accumulation of carboxyl terminal PTH fragments. Perfusate containing high Ca++ concentrations retarded, and perfusate with low Ca++ concentrations accelerated the rate of degradation of b-PTH 1-84 by the kidney. These studies, therefore document the production of PTH fragments during the course of intact hormone degradation by the kidney. They also demonstrate renal clearance of the PTH fragments produced and define the effects of glomerular filtration rate and calcium concentrations on degradation of intact hormone and the clearance of PTH fragments.
Hereditary hypotrichosis
Authors: B. BENTLEY-PHILLIPS, H.J. GRACE
Journal: British Journal of Dermatology (2006)

A syndrome of hereditary hypotrichosis with an unusual natural history and clinical features was encountered in a Caucasian family of four generations with a total of twenty-four members of whom eleven were affected. The mode of inheritance was autosomal dominant with variable penetrance. The loss of hair involved the scalp, eyebrows, eyelashes and body hair, manifesting itself in the school years and progressing to almost complete baldness. There were no associated abnormalities and no sex limitation. Clinical, genetic, biochemical, mechanical, histological and immunological aspects were studied. Essential differences between this type of hereditary hypotrichosis and others previously recorded are stressed.
Can we tame the monster?
Authors: Fiona Godlee
Journal: BMJ (2006)

What can we learn from the New England Journal of Medicine 's correction last week of its study on rofecoxib ( BMJ 2006;333: 12, 1 Jul)? The simple message is that increased cardiovascular risks were visible as early as four months into treatment, rather than the 18 months that Merck had claimed. But rofecoxib was withdrawn two years ago, so why all the fuss?

Well, reputations are at stake. The journal wants to show that it had made no mistakes in peer reviewing the study. And Merck, having already incurred financial loss, needs to protect its …
An Unusual Case of Cardiomegaly
Authors: Antonia Delgado-Montero, Covadonga Fernández-Golfín, Laura Morán, José M. Garrido, Blanca Romera, Alicia Megías, Ana Gutierrez Pecharromán, Amparo Benito, María Eugenia Olmedo, Miguel Castillo, Jose L. Zamorano
Journal: Circulation (2014)
Pyruvate Dehydrogenase Complex Activity in Normal and Deficient Fibroblasts
Authors: Kwan-Fu Rex Sheu, Chii-Whei C. Hu, Merton F. Utter
Journal: Journal of Clinical Investigation (1981)

Pyruvate dehydrogenase complex (PDC) activity in human skin fibroblasts appears to be regulated by a phosphorylation-dephosphorylation mechanism, as is the case with other animal cells. The enzyme can be activated by pretreating the cells with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, before they are disrupted for measurement of PDC activity. With such treatment, the activity reaches 5-6 nmol/min per mg of protein at 37°C with fibroblasts from infants. Such values represent an activation of about 5-20-fold over those observed with untreated cells. That this assay, based on [1-14C]pyruvate decarboxylation, represents a valid measurement of the overall PDC reaction is shown by the dependence of 14CO2 production on the presence of thiamin-PP, coenzyme A (CoA), Mg++, and NAD+. Also, it has been shown that acetyl-CoA and 14CO2 are formed in a 1:1 ratio. A similar degree of activation of PDC can also be achieved by adding purified pyruvate dehydrogenase phosphatase and high concentrations of Mg++ and Ca++, or in some cases by adding the metal ions alone to the cell homogenate after disruption. These results strongly suggest that activation is due to dephosphorylation. Addition of NaF, which inhibits dephosphorylation, leads to almost complete loss of PDC activity.
Trypanosomiasis in the Anglo-Egyptian Soudan: [Preliminary Note.]
Authors: A. Balfour
Journal: BMJ (1904)

Togo, proved that at least two species of flies can transmit the infection in dogs, while Curry,4 in Manila, found StomoxY8 calcitrans to be the principal agent in the transmission of the disease among horses, etc., active trypanosoma being found in the proboscis and stomach twenty-tour hours after feeding them on infected blood.In the same year Sivori and Lecler,r in South America, proved that the Mutm a brava, the Stomo.7y8
Thromboxane-mediated hypertension and vascular leakage evoked by low doses of Escherichia coli hemolysin in rabbit lungs.
Authors: W Seeger, H Walter, N Suttorp, M Muhly, S Bhakdi
Journal: Journal of Clinical Investigation (1989)

Escherichia coli hemolysin has been implicated as a pathogenicity factor in extraintestinal E. coli infections including sepsis. In the present study the effects of intravascular administration of hemolysin were investigated in isolated blood-free perfused rabbit lungs. Low concentrations of the toxin in the perfusate (0.05-5 hemolytic units/ml, corresponding to approximately 5-500 ng/ml), caused a dose- and time-dependent release of potassium, thromboxane A2, and prostaglandin I2, but not of lactate dehydrogenase, into the recirculating medium, as well as a dose-dependent liberation of the prostanoids into the bronchoalveolar space. These events were paralleled by a dose-dependent pulmonary hypertension, and studies with different inhibitors collectively indicated that the vasoconstrictor response was mediated predominantly by pulmonary thromboxane generation. In addition, E. coli hemolysin elicited a protracted, dose-dependent increase in the lung capillary filtration coefficient, which was independent of the prostanoid-mediated pressor response and resulted in severe pulmonary edema formation. We conclude that E. coli hemolysin can elicit thromboxane-mediated pulmonary hypertension combined with severe vascular leakage in isolated lungs in the absence of circulating inflammatory cells and humoral mediator systems, mimicking the key events in the development of acute respiratory failure in states of septicemia.
Chronic insomnia: multidimensional in cause
Authors: C. Goldstein
Journal: JAMA (1985)

Whatever its causes, chronic insomnia often has disruptive—even devastating—effects on the lives of its sufferers." So caution Anthony Kales, MD, director of the Sleep Research and Treatment Center, and Joyce D. Kales, MD, director of the Sleep Disorders Clinic at the College of Medicine, Pennsylvania State University, Hershey. Their recent book,<i>Evaluation and Treatment of Insomnia</i>(New York, Oxford University Press, 1984), is a "guide to the general practitioner who almost daily is confronted with the problem of evaluating and treating patients with chronic insomnia," the two physicians say. A 1979 survey of almost 4,500 physicians in the United States indicated that, across all specialties, the physicians estimated that about 20% of adult patients complained of difficulty falling asleep or staying asleep. Psychiatrists reported the highest prevalence, with approximately 32% of their patients suffering from insomnia (<i>Am J Psychiatry</i>1979; 136:1257-1262;<i>Soc Sci Med</i>1976;10:239-244;<i>Selected Symptoms of Psychological Distress</i>