tbuckley/cabot-search huggingface dataset:
Impaired Skin and Mammary Gland Development and Increased γ-Irradiation–Induced Tumorigenesis in Mice Carrying a Mutation of S1152-ATM Phosphorylation Site in Brca1
Authors: Sang Soo Kim, Liu Cao, Hye Jung Baek, Sung-Chul Lim, Cuiling Li, Rui-Hong Wang, Xiaoling Xu, Kwan Ho Cho, Chu-Xia Deng
Journal: Cancer Research (2009)

Abstract The tumor suppressor BRCA1 interacts with many proteins and undergoes multiple modifications on DNA damage. ATM, a key molecule of the DNA damage response, phosphorylates S1189 of BRCA1 after γ-irradiation. S1189 of BRCA1 is known as a unique ATM phosphorylation site in BRCA1 exon 11. To study the functions of ATM-dependent phosphorylation of BRCA1-S1189, we generated a mouse model carrying a mutation of S1152A (S1152 in mouse Brca1 corresponds to S1189 in human BRCA1) by gene targeting. Brca1S1152A/S1152A mice were born at the expected ratio, unlike that seen in previous studies of Brca1-null mice. However, 36% of Brca1S1152A/S1152A mice exhibited aging-like phenotypes including growth retardation, skin abnormalities, and delay of the mammary gland morphogenesis, with an increase in apoptosis. Mutant mice were hypersensitive to high doses of γ-irradiation, displaying shortened life span and reduction in intestinal villus size, associated with increased apoptosis. Aging-unaffected 18-month-old Brca1S1152A/S1152A female mice also showed mammary gland abnormalities with increased levels of cyclin D1 and phospho-ER-α, such as Brca1-Δ11 mutation. On low-dose γ-irradiation, they suffered a marked increase in tumor formation with an abnormal coat pattern. Furthermore, Brca1S1152A/S1152A embryonic fibroblasts failed to accumulate p53 on γ-irradiation with delayed phosphorylation of p53-S23. These observations indicate that ATM-mediated phosphorylation of S1189 is required for BRCA1 functions in the modulation of DNA damage response and in the suppression of tumor formation by regulating p53 and apoptosis. [Cancer Res 2009;69(24):9291–300]
Influence of Diphenylhydantoin on Electrophysiological Properties of the Canine Heart
Authors: ROBERT A. ROSATI, JAMES A. ALEXANDER, STEPHEN F. SCHOOL, ANDREW G. WALLACE
Journal: Circulation Research (1967)

These studies were designed to examine the electrophysiological effects of diphenylhydantoin (Dilantin) on the heart of awake dogs. Recording electrodes were implanted over the sinoatrial node, bundle of His, and right bundle branch, and studies were performed 2 to 6 weeks following recovery. Diphenylhydantoin (10 mg/kg) increased heart rate, shortened A-V conduction time and had little or no effect on conduction velocity in Purkinje tissue or total ventricular activation time. Similar effects were noted when heart rate was controlled by pacing. Following cardiac denervation, diphenylhydantoin decreased heart and prolonged A-V conduction time. It raised the threshold of atrial and ventricular muscle with no change of refractory periods. In dogs with heart block, it decreased the maximal rate at which the atria would respond to stimulation. When ventricular tachycardia was induced in dogs with heart block, by toxic doses of deslanoside, diphenylhydantoin abolished the ectopic tachycardia and restored the control rhythm.
Loss of Central Nervous System Component of Dopaminergic Inhibition of Prolactin Secretion in Patients with Prolactin-Secreting Pituitary Tumors
Authors: Stuart A. Fine, Lawrence A. Frohman
Journal: Journal of Clinical Investigation (1978)

The administration of l-dopa suppresses prolactin (PRL) secretion in normal subjects and in patients with hyperprolactinemia, although it is not known whether this effect, which requires the conversion of dopa to dopamine, is mediated peripherally or through the central nervous system. To distinguish between these effects, 10 normal subjects (6 male, 4 female) and 8 patients with hyperprolactinemia associated with pituitary tumors were given l-dopa, 0.5 g alone, or 0.1 g after a 24-h pretreatment with carbidopa, 50 mg every 6 h, which produces peripheral dopa decarboxylase inhibition. Similar degrees of PRL suppression were observed in normal subjects (basal plasma PRL 13±2 ng/ml) after l-dopa alone (48±4%) and after l-dopa plus carbidopa (58±6%). In patients with pituitary tumors and elevated plasma PRL (73±14 ng/ml), l-dopa alone led to PRL suppression comparable with that in normal subjects (47±6%). However, l-dopa plus carbidopa resulted in only minimal suppression of plasma PRL (19±4%) which was significantly less than after l-dopa alone (P < 0.001). Urinary homovanillic acid excretion, which reflected peripheral dopa decarboxylation was similar in controls and tumor patients after l-dopa both alone and after carbidopa pretreatment. Comparable suppression of PRL levels in response to a dopamine infusion (4 μg/kg per min for 3 h) was observed in controls and tumor patients. The results indicate that although peripheral conversion of exogenous dopa to dopamine can suppress PRL secretion, in normals, the central nervous system conversion of dopa to dopamine in the presence of peripheral dopa decarboxylase inhibition is sufficient to account for its PRL-suppressive effects. In contrast, patients with tumors, while retaining peripheral dopaminergic inhibitory effects on PRL secretion, exhibit a marked reduction of central dopaminergic inhibition of PRL secretion.
Effect of Calcium on Superoxide Production by Phagocytic Vesicles from Rabbit Alveolar Macrophages
Authors: P. Daniel Lew, Thomas P. Stossel
Journal: Journal of Clinical Investigation (1981)

Phagocytic vesicles from rabbit lung macrophages produced superoxide in the presence of NADH or NADPH. At 37 degrees C, these vesicles generated 51+/-7.8 nmol O(2) (-)/min per mg protein in the presence of 0.5 mM NADPH. The apparent K(m) for NADPH and NADH (66 and 266 muM, respectively), the pH optimum for the reaction (6.9), and the cyanide insensitivity were similar to properties of plasma membrane-rich fractions of stimulated polymorphonuclear leukocytes studied by others. The activity of the phagocytic vesicles was trypsin sensitive. The specific superoxide-generating activity of macrophage phagocytic vesicles isolated from cells incubated up to 90 min with phagocytic particles remained constant. Calcium in micromolar concentrations inhibited the NADPH-dependent O(2) (-)-generating activity of phagocytic vesicles. In a physiological ionic medium (100 mM KCl, 2.5 mM MgCl(2), 30 mM imidazole-HCl, pH 6.9), a maximal inhibition of O(2) (-) generation by phagocytic vesicles of 80% was observed at 40 muM free Ca(2+). The half maximum inhibitory effect was at 0.7 muM Ca(2+). Variations of the calcium concentration resulted in rapid and reversible alterations in O(2) (-)-forming activity. Preincubation of phagocytic vesicles in the presence of EGTA rendered their O(2) (-) generation rate in the presence of NADPH insensitive to alterations in the free calcium concentration. This desensitization by low EGTA concentrations (</=100 muM) was reversible by the addition of excess calcium, but desensitization by high EGTA concentrations (>1 mM) was not reversible by the addition of calcium either in the presence or absence of purified rabbit lung macrophage or bovine brain calmodulins. Furthermore, trifluoperazine, a drug that inhibits calmodulin-stimulated reactions, did not alter the activity or the calcium sensitivity of the superoxide-generating system of sensitive phagocytic vesicles. Peripheral plasma membrane vesicles (podosomes) prepared by gentle sonication of macrophages possessed on O(2) (-)-generating system with similar properties to those of phagocytic vesicles. We conclude that the activated O(2) (-)-generating system of rabbit lung macrophages has its initial localization in the plasmalemma and undergoes subsequent internalization into phagocytic vesicles, where it can function for prolonged periods of time. Calcium at concentrations likely to exist in macrophage cytoplasm exerts a regulatory effect on the activated system.
What Is New in Dilatation of the Ascending Aorta?
Authors: Luc Cozijnsen, Richard L. Braam, Reinier A. Waalewijn, Marc A.A.M. Schepens, Bart L. Loeys, Matthijs F.M. van Oosterhout, Daniela Q.C.M. Barge-Schaapveld, Barbara J.M. Mulder
Journal: Circulation (2011)
The Association between Quality of Care and the Intensity of Diabetes Disease Management Programs
Authors: Carol M. Mangione
Journal: Annals of Internal Medicine (2006)

Although disease management programs are widely implemented, little is known about their effectiveness.To determine whether disease management by physician groups is associated with diabetes care processes, control of intermediate outcomes, or the amount of medication used when intermediate outcomes are above target levels.Cross-sectional study.Patients were randomly sampled from 63 physician groups nested in 7 health plans sponsored by Translating Research into Action for Diabetes (87%) and from 4 health plans with individual physician contracts (13%).8661 adults with diabetes who completed a survey (2000-2001) and had medical record data.Physician group and health plan directors described their organizations' use of physician reminders, performance feedback, and structured care management on a survey; their responses were used to determine measures of intensity of disease management. The current study measured 8 processes of care, including most recent hemoglobin A1c level, systolic blood pressure, serum low-density lipoprotein cholesterol level, and several measures of medication use.Increased use of any of 3 disease management strategies was significantly associated with higher adjusted rates of retinal screening, nephropathy screening, foot examinations, and measurement of hemoglobin A1c levels. Serum lipid level testing and influenza vaccine administration were associated with greater use of structured care management and performance feedback. Greater use of performance feedback correlated with an increased rate of foot examinations (difference, 5 percentage points [95% CI, 1 to 8 percentage points]), and greater use of physician reminders was associated with an increased rate of nephropathy screening (difference, 15 percentage points [CI, 6 to 23 percentage points]). No strategies were associated with intermediate outcome levels or level of medication management.Physician groups were not randomly sampled from population-based listings, and disease management strategies were not randomly allocated across groups.Disease management strategies were associated with better processes of diabetes care but not with improved intermediate outcomes or level of medication management. A greater focus on direct measurement, feedback, and reporting of intermediate outcome levels or of level of medication management may enhance the effectiveness of these programs.
RESOURCERER: a database for annotating and linking microarray resources within and across species
Authors: Jennifer Tsai, Razvan Sultana, Yudan Lee, Geo Pertea, Svetlana Karamycheva, Valentin Antonescu, Jennifer Cho, Babak Parvizi, Foo Cheung, John Quackenbush
Journal: Genome biology (2001)

Microarray expression analysis is providing unprecedented data on gene expression in humans and mammalian model systems. Although such studies provide a tremendous resource for understanding human disease states, one of the significant challenges is cross-referencing the data derived from different species, across diverse expression analysis platforms, in order to properly derive inferences regarding gene expression and disease state. To address this problem, we have developed RESOURCERER, a microarray-resource annotation and cross-reference database built using the analysis of expressed sequence tags (ESTs) and gene sequences provided by the TIGR Gene Index (TGI) and TIGR Orthologous Gene Alignment (TOGA) databases [now called Eukaryotic Gene Orthologs (EGO)].
Addressing biochemical deficiencies in athletes for performance enhancement
Authors: S Pettersen
Journal: British Journal of Sports Medicine (2011)

Lecture 24 Introduction In order for an athlete to achieve the highest level of performance, every cell of their organism must be functioning efficiently. Nutrient deficiencies limit metabolic function of their respective biochemical pathways and possibly any subsequent reactions. Optimal biochemical regulation will determine performance whether an athlete is attempting to set a record or heal from an injury. Because every athlete has unique biochemistry, diet analysis cannot predict nutrient status even among athletes of the same sport. Every sport has different nutrient requirements and every athlete in that sport will have distinctive needs based on age, medical history, nutrient absorption, metabolism, genetic predisposition and medications. Even high-performing athletes who appear healthy can have deficiencies that make them prone to injury or poor recovery. Methods Laboratory testing reveals the health status of an athlete without bias or judgement allowing for accurate supplementation. Urine and blood analysis are performed to determine direct and indirect measures of specific nutrients. Genetic testing can be performed from the DNA through blood or saliva. Conclusion Identifying and correcting biochemical imbalances is the fastest way to balance the athlete and allows them to reach their maximal genetic potential.
Summary of Clinical Trials with Zafirlukast
Authors: WILLIAM J. CALHOUN
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Zafirlukast is an orally active and selective cysteinyl leukotriene (cysLT) receptor antagonist. In humans, zafirlukast antagonized the effects of exogenously administered LTD4 and cysLTs released endogenously in response to physical and chemical stimuli. Zafirlukast antagonized LTD4-induced bronchoconstriction, with effects still evident 12 h after drug administration. In clinical models of asthma, zafirlukast inhibited bronchospasm after allergen or exercise challenge in patients with asthma. In multicenter trials in patients with chronic, stable asthma, zafirlukast reduced asthma symptoms, decreased as-needed beta-agonist use, and improved pulmonary function without increasing the number of adverse events. Zafirlukast also exhibited evidence of an anti-inflammatory effect in the lung in preliminary studies involving segmental antigen challenge. The results from these clinical trials demonstrate that zafirlukast is effective and safe for the prophylactic treatment of asthma.
449 OVERALL SAFETY PROFILE OF BOCEPREVIR PLUS PEGINTERFERON ALFA-2B/RIBAVIRIN
Authors: M.P. Manns, F. Felizarta, E. Schiff, M. Burroughs, V. Sniukiene, N. Boparai, C.A. Brass, J.K. Albrecht, J.M. Vierling
Journal: Journal of Hepatology (2011)
NUP98 Fusion Oncoproteins Promote Aneuploidy by Attenuating the Mitotic Spindle Checkpoint
Authors: Valentina Salsi, Silvia Ferrari, Paolo Gorello, Sebastian Fantini, Francesca Chiavolelli, Cristina Mecucci, Vincenzo Zappavigna
Journal: Cancer Research (2013)

Abstract NUP98 is a recurrent fusion partner in chromosome translocations that cause acute myelogenous leukemia. NUP98, a nucleoporin, and its interaction partner Rae1, have been implicated in the control of chromosome segregation, but their mechanistic contributions to tumorigenesis have been unclear. Here, we show that expression of NUP98 fusion oncoproteins causes mitotic spindle defects and chromosome missegregation, correlating with the capability of NUP98 fusions to cause premature securin degradation and slippage from an unsatisfied spindle assembly checkpoint (SAC). NUP98 fusions, unlike wild-type NUP98, were found to physically interact with the anaphase promoting complex/cyclosome (APC/C)Cdc20 and to displace the BubR1 SAC component, suggesting a possible mechanistic basis for their interference with SAC function. In addition, NUP98 oncoproteins displayed a prolonged half-life in cells. We found that NUP98 stability is controlled by a PEST sequence, absent in NUP98 oncoproteins, whose deletion reproduced the aberrant SAC-interfering activity of NUP98 oncoproteins. Together, our findings suggest that NUP98 oncoproteins predispose myeloid cells to oncogenic transformation or malignant progression by promoting whole chromosome instability. Cancer Res; 74(4); 1079–90. ©2013 AACR.
Prosody as an intermediary evolutionary stage between a manual communication system and a fully developed language faculty
Authors: Andreas Rogalewski, Caterina Breitenstein, Agnes Floel, Stefan Knecht
Journal: Behavioral and Brain Sciences (2004)

Based on the motor theory of language, which asserts an evolution from gestures along several stages to today's speech and language, we suggest that speech ontogeny may partly reflect speech phylogeny, in that perception of prosodic contours is an intermediary stage between a manual communication system and a fully developed language faculty.
Activated macrophages induce structural abnormalities of the T cell receptor-CD3 complex.
Authors: T Aoe, Y Okamoto, T Saito
Journal: The Journal of Experimental Medicine (1995)

The mechanism of the structural alterations of the T cell receptor (TCR)-CD3 complex, which appear to be greatly responsible for immunosuppression in the tumor-bearing status, was investigated in tumor-bearing mice. Splenic T cells from tumor-bearing hosts lost the expression of the CD3 zeta chain without being replaced by FcR gamma, despite the normal expression of other components of the TCR complex. Tumor growth induced the accumulation of non-T, non-B cells in the spleen in correlation with the loss of zeta. Those cells were found to be macrophages that were able to induce the loss of zeta, as well as structural changes of CD3 gamma delta epsilon, even in freshly isolated normal T cells by cell contact-dependent interaction. More importantly, macrophages activated with zymosan A+LPS but not residential macrophages were able to induce the similar abnormality of the TCR complex. These results indicate that macrophages in certain activation stages play a crucial role in causing an abnormal TCR complex in tumor-bearing conditions, as well as in regulating the structure of the TCR complex in immune responses.
Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study
Authors: J.K. Lee, J.-Y. Shin, S. Kim, S. Lee, C. Park, J.-Y. Kim, Y. Koh, B. Keam, H.S. Min, T.M. Kim, Y.-K. Jeon, D.-W. Kim, D.H. Chung, D.S. Heo, S.-H. Lee, J.-I. Kim
Journal: Annals of Oncology (2013)
Private firm will operate entire NHS hospital
Authors: A. O'Dowd
Journal: BMJ (2010)

An NHS district general hospital will be run by a private organisation for the first time after the decision by a fellow NHS body to drop out of a bidding process.

Hinchingbrooke Health Care NHS Trust in Huntingdonshire is the first NHS trust to invite potential partners from within and outside the NHS to apply for a franchise to operate the hospital. The only remaining NHS organisation that was bidding to manage the hospital—Cambridge University Hospitals NHS Foundation Trust—withdrew from the bidding saying that the costs were too high.

Unions are worried about the development and fear it is a “dangerous experiment” that goes against recent comments from the Department of Health and health secretary Andy Burnham that the NHS should be the “preferred provider” of services.

The trust, which has an accumulated deficit of £38.9m ($60m €44m) as of March 2009, is keen to proceed with the bidding process that now involves five private …
Salicylates and Thyroid Function. II. The Effect on the Thyroid-Pituitary Interrelation
Authors: J. Wolff, Frank K. Austen
Journal: Journal of Clinical Investigation (1958)

In the preceding paper (1) it was pointed out that the administration of sodium salicylate to man induces a number of changes suggestive of thyrotoxicosis. There is an elevated basal metabolic rate (BMR), negative nitrogen balance, a fall in the cholesterol level of the hypothyroid subject, and an accelerated fractional disappearance rate of labeled thyroxine from the circulation. Paradoxically, salicylate-induced hypermetabolism is not accompanied by certain of the clinical characteristics of hyperthyroidism and is associated with depressed thyroid function as measured by thyroidal radioiodine uptake and clearance, or the serum protein bound iodine (PBI) concentration. The salicylate level in the serum of such patients is not high enough to interfere with in vitro iodine metabolism in rat thyroid slices, and in acute experiments in rats no depression of the iodide concentrating mechanism can be demonstrated at blood salicylate levels comparable to those attained in the above patients (1). Similar findings had previously been recorded in rats and in man
Activation of Estrogen Receptor-α Reduces Aortic Smooth Muscle Differentiation
Authors: Christine R. Montague, Melissa G. Hunter, Mikhail A. Gavrilin, Gary S. Phillips, Pascal J. Goldschmidt-Clermont, Clay B. Marsh
Journal: Circulation Research (2006)

Women are at high risk of dying from unrecognized cardiovascular disease. Many differences in cardiovascular disease between men and women appear to be mediated by vascular smooth muscle cells (SMC). Because estrogen reduces the proliferation of SMC, we hypothesized that activation of estrogen receptor-alpha (ERalpha) by agonists or by growth factors altered SMC function. To determine the effect of growth factors, estrogen, and ERalpha expression on SMC differentiation, human aortic SMC were cultured in serum-free conditions for 10 days. SMC from men had lower spontaneous expression of ERalpha and higher levels of the differentiation markers calponin and smooth muscle alpha-actin than SMC from women. When SMC containing low expression of ERalpha were transduced with a lentivirus containing ERalpha, activation of the receptor by ligands or growth factors reduced differentiation markers. Conversely, inhibiting ERalpha expression by small interfering RNA (siRNA) in cells expressing high levels of ERalpha enhanced the expression of differentiation markers. ERalpha expression and activation reduced the phosphorylation of Smad2, a signaling molecule important in differentiation of SMC and initiated cell death through cleavage of caspase-3. We conclude that ERalpha activation switched SMC to a dedifferentiated phenotype and may contribute to plaque instability.
A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP.
Authors: J Rey-Campos, P Rubinstein, S Rodriguez de Cordoba
Journal: The Journal of Experimental Medicine (1988)

We report the organization of the human genes encoding the complement components C4-binding protein (C4BP), C3b/C4b receptor (CR1), decay accelerating factor (DAF), and C3dg receptor (CR2) within the regulator of complement activation (RCA) gene cluster. Using pulsed field gel electrophoresis analysis these genes have been physically linked and aligned as CR1-CR2-DAF-C4BP in an 800-kb DNA segment. The very tight linkage between the CR1 and the C4BP loci, contrasted with the relative long DNA distance between these genes, suggests the existence of mechanisms interfering with recombination within the RCA gene cluster.