tbuckley/cabot-search huggingface dataset:
Mechanical and Chemical Regulation of Endothelial Cell Polarity
Authors: Shu Chien
Journal: Circulation Research (2006)

cCue et al 1 showed by a combination of in vitro and in vivo studies that shear stress regulates planar cell polarity (PCP) of endothelial cells (ECs) and that glycogen synthase kinase 3␤ (GSK3␤) plays a significant role in this process. In Vitro Studies on Effects of Shear Stress on PCP and GSK-3␤The application of shear stress at 15 dyn/cm 2 to cultured porcine aortic ECs caused tubulin acetylation and stabilization of microtubules (MTs), downstream polarization of microtubule-organizing centers (MTOCs), as well as MT orientation and EC elongation in the shear direction.The importance of tubulin dynamics in these shear-induced changes was demonstrated by their elimination by the MTdisrupting agent nocodazole and also the MT-stabilizing agent taxol.A novel finding is the role of GSK-3␤ in shear-induced MT orientation.GSK-3␤ is a regulatory serine/threonine kinase 2 that has high activity under basal state, and its activity is inhibited after serine-9 phosphorylation (p-GSK-3␤); this would lead to downstream signaling 3 and MT stabilization, 4 eg, through the binding of adenomatous polyposis cell protein (APC). 4,5GSK-3␤ can be inhibited by lithium and SB415286, which interfere with the binding of ATP to GSK-3 6 rather than acting directly on GSK-3 phosphorylation.The evidence that GSK-3␤ plays a role in mediating the shear-induced MT orientation and cell shape change is as follows.First, shear stress caused an increase in p-GSK-3␤ (at 1 and 4 hours, though waned at 24 hours).Second, inhibition of GSK-3␤ by LiCl and SB415286 blocked the shear-induced EC elongation.SB415286 was also shown to reverse the shear-induced downstream localization of MTOCs to become upstream.Third, overexpression of a constitutively active GSK-3␤ (GSK S9A ), which cannot be phosphorylated, attenuated tubulin acetylation, blocked cell elongation, and caused MTOC distribution to be more random.
Systolic Hypertension and Subendocardial Hemorrhages Produced by Electrical Stimulation of the Stellate Ganglion
Authors: MICHAEL P. KAYE, ROBERT H. MCDONALD, WALTER C. RANDALL
Journal: Circulation Research (1961)

During prolonged electrical stimulation of the stellate ganglion in the dog, blood pressure, and more specifically systolic pressure, is significantly elevated. The amount of augmentation in pulse pressure is related to the frequency of stimulation, as is the duration of the sustained pressor response. Postmortem examination of the hearts revealed a distinctive pattern of subendocardial hemorrhages distributed along the long axis of the papillary muscles and the trabeculae carneae. They also frequently marked the endocardium at the base of the mitral valve. These lesions appeared in the left ventricle in 29 of 33 animals in which the left stellate ganglion was stimulated at a frequency of three to ten per second. They were found in only five instances in the right ventricles of these animals. The incidence of lesions in the ventricular wall was low during stimulation of the right stellate ganglion, although the mitral valve became involved in about 50 per cent of the animals. The similarity of the lesions to those induced during hemorrhagic hypotension, elevated intracranial pressures, and infusion of large quantities of the catecholamines suggests the possibility of a similar etiology. A satisfactory explanation of the lesion, however, is not yet available.
Community Lay Rescuer Automated External Defibrillation Programs
Authors: Tom Aufderheide, Mary Fran Hazinski, Graham Nichol, Suzanne Smith Steffens, Andrew Buroker, Robin McCune, Edward Stapleton, Vinay Nadkarni, Jerry Potts, Raymond R. Ramirez, Brian Eigel, Andrew Epstein, Michael Sayre, Henry Halperin, Richard O. Cummins
Journal: Circulation (2006)

Cardiovascular disease is a leading cause of death for adults > or =40 years of age. The American Heart Association (AHA) estimates that sudden cardiac arrest is responsible for about 250,000 out-of-hospital deaths annually in the United States. Since the early 1990s, the AHA has called for innovative approaches to reduce time to cardiopulmonary resuscitation (CPR) and defibrillation and improve survival from sudden cardiac arrest. In the mid-1990s, the AHA launched a public health initiative to promote early CPR and early use of automated external defibrillators (AEDs) by trained lay responders in community (lay rescuer) AED programs. Between 1995 and 2000, all 50 states passed laws and regulations concerning lay rescuer AED programs. In addition, the Cardiac Arrest Survival Act (CASA, Public Law 106-505) was passed and signed into federal law in 2000. The variations in state and federal legislation and regulations have complicated efforts to promote lay rescuer AED programs and in some cases have created impediments to such programs. Since 2000, most states have reexamined lay rescuer AED statutes, and many have passed legislation to remove impediments and encourage the development of lay rescuer AED programs. The purpose of this statement is to help policymakers develop new legislation or revise existing legislation to remove barriers to effective community lay rescuer AED programs. Important areas that should be considered in state legislation and regulations are highlighted, and sample legislation sections are included. Potential sources of controversy and the rationale for proposed legislative components are noted. This statement will not address legislation to support home AED programs. Such recommendations may be made after the conclusion of a large study of home AED use.
JEM content to be deposited automatically in PubMed Central
Authors: Mike Rossner
Journal: The Journal of Experimental Medicine (2007)

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©cartoonbank.com. All Rights Reserved. The Rockefeller University Press is pleased to announce that, as of December 2007, all of the content of the Journal of Experimental Medicine will be deposited in PubMed Central. The content will be mirrored on the UK PubMed
Concurrent vs Sequential Adjuvant Chemotherapy and Hormone Therapy in Breast Cancer: A Multicenter Randomized Phase III Trial
Authors: Davide Bedognetti, Mario Roberto Sertoli, Paolo Pronzato, Lucia Del Mastro, Marco Venturini, Paola Taveggia, Elisa Zanardi, Guido Siffredi, Simona Pastorino, Paola Queirolo, Giovanni Gardin, Ena Wang, Clara Monzeglio, Francesco Boccardo, Paolo Bruzzi
Journal: JNCI Journal of the National Cancer Institute (2011)

The most appropriate timing of chemotherapy and hormone therapy administration is a critical issue in early breast cancer patients. The purpose of our study was to compare the efficacy of concurrent vs sequential administration of adjuvant chemotherapy and tamoxifen. Women with node-positive primary breast cancer were randomly assigned to receive tamoxifen (20 mg/d for 5 years) during (concurrent arm) or after (sequential arm) adjuvant chemotherapy. Chemotherapy consisted of alternating regimens of cyclophosphamide, epidoxorubicin, and 5-fluorouracil and cyclophosphamide, methotrexate, and 5-fluorouracil every 21 days for a total of 12 cycles. The primary endpoint was overall survival (OS), and secondary endpoints were toxic effects and disease-free survival (DFS). No provision for interim analyses was made in the original study protocol. Survival curves were estimated by the Kaplan–Meier method. Multivariable Cox regression models, adjusted for age, menopausal status, tumor stage, and lymph node and hormone receptor status, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. From 1985 to 1992, 431 patients were randomly assigned and studied according to the intention-to-treat principle. After a maximum of 15.4 years of follow-up (median 12.3 years), the estimated actuarial 10-year OS was equivalent for the two study arms (concurrent arm: 111 patients, 66%, 95% CI = 59% to 72%; sequential arm: 114 patients, 65%, 95% CI = 59% to 72%, P = .86). No differences in DFS and toxic effects were evident. Four interim analyses were performed, but no alpha error adjustment was necessary because of the largely negative results of this final analysis (sequential vs concurrent arm: HR of death = 1.06, 95% CI = 0.78 to 1.44, P = .76; HR of relapse = 1.16, 95% CI = 0.88 to 1.52, P = .36). No statistically significant differences in OS, DFS, and toxic effects between concurrent and sequential adjuvant chemo- and hormone therapies were observed. Our study does not support the superiority of one schedule of chemo- and hormone-therapy administration over the other. However, because of the limited statistical power of the study, these results must be considered with caution.
Acromegaly pathogenesis and treatment
Authors: Shlomo Melmed
Journal: Journal of Clinical Investigation (2009)

Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly — a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Somatostatin receptor (SSTR) ligands inhibit GH release, control tumor growth, and attenuate peripheral GH action, while GH receptor antagonists block GH action and effectively lower IGF1 levels. Novel peptides, including SSTR ligands, exhibiting polyreceptor subtype affinities and chimeric dopaminergic-somatostatinergic properties are currently in clinical trials. Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder.
Repolarizing currents in ventricular myocytes from young patients with tetralogy of Fallot
Authors: P Schaffer
Journal: Cardiovascular Research (1999)

It was the aim of our study to describe repolarizing currents in ventricular myocytes isolated from children with tetralogy of Fallot. This is the first report on outward currents in ventricular myocytes from children.Ventricular myocytes were isolated from tissue samples of the outflow tract of the right ventricle which were obtained during corrective surgery of tetralogy of Fallot. Action potentials and whole-cell currents were recorded with the patch clamp technique at a temperature of 36-37 degrees C.The mean resting potential was -71.7 +/- 1.92 mV, action potential amplitude was 110 +/- 2.96 mV and action potential duration at 90% repolarization was 794 +/- 99.5 ms (n = 12). In four out of 12 myocytes early afterdepolarizations (EADs) were observed. Upon hyperpolarization Ba(2+)-sensitive inward currents similar to the inward rectifier current (IKl) could be observed. The current density at -120 mV was -22.8 +/- 2.47 pA/pF (n = 14). A transient outward current (Itol) could be recorded in all myocytes studied, the current density varied from 0.3 to 8.6 pA/pF with a mean of 3.77 +/- 0.47 pA/pF at +40 mV (n = 38). Recovery of Itol from inactivation was fast (70% recovery within 100 ms), rate-dependent reduction amounted to 38.2% at 4 Hz. A delayed rectifier current was seen in only two out of 38 myocytes (rapid component IKr).The electrophysiological characteristics of right ventricular myocytes isolated from children with tetralogy of Fallot resemble in most cases subendocardial myocytes from adults. The most prominent difference is a fast recovery from inactivation as well as a small rate dependent reduction of Itol. The observed EADs may have clinical implications.
Metastasis Dormancy in Estrogen Receptor–Positive Breast Cancer
Authors: Xiang H.-F. Zhang, Mario Giuliano, Meghana V. Trivedi, Rachel Schiff, C. Kent Osborne
Journal: Clinical Cancer Research (2013)

Abstract About 20% to 40% of patients with breast cancer eventually develop recurrences in distant organs, which are often not detected until years to decades after the primary tumor diagnosis. This phenomenon is especially pronounced in estrogen receptor–positive (ER+) breast cancer, suggesting that ER+ cancer cells may stay dormant for a protracted period of time, despite adjuvant therapies. Multiple mechanisms have been proposed to explain how cancer cells survive and remain in dormancy, and how they become reactivated and exit dormancy. These mechanisms include angiogenic switch, immunosurveillance, and interaction with extracellular matrix and stromal cells. How to eradicate or suppress these dormant cancer cells remains a major clinical issue because of the lack of knowledge about the biologic and clinical nature of these cells. Herein, we review the clinical manifestation of metastasis dormancy in ER+ tumors, the current biologic insights regarding tumor dormancy obtained from various experimental models, and the clinical challenges to predict, detect, and treat dormant metastases. We also discuss future research directions toward a better understanding of the biologic mechanisms and clinical management of ER+ dormant metastasis. Clin Cancer Res; 19(23); 6389–97. ©2013 AACR.
Dora Colebrook and the evaluation of light therapy
Authors: Martin Edwards
Journal: Journal of the Royal Society of Medicine (2011)

At the end of the 19th century, Niels Finsen – a Dane – had shown convincing evidence that tuberculous infection of the skin (lupus vulgaris) could be treated successfully with intensive light therapy,1 and he received the Nobel Prize for this work in 1903.2 Experiments using artificially-produced ultraviolet or visible light for treatment continued in the early 20th century, and they led to growing enthusiasm for light therapy of a variety of disorders, albeit predominantly skin conditions.

By the mid 1920s, light therapy was enjoying a boom in popularity. The public ‘began to demand the treatment for every ill under the sun’,3 and medical practitioners, including the most eminent and influential of the day, adopted it widely. King George V received light treatment for his near-fatal pneumonia in 1928. The conditions said to benefit from it would ‘begin with acne and go through to zona [shingles], including housemaid’s knee and minor psychosis'.4 Furthermore, the supply of lamps to physicians, unqualified light-therapy practitioners, and the public, was a lucrative enterprise. Enthusiasm ran high, and opposition to light therapy, particularly among the medical establishment, was almost non-existent. Unsurprisingly, therefore, meticulous research done by Dora Colebrook in the late 1920s, which was unable to detect any beneficial effects of light therapy, was a slap in the face to its proponents.

Dora Colebrook (1884–1965) had come rather late to medicine, qualifying MB at the Royal Free Hospital in 1915 and MD at London University in 1919. After spells as a gynaecologist at the Jessop Hospital in Sheffield and in general practice in Cambridge, she moved to London, where she worked at the North Islington Infant Welfare Centre, enthusiastically employing light therapy to promote ‘an almost monotonous record of increased liveliness, brightness and vigour’ among her charges.5 It was at that point, however, that she decided on a career in medical research.
U-Shaped Dose-Responses in Biology, Toxicology, and Public Health
Authors: Edward J Calabrese, Linda A Baldwin
Journal: Annual Review of Public Health (2001)

▪ Abstract The occurrence of U-shaped dose-response relationships (often termed hormesis) has been documented in numerous biological, toxicological, and pharmacological investigations. Many of the endpoints studied are of considerable significance to public health (e.g. body weight, cholesterol levels, ethanol consumption, longevity, cancer incidence, etc). Despite the fact that U-shaped dose-responses are widely and independently observed, little attempt has been made to assess this phenomenon in an integrative manner. This review provides an overview of the historical foundations of hormesis and a discussion of its definition within a mechanistic framework. The occurrence, generalizability, and biological significance of U-shaped dose-response relationships along with the concept of biological optimality are addressed.
Racial Ethnic Differences in Rates and Determinants of Deceased Donor Kidney Transplantation
Authors: Yoshio N. Hall, Andy I. Choi, Ping Xu, Ann M. O'Hare, Glenn M. Chertow
Journal: Journal of the American Society of Nephrology (2011)

Contemporary studies have not comprehensively compared waiting times and determinants of deceased donor kidney transplantation across all major racial ethnic groups in the Unites States. Here, we compared relative rates and determinants of waitlisting and deceased donor kidney transplantation among 503,090 nonelderly adults of different racial ethnic groups who initiated hemodialysis between1995 and 2006 with follow-up through 2008. Annual rates of deceased donor transplantation from the time of dialysis initiation were lowest in American Indians/Alaska Natives (2.4%) and blacks (2.8%), intermediate in Pacific Islanders (3.1%) and Hispanics (3.2%), and highest in whites (5.9%) and Asians (6.4%). Lower rates of deceased donor transplantation among most racial ethnic minority groups appeared primarily to reflect differences in time from waitlisting to transplantation, but this was not the result of higher rates of waitlist inactivity or removal from the waitlist. The fraction of the reduced transplant rates attributable to measured factors (e.g., demographic, clinical, socioeconomic, linguistic, and geographic factors) varied from 14% in blacks to 43% in American Indians/Alaska Natives compared with whites. In conclusion, adjusted rates of deceased donor kidney transplantation remain significantly lower among racial ethnic minorities compared with whites; generally, differences in time to waitlisting were not as pronounced as differences in time between waitlisting and transplantation. Determinants of delays in time to transplantation differed substantially by racial ethnic group. Area-based efforts targeted to address racial- and ethnic-specific delays in transplantation may help to reduce overall disparities in deceased donor kidney transplantation in the United States.
Cellular basis of neonatal induction of in vitro tolerance.
Authors: O J Kuperman, F H Bach
Journal: The Journal of Experimental Medicine (1976)

The LD and SD antigens of the major histocompatibility complex subserve differential roles in the induction of the proliferative phase in mixed lymphocyte culture and in the cytotoxic reaction seen in cell-mediated lympholysis. The present study suggests that they also behave differently in the neonatal induction of tolerance. SD antigens appear to induce tolerance in the cytotoxic T lymphocytes very effectively, whereas LD antigens (or the cytotoxic targets coded by genes in the I and/or S regions) are relatively ineffective in this regard. LD antigens presented neonatally are effective at inducing tolerance in the proliferating helper cells.
Effects of dietary cholesterol and fat saturation on plasma lipoproteins in an ethnically diverse population of healthy young men.
Authors: C J Fielding, R J Havel, K M Todd, K E Yeo, M C Schloetter, V Weinberg, P H Frost
Journal: Journal of Clinical Investigation (1995)

The individual effects of dietary cholesterol and fat saturation on plasma lipoprotein concentrations were determined in an ethnically diverse population of normolipidemic young men (52 Caucasian, 32 non-Caucasian). The experimental diets contained approximately 200 or 600 mg/d of cholesterol, 36-38% of calories as fat, and high or low proportions of saturated and polyunsaturated fat (polyunsaturated/saturated fat ratio approximately 0.8 vs 0.3). At the lower cholesterol intake, the high saturated fat diet had only a modest effect on LDL cholesterol in Caucasians (+ 6 mg/dl-1) and none in non-Caucasians. 600 mg cholesterol with high saturated fat led to a substantial mean increase in LDL cholesterol, which was significantly greater in Caucasian than in non-Caucasian subjects (+ 31 mg/dl vs 16 mg/dl, P < 0.005). 600 mg cholesterol with increased polyunsaturated fat gave a mean LDL increase of 16 mg/dl, lower than found when the same high cholesterol intake was coupled with increased saturated fat. Variation in cholesterol rather than the proportions of saturated and polyunsaturated fat had the most influence on LDL-cholesterol levels. Among non-Caucasians it was the only significant factor.
Human small cell lung cancer cell lines expressing the proopiomelanocortin gene have aberrant glucocorticoid receptor function.
Authors: D W Ray, A C Littlewood, A J Clark, J R Davis, A White
Journal: Journal of Clinical Investigation (1994)

Some human small cell lung carcinomas (SCLC) secrete proopiomelanocortin (POMC) derived peptides, but in contrast to the pituitary, glucocorticoids fail to inhibit this hormone production. We have previously described an in vitro model using human SCLC cell lines that express POMC and are resistant to glucocorticoids. We have now identified the glucocorticoid receptor (GR) in the SCLC cell line COR L24 using a whole cell ligand binding assay (Kd = 5.7 nM; Bmax = 11 fmol/million cells), while another cell line, DMS 79, lacked significant glucocorticoid binding. To analyze GR function both positive (GMCO) and negative (TRE)3-tkCAT), glucocorticoid-regulated reporter gene constructs were transfected into COR L24 cells. In the SCLC cell line, neither hydrocortisone nor dexamethasone (500-2,000 nM) significantly induced chloramphenicol acetyltransferase expression from GMCO; in addition, they did not suppress chloramphenicol acetyltransferase expression from (TRE)3-tkCAT. Similar results were obtained with two other POMC-expressing SCLC cell lines. Expression of wild type GR in COR L24 cells restored glucocorticoid signaling, with marked induction of GMCO reporter gene expression by dexamethasone (9,100 +/- 910%; n = 3), and an estimated EC50 of 10 nM. This failure of the GR explains the resistance of the POMC gene to glucocorticoid inhibition and may have implications for cell growth in SCLC.
Fibrinolytic Activity of Arterial Tissues
Authors: JACK LIEBERMAN, FREDERICK KELLOGG
Journal: Circulation Research (1961)

Arterial tissues were studied for plasminogen activator to demonstrate the possible relationship of its deficiency within the arterial wall to atherosclerosis. Activator was found primarily within the adventitia. The enzyme seemed to appear in fetuses at about the 2,000-Gm. stage of development. Different arteries showed varying activity, with the basilar artery showing least activity; the coronary and renal arteries showing the greatest activity; and the aortic arch; abdominal aorta, and pulmonary arteries falling between. The coronary arteries of females and the aortie arches of females under 60 years of age showed greater activity than those of comparable males. The degree of atherosclerotic in volvement of the coronahes or aorta could not be correlated with the level of plasminogen activator.