tbuckley/cabot-search huggingface dataset:
International Union of Pharmacology. XXXVI. Current Status of the Nomenclature for Receptors for Corticotropin-Releasing Factor and Their Ligands
Authors: Richard L. Hauger, Dimitri E. Grigoriadis, Mary F. Dallman, Paul M. Plotsky, Wylie W. Vale, Frank M. Dautzenberg
Journal: Pharmacological Reviews (2003)

Receptors for corticotropin-releasing factor (CRF) are members of a family of G protein-coupled receptors ("Family B") that respond to a variety of structurally dissimilar releasing factors, neuropeptides, and hormones (including secretin, growth hormone-releasing factor, calcitonin, parathyroid hormone, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal polypeptide) and signal through the cyclic AMP and/or calcium pathways. To date, three genes encoding additional CRF-like peptides (urocortins) have been identified in mammals. The urocortins and CRF bind with differential ligand selectivity at the two mammalian CRF receptors. This report was prepared by the International Union of Pharmacology Subcommittee on CRF Receptors, to summarize the current state of CRF receptor biology and to propose changes in the classification and nomenclature of CRF ligands and receptors.
Activation of Vascular Smooth Muscle Parathyroid Hormone Receptor Inhibits Wnt/β-Catenin Signaling and Aortic Fibrosis in Diabetic Arteriosclerosis
Authors: Su-Li Cheng, Jian-Su Shao, Linda R. Halstead, Kathryn Distelhorst, Oscar Sierra, Dwight A. Towler
Journal: Circulation Research (2010)

Vascular fibrosis and calcification contribute to diabetic arteriosclerosis, impairing Windkessel physiology necessary for distal tissue perfusion. Wnt family members, upregulated in arteries by the low-grade inflammation of "diabesity," stimulate type I collagen expression and osteogenic mineralization of mesenchymal progenitors via beta-catenin. Conversely, parathyroid hormone (PTH) inhibits aortic calcification in low-density lipoprotein receptor (LDLR)-deficient mice fed high fat diabetogenic diets (HFD).We sought to determine the impact of vascular PTH receptor (PTH1R) activity on arteriosclerotic Wnt/beta-catenin signaling in vitro and in vivo. We generated SM-caPTH1R transgenic mice, a model in which the constitutively active PTH1R variant H223R (caPTH1R) is expressed only in the vasculature.The caPTH1R inhibited Wnt/beta-catenin signaling, collagen production, and vascular smooth muscle cell proliferation and calcification in vitro. Transgenic SM-caPTH1R;LDLR(+/-) mice fed HFD develop diabesity, with no improvements in fasting serum glucose, cholesterol, weight, body composition, or bone mass versus LDLR(+/-) siblings. SM-caPTH1R downregulated aortic Col1A1, Runx2, and Nox1 expression without altering TNF, Msx2, Wnt7a/b, or Nox4. The SM-caPTH1R transgene decreased aortic beta-catenin protein accumulation and signaling in diabetic LDLR(+/-) mice. Levels of aortic superoxide (a precursor of peroxide that activates pro-matrix metalloproteinase 9 and osteogenic signaling in vascular smooth muscle cells) were suppressed by the SM-caPTH1R transgene. Aortic calcification, collagen accumulation, and wall thickness were concomitantly reduced, enhancing vessel distensibility.Cell-autonomous vascular smooth muscle cell PTH1R activity inhibits arteriosclerotic Wnt/beta-catenin signaling and reduces vascular oxidative stress, thus limiting aortic type I collagen and calcium accrual in diabetic LDLR-deficient mice.
Feasibility, Acceptability, and Predictive Validity of a Psychosocial Screening Program for Children and Youth Newly Diagnosed With Type 1 Diabetes
Authors: David D. Schwartz, Virginia Depp Cline, Marni E. Axelrad, Barbara J. Anderson
Journal: Diabetes Care (2011)

Psychosocial screening has been recommended for pediatric patients with newly diagnosed type 1 diabetes and their families. Our objective was to assess a psychosocial screening protocol in its feasibility, acceptability to families, and ability to predict early emerging complications, nonadherent family behavior, and use of preventive psychology services.A total of 125 patients and their caregivers were asked to participate in a standardized screening interview after admission at a large urban children's hospital with a new diagnosis of type 1 diabetes. Medical records were reviewed for subsequent diabetes-related emergency department (ED) admissions, missed diabetes clinic appointments, and psychology follow-up within 9 months of diagnosis.Of 125 families, 121 (96.8%) agreed to participate in the screening, and a subsample of 30 surveyed caregivers indicated high levels of satisfaction. Risk factors at diagnosis predicted subsequent ED admissions with a sensitivity of 100% and a specificity of 98.6%. Children from single-parent households with a history of behavior problems were nearly six times more likely to be seen in the ED after diagnosis. Missed appointments were likeliest among African Americans, 65% of whom missed at least one diabetes-related appointment. Psychology services for preventive intervention were underutilized, despite the high acceptability of the psychosocial screening.Psychosocial screening of newly diagnosed patients with type 1 diabetes is feasible, acceptable to families, and able to identify families at risk for early emerging complications and nonadherence. Challenges remain with regards to reimbursement and fostering follow-up for preventive care.
Does a population-based multifactorial lifestyle intervention increase social inequality in physical activity? The Inter99 study
Authors: M Aadahl, L von Huth Smith, U Toft, C Pisinger, T Jørgensen
Journal: British Journal of Sports Medicine (2009)

To examine the effect of a multifactorial lifestyle intervention on 5-year change in physical activity (PA) and to explore whether length of education had an impact on the effect of the intervention.Two random samples (high intervention group A, n=11 708; low intervention group B, n=1308) were invited for a health examination, assessment of absolute risk of ischemic heart disease and individual lifestyle counselling. The participation rate was 52.5%. High-risk individuals in group A were also offered group-based counselling on diet and PA and/or smoking cessation. High-risk individuals in group B were referred to usual care. All high-risk individuals were reinvited for examination and counselling after 1 and 3 years, and all participants were reexamined after 5 years. The control group (group C, n=5264, response rate 61.1%) answered a mailed questionnaire. Change in self-reported PA from baseline to 5-year follow-up was the main outcome. Level of education was classified as no vocational training, ≤4 years and >4 years. Data were analysed using longitudinal linear regression models with random intercepts.In men, the high-intensity intervention had a beneficial effect on PA level after 5 years. The age- or time-related decrease in PA was approximately 30 min/week less compared to men in the control group (p<0.0001). Level of education had no significant impact on the effect of the intervention neither in men (p=0.39) nor in women (p=0.32).A population-based multifactorial lifestyle intervention did not influence social inequality in PA.
Is Asthma Really Due to a Polarized T Cell Response Toward a Helper T Cell Type 2 Phenotype?
Authors: SUNDEEP S. SALVI, K. SURESH BABU, STEPHEN T. HOLGATE
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Our understanding of  pathogenesis has changed dramatically with time. Records, which date back to 1500 BC, indicate that  was considered to be a disease caused by spirits. This viewpoint remained until 1678, when Thomas Willis described  to be due to  of bronchi by thick humors, swelling of their walls and obstruction from without. That  was due to spasm of bronchial smooth muscles was first suggested by Sir John Floyer in 1698. With the advent of fiberoptic bronchoscopy in the 1970s and the use of modern molecular biology tools, it became clear that  was a chronic inflammatory disorder of the airways mediated by a multitude of cell types and inflammatory mediators. Mast cells and eosinophils were initially believed to play a central role in driving the airway inflammation associated with asthma; however, the emphasis has now shifted to T lymphocytes. In particular, helper T type 2 (Th2) cells (a subset of T cells) are believed to play a central role in initiating and orchestrating the asthmatic airway inflammatory response (1). The  hypothesis for asthma was first suggested by Mosmann in 1989 (2), who had earlier discovered the presence of two distinct subtypes of helper T cells in mice, namely, Th1 and Th2 (3). These two subclasses of helper T cells differ in their production of cytokines and are reciprocally inhibitory. The Th2 lymphocytes produce interleukin 4 (IL-4), IL-5, IL-9, and IL-13, which activate mechanisms important in defense against parasites and in allergic inflammation. Such mechanisms include IgE production, mast cell differentiation, and eosinophil growth, migration, and activation. Th1 lymphocytes produce interferon gamma (IFN-gamma ) and IL-2, which activate mechanisms important in defense against viruses and bacteria (2). A mechanism accounting for the predominance of Th2 cells in asthmatic airway was suggested by the discovery that the context in which antigen-presenting cells process and present allergens critically influences the pattern of helper T cell differentiation. The Th2 hypothesis for  describes that  is caused by a relative increase in Th2 cellular response in combination with a decrease in Th1 (helper T type 1) response. The consequent alteration in cytokine milieu (most likely in the lung), with excess Th2 products (e.g., IL-4, IL-5, and IL-13) in concert with decreased Th1 products (e.g., IFN-gamma and IL-12), is predicted to drive the  phenotype (4). Evidence of such a shift in the Th1/Th2 balance derives from studies of  in cellular and murine models, where Th cell polarization and allergen dependence of Th2 responses are most easily defined and from human studies that profile cytokine production. Although this viewpoint has remained popular over the last decade, more recent studies suggest that the Th2 hypothesis for  is too simplistic (5). We now provide evidence to argue against the Th2 hypothesis for asthma.
Linking the Cellular Functions of<i>BRCA</i>Genes to Cancer Pathogenesis and Treatment
Authors: Ashok R. Venkitaraman
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Single-gene disorders that predispose to cancer afford a unique window into the mechanisms of carcinogenesis. I argue that the instability in chromosome structure and number provoked by inactivation of the breast cancer–susceptibility genes BRCA1 and BRCA2 arises from the distinct functions served by their products in DNA repair or mitosis, explains many features of cancer pathogenesis in this setting, and has important implications for treatment. The chromosomal instability model proposed here suggests a conceptual framework for the connections between chromosomal aberrations and cancer.
Childhood lead poisoning: the torturous path from science to policy
Authors: D. C. Bellinger
Journal: Journal of Clinical Investigation (2006)

The long history of lead poisoning provides many lessons about the process by which scientific knowledge is translated into public health policy. In the United States, lead was added to paint and to gasoline in enormous quantities long after medical evidence clearly showed that excessive lead exposure caused considerable morbidity in the population. This article discusses some of the factors that contributed to the slow pace of efforts to address this problem, including the ubiquity and magnitude of lead exposure during much of the twentieth century, which produced a distorted notion about the blood lead level that can be considered "normal"; the prevailing model of disease during this period, notably the novelty of the concept of subclinical disease; the fact that childhood lead poisoning affected mostly families that were politically and economically disenfranchised, fostering a "blame the victim" attitude; and that controlling lead exposure would have impeded efforts to achieve other desirable goals, illustrating the role that value trade-offs often play in policy decisions.
Induction of the MMP-14 Gene in Macrophages of the Atherosclerotic Plaque
Authors: Bimal K. Ray, Arvind Shakya, James R. Turk, Suneel S. Apte, Alpana Ray
Journal: Circulation Research (2004)

Based on epidemiological and pathological studies, it is becoming increasingly clear that matrix metalloproteinases (MMPs) play an important role in the pathogenesis of atherosclerosis by participating in vascular remodeling, smooth muscle cell migration, and plaque disruption. MMP-14, because of its unique ability to cause pericellular degradation, its broad substrate specificity, its synthesis in an active form, and its ability to activate other matrix metalloproteinases, is recognized as a prominent member of this family. MMP-14 is detected at high levels in the atherosclerotic plaque. To understand the induction mechanism of MMP-14 under atherogenic conditions, we examined its expression pattern in response to oxidized low-density lipoproteins (ox-LDLs) that are believed to play an important role in atherogenesis. We report that in macrophages, ox-LDLs markedly elevate the levels of MMP-14 mRNA and protein. The cis-acting elements supporting this increase were identified to be present within -213 and -1 nucleotides of the MMP-14 promoter. DNase I protection assay revealed, within this region, two major elements, of which one serves as the DNA-binding site for SAF-1 transcription factor. Increased binding of SAF-1 to the MMP-14 promoter correlated with the transcriptional upregulation of MMP-14 gene. Furthermore, induction of endogenous MMP-14 gene, MMP-14 promoter driven reporter gene expression and MMP-2 processing activity during overexpression of SAF-1 and coexpression of SAF-1 and MMP-14 in the macrophages present in the atherosclerotic plaque implicate SAF-1 as a key regulator of MMP-14 gene induction in macrophage cells.
ADAMTS1 Contributes to the Acquisition of an Endothelial-like Phenotype in Plastic Tumor Cells
Authors: Carmen Casal, Antoni Xavier Torres-Collado, María del Carmen Plaza-Calonge, Estefanía Martino-Echarri, Santiago Ramón y Cajal, Federico Rojo, Arjan W. Griffioen, Juan Carlos Rodríguez-Manzaneque
Journal: Cancer Research (2010)

Cancer stem cells have been hypothesized to explain tumor plasticity, including the capability to adopt distinct differentiation commitments. Among the mechanisms of tumor neovascularization, the ability of some malignant cells to mimic an endothelial phenotype has been recognized by a capacity to form matrix-enriched pseudovascular structures. In addition to the expression of genes associated with an endothelial nature, the molecular dynamism of specific microenvironments may also be critical. Here, we report the identification of the extracellular protease ADAMTS1 as a critical molecule for tumor cells to acquire endothelial-like properties. In a fibrosarcoma model, ADAMTS1 increased tumor growth rate in an angiogenesis-independent manner, influencing the tumor cells to display an exclusive endothelial-like gene signature. We documented the relevant expression of ADAMTS1 in aggressive and highly plastic melanoma and Ewing sarcoma cells. Notably, inhibiting ADAMTS1 action compromised the endothelial mimetic attributes observed in this setting. Our findings provide insights into how the tumor microenvironment can elicit endothelial mimicry by tumor cells.
THE FLUCTUATION OF INSANITY IN CONNECTICUT AS SHOWN BY A STUDY OF CASES ADMITTED TO THE CONNECTICUT HOSPITAL FOR INSANE
Authors: Rollin H. Burr
Journal: American Journal of Psychiatry (1903)

A study of the histories of seven thousand six hundred and fifty-seven cases of insanity covering a period of thirty-two years may be summarized briefly in the following general observations: (1) The ratio of the insane to the general population is much larger than most statisticians have estimated it to be, but the increase in the proportion of the insane is very much smaller than has been determined heretofore. (2) The foreign element of our community shows much the larger proportion of insane than does the native. The native insane, however, have increased to a considerable extent, but not in the same proportion as the foreign insane. (3) The cities show a much larger percentage of the insane than do the counties, but the counties show an increasing proportion of insane in the later years. (4) We have also seen that the large proportion coming from the cities is due to the larger percentage of the foreign element in the city, also that with increase of the foreign element in the country there is an increase in the insane. (5) The Irish show the largest percentage of the insane. The Germans are next in proportion. The native Americans show the least insane to population. In general the middle period (1880-1890) shows the largest proportion of the foreign insane. (6) In proportion to population, the Irish lead all other nationalities in the production of insanity. (7) The cities, as a whole, send much larger numbers of foreign insane in proportion to the population than the counties. (8) As compared with the whole State, Hartford and New Haven have larger proportions of foreign insane than the cities as a whole over the counties of the State. (9) Fairfield, Litchfield and Windham counties show the lowest proportion of native insane. I have to acknowledge the hearty cooperation of Dr. Allen R. Diefendorf, psychiatrist and pathologist at the Connecticut Hospital for the Insane, who has given much time to the supervision and criticism of the work. I am also greatly indebted to Dr. Charles W. Page, former Superintendent of the Institution, for many privileges granted. To these and to all others, who by criticism and suggestion have aided in the work and especially to those who have helped in the laborious collaboration of the tables which have made this work possible, I am exceedingly grateful.
CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells.
Authors: P J Morrissey, K Charrier, S Braddy, D Liggitt, J D Watson
Journal: The Journal of Experimental Medicine (1993)

Purified CD4+ lymph node T cells were sorted into two populations on the basis of their expression of CD45RB (CD45RBhi and CD45RBlo) and injected into congenic severe combined immunodeficient (SCID) mice. After a period of time that was dependent on the number of cells injected, the SCID mice that received CD45RBhi/CD4+ T cells developed a wasting disease that was not seen in SCID mice that received the CD4+/CD45RBlo cells or whole lymph node cells. At death, SCID mice that received the CD4+/CD45RBhi cells had increased spleen and lymph node cellularity compared with normal SCID mice and SCID mice that received the CD4+/CD45RBlo T cells. The spleen and lymph node contained CD4+ cells and neither CD8+ nor surface immunoglobulin M-positive cells, plus a population of cells that did not express any of those markers. At necropsy, the SCID mice that received the CD4+/CD45RBhi cells had significant hyperplasia of the intestinal mucosa with significant lymphoid cell accumulation in the lamina propria. Interestingly, mice that received mixtures of whole lymph node or purified CD4+ cells with CD4+/CD45RBhi cells did not develop weight loss, indicating that the unseparated CD4+ population contained cells that were capable of regulating the reactivity of the CD4+/CD45RBhi cells.
Early and Late Therapy Response Assessment With [<sup>18</sup>F]Fluorodeoxyglucose Positron Emission Tomography in Pediatric Hodgkin's Lymphoma: Analysis of a Prospective Multicenter Trial
Authors: Christian Furth, Ingo G. Steffen, Holger Amthauer, Juri Ruf, Daniel Misch, Stefan Schönberger, Carsten Kobe, Timm Denecke, Brigitte Stöver, Hubertus Hautzel, Günter Henze, Patrick Hundsdoerfer
Journal: Journal of Clinical Oncology (2009)

Purpose In adult Hodgkin's lymphoma (HL) risk stratification after early therapy response assessment with [ 18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET) seems to allow tailoring therapy with less toxicity for patients with adequate metabolic response. This study delivers the first prospective data on the potential of FDG-PET for response assessment in pediatric HL. Patients and Methods FDG-PET was performed in 40 pediatric HL patients before polychemotherapy (PET-1), after two cycles of polychemotherapy (PET-2), and after completion of polychemotherapy (PET-3). Mean follow-up was 46 months (range, 26 to 72 months). Results At early and late response assessment, the proportion of PET-negative patients was significantly higher compared with those patients with negative findings in conventional imaging methods (CIMs; PET-2, 26 of 40 v CIM-2, one of 40; P &lt; .001; PET-3, 21 of 29 v CIM-3, four of 29; P &lt; .001). Sensitivity and negative predictive value were 100% for early and late therapy response assessment by PET. Both patients suffering a relapse during follow-up were identified by PET-2/3, whereas one of these patients was not detected by CIM-3. PET was superior to CIMs with regard to specificity in early and late therapy response assessment (68% v 3%, and 78% v 11%, respectively; both P &lt; .001). Specificity of early therapy response assessment by PET was improved to 97% by quantitative analysis of maximal standardized uptake value reduction using a cutoff value of 58%. Conclusion Pediatric HL patients with a negative PET in response assessment have an excellent prognosis while PET-positive patients have an increased risk for relapse.
DDX5 Regulates DNA Replication and Is Required for Cell Proliferation in a Subset of Breast Cancer Cells
Authors: Anthony Mazurek, Weijun Luo, Alexander Krasnitz, James Hicks, R. Scott Powers, Bruce Stillman
Journal: Cancer Discovery (2012)

Understanding factors required for DNA replication will enrich our knowledge of this important process and potentially identify vulnerabilities that can be exploited in cancer therapy. We applied an assay that measures the stability of maintenance of an episomal plasmid in human tissue culture cells to screen for new DNA replication factors. We identify an important role for DDX5 in G(1)-S-phase progression where it directly regulates DNA replication factor expression by promoting the recruitment of RNA polymerase II to E2F-regulated gene promoters. We find that the DDX5 locus is frequently amplified in breast cancer and that breast cancer-derived cells with amplification of DDX5 are much more sensitive to its depletion than breast cancer cells and a breast epithelial cell line that lacks DDX5 amplification. Our results show a novel role for DDX5 in cancer cell proliferation and suggest DDX5 as a therapeutic target in breast cancer treatment.DDX5 is required for cell proliferation by controlling the transcription of genes expressing DNA replication proteins in cancer cells in which the DDX5 locus is amplified, and this has uncovered a dependence on DDX5 for cell proliferation. Given the high frequency of DDX5 amplification in breast cancer, our results highlight DDX5 as a promising candidate for targeted therapy of breast tumors with DDX5 amplification, and indeed we show that DDX5 inhibition sensitizes a subset of breast cancer cells to trastuzumab.
An Introduction to Medical Genetics.
Journal: Annals of Internal Medicine (1979)

A major revision of this text. Since the previous edition was published, there have been substantial advances in understanding of the scientific basis of human genetics, and clinical genetics has finally emerged as a separate clinical specialty. The book retains its distinctive system of numbered sections. There are 162 of which 33 are completely new and 47 are very substantially rewritten. Previous editions have gained a reputation for simple exposition of complex and difficult subjects. In this revision Dr Pembrey has made every effort to carry on this tradition.