tbuckley/cabot-search huggingface dataset:
Accelerated Bone Resorption, Due to Dietary Calcium Deficiency, Promotes Breast Cancer Tumor Growth in Bone
Authors: Yu Zheng, Hong Zhou, James R.K. Modzelewski, Robert Kalak, Julie M. Blair, Markus J. Seibel, Colin R. Dunstan
Journal: Cancer Research (2007)

The skeleton is a major site of breast cancer metastases. High bone turnover increases risk of disease progression and death. However, there is no direct evidence that high bone turnover is causally associated with the establishment and progression of metastases. In this study, we investigate the effects of high bone turnover in a model of breast cancer growth in bone. Female nude mice commenced a diet containing normal (0.6%; 'Normal-Ca') or low (0.1%; 'Low-Ca') calcium content. Mice were concurrently treated with vehicle or osteoprotegerin (1 mg/kg/d s.c; n = 16 per group). Three days later (day 0), 50,000 Tx-SA cells (variant of MDA-MB-231 cells) were implanted by intratibial injection. On day 0, mice receiving Low-Ca had increased serum parathyroid hormone (PTH) and tartrate-resistant acid phosphatase 5b levels, indicating secondary hyperparathyroidism and high bone turnover, which was maintained until day 17. Osteoprotegerin increased serum PTH but profoundly reduced bone resorption. On day 17, in mice receiving Low-Ca alone, lytic lesion area, tumor area, and cancer cell proliferation increased by 43%, 24%, and 24%, respectively, compared with mice receiving Normal Ca (P < 0.01). Osteoprotegerin treatment completely inhibited lytic lesions, reduced tumor area, decreased cancer cell proliferation, and increased cancer cell apoptosis. Increased bone turnover, due to dietary calcium deficiency, promotes tumor growth in bone, independent of the action of PTH. Breast cancer patients frequently have low dietary calcium intake and high bone turnover. Treatment to correct calcium insufficiency and/or treatment with antiresorptive agents, such as osteoprotegerin, may be of benefit in the adjuvant as well as palliative setting.
Risk Assessment of Tuberculosis in Contacts by IFN-γ Release Assays. A Tuberculosis Network European Trials Group Study
Authors: Jean-Pierre Zellweger, Giovanni Sotgiu, Michael Block, Simone Dore, Neus Altet, Rebecca Blunschi, Matthias Bogyi, Graham Bothamley, Christina Bothe, Luigi Codecasa, Patrizia Costa, Jose Dominguez, Raquel Duarte, Andreas Fløe, Isabelle Fresard, José-María García-García, Delia Goletti, Petra Halm, Doris Hellwig, Eveline Henninger, Helga Heykes-Uden, Liane Horn, Katarzyna Kruczak, Irene Latorre, Geneviève Pache, Heidrun Rath, Felix C. Ringshausen, Asunción Seminario Ruiz, Ivan Solovic, Maria-Luiza de Souza-Galvão, Ursula Widmer, Peter Witte, Christoph Lange
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Latent infection with Mycobacterium tuberculosis is defined by a positive IFN-γ release assay (IGRA) result in the absence of active tuberculosis. Only few, mostly monocentric studies have evaluated the role of IGRAs to predict the development of tuberculosis in recent contacts in low-incidence countries of tuberculosis.To analyze IGRA results and the effect of preventive chemotherapy on tuberculosis progression rates among recent contacts.Results from contact investigations at 26 centers in 10 European countries including testing for latent infection with M. tuberculosis by the QuantiFERON-TB Gold In-Tube (QFT) test or the T-SPOT.TB (TSPOT) were prospectively collected and analyzed.Among 5,020 contacts of 1,023 index cases, 25 prevalent secondary cases were identified at screening. Twenty-four incident cases occurred among 4,513 contacts during 12,326 years of cumulative follow-up. In those with a positive IGRA result, tuberculosis incidence was 0.2 (QFT) and 0 (TSPOT) per 100 patient-years when contacts received preventive chemotherapy versus 1.2 (QFT) and 0.8 (TSPOT) per 100 patient-years in those not treated (38 and 37 patients needed to be treated to prevent one case, respectively). Positive and negative predictive values were 1.9% (95% confidence interval [CI], 1.1-3.0) and 99.9% (95% CI, 99.7-100) for the QFT and 0.7% (95% CI, 0.1-2.6) and 99.7% (95% CI, 99.1-99.9) for the TSPOT.Tuberculosis rarely developed among contacts, and preventive chemotherapy effectively reduced the tuberculosis risk among IGRA-positive contacts. Although the negative predictive value of IGRAs is high, the risk for the development of tuberculosis is poorly predicted by these assays.
Circulating catecholamine levels in human and experimental hypertension.
Authors: J de Champlain, L Farley, D Cousineau, M R van Ameringen
Journal: Circulation Research (1976)

The radiometric enzymatic technique of Coyle and Henry (J. Neurochem. 21: 61-67, 1973) was adapted to the measurement of serum catecholamines. This technique requires less time than other enzymatic techniques and is sensitive to quantities as small as 25 pg. In normotensive subjects lying supine for 20 minutes serum catecholamine levels averaged 0.218 ng/ml, with no obvious sex or age difference. Under these standardized conditions, the circulating catecholamine levels for a given individual are highly reproducible on different days over a period of several months. In 22 patients with essential hypertension, circulating levels were significantly higher, with an average of 0.370 ng/ml. More than 50% of the hypertensive patients had values greater than the highest value measured in normotensives. Systolic blood pressure and heart rate were significantly higher in the hypertensive group with elevated levels of circulating catecholamines than in the hypertensive group with normal levels. In one model of experimental hypertension, produced in the rat by administration of deoxycorticosterone acetate (DOCA) and saline for 4-8 weeks, serum catecholamines were significantly elevated. These findings suggest that the sympathetic system may play an important role in maintaining an elevated blood pressure in experimental hypertension and in a significant proportion of patients with essential hypertension.
Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement
Authors: M A Dimopoulos, A Palumbo, M Attal, M Beksaç, F E Davies, M Delforge, H Einsele, R Hajek, J-L Harousseau, F Leal da Costa, H Ludwig, U-H Mellqvist, G J Morgan, J F San-Miguel, S Zweegman, P Sonneveld
Journal: Leukemia (2011)
Leukotriene D4 induces gene expression in human monocytes through cysteinyl leukotriene type I receptor
Authors: Grzegorz Woszczek, Li-Yuan Chen, Sahrudaya Nagineni, Steven Kern, Jennifer Barb, Peter J. Munson, Carolea Logun, Robert L. Danner, James H. Shelhamer
Journal: Journal of Allergy and Clinical Immunology (2007)
Potassium Citrate and Potassium Gluconate Versus Potassium Chloride
Authors: Scott J. Boley
Journal: JAMA (1967)

IN LATE 1964 a sudden increase in the occurrence of circumferential ulcerating, stenosing lesions of the small bowel was noted both in Europe and the United States. Lindholmer et al<sup>1</sup>in Sweden and Baker et al<sup>2</sup>in this country first suggested the association of these lesions with enteri-coated thiazide diuretic potassium chloride preparations. Extensive experimental and clinical investigations<sup>3-6</sup>quickly identified enteric-coated potassium chloride as the responsible agent, and led to recognition of perforating areas of necrosis as a more severe form of the same lesion. The mechanism of damage is believed to be the release and absorption of high concentrations of potassium chloride over short segments of small bowel acting upon submucosal and mural veins to produce venous spasm or paralysis. The resultant venous stasis causes segmental hemorrhagic infarction of varying severity with ulceration and stenosis.<sup>7</sup> Recognition of this complication of enteric-coated potassium chloride ingestion has
Liverpool care pathway: doctors speak out
Authors: Adrian O'Dowd
Journal: BMJ (2012)

<b>Study objectives:</b> Depression and falls are two common conditions that impair the health of older people. Both are relatively underdiagnosed and undertreated problems in primary care. The study objective was to investigate whether there was a common set of risk factors that could predict an increased risk of both falls and depression. <b>Design:</b> This was a cohort study drawn from a primary care clinic, with a one year follow up. Dependent measures included: reporting two or more falls in the past year and a score of 7 or over on the S-GDS (Short Geriatric Depression Scale). A parsimonious set of risk factors was selected that predicted both outcomes based on a series of discriminant function analyses. <b>Participants and setting:</b> The setting was a primary care clinic serving a mixed socioeconomic population, in Beer Sheva, Israel. The sample included 283 General Sick Fund members, aged 60 and over, who completed both baseline assessments and one year follow up interviews. <b>Main results:</b> At the one year follow up, 12% of the sample reported frequent falls in the past year and 25.5% of the sample screened positive for depressive symptoms. A set of five risk factors that included: poor self rated health, poor cognitive status, impaired ADL, two or more clinic visits in the past month, and slow walking speed (g10 seconds over five metres) was successful at discriminating between fallers and non-fallers (86% discrimination) and between those with and without depressive symptoms (76%). For every risk factor added, there was a significant increase in the proportion of respondents who had depressive symptoms. A similar result was found for falls. <b>Conclusions:</b> These results show that there is a common set of risk factors that increase the risk of two common outcomes in geriatric medicine, falls and depression. For a general practitioner or a geriatric physician, it might be easier to detect these risk factors than to diagnose depression or high risk for falls. When these risk factors are detected in patients the physician can then be more active in direct probing about depression and falls.
Dysregulated Expression of Adamalysin-Thrombospondin Genes in Human Breast Carcinoma
Authors: Sarah Porter, Stuart D. Scott, Elaine M. Sassoon, Mark R. Williams, J. Louise Jones, Anne C. Girling, Richard Y. Ball, Dylan R. Edwards
Journal: Clinical Cancer Research (2004)

Abstract The adamalysin-thrombospondin (ADAMTS) proteinases are a relatively newly described branch of the metzincin family that contain metalloproteinase, disintegrin, and thrombospondin motifs. They have been implicated in various cellular events, including cleavage of proteoglycans, extracellular matrix degradation, inhibition of angiogenesis, gonadal development, and organogenesis. However, in many cases, their normal physiological roles and their potential for dysregulation in malignancy remain to be established. The expression profile of ADAMTS1–20 in human breast carcinoma was undertaken by real-time PCR using RNA isolated from malignant tumors, nonneoplastic mammary tissue, and breast cancer cell lines to identify altered regulation that may have potential pathogenetic and prognostic significance. Our studies show that seven of the ADAMTS genes (ADAMTS1, 3, 5, 8, 9, 10, and 18) are consistently down-regulated in breast carcinomas with respect to nonneoplastic mammary tissue, irrespective of the heterogeneity of the samples and the tumor type or grade (Mann-Whitney U test, P &amp;lt; 0.0001 for each gene). Conversely, ADAMTS4, 6, 14, and 20 are consistently up-regulated in breast carcinomas (P = 0.005, P &amp;lt; 0.0001, P = 0.003, and P = 0.001, respectively). ADAMTS2, 7, 12, 13, 15, 16, 17, and 19 show no significant difference between the sample types. ADAMTS1, 2, 7, 8, 10, and 12 are expressed predominantly in stromal fibroblasts. ADAMTS3, 4, 5, 6, 9, and 13–20 inclusive are expressed predominantly in myoepithelial cells; all appear to be relatively poorly expressed in luminal epithelial cells. ADAMTS15 has emerged as being an independent predictor of survival, with RNA expression levels significantly lower (P = 0.007) in grade 3 breast carcinoma compared with grade 1 and 2 breast carcinoma.
Predicting Posttraumatic Distress in Hospitalized Trauma Survivors With Acute Injuries
Authors: Douglas F Zatzick, Sun-Mee Kang, Hans-Georg Müller, Joan E Russo, Frederick P Rivara, Wayne Katon, Gregory J Jurkovich, Peter Roy-Byrne
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Each year approximately 2.5 million Americans are hospitalized after sustaining traumatic physical injuries. Few investigations have comprehensively screened for posttraumatic symptomatic distress or identified predictors of posttraumatic stress disorder (PTSD) in representative samples of surgical inpatients. METHOD: The subjects were 101 randomly selected survivors of motor vehicle crashes or assaults who were interviewed while hospitalized and 1, 4, and 12 months after injury. In the surgical ward, inpatients were screened for PTSD, depressive, and dissociative symptoms, for prior trauma, for pre-event functioning, and for alcohol and drug intoxication. Patient demographic and injury characteristics were also recorded. Random coefficient regression models were used to assess the association between these clinical, injury, and demographic characteristics and PTSD symptom levels over the year after the injury. RESULTS: Of the 101 surgical inpatients, 73% screened positive for high levels of symptomatic distress and/or substance intoxication. At 1, 4, and 12 months after the injury, 30%–40% reported symptoms consistent with a diagnosis of PTSD. High ward PTSD symptom levels were the strongest and most parsimonious predictor of persistent symptoms over the course of the year. Greater prior trauma, stimulant intoxication, and female gender were also associated with higher symptom levels. Increasing injury severity, however, was not associated with higher PTSD symptom levels. CONCLUSIONS: Clinical and demographic characteristics readily identifiable at the time of surgical inpatient hospitalization predict PTSD symptoms over the year after injury. Effectiveness trials that test screening and intervention procedures for at-risk inpatients should be developed.
MicroRNA-214 Antagonism Protects against Renal Fibrosis
Authors: Laura Denby, Vasudev Ramdas, Ruifang Lu, Bryan R. Conway, Jennifer S. Grant, Brent Dickinson, Arin B. Aurora, John D. McClure, David Kipgen, Christian Delles, Eva van Rooij, Andrew H. Baker
Journal: Journal of the American Society of Nephrology (2013)

Renal tubulointerstitial fibrosis is the common end point of progressive renal disease. MicroRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the function of miR-214 in this setting and the effect of its manipulation remain unknown. We assessed the effect of inhibiting miR-214 in an animal model of renal fibrosis. In mice, genetic deletion of miR-214 significantly attenuated interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects, and in vivo biodistribution studies demonstrated that anti-miR-214 accumulated at the highest levels in the kidney. Notably, in vivo inhibition of canonical TGF-β signaling did not alter the regulation of endogenous miR-214 or miR-21. Whereas miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, suggesting that miR-214 induces antifibrotic effects independent of Smad 2/3. Furthermore, TGF-β blockade combined with miR-214 deletion afforded additional renal protection. These phenotypic effects of miR-214 depletion were mediated through broad regulation of the transcriptional response to injury, as evidenced by microarray analysis. In human kidney tissue, miR-214 was detected in cells of the glomerulus and tubules as well as in infiltrating immune cells in diseased tissue. These studies demonstrate that miR-214 functions to promote fibrosis in renal injury independent of TGF-β signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney.
Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice
Authors: Ela Karshovska, Zhen Zhao, Xavier Blanchet, Martin M.N. Schmitt, Kiril Bidzhekov, Oliver Soehnlein, Philipp von Hundelshausen, Nadine J. Mattheij, Judith M.E.M. Cosemans, Remco T.A. Megens, Thomas A. Koeppel, Andreas Schober, Tilman M. Hackeng, Christian Weber, Rory R. Koenen
Journal: Circulation Research (2014)

Besides their essential role in hemostasis, platelets also have functions in inflammation. In platelets, junctional adhesion molecule (JAM)-A was previously identified as an inhibitor of integrin αIIbβ3-mediated outside-in signaling and its genetic knockdown resulted in hyperreactivity.This gain-of-function was specifically exploited to investigate the role of platelet hyperreactivity in plaque development.JAM-A-deficient platelets showed increased aggregation and cellular and sarcoma tyrosine-protein kinase activation. On αIIbβ3 ligation, JAM-A was shown to be dephosphorylated, which could be prevented by protein tyrosine phosphatase nonreceptor type 1 inhibition. Mice with or without platelet-specific (tr)JAM-A-deficiency in an apolipoprotein e (apoe(-/-)) background were fed a high-fat diet. After ≤12 weeks of diet, trJAM-A(-/-)apoe-/- mice showed increased aortic plaque formation when compared with trJAM-A(+/+) apoe(-/-) controls, and these differences were most evident at early time points. At 2 weeks, the plaques of the trJAM-A(-/-) apoe(-/-) animals revealed increased macrophage, T cell, and smooth muscle cell content. Interestingly, plasma levels of chemokines CC chemokine ligand 5 and CXC-chemokine ligand 4 were increased in the trJAM-A(-/-) apoe(-/-)mice, and JAM-A-deficient platelets showed increased binding to monocytes and neutrophils. Whole-blood perfusion experiments and intravital microscopy revealed increased recruitment of platelets and monocytes to the inflamed endothelium in blood of trJAM-A(-/-) apoe(-/-)mice. Notably, these proinflammatory effects of JAM-A-deficient platelets could be abolished by the inhibition of αIIbβ3 signaling in vitro.Deletion of JAM-A causes a gain-of-function in platelets, with lower activation thresholds and increased inflammatory activities. This leads to an increase of plaque formation, particularly in early stages of the disease.
Impact of Immediate Primary Lung Allograft Dysfunction on Bronchiolitis Obliterans Syndrome
Authors: Shiraz A. Daud, Roger D. Yusen, Bryan F. Meyers, Murali M. Chakinala, Michael J. Walter, Aviva A. Aloush, G. Alexander Patterson, Elbert P. Trulock, Ramsey R. Hachem
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Primary graft dysfunction is a common complication after lung transplantation and a significant risk factor for short- and long-term mortality.We examined the impact of primary graft dysfunction on bronchiolitis obliterans syndrome.We performed a retrospective cohort study of 334 adult lung transplant recipients at our program and graded the severity of primary graft dysfunction according to the International Society for Heart and Lung Transplantation definition. We evaluated the impact of primary graft dysfunction on acute rejection, lymphocytic bronchitis, and bronchiolitis obliterans syndrome stage 1, using univariable and multivariable Cox proportional hazards models.Among the 334 recipients, 65 did not have primary graft dysfunction (grade 0), 130 had grade 1, 69 had grade 2, and 70 had grade 3. In the univariable analysis, all grades of primary graft dysfunction were associated with a significantly increased risk of bronchiolitis obliterans syndrome stage 1 (grade 1: relative risk [RR] = 1.73; grade 2: RR = 2.13; and grade 3: RR = 2.53, compared with grade 0). The multivariable model demonstrated that the increased risk of bronchiolitis obliterans syndrome associated with primary graft dysfunction was independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections. However, there was no association between primary graft dysfunction and acute rejection or lymphocytic bronchitis.Primary graft dysfunction is associated with an increased risk of bronchiolitis obliterans syndrome independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections, and this risk is directly related to the severity of primary graft dysfunction.
Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease
Authors: Scot J. Matkovich, Derek J. Van Booven, Anna Hindes, Min Young Kang, Todd E. Druley, Francesco L.M. Vallania, Robi D. Mitra, Muredach P. Reilly, Thomas P. Cappola, Gerald W. Dorn
Journal: Journal of Clinical Investigation (2009)

Sporadic heart failure is thought to have a genetic component, but the contributing genetic events are poorly defined. Here, we used ultra-high-throughput resequencing of pooled DNAs to identify SNPs in 4 biologically relevant cardiac signaling genes, and then examined the association between allelic variants and incidence of sporadic heart failure in 2 large Caucasian populations. Resequencing of DNA pools, each containing DNA from approximately 100 individuals, was rapid, accurate, and highly sensitive for identifying common and rare SNPs; it also had striking advantages in time and cost efficiencies over individual resequencing using conventional Sanger methods. In 2,606 individuals examined, we identified a total of 129 separate SNPs in the 4 cardiac signaling genes, including 23 nonsynonymous SNPs that we believe to be novel. Comparison of allele frequencies between 625 Caucasian nonaffected controls and 1,117 Caucasian individuals with systolic heart failure revealed 12 SNPs in the cardiovascular heat shock protein gene HSPB7 with greater proportional representation in the systolic heart failure group; all 12 SNPs were confirmed in an independent replication study. These SNPs were found to be in tight linkage disequilibrium, likely reflecting a single genetic event, but none altered amino acid sequence. These results establish the power and applicability of pooled resequencing for comparative SNP association analysis of target subgenomes in large populations and identify an association between multiple HSPB7 polymorphisms and heart failure.
Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing
Authors: Marco Gerlinger, Andrew J. Rowan, Stuart Horswell, James Larkin, David Endesfelder, Eva Gronroos, Pierre Martinez, Nicholas Matthews, Aengus Stewart, Patrick Tarpey, Ignacio Varela, Benjamin Phillimore, Sharmin Begum, Neil Q. McDonald, Adam Butler, David Jones, Keiran Raine, Calli Latimer, Claudio R. Santos, Mahrokh Nohadani, Aron C. Eklund, Bradley Spencer-Dene, Graham Clark, Lisa Pickering, Gordon Stamp, Martin Gore, Zoltan Szallasi, Julian Downward, P. Andrew Futreal, Charles Swanton
Journal: New England Journal of Medicine (2012)

Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.