tbuckley/cabot-search huggingface dataset:
Nm23-H1 Suppresses Metastasis by Inhibiting Expression of the Lysophosphatidic Acid Receptor <i>EDG2</i>
Authors: Christine E. Horak, Arnulfo Mendoza, Eleazar Vega-Valle, Mary Albaugh, Cari Graff-Cherry, William G. McDermott, Emily Hua, Maria J. Merino, Seth M. Steinberg, Chand Khanna, Patricia S. Steeg
Journal: Cancer Research (2007)

Abstract Nm23-H1 transcriptionally down-regulates expression of the lysophosphatidic acid receptor EDG2 and this down-regulation is critical for Nm23-H1–mediated motility suppression in vitro. We investigated the effect of altered EDG2 expression on Nm23-H1–mediated metastasis suppression in vivo. Clonal MDA-MB-435–derived tumor cell lines transfected with Nm23-H1 together with either a vector control or EDG2 had similar anchorage-dependent and anchorage-independent growth rates in vitro. However, a 45- and 300-fold inhibition of motility and invasion (P &amp;lt; 0.0001), respectively, was observed in Nm23-H1/vector lines, whereas coexpression of EDG2 restored activity to levels observed in the parental line. Using fluorescently labeled cells and ex vivo microscopy, the capacity of these cells to adhere, arrest, extravasate, and survive in the murine lung over a 24-h time course was measured. Only 5% of Nm23-H1/vector–transfected cells were retained in the murine lung 6 h following tail vein injection; coexpression of EDG2 enhanced retention 8- to 13-fold (P &amp;lt; 0.01). In a spontaneous metastasis assay, the primary tumor size of Nm23-H1/vector and Nm23-H1/EDG2 clones was not significantly different. However, restoration of EDG2 expression augmented the incidence of pulmonary metastasis from 51.9% to 90.4% (P = 2.4 × 10−5), comparable with parental MDA-MB-435 cells. To determine the relevance of this model system to human breast cancer, a cohort of breast carcinomas was stained for Nm23-H1 and EDG2 and a statistically significant inverse correlation between these two proteins was revealed (r = −0.73; P = 0.004). The data indicate that Nm23-H1 down-regulation of EDG2 is functionally important to suppression of tumor metastasis. [Cancer Res 2007;67(24):11751–9]
Exaggerated Blood Pressure Responses During Mental Stress Are Prospectively Related to Enhanced Carotid Atherosclerosis in Middle-Aged Finnish Men
Authors: J. Richard Jennings, Thomas W. Kamarck, Susan A. Everson-Rose, George A. Kaplan, Stephen B. Manuck, J.T. Salonen
Journal: Circulation (2004)

Hemodynamic reactions to mental stress may contribute to atherosclerosis. We previously observed cross-sectional relationships between blood pressure reactions to a standardized stress battery and carotid intima-media thickness (IMT) in the Kuopio Ischemic Heart Disease (KIHD) study. These are the first prospective results on this relationship.Men from 4 age cohorts (42 to 60 years old at study onset) were challenged with a standardized mental stress battery, and heart rate and blood pressure reactions were assessed. Ultrasound measures of common carotid IMT were collected at this time and 7 years later as noninvasive markers of atherosclerosis. Data were collected from a sample of 756 men at both times. Systolic blood pressure reactions to mental stress at study onset were positively related to mean carotid IMT 7 years later (beta=0.035, P=0.001, by blood pressure quartile, IMT=0.91, 0.93, 0.96, 1.00 mm) and to the progression of IMT (beta=0.020, P=0.006, by blood pressure quartile, DeltaIMT=0.08, 0.09, 0.11, 0.11 mm). Similar significant relations were shown for maximal IMT and plaque height. Diastolic blood pressure responses were less strongly related to carotid IMT than were systolic responses. Heart-rate responses were unrelated. Adjustment for standard risk factors did not substantially reduce the relation between systolic blood pressure reactivity and the progression of mean carotid IMT (standardized beta=0.059, P=0.026), maximal carotid IMT (standardized beta=0.084, P=0.006), or plaque height (standardized beta=0.093, P=0.008).The degree of systolic blood pressure reactivity to mental challenge is prospectively related to carotid IMT in middle-aged and older men, independent of known risk factors.
p44 Mitogen-Activated Protein Kinase (Extracellular Signal-Regulated Kinase 1)–Dependent Signaling Contributes to Epithelial Skin Carcinogenesis
Authors: Christine Bourcier, Arnaud Jacquel, Jochen Hess, Isabelle Peyrottes, Peter Angel, Paul Hofman, Patrick Auberger, Jacques Pouysségur, Gilles Pagès
Journal: Cancer Research (2006)

Abstract Extracellular signal-regulated kinases (ERK) regulate cellular functions in response to a variety of external signals. However, the specific functions of individual ERK isoforms are largely unknown. Hence, we have investigated the specific function of ERK1 in skin homeostasis and tumorigenesis in ERK1 knockout mice. They spontaneously develop cutaneous lesions and hyperkeratosis with epidermis thickness. Skin hyperproliferation and inflammation induced by application of 12-O-tetradecanoylphorbol-13-acetate (TPA) is strongly reduced in mutant mice. ERK1−/− mice are resistant to development of skin papillomas induced by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by TPA. Tumor appearance was delayed, their formation was less frequent, and their number and size were reduced. Keratinocytes obtained from knockout mice showed reduced growth and resistance to apoptotic signals, accompanied by an impaired expression of genes implicated in growth control and invasiveness. These results highlight the importance of ERK1 in skin homeostasis and in the process of skin tumor development. (Cancer Res 2006; 66(5): 2700-7)
Stress and Vulnerability to Posttraumatic Stress Disorder in Children and Adolescents
Authors: R R Silva, M Alpert, D M Munoz, S Singh, F Matzner, S Dummit
Journal: American Journal of Psychiatry (2000)

This study examined the experiential factors and interacting vulnerabilities that contribute to the development of posttraumatic stress disorder (PTSD) in children and adolescents.Of 100 consecutive referrals to an inner-city child and adolescent psychiatry clinic, 59 had experienced a trauma that qualified as a precipitant of PTSD. For those with trauma, ages ranged from 3 to 18 years (mean=9.9, SD=4.10); 39 (66%) were males. The authors used a series of multiple regression analyses to examine the contribution of demographic characteristics, the nature of the stressor(s), and the role of preexisting clinical signs in the development of PTSD.Twenty-two percent of the 59 children who had been traumatized met full criteria for PTSD, 32% had some symptoms of PTSD but did not meet full criteria, and 46% had no symptoms of PTSD. Witnessing domestic violence or being physically abused predicted severity of PTSD. Children with preexisting aggressive behavior were more likely to be victims of physical abuse.Traumatic experience interacts with factors in the child and family to contribute to the development of PTSD. Trauma that threatens family integrity appears to make a strong contribution to the development of PTSD. Increased understanding of the factors contributing to PTSD may provide additional opportunities for developing effective interventions.
Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window
Authors: Brian D. Polizzotti, Balakrishnan Ganapathy, Stuart Walsh, Sangita Choudhury, Niyatie Ammanamanchi, David G. Bennett, Cristobal G. dos Remedios, Bernhard J. Haubner, Josef M. Penninger, Bernhard Kühn
Journal: Science Translational Medicine (2015)

The growth factor neuregulin stimulates heart muscle repair in newborn mice and heart muscle from human infants if given during a specific therapeutic time period.
Comparing performance and cost of EBUS-TBNA versus other methods for diagnosis and staging of non-small cell lung cancer (NSCLC)
Authors: Shera Tan, Kiran Sharma, Kah Yee Tham, Shin Yuh Ang, Van Hai Nguyen, Therese Sophie Lapperre, Chian Min Loo, Mariko Siyue Koh
Journal: European Respiratory Journal (2014)

Background :Endobronchial ultrasound (EBUS) is the best first diagnostic tool to obtain tissue and for accurate mediastinal staging. Its cost has yet to be compared to other methods. This has implications on health policy and planning.

Aim :To compare the performance characteristics and costs of EBUS-Transbronchial Needle Aspiration (TBNA) for diagnosis and staging with other modalities i.e. EBUS-Transbronchial lung biopsy (TBLB) and Positron Emission Tomography (PET) or transthoracic needle aspiration (TTNA) and PET.

Methods :Retrospective analysis of EBUS-TBNA performed from August 2008 to June 2013 at our hospital was done. All patients with NSCLC were included. Final diagnoses and staging were determined by EBUS-TBNA, TTNA-PET, TBLB-PET or surgery. Sensitivity, specificity and accuracy were determined. Calculations were based on real costs derived from actual patient data. Decision analytic models were developed to evaluate the cost effectiveness of EBUS-TBNA compared to other modalities.

Results :297 patients with NSCLC were diagnosed during this period. The sensitivity of EBUS-TBNA for accurate mediastinal staging was 85.8%. The overall complication rate was 6%, all minor. The sensitivity of TTNA was 92%, with complication rate of 45.5% (6.8% major) and the sensitivity of EBUS-TBLB was 62.8%, with complication rate of 2.5 %. Using the abovementioned model, the overall costs were S$2837, S$6790 and S$8395 for EBUS-TBNA, TTNA-PET and EBUS-TBLB-PET respectively.

Conclusion :EBUS-TBNA has high diagnostic accuracy and results in cost savings of up to S$5558(€3473) per patient. It is the preferred modality for the staging and diagnosis of NSCLC.
ULCERATION OF THE SKIN IN MULTIPLE MYELOMA.
Authors: M.A. COWAN
Journal: British Journal of Dermatology (1961)

Journal Article ULCERATION OF THE SKIN IN MULTIPLE MYELOMA. Get access M.A. COWAN M.A. COWAN Senior Registrar in Dermatology, The Radeliffe Infirmary, Oxford Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 73, Issue 11, 1 November 1961, Pages 415–418, https://doi.org/10.1111/j.1365-2133.1961.tb14989.x Published: 01 November 1961
Bronchiolitis Obliterans after Human Lung Transplantation
Authors: Marc Estenne, Marshall I. Hertz
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Over the last decade, improvements in surgical techniques, lung preservation, immunosuppression, and management of ischemia–reperfusion injury and infections have contributed to increase the 1-year patient survival after lung transplantation to 70–80% (1). However, long-term survival is threatened by bronchiolitis obliterans, which is thought to be a form of chronic allograft rejection. Bronchiolitis obliterans after lung transplantation was first described in 1984 at Stanford University in heart–lung transplant recipients who showed a progressive decline in FEV 1 (2). Lung biopsies from these patients showed intraluminal polyps comprised of fibromyxoid granulation tissue and plaques of dense submucosal eosinophilic scar. Obliteration of the small airways by these lesions produces progressive airflow obstruction, often accompanied by recurrent lower respiratory tract infection. Bronchiolitis obliterans, and its clinical correlate bronchiolitis obliterans syndrome, affect up to 50–60% of patients who survive 5 years after transplantation (3). In most patients, bronchiolitis obliterans is a progressive process that responds poorly to augmented immunosuppression, and it accounts for more than 30% of all deaths occurring after the third postoperative year (1). Survival at 5 years after the onset of bronchiolitis obliterans is only 30–40%, and survival at 5 years after transplantation is 20–40% lower in patients with than in patients without bronchiolitis obliterans (4). In this review, we present current concepts regarding post-transplant bronchiolitis obliterans, including: ( 1 ) the recently updated classification system for bronchiolitis obliterans syndrome (BOS), ( 2 ) an overview of current concepts regarding its pathogenesis and risk factors, ( 3 ) potential surrogate markers that may contribute to early detection, and ( 4 ) approaches to the management of this devastating complication.
Prognostic Significance of Vascular Endothelial Growth Factor Immunohistochemical Expression in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis
Authors: Panayiotis A. Kyzas, Isabella W. Cunha, John P.A. Ioannidis
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Vascular endothelial growth factor (VEGF) is considered as a prime mediator of angiogenesis. Various studies examining the relationship between VEGF protein overexpression with the clinical outcome in patients with head and neck squamous cell carcinoma have yielded inconclusive results. Experimental Design: We conducted a meta-analysis of 12 studies (n = 1.002 patients) that evaluated the correlation between VEGF (detected by immunohistochemistry) and 2-year overall survival. The relation between VEGF and lymph node involvement (11 studies, n = 722) was also examined. Data were synthesized with random effect and fixed effect risk ratios. Results: The estimated risk of death in 2 years was 1.88-fold higher in the VEGF-positive patients [95% confidence interval, 1.43-2.45; P &amp;lt; 0.001 random effect calculations]. Between-study heterogeneity was nonsignificant (P = 0.15) but larger studies tended to provide more conservative estimates (P = 0.097). VEGF overexpression was not significantly associated with the presence of lymph node metastasis (risk ratio, 1.20; 95% confidence interval, 0.97-1.49; P = 0.087) and there was significant between-study heterogeneity (P = 0.08). Conclusions: Although some modest bias cannot be excluded, VEGF positivity seems to be associated with worse overall survival in patients with head and neck squamous cell carcinoma.
Effect of the Secretory Small GTPase Rab27B on Breast Cancer Growth, Invasion, and Metastasis
Authors: An Hendrix, Dawn Maynard, Patrick Pauwels, Geert Braems, Hannelore Denys, Rudy Van den Broecke, Jo Lambert, Simon Van Belle, Veronique Cocquyt, Christian Gespach, Marc Bracke, Miguel C. Seabra, William A. Gahl, Olivier De Wever, Wendy Westbroek
Journal: JNCI Journal of the National Cancer Institute (2010)

BACKGROUND Secretory GTPases like Rab27B control vesicle exocytosis and deliver critical proinvasive growth regulators into the tumor microenvironment. The expression and role of Rab27B in breast cancer were unknown. METHODS Expression of green fluorescent protein (GFP) fused with wild-type Rab3D, Rab27A, or Rab27B, or Rab27B point mutants defective in GTP/GDP binding or geranylgeranylation, or transient silencing RNA to the same proteins was used to study Rab27B in estrogen receptor (ER)-positive human breast cancer cell lines (MCF-7, T47D, and ZR75.1). Cell cycle progression was evaluated by flow cytometry, western blotting, and measurement of cell proliferation rates, and invasion was assessed using Matrigel and native type I collagen substrates. Orthotopic tumor growth, local invasion, and metastasis were analyzed in mouse xenograft models. Mass spectrometry identified proinvasive growth regulators that were secreted in the presence of Rab27B. Rab27B protein levels were evaluated by immunohistochemistry in 59 clinical breast cancer specimens, and Rab3D, Rab27A, and Rab27B mRNA levels were analyzed by quantitative real-time polymerase chain reaction in 20 specimens. Statistical tests were two-sided. RESULTS Increased expression of Rab27B promoted G(1) to S phase cell cycle transition, proliferation and invasiveness of cells in culture, and invasive tumor growth and hemorrhagic ascites production in a xenograft mouse model (n = 10; at 10 weeks, survival of MCF-7 GFP- vs GFP-Rab27B-injected mice was 100% vs 62.5%, hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.88, P = .03). Mass spectrometric analysis of purified Rab27B-secretory vesicles identified heat-shock protein 90alpha as key proinvasive growth regulator. Heat-shock protein 90alpha secretion was Rab27B-dependent and was required for matrix metalloproteinase-2 activation. All Rab27B-mediated functional responses were GTP- and geranylgeranyl-dependent. Presence of endogenous Rab27B mRNA and protein, but not of Rab3D or Rab27A mRNA, was associated with lymph node metastasis (P < .001) and differentiation grade (P = .001) in ER-positive human breast tumors. CONCLUSIONS Rab27B regulates invasive growth and metastasis in ER-positive breast cancer cell lines, and increased expression is associated with poor prognosis in humans.
Ruptured Aneurysm of a Sinus of Valsalva
Authors: Bernard Chojnacki
Journal: JAMA (1963)

THE SINUSES OF VALSALVA are outpouchings of the base of the aorta. There are three of them adjacent to the cusps of the aortic valve. The sinuses, named appropriately to the coronary artery relationship, are the left, right, and non-coronary sinuses. The rupture of an aneurysm of the sinuses is a dramatic event leading to a progression of symptoms which frequently terminate in death. Present-day surgical techniques permit correction of this defect. A review by Thurman<sup>1</sup>in 1840 includes 18 instances of this disorder with demonstration of fistulous communication of the aneurysm to each of the individual heart chambers. Aneurysms originate primarily in the right coronary and non-coronary sinuses, which are derived embryologically from the distal bulbar septum. Involvement of the left coronary sinus has been noted rarely.<sup>2,3</sup> The location of the sinuses at the base of the aorta, where the greatest forces sustained by the vascular system
Strategies to Discover Unexpected Targets for Drugs Active at G Protein–Coupled Receptors
Authors: John A. Allen, Bryan L. Roth
Journal: The Annual Review of Pharmacology and Toxicology (2011)

G protein–coupled receptors (GPCRs) are an evolutionarily conserved family of signaling molecules comprising approximately 2% of the human genome; this receptor family remains a central focus in basic pharmacology studies and drug discovery efforts. Detailed studies of drug action at GPCRs over the past decade have revealed existing and novel ligands that exhibit polypharmacology—that is, drugs with activity at more than one receptor target for which they were designed. These “off-target” drug actions can be a liability that causes adverse side effects; however, in several cases, drugs with less selectivity demonstrate better clinical efficacy. Here we review physical screening and cheminformatic approaches that define drug activity at the GPCR receptorome. In many cases, such profiling has revealed unexpected targets that explain therapeutic actions as well as off-targets underlying drug side effects. Such drug-receptor profiling has also provided new insights into mechanisms of action of existing drugs and has suggested directions for future drug development.
Apparent Mineralocorticoid Excess
Authors: Gilles Morineau, Véronique Sulmont, Remi Salomon, Beatrice Fiquet-Kempf, Xavier Jeunemai[Combining Circumflex Accent]tre, Jéro[Combining Circumflex Accent]me Nicod, Paolo Ferrari
Journal: Journal of the American Society of Nephrology (2006)

In mineralocorticoid target tissues such as the cortical collecting duct in the kidney, the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is responsible for the peripheral inactivation of cortisol to cortisone, thereby protecting the mineralocorticoid receptor from inappropriate activation by cortisol. Mutations in the HSD11B2 gene cause the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of inherited hypertension in which cortisol acts as a potent mineralocorticoid. Herein are described six new families with mutations in the HSD11B2 gene causing hypokalemic hypertension, with low plasma aldosterone and low renin levels in affected individuals, indicating mineralocorticoid hypertension. Profiling of urinary steroid metabolites showed decreased cortisol inactivation, with urinary tetrahydrocortisol and tetrahydrocortisone ratio (THF + 5alphaTHF)/THE ranging 2.4 to 40 and nearly absent urinary free cortisone in all but one case. Genetic analysis of the HSD11B2 gene from these patients with apparent mineralocorticoid excess revealed distinct homozygous point mutations in four families, a compound heterozygous mutation in one family, and a large 23-bp exonic insert with frameshift and disruption of the amino acid sequence in another family. Expression studies of mutants that were expressed in HEK-293 cells showed marked reduction or abolition of 11betaHSD2 enzymatic activity. These cases are reviewed along with previous ones from the authors' extensive personal experience to highlight the importance of 11betaHSD2 in the understanding of a new biologic principle in hormone action, demonstrating that local metabolism of the glucocorticoid hormones into inactive derivatives by the enzyme 11betaHSD2 is one of the mechanisms that intervene to allow specific aldosterone regulatory effects.
The asbestos disease epidemic: here today, here tomorrow
Authors: Paul Cullinan, Neil Pearce
Journal: Thorax (2011)

In what may be the best ever use of a Wellcome grant, Geoffrey Tweedale, in his fascinating history of the multinational asbestos company Turner & Newall,1 reminds us that asbestos was once known as the ‘magic mineral’. Indeed, in many ways, it is the ideal construction material: tough, durable, light in weight, fire-resistant and very cheap. Unfortunately, asbestos is also, as every respiratory physician knows, highly toxic when inhaled. Total bans on its use are in place in 52 countries including those of the European Union, Australia, Japan and South Africa2; and its use is tightly restricted in the USA, New Zealand and Canada—the last, ironically, among the world's largest exporters of the material.

Readers from these countries may be surprised to learn that elsewhere the production, sale and use of asbestos continue to flourish and even increase. In 1994, one of us (NP) edited a book3 on occupational cancer in developing countries for the International Agency for Research on Cancer and reported that global asbestos production and use had not declined; rather, the problem was simply being moved from Western countries to emergent economies. Unhappily, the situation has not improved in the intervening 17 years. In India, for example, the use of asbestos has doubled in the last decade to about 300 000 tonnes a year by an industry that now employs an estimated 100 000 workers.4 Other major users include China, Brazil, Russia, Ukraine, Kazakhstan and Indonesia. In these parts of the world, where occupational exposures may be difficult to control and enforce, the great majority of …