tbuckley/cabot-search huggingface dataset:
Abstract 4161: Rab25 cooperates with RIN1 to suppress p21 Ras
Authors: Jiming Cheng, Vijayalakshmi Ayyagari, Krishna Rao
Journal: Cancer Research (2012)

Abstract Introduction: Our previous work has shown that the loss of Rab25 occurs in estrogen receptor (ER) and progesterone receptor (PR) negative breast cancer cell lines and human tumor samples and seems to correlate with an active Ras pathway. Loss of Rab25 cooperates with mutant Ras to promote tumorigenesis. RIN1 is a protein inhibitor of Ras, and our current works confirms that Rab25 binds to RIN1 and cooperates to inhibit Ras. Rab25 also has multiple effects on microRNAs. Materials and Methods: Cell culture -RAO-1-4 cell lines was grown in DFCI-1 medium. Immunoprecipitation- Protein extracts from RAO-1, RAO-2, and RAO-3/Rab25 were tested for RIN1expression. Immunoprecipitated extracts were then assayed by western blot for RAB25 expression. Chemiluminescence Assay- Cell extract from MDA-MB-231 cells with shRIN1 was used. These cells contained no Rab25 as well. Recombinant RIN1 and recombinant Rab25 were tested in various combinations for ras inhibition using the Active Motif kit. MicroRNA assay- RNA was extracted from RAO-2, RAO-4, and RAO-4/Rab25 and sent to Phalanx Biotech for microRNA profiling. Results: 1. Rab25 binds to RIN1 in a ternary complex with Ras. 2. Rab25 coopeates with RIN1 in an additive manner to inhibit Ras. 3. Rab25 expression impacts several microRNAs including 29b, 100, 138, 146a, 205, 524-5p, 762, 1246, 1260b, 1307, 1826, 3172, 3175, and 3178. Conclusions: 1. Rab25 is a tumor modulator. It can regulate tumor growth and angiogenesis through inhibition of ras in cooperation with RIN1. 2. Our data previous indicated that Rab25 could localize to the nucleus, and it appears to effect the expression of several microRNAs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4161. doi:1538-7445.AM2012-4161
Role of microRNAs in vascular diseases, inflammation, and angiogenesis
Authors: C. Urbich, A. Kuehbacher, S. Dimmeler
Journal: Cardiovascular Research (2008)

The integrity of the endothelial monolayer is fundamental for the homoeostasis of the vascular system. Functional endothelial cells are also required for the growth of new blood vessels during neovascularization. Although multiple growth factors have been shown to regulate angiogenesis and vascular development, little is known about the complex upstream regulation of gene expression and translation. MicroRNAs (miRNAs) are an emerging class of highly conserved, non-coding small RNAs that regulate gene expression on the post-transcriptional level by inhibiting the translation of protein from mRNA or by promoting the degradation of mRNA. More than 500 human miRNAs have been identified so far, and increasing evidence indicates that miRNAs have distinct expression profiles and play crucial roles in various physiological and pathological processes such as cardiogenesis, haematopoietic lineage differentiation, and oncogenesis. Meanwhile, a few specific miRNAs that regulate endothelial cell functions and angiogenesis have been described. Let7-f, miR-27b, and mir-130a were identified as pro-angiogenic miRNAs. In contrast, miR-221 and miR-222 inhibit endothelial cell migration, proliferation, and angiogenesis in vitro by targeting the stem cell factor receptor c-kit and indirectly regulating endothelial nitric oxide synthase expression. Moreover, some miRNAs are involved in tumour angiogenesis such as the miR-17-92 cluster and miR-378. Early studies also indicate the contribution of specific miRNAs (e.g. miR-155, miR-21, and miR-126) to vascular inflammation and diseases. Thus, the identification of miRNAs and their respective targets may offer new therapeutic strategies to treat vascular diseases such as atherosclerosis, to improve neovascularization after ischaemia, or to prevent tumour progression.
Role of Promyelocytic Leukemia (Pml) Protein in Tumor Suppression
Authors: Eduardo M. Rego, Zhu-Gang Wang, Daniela Peruzzi, Le-Zhen He, Carlos Cordon-Cardo, Pier Paolo Pandolfi
Journal: The Journal of Experimental Medicine (2001)

The promyelocytic leukemia (PML) gene encodes a putative tumor suppressor gene involved in the control of apoptosis, which is fused to the retinoic acid receptor α (RARα) gene in the vast majority of acute promyelocytic leukemia (APL) patients as a consequence of chromosomal translocations. The PMLRARα oncoprotein is thought to antagonize the function of PML through its ability to heterodimerize with and delocalize PML from the nuclear body. In APL, this may be facilitated by the reduction to heterozygosity of the normal PML allele. To determine whether PML acts as a tumor suppressor in vivo and what the consequences of deregulated programmed cell death in leukemia and epithelial cancer pathogenesis are, we crossed PML−/− mice with human cathepsin G (hCG)-PMLRARα or mammary tumor virus (MMTV)/neu transgenic mice (TM), models of leukemia and breast cancer, respectively. The progressive reduction of the dose of PML resulted in a dramatic increase in the incidence of leukemia, and in an acceleration of leukemia onset in PMLRARα TM. By contrast, PML inactivation did not affect neu-induced tumorigenesis. In hemopoietic cells from PMLRARα TM, PML inactivation resulted in impaired response to differentiating agents such as RA and vitamin D3 as well as in a marked survival advantage upon proapoptotic stimuli. These results demonstrate that: (a) PML acts in vivo as a tumor suppressor by rendering the cells resistant to proapoptotic and differentiating stimuli; (b) PML haploinsufficiency and the functional impairment of PML by PMLRARα are critical events in APL pathogenesis; and (c) aberrant control of programmed cell death plays a differential role in solid tumor and leukemia pathogenesis.
Stress Doppler Echocardiography in Relatives of Patients With Idiopathic and Familial Pulmonary Arterial Hypertension
Authors: Ekkehard Grünig, Sylvia Weissmann, Nicola Ehlken, Anna Fijalkowska, Christine Fischer, Thierry Fourme, Nazzareno Galié, Ardeschir Ghofrani, Rachel E. Harrison, Sandrine Huez, Marc Humbert, Bart Janssen, Jaroslaw Kober, Rolf Koehler, Rajiv D. Machado, Derliz Mereles, Robert Naeije, Horst Olschewski, Steeve Provencher, Frank Reichenberger, Kathleen Retailleau, Guido Rocchi, Gérald Simonneau, Adam Torbicki, Richard Trembath, Werner Seeger
Journal: Circulation (2009)

This large, prospective, multicentric study was performed to analyze the distribution of tricuspid regurgitation velocity (TRV) values during exercise and hypoxia in relatives of patients with idiopathic and familial pulmonary arterial hypertension (PAH) and in healthy control subjects. We tested the hypothesis that relatives of idiopathic/familial PAH patients display an enhanced frequency of hypertensive TRV response to stress and that this response is associated with mutations in the bone morphogenetic protein receptor II (BMPR2) gene.TRV was estimated by Doppler echocardiography during supine bicycle exercise in normoxia and during 120 minutes of normobaric hypoxia (FIO(2)=12%; approximately 4500 m) in 291 relatives of 109 PAH patients and in 191 age-matched control subjects. Mean maximal TRVs were significantly higher in PAH relatives during both exercise and hypoxia. During exercise, 10% of control subjects but 31.6% of relatives (P<0.0001) exceeded the 90% quantile of mean maximal TRV seen in control subjects. Hypoxia revealed hypertensive TRV in 26% of relatives (P=0.0029). Among control subjects, TRV at rest was not related to age, sex, body mass index, systemic blood pressure, smoking status, or heart rate. Within kindreds identified as harboring deleterious mutations of the BMPR2 gene, a hypertensive TRV response occurred significantly more often compared with those without detected mutations.Pulmonary hypertensive response to exercise and hypoxia in idiopathic/familial PAH relatives appears as a genetic trait with familial clustering, being correlated to but not caused by a BMPR2 mutation. The suitability of this trait to predict manifest PAH development should be addressed in long-term follow-up studies.
Abstract S3-05: Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP trial B-31
Authors: Soonmyung Paik, Katherine L Pogue-Geile, Nan Song, Patrick G Gavin, Seong-Rim Kim
Journal: Cancer Research (2015)

Abstract Purpose: Considerable molecular heterogeneity exists among HER2-positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from NSABP trial B-31. Methods: Expression data for 49 genes using the nCounter platform was used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from B-31. Five PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (N=671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease free survival as the endpoint. Results: 741/1578 (47.0%) tumors were classified as HER2E subtype; and 166/671 (24.7%) had PIK3CA mutations. Hazard ratios (HR) for trastuzumab in HER2E and other subtypes were 0.44 (95%CI: 0.34-0.58, p&amp;lt;0.001) and 0.47 (95% CI: 0.35-0.62, p&amp;lt;0.001), respectively (interaction p=0.67). HRs for trastuzumab in PIK3CA wild type and mutated were 0.51 (95%CI: 0.37-0.71, p&amp;lt;0.001) and 0.44 (95%CI: 0.24-0.82, p=0.009), respectively (interaction p=0.64). Conclusion: Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not biomarkers for differential response to trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting. Support: National Cancer Institute, Department of Health and Human Services, Public Health Service, Grants U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974, and by a grant from the Pennsylvania State Department of Health. The latter Department specifically disclaims responsibility for any analysis, interpretations or conclusions. Citation Format: Soonmyung Paik, Katherine L Pogue-Geile, Nan Song, Patrick G Gavin, Seong-Rim Kim. Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in NSABP trial B-31 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-05.
The systemic face of airway diseases: the role of C-reactive protein
Authors: E. F. M. Wouters
Journal: European Respiratory Journal (2006)

Airway diseases, predominantly asthma and chronic obstructive pulmonary disease (COPD), are highly prevalent diseases, constituting a major financial burden to society. Both asthma and COPD are identified by the presence of characteristic symptoms and functional abnormalities. Airflow limitation is the dominant physiological characteristic of both diseases. The airflow limitation in asthma must be reversible to establish a diagnosis, whereas in COPD the airflow limitation does not change markedly over periods of several months and the disease is characterised by a steady downhill course over time. Asthma usually commences in childhood, whereas COPD is generally diagnosed at an older age. Lung inflammation induced by different initiating factors is now recognised as an important characteristic in both diseases. The airway inflammation in asthma is characterised by an increase in eosinophils, lymphocytes (predominantly of the CD4+ type) and mast cells. In contrast, inflammation in COPD can be described by a predominance of lymphocytes, in particular CD8+ lymphocytes, and large numbers of neutrophils in the airway lumen.

While achievement of asthma control and suppression of airway inflammation are considered as important management goals in asthma, particularly as a consequence of the effects of inhaled steroids in this disease process, the focus of research in COPD has moved from the typical pulmonary pathology of COPD to the role of numerous abnormalities outside the lung. At present, COPD is considered as a multicomponent disease, including skeletal muscle dysfunction and cachexia, as well as cardiovascular and osteoskeletal alterations. Particularly in order to explain the process of muscle wasting, the presence of a chronic low-grade systemic inflammatory response has been identified as one of the catabolic factors, although the precise role, as well as the intracellular pathways, remain to be defined 1. In this issue of the European Respiratory Journal (ERJ) , two clinical papers focus attention …
Flow cytometric detection of cell-associated cytokines in alveolar macrophages
Authors: H Nakamura, S Fujishima, K Soejima, Y Waki, M Nakamura, A Ishizaka, M Kanazawa
Journal: European Respiratory Journal (1996)

To elucidate the cytokine-producing capacity of alveolar macrophages (AMs), we have introduced a method of flow cytometry combined with saponin treatment to detect the cell-associated cytokines. We studied bronchoalveolar lavage fluid cells from six patients with sarcoidosis (SAR) and six control (CTL) subjects. Cells were either left uncultured, or cultured with and without lipopolysaccharide (LPS), then treated with paraformaldehyde and saponin and analysed for cell-associated interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) by flow cytometry. Cell-associated IL-1 beta and TNF-alpha were also analysed by immunoassays. The flow cytometric cytokine values were correlated with the immunoreactive cell-associated cytokines (IL-1 beta: r = 0.45, p &lt; 0.05; TNF-alpha: r = 0.82, p &lt; 0.001). The histograms of cell-associated IL-1 beta yielded a single peak both in the patients and controls, whereas the histograms of cell-associated TNF-alpha exhibited two peaks in SAR patients, but just a single peak in the CTL subjects. The mean value of the cell-associated TNF-alpha in LPS+ AMs was higher in the SAR patients than in the CTL subjects (p &lt; 0.001). In conclusion, the flow cytometric method can be applied to the semiquantitative detection of cell-associated cytokines in alveolar macrophages at the single cell level.
Differences in the Pattern of Antibiotic Prescription Profile and Recurrence Rate for Possible Urinary Tract Infections in Women With and Without Diabetes
Authors: Caroline Schneeberger, Ronald P. Stolk, J. Hans DeVries, Peter M. Schneeberger, Ron M. Herings, Suzanne E. Geerlings
Journal: Diabetes Care (2008)

Women with diabetes have a high incidence and complication rate of urinary tract infections (UTIs). Our aims were to compare current treatment strategies with respect to recurrence rates in women with diabetes with those without diabetes.We used a Dutch registration database containing pharmacy dispensing data. A total of 10,366 women with diabetes (17.5% premenopausal) (aged < or =55 years) and 200,258 women without diabetes (68% premenopausal) who received a first course of trimethoprim, nitrofurantoin, fosfomycin, or norfloxacin between January 1999 and January 2006 were included. We compared short (< or or =5 days) with long (>5 days) prescriptions and norfloxacin with trimethoprim, nitrofurantoin, and fosfomycin. A recurrence was defined as a second prescription for one of the above-mentioned agents or a first with amoxicillin (clavulanic acid), fluoroquinolones, or trimethoprim/sulfamethoxazole between 6 and 30 days after inclusion.Premenopausal women with diabetes more often received a long (26.5 vs. 19.2%; P < 0.001) treatment with norfloxacin (10.7 vs. 6.2%; P < 0.001) but still had a higher recurrence rate (16.1 vs. 12.2%; P = 0.003) compared with those without diabetes. Similarly, postmenopausal women with diabetes more often received a longer (32.8 vs. 28.8%; P < 0.001) treatment with norfloxacin (15.2 vs. 12.7%; P < 0.001) but had a higher recurrence rate (19.1 vs. 16.4%; P < 0.001) compared with those without diabetes.Despite the fact that patients with diabetes more often received longer and more potent initial treatment than patients without diabetes, pre- and postmenopausal women with diabetes more often had recurrences of their UTIs.
Differences in red cell behaviour between patients with Raynaud's phenomenon and systemic sclerosis and patients with Raynaud's disease
Authors: M.H.A. RUSTIN, I.B. KOVACS, S.O. SOWEMIMO-COKER, P.J. MADDISON, J.D.T. KIRBY
Journal: British Journal of Dermatology (1985)

Journal Article Differences in red cell behaviour between patients with Raynaud's phenomenon and systemic sclerosis and patients with Raynaud's disease Get access M.H.A. RUSTIN, M.H.A. RUSTIN Departments of Dermatology, St Bartholomew's Hospital, West Smithfield, London EC1A7BE Dr M.H.A.Rustin, Department of Dermatology, St Bartholemew's Hospital, London EC1A 7BE, U.K. Search for other works by this author on: Oxford Academic Google Scholar I.B. KOVACS, I.B. KOVACS Departments of Dermatology, St Bartholomew's Hospital, West Smithfield, London EC1A7BE Search for other works by this author on: Oxford Academic Google Scholar S.O. SOWEMIMO‐COKER, S.O. SOWEMIMO‐COKER Clinical Pharmacology, St Bartholomew's Hospital, West Smithfield, London EC1A7BE Search for other works by this author on: Oxford Academic Google Scholar P.J. MADDISON, P.J. MADDISON †Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath AB1 1RL U.K. Search for other works by this author on: Oxford Academic Google Scholar J.D.T. KIRBY J.D.T. KIRBY Departments of Dermatology, St Bartholomew's Hospital, West Smithfield, London EC1A7BE Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 113, Issue 3, 1 September 1985, Pages 265–272, https://doi.org/10.1111/j.1365-2133.1985.tb02077.x Published: 01 September 1985 Article history Accepted: 27 February 1985 Published: 01 September 1985
Physical Activity and Reduced Risk of Cardiovascular Events
Authors: Samia Mora, Nancy Cook, Julie E. Buring, Paul M Ridker, I-Min Lee
Journal: Circulation (2007)

Background— Higher levels of physical activity are associated with fewer cardiovascular disease (CVD) events. Although the precise mechanisms underlying this inverse association are unclear, differences in several cardiovascular risk factors may mediate this effect. Methods and Results— In a prospective study of 27 055 apparently healthy women, we measured baseline levels of hemoglobin A1c, traditional lipids (total, low-density lipoprotein, and high-density lipoprotein cholesterol), novel lipids [lipoprotein(a) and apolipoprotein A1 and B-100], creatinine, homocysteine, and inflammatory/hemostatic biomarkers (high-sensitivity C-reactive protein, fibrinogen, soluble intracellular adhesion molecule-1) and used women’s self-reported physical activity, weight, height, hypertension, and diabetes. Mean follow-up was 10.9±1.6 years, and 979 incident CVD events occurred. The risk of CVD decreased linearly with higher levels of activity ( P for linear trend &lt;0.001). Using the reference group of &lt;200 kcal/wk of activity yielded age- and treatment-adjusted relative risk reductions associated with 200 to 599, 600 to 1499, and ≥1500 kcal/wk of 27%, 32%, and 41%, respectively. Differences in known risk factors explained a large proportion (59.0%) of the observed inverse association. When sets of risk factors were examined, inflammatory/hemostatic biomarkers made the largest contribution to lower risk (32.6%), followed by blood pressure (27.1%). Novel lipids contributed less to CVD risk reduction compared with traditional lipids (15.5% and 19.1%, respectively). Smaller contributions were attributed to body mass index (10.1%) and hemoglobin A1c/diabetes (8.9%), whereas homocysteine and creatinine had negligible effects (&lt;1%). Conclusions— The inverse association between physical activity and CVD risk is mediated in substantial part by known risk factors, particularly inflammatory/hemostatic factors and blood pressure.
Evaluation of QuantiFERON microtube, using 0.9 mL blood, for diagnosing tuberculosis infection
Authors: Michala V. Rose, Godfather Kimaro, Inge Kroidl, Michael Hoelscher, Ib C. Bygbjerg, Sayoki M. Mfinanga, Pernille Ravn
Journal: European Respiratory Journal (2012)

The performance of QuantiFERON microtube (QFT-MT), using 0.9 mL blood, and QuantiFERON-TB Gold in-tube test (QFT-IT) (3 mL blood), for diagnosing tuberculosis (TB) was compared in children and adults in an endemic setting. In 152 children with suspected TB and 87 adults with confirmed TB, QFT-IT was compared with two QFT-MT concentrations (QFT-MT A and B). Proportions of positive and indeterminate results, interferon (IFN)-γ responses, interassay agreement and sensitivity were assessed. We found similar proportions of indeterminate results, levels of IFN-γ and comparable sensitivity. The interassay agreement was moderate in all children (QFT-IT <i>versus</i> QFT-MT A: 85%, k=0.44 and QFT-IT <i>versus</i> QFT-MT B: 88%, k=0.50) and adults (QFT-IT <i>versus</i> QFT-MT A: 88%, k=0.50 and QFT-IT <i>versus</i> QFT-MT B: 89%, k=0.49). Sensitivity was low (QFT-IT 23%, QFT-MT A 18% and B 19%) in children with confirmed or highly probable TB compared with adults (83%, 86% and 88%, respectively). The QFT-MT test can be reliably performed using less than one-third of the blood volume used in QFT-IT. The reduced volume may be useful for research and future diagnosis of paediatric TB. The poor sensitivity and high indeterminate rate of both IFN-γ release assays in severely ill children, with immature or impaired immunity in an endemic setting, warrants further investigations.
Mutagen Sensitivity Has High Heritability: Evidence from a Twin Study
Authors: Xifeng Wu, Margaret R. Spitz, Christopher I. Amos, Jie Lin, Lina Shao, Jian Gu, Mariza de Andrade, Neal L. Benowitz, Peter G. Shields, Gary E. Swan
Journal: Cancer Research (2006)

Abstract Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, γ-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor. (Cancer Res 2006; 66(12): 5993-6)
Causes of venous ulceration.
Authors: P. M. Gaylarde, H. J. Dodd, I. Sarkany
Journal: BMJ (1988)

authority databases will improve the planning process in the 1990s.Doctors need to remain interested in and familiar with these debates at the local level.Non-medical planners may tend to use such data in isolation.Complementary data and qualitative studies should be available to aid general practitioners and others to interpret routine statistics from small areas.