tbuckley/cabot-search huggingface dataset:
Imatinib Mesylate (Gleevec) Inhibits Ovarian Cancer Cell Growth through a Mechanism Dependent on Platelet-Derived Growth Factor Receptor α and Akt Inactivation
Authors: Daniela Matei, David D. Chang, Meei-Huey Jeng
Journal: Clinical Cancer Research (2004)

Abstract Purpose: We identified the platelet-derived growth factor receptor α (PDGFRα) as an ovarian cancer-specific gene by microarray hybridization using primary cultures. The purpose of this study is to evaluate whether disruption of the platelet-derived growth factor-regulated growth pathway by Imatinib mesylate (Gleevec), a partially selective PDGFR inhibitor, inhibits growth of ovarian cancer cells expressing PDGFR. Experimental Design: To investigate the effects of Imatinib mesylate in ovarian cancer, we established an in vitro model by immortalizing primary ovarian cells, which express endogenous PDGFR, and we evaluated the effects of Imatinib on cell proliferation. In addition, we investigated the involvement of Akt in mediating Imatinib-inhibited cell growth inhibition. Results: We found that 39% of ovarian tumors express PDGFR by immunohistochemistry. We showed that Imatinib inhibits the growth of ovarian cancer cells in a PDGFR-specific manner, at clinically relevant concentrations (IC50 &amp;lt; 1 μm). Imatinib inhibits the growth of three primary ovarian cultures and two immortalized cultures (PDGFR positive), but has no effects on SkOv3 and CaOv3 cell lines (PDGFR negative). Imatinib exerts antiproliferative effects by arresting cells at G0-G1 and preventing progression through S phase. Imatinib inhibits both PDGFRα and Akt phosphorylation at a concentration of 1 μm. Stable expression of constitutively active Akt induces partial resistance to PDGFR inhibition in ovarian cancer cells, as demonstrated by cell proliferation assay and cell cycle analysis. Conclusions: Our data indicate that Imatinib mesylate inhibits the growth of ovarian cancer cells through PDGFR inactivation. In addition, our results suggest that constitutive Akt activation modulates sensitivity to Imatinib in ovarian cancer cells.
Treatment of progressive metastatic glomus jugulare tumor (paraganglioma) with gemcitabine
Authors: J. Marc Pipas, Robert F. Krywicki
Journal: Neuro-Oncology (2000)

Paragangliomas are rare tumors of the paraganglia composed of specialized neural crest cells arising in association with sympathetic ganglia. Here we report a case of progressive, metastatic paraganglioma (glomus jugulare tumor) responsive to single agent gemcitabine. In addition, a brief review of chemotherapy for paraganglioma follows the case presentation.
Pulmonary rehabilitation in chronic respiratory insufficiency. 7. Health-related quality of life among patients with chronic obstructive pulmonary disease.
Authors: J R Curtis, R A Deyo, L D Hudson
Journal: Thorax (1994)

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in industrialised nations. It is essentially incurable and, for many, inexorably progressive; health care providers spend much effort trying to minimise patients' symptoms and to improve their ability to function in dayto-day life. While improved survival time is an important aim of treatment, there is growing recognition that improving the quantity of an individual's life may not be the only goal; for some, improving the quality of life may be far more important. Since reducing symptoms, increasing function, and improving the quality of life are central therapeutic goals for patients with COPD, as for many chronic diseases, it is important for researchers and clinicians to develop a common understanding of what is meant by these phrases and how these concepts can be measured. In the past 10 years there has been an increasing body of literature on measurement of quality of life in patients with COPD and, more recently, on the efficacy of therapeutic agents based on quality of life measures. Studies measuring the quality of life in these patients appeared in the mid 1980s'4 when quality of life measures were used to assess continuous oxygen therapy,' intermittent positive pressure breathing,6 and, more recently, in the assessment of theophylline,7 inhaled bronchodilators,8 home respiratory nursing care,9 and pulmonary rehabilitation programmes.'0 As this trend continues it is important for clinicians to understand and assess these measures to help decide whether a new treatment is valuable. We will review quality of life measures in patients with COPD with the emphasis on issues important to the clinician who seeks an understanding of quality of life measures as they are used in therapeutic trials.
Dynamics of gene silencing during X inactivation using allele-specific RNA-seq
Authors: Hendrik Marks, Hindrik H. D. Kerstens, Tahsin Stefan Barakat, Erik Splinter, René A. M. Dirks, Guido van Mierlo, Onkar Joshi, Shuang-Yin Wang, Tomas Babak, Cornelis A. Albers, Tüzer Kalkan, Austin Smith, Alice Jouneau, Wouter de Laat, Joost Gribnau, Hendrik G. Stunnenberg
Journal: Genome biology (2015)

During early embryonic development, one of the two X chromosomes in mammalian female cells is inactivated to compensate for a potential imbalance in transcript levels with male cells, which contain a single X chromosome. Here, we use mouse female embryonic stem cells (ESCs) with non-random X chromosome inactivation (XCI) and polymorphic X chromosomes to study the dynamics of gene silencing over the inactive X chromosome by high-resolution allele-specific RNA-seq. Induction of XCI by differentiation of female ESCs shows that genes proximal to the X-inactivation center are silenced earlier than distal genes, while lowly expressed genes show faster XCI dynamics than highly expressed genes. The active X chromosome shows a minor but significant increase in gene activity during differentiation, resulting in complete dosage compensation in differentiated cell types. Genes escaping XCI show little or no silencing during early propagation of XCI. Allele-specific RNA-seq of neural progenitor cells generated from the female ESCs identifies three regions distal to the X-inactivation center that escape XCI. These regions, which stably escape during propagation and maintenance of XCI, coincide with topologically associating domains (TADs) as present in the female ESCs. Also, the previously characterized gene clusters escaping XCI in human fibroblasts correlate with TADs. The gene silencing observed during XCI provides further insight in the establishment of the repressive complex formed by the inactive X chromosome. The association of escape regions with TADs, in mouse and human, suggests that TADs are the primary targets during propagation of XCI over the X chromosome.
Conflicting Results from Clinical Observations and Murine Models: What Is the Role of Plasminogen Activators in Tumor Growth?
Authors: Masashi Narazaki, Giovanna Tosato
Journal: JNCI Journal of the National Cancer Institute (2006)

Tissue invasion and metastasis can compromise vital body functions and are the main causes of death from cancer. By invading locally and dislodging cells or fragments to distant sites, primary tumors can access a rich supply of oxygen and nutrients that is limited at the primary site. Invasion and metastasis are exceedingly complex and incompletely understood multistep processes. Often, they are accompanied by the activation of proteases, which degrade proteins that tether tumor cells to surrounding cells and extracellular matrix. By changing the physical coupling of tumor cells to their microenvironment, proteases are thought to promote local cancer spread and formation of metastases ( 1 – 3 ) . Proteases can also promote tumor angiogenesis ( 4 ) and stimulate tumor cell growth ( 5 , 6 ) . Invasive tumor cells and reactive stromal cells recruited to the tumor site secrete proteinases such as matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs), urokinasetype plasminogen activator (uPA) and its inhibitors (PAIs), and cathepsins. Many studies have focused on the precise identifi cation of these enzymes, evaluation of their contribution to tumor pathogenesis, predictive prognostic value, and their potential as therapeutic targets. Considerable progress has been made. We now know, for example, that many MMPs and TIMPs secreted by cancer cells can facilitate tumor invasion and that elevated serum TIMP-1 levels are associated with poor cancer survival ( 7 , 8 ) . We also know that active enzymes of the cysteine cathepsin family localize to the invasive front of tumors and to the angiogenic tumor vasculature ( 9 ) . Importantly, we have learned from several large studies that high tumor levels of uPA and its inhibitor PAI-1 are poor prognostic factors for patients with breast cancer ( 10 – 12 ) and gastrointestinal, lung, brain, kidney, bladder, and soft tissue tumors ( 11 , 13 – 15 ) .
Physicians and the (Woman's) Body Politic
Authors: R. Alta Charo
Journal: New England Journal of Medicine (2014)

Interview with Prof. R. Alta Charo on laws that restrict women's rights, especially in pregnancy and contraception. (14:46)Download Alicia Beltran's Kafka-esque pregnancy experience is part of an ongoing struggle in which pregnant women and their physicians are marked for intense attention by legislators and judges acting as arbiters of medical knowledge despite a lack of expertise or detachment.
Contractile hyporesponsiveness of hepatic arteries in humans with cirrhosis: Evidence for a receptor-specific mechanism
Authors: Michael Schepke, Jörg Heller, Sebastian Paschke, Julia Thomas, Martin Wolff, Markus Neef, Max Malago, Gerhard J. Molderings, Ulrich Spengler, Tilman Sauerbruch
Journal: Hepatology (2001)

Splanchnic vasodilatation and vascular hyporesponsiveness to vasopressors are characteristic features of patients with cirrhosis. Although the vascular response to different vasopressors has been shown to be attenuated in cirrhosis, alterations on the receptor level are discussed controversially. Thus, impaired postreceptor signaling has been postulated. However, so far this has not been studied in human splanchnic vessels. Therefore, we assessed the vascular response of human hepatic arteries after activating the G-protein-dependent signal transduction pathway by stimulation with angiotensin II, the thromboxane A(2) analog U46619, or by G-protein activation with NaF/AlCl(3). After endothelium denudation, cumulative isometric concentration contraction curves were obtained for hepatic arteries from 32 cirrhotic patients undergoing liver transplantation and from 40 organ donors after stimulation with either angiotensin II (10(-11)-10(-5) mol/L), U46619 (10(-10)-10(-6) mol/L) or AlCl(3) (30 micromol/L)/NaF (10(-4)-3 x 10(-2) mol/L). Hepatic arteries from cirrhotic patients were markedly less responsive to angiotensin II (P <.0001) than those from organ donors. Both stimulation of the G-protein phospholipase C pathway via the thromboxane A(2) receptor and receptor-independent G-protein stimulation with AlCl(3)/NaF, induced an intact contractile response. In conclusion, the G-protein-dependent signal transduction system itself is unaltered in cirrhosis. Hence, the cause of the hyporesponsiveness to some vasoconstrictors in cirrhosis appears to be a receptor-specific phenomenon localized upstream from the G-protein level.
High-dose therapy with autologous stem-cell transplantation (ASCT) after first progression prolonged survival of follicular lymphoma patients included in the prospective GELF 86 protocol
Authors: P. Brice, D. Simon, R. Bouabdallah, C. Bélanger, C. Haïoun, C. Thieblemont, H. Tilly, J.L. Harousseau, C. Doyen, C. Martin, N. Brousse, Ph. Solal-Céligny
Journal: Annals of Oncology (2000)
Clinical correlates of subnormal vitamin B12 levels in patients infected with the human immunodeficiency virus
Authors: Ora Paltiel, Julian Falutz, Martin Veilleux, David S. Rosenblatt, Kathleen Gordon
Journal: American Journal of Hematology (1995)

To determine the prevalence and describe the clinical correlates of subnormal cobalamin levels in subjects infected with the human immunodeficiency virus (HIV), and to assess its relationship to virus-mediated immunosuppression and/or anti-viral therapy.Outpatient referral clinic in tertiary care hospital.200 HIV infected individuals.Descriptive cross sectional survey, with prospective follow-up in a subgroup of patients before and after initiation of zidovudine therapy.Routine complete blood count, serum B12 assay, CD4 counts. Serum homocysteine levels, and Schilling tests were performed on subgroups of study subjects.Subnormal serum B12 levels were found in 61 subjects (30.5%). B12 deficient subjects were more likely to be taking zidovudine. (P = .007). Serum homocysteine levels were significantly higher in patients with subnormal cobalamin levels but were unrelated to CD4 counts or zidovudine use, and were rarely outside of the normal range. Malabsorption of vitamin B12 as evidenced by abnormal Schilling tests was more likely among patients with more advanced HIV disease, or gastrointestinal symptoms but was not necessarily associated with low B12 levels.Decreased cobalamin levels are found frequently in HIV disease, especially among those treated with zidovudine. Evidence of B12 malabsorption is found among those with more advanced disease and gastrointestinal symptoms.
Effect of the first infliximab infusion on sleep and alertness in patients with active rheumatoid arthritis
Authors: C Zamarron
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> To assess the benefit of the first infliximab infusion on sleep disturbances in patients with RA <b>Material and methods:</b> Evaluation of RA activity, sleepiness (Epworth scale and multiple sleep latency test), alertness (steer clear test), and sleep structure (polysomnography) were conducted before and after the first infusion of infliximab in six female patients with RA. <b>Results:</b> The day after the first infliximab infusion, the mean (SD) number of tender (20 (2.4)) or swollen (15.3 (2)) joints and the morning stiffness (140 (61.9) min) had not changed. There were significant improvements in the median number of total sleep stage transitions per hour (median (IR) before <i>v</i> after infusion: 20.5 (43) <i>v</i> 7.5 (6); Wilcoxon paired test, p = 0.014), median percentage of phase I+II (83.5 (8) <i>v</i> 54.5 (24); p = 0.023), percentage of REM stages (2 (10) <i>v</i> 11.5 (8); p = 0.014), median percentage sleep efficiency (44 (22) <i>v</i> 75 (18); p = 0.014), median sleep latency (77.5 (150) <i>v</i> 25.5 (23) min; p = 0.023), and median number of hits in the steer clear test (48.5 (86) <i>v</i> 6 (45); p = 0.023). Neither objective nor subjective daytime sleepiness was noted. One obese patient had obstructive sleep apnoea syndrome. <b>Conclusions:</b> Sleep and the alertness disturbances in RA improve with infliximab treatment. Improvement appears unrelated to joint discomfort amelioration but suggests a central effect through inhibition of circulating TNFα levels.
Identification of PSD-95 as a Regulator of Dopamine-Mediated Synaptic and Behavioral Plasticity
Authors: Wei-Dong Yao, Raul R Gainetdinov, Margaret I Arbuckle, Tatyana D Sotnikova, Michel Cyr, Jean-Martin Beaulieu, Gonzalo E Torres, Seth G.N Grant, Marc G Caron
Journal: Neuron (2004)
Octogenarians Reaching End-Stage Renal Disease
Authors: Dominique Joly, Dany Anglicheau, Corinne Alberti, Anh-Thu Nguyen, Malik Touam, Jean-Pierre Grünfeld, Paul Jungers
Journal: Journal of the American Society of Nephrology (2003)

The fate of octogenarians reaching end-stage renal disease (ESRD) is poorly defined, and implicit dialysis rationing may be practiced in this age group. The main objectives of this study were to analyze the characteristics of pre-ESRD octogenarians offered dialysis or not and to identify factors influencing mortality while on dialysis, to improve prognosis assessment and decision-making. In this single-center cohort, 146 consecutive pre-ESRD octogenarians were referred to a nephrology unit over a 12-yr period (1989 to 2000). Main outcome measures were baseline characteristics of patients offered dialysis and conservative therapy and overall and 1-yr survival according to effective treatment. A therapeutic decision was made for 144 patients. Octogenarians who were not proposed dialysis (n = 37) differed from those who were proposed dialysis (n = 107) mainly in terms of social isolation (43.3% versus 14.7%; P = 0.03), late nephrologic referral (51.4% versus 28.9%; P = 0.01), Karnofsky score (55 +/- 18 versus 63 +/- 20; P = 0.03), and diabetic status (22.2% versus 6.5%, P = 0.008). Six patients refused the dialysis proposal. During the 12-yr observation period, 99 patients died (68.7%). Median survival was 28.9 mo (95% CI, 24 to 38) in patients undergoing dialysis, compared with 8.9 mo (95% CI, 4 to 10) in patients treated conservatively (P < 0.0001). In multivariable piecewise Cox analysis, independent predictors of death within 1 yr on dialysis were poor nutritional status, late referral, and functional dependence. Included in a survivor function, these covariates predict groups with low and high 1-yr mortality risk. Beyond 1 yr on dialysis, the only independent predictor of death was the presence of peripheral vascular disease. It is concluded that beside a patient's individual refusal, late referral, social isolation, low functional capacity, and diabetes may have oriented medical decision toward withholding dialysis in a significant proportion of pre-ESRD octogenarians. Although most patients on dialysis experienced a substantial prolongation of life, identification of mortality predictors in this age group should improve the process of decision-making regarding the expected benefit of renal replacement therapy.
Measure is treasure
Authors: M van den Hoff
Journal: Cardiovascular Research (1999)

See article by Ribadeau-Dumas et al. [1] ( pages 426 -specific protein or activity are to be evaluated.Not only is 436) in this issue.it often implicitly assumed that the tissue base (total RNA, or total protein) does not change during the conditions The paper of studied, it is also often implicitly assumed that the two deals with the interesting, but complex regulation of the SERCA2 gene.This gene encodes the sarcoplasmatic calcium pump, which is a crucial enzyme in the calcium handling of the cardiomyocyte.Insight into the regulation of this gene is therefore of paramount importance.A proper understanding of the regulation of the expression of a gene in adult, developing, experimental or diseased (cardiac) tissue requires precise knowledge of the control at each step from gene to the function of the encoded protein, comprising RNA and protein accumulation (being the product of synthesis and degradation) and biological activity of the studied protein.This list can of course be extended (Fig. 1).If we are to appreciate at which step in this pathway control is predominantly exerted, it is important to quantify as many of the parameters as possible.It is equally important to relate the disparate parameters with one another, to evaluate, for example, whether or not the increase in biological activity is proportional with the increase in the amount of protein, or whether the increase in protein follows a proportionate increase in the encoding mRNA.The vital role of quantification of the distinct parameters for our understanding of the regulation of (cardiac) gene expression is beyond any dispute.The lightheartedness concerning this topic is therefore surprising.It is convention to use total RNA (UV-measurement, ethidium bromide staining, 18S or 28S hybridization) or a housekeeping gene (GAPDH-mRNA or EF1a-mRNA) as tissue base if the levels of a specific mRNA are to be evaluated (e.g. by Northern blotting, or RNase-protection assay) and to use total protein as tissue base if levels of a
Genetic analysis reveals cell type-specific regulation of receptor tyrosine kinase c-Kit by the protein tyrosine phosphatase SHP1.
Authors: U Lorenz, A D Bergemann, H N Steinberg, J G Flanagan, X Li, S J Galli, B G Neel
Journal: The Journal of Experimental Medicine (1996)

Receptor protein tyrosine kinases (RTKs) transmit downstream signals via interactions with secondary signaling molecules containing SH2 domains. Although many SH2-phosphotyrosyl interactions have been defined in vitro, little is known about the physiological significance of specific RTK/SH2 interactions in vivo. Also, little is known about the mechanisms by which specific RTKs interact with and/or are regulated by specific protein tyrosine phosphatases (PTPs). To address such issue, we carried out a genetic analysis of the previously reported biochemical interaction between the RTK c-Kit, encoded at the W locus, and the SH2-containing non-transmembrane PTP SHP1, encoded at the motheaten (me) locus (1). Mice carrying a kinase-defective allele of c-Kit (Wv/+) were crossed with me/+ mice, which carry one effectively null allele of SHP1, and then backcrossed to generate all possible allelic combinations. Our results indicate strong intergenic complementation between these loci in hematopoietic progenitor cells. Compared to progenitors purified from normal mice, bone marrow progenitor cells (lin-) from me/me mice markedly hyper-proliferated in response to Kit ligand (KL). stimulation. Superimposition of the me/me genotype increased the number of one marrow-derived CFU-E from Wv/+ mice. Conversely, the presence of one or two copies of Wv decreased the number of macrophages and granulocytes in me/me lung, skin, peripheral blood and bone marrow, thereby decreasing the severity of the me/me phenotype. The decrease in dermal mast cells in Wv/Wv mice was rescued to levels found in Wv/+mice by superimposition of the me/me genotype. Surprisingly, however, the presence or absence of SHP1 had no effect on the proliferative response of bone marrow-derived cultured mast cells to KL or IL3 ex vivo. Nevertheless, the immediate-early response to KL stimulation, as measured by KL-induced tyrosyl phosphorylation, was substantially increased in mast cells from Wv/+:me/me compared to Wv/ +:+/+ mice, strongly suggesting that SHP1 directly dephosphorylates and regulates c-Kit. Taken together, our results establish that SHP1 negatively regulates signaling from c-Kit in vivo, but in a cell type-specific manner.
Different effects of the BIM deletion polymorphism on treatment of solid tumors by the tyrosine kinase inhibitors (TKI) pazopanib, sunitinib, and lapatinib
Authors: C.F. Spraggs, L.R. Parham, K. Song, L.P. Briley, T. Johnson, M. Russo, H. Tada, A. du Bois, C.-F. Xu
Journal: Annals of Oncology (2015)
Lack of Neutrophil-Derived CRAMP Reduces Atherosclerosis in Mice
Authors: Yvonne Döring, Maik Drechsler, Sarawuth Wantha, Klaus Kemmerich, Dirk Lievens, Santosh Vijayan, Richard L. Gallo, Christian Weber, Oliver Soehnlein
Journal: Circulation Research (2012)

Rationale: Neutrophils have been reported to contribute to early atherosclerotic lesion formation. Mechanisms of neutrophil-driven atherosclerosis remain unclear so far. Objective: Investigation of the role of the neutrophil granule protein cathelicidin (CRAMP in mouse, LL37 in human) in atherosclerosis. Methods and Results: Compared to Apoe −/− mice, Cramp −/− Apoe −/− mice exhibit reduced lesion sizes with lower macrophage numbers. In atherosclerotic aortas, we could detect CRAMP specifically in neutrophils, but not in monocytes or macrophages. By use of intravital microscopy, CRAMP was found to be deposited by activated neutrophils on inflamed endothelium of large arteries. In this location cathelicidins promote adhesion of classical monocytes and neutrophils, but not nonclassical monocytes in a formyl-peptide receptor-dependent manner. Conclusions: Cathelicidins promote atherosclerosis by enhancement of the recruitment of inflammatory monocytes.