tbuckley/cabot-search huggingface dataset:
<i>EML4-ALK</i>Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer
Authors: Jussi P. Koivunen, Craig Mermel, Kreshnik Zejnullahu, Carly Murphy, Eugene Lifshits, Alison J. Holmes, Hwan Geun Choi, Jhingook Kim, Derek Chiang, Roman Thomas, Jinseon Lee, William G. Richards, David J. Sugarbaker, Christopher Ducko, Neal Lindeman, J. Paul Marcoux, Jeffrey A. Engelman, Nathanael S. Gray, Charles Lee, Matthew Meyerson, Pasi A. Jänne
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The EML4-ALK fusion gene has been detected in ∼7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLC and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK-containing cell lines in vitro and in vivo. Experimental Design: We screened 305 primary NSCLC [both U.S. (n = 138) and Korean (n = 167) patients] and 83 NSCLC cell lines using reverse transcription-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo. Results: We detected four different variants, including two novel variants, of EML4-ALK using reverse transcription-PCR in 8 of 305 tumors (3%) and 3 of 83 (3.6%) NSCLC cell lines. All EML4-ALK-containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (&amp;lt;10 pack-years) cigarette smokers compared with current/former smokers (6% versus 1%; P = 0.049). TAE684 inhibited the growth of one of three (H3122) EML4-ALK-containing cell lines in vitro and in vivo, inhibited Akt phosphorylation, and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to coactivation of epidermal growth factor receptor and ERBB2. The combination of TAE684 and CL-387,785 (epidermal growth factor receptor/ERBB2 kinase inhibitor) inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line. Conclusions: EML4-ALK is found in the minority of NSCLC. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK.
Randomized Trial of a Specialist Genetic Assessment Service for Familial Breast Cancer
Authors: K. Brain, J. Gray, P. Norman, E. France, C. Anglim, G. Barton, E. Parsons, A. Clarke, H. Sweetland, M. Tischkowitz, J. Myring, K. Stansfield, D. Webster, K. Gower-Thomas, R. Daoud, C. Gateley, I. Monypenny, H. Singhal, L. Branston, J. Sampson, E. Roberts, R. Newcombe, D. Cohen, C. Rogers, R. Mansel, P. Harper
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Because of the growing demand for genetic assessment, there is an urgent need for information about what services are appropriate for women with a family history of breast cancer. Our purpose was to compare the psychologic impact and costs of a multidisciplinary genetic and surgical assessment service with those of current service provisions. Methods: We carried out a prospective randomized trial of surgical consultation with (the trial group) and without (the control group) genetic assessment in 1000 women with a family history of breast cancer. All P values are from two-sided tests. Results: Although statistically significantly greater improvement in knowledge about breast cancer was found in the trial group (P = .05), differences between groups in other psychologic outcomes were not statistically significant. Women in both groups experienced statistically significant reductions in anxiety and found attending the clinics to be highly satisfying. An initial specialist genetic assessment cost £14.27 (U.S. $22.55) more than a consultation with a breast surgeon. Counseling and genetic testing of affected relatives, plus subsequent testing of family members of affected relatives identified as mutation carriers, raised the total extra direct and indirect costs per woman in the trial group to £60.98 (U.S. $96.35) over costs for the control subjects. Conclusions: There may be little benefit in providing specialist genetics services to all women with a family history of breast cancer. Further investigation of factors that may mediate the impact of genetic assessment is in progress and may reveal subgroups of women who would benefit from specialist genetics services.
Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study
Authors: Jeeyun Lee, Se Hoon Park, Heung-Moon Chang, Jun Suk Kim, Hye Jin Choi, Myung Ah Lee, Joung Soon Jang, Joung Soon Chang, Hei Cheul Jeung, Jung Hun Kang, Hyun Woo Lee, Dong Bok Shin, Hye Jin Kang, Jong-Mu Sun, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim
Journal: The Lancet Oncology (2011)
Influence of Comorbid Alcohol and Psychiatric Disorders on Utilization of Mental Health Services in the National Comorbidity Survey
Authors: L T Wu, A C Kouzis, P J Leaf
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: This study sought to determine how comorbidity of psychiatric and substance abuse disorders affects the likelihood of using mental health services. METHOD: The analysis was based on data on adults aged 18–54 years in the National Comorbidity Survey (N=5,393). Users and nonusers of mental health and substance abuse services were compared in terms of their demographic characteristics, recent stressful life events, social support, parental history of psychopathology, self-medication, and symptoms of alcohol abuse/dependence. RESULTS: The prevalence of service utilization varied by diagnostic configurations. Comorbid psychiatric or alcohol disorders were stronger predictors of service utilization than a pure psychiatric or alcohol disorder. Factors predicting utilization of services differed for each disorder. CONCLUSIONS: Since comorbidity increases the use of mental health and substance abuse services, research on the relationship of psychiatric and alcohol-related disorders to service utilization needs to consider the coexistence of mental disorders. Attempts to reduce barriers to help seeking for those in need of treatment should be increased.
Anti–Endothelial Cell Autoantibodies Selectively Activate SAPK/JNK Signalling in Wegener’s Granulomatosis
Authors: Carolina Holme[Combining Acute Accent]n, Elzafir Elsheikh, Marta Christensson, Jining Liu, Anne-Sofie Johansson, Abdul Rashid Qureshi, Sirpa Jalkanen, Suchitra Sumitran-Holgersson
Journal: Journal of the American Society of Nephrology (2007)

The pathogenic role of anti-endothelial cell antibodies (AECA) in vascular injury is debated. It was previously shown that many patients with Wegener's granulomatosis (WG) have AECA that react with human kidney microvascular endothelial cells (EC). In addition, during active disease, renal endothelium strongly expresses the inflammatory molecules vascular adhesion protein-1 (VAP-1) and MHC class I-related antigen A (MICA). This study sought to determine whether AECA mediates this upregulation of VAP-1 and MICA and to define better the signaling pathways that are activated by these autoantibodies upon binding to EC in the kidney. Stimulation of human kidney microvascular EC with AECA IgG upregulated surface expression of MICA and VAP-1, elicited a rapid Ca2+ flux, induced high levels of the chemokines monocyte chemoattractant protein-1 and granulocyte chemotactic protein-2, induced specific phosphorylation of stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and the transcription factors c-Jun and activating transcription factor-2, and activated NF-kappaB. Specific inhibitors of SAPK/JNK significantly reduced AECA-induced chemokine production and phosphorylation of c-Jun and activating transcription factor-2 and abrogated protein expression of MICA but not VAP-1. In kidney sections from patients with WG, infiltrating cells that expressed the ligand for MICA (NKG2D+) were identified, as were CD8+ and 32 gamma delta+ T cells. In conclusion, AECA may be involved in the pathogenesis of WG, and the SAPK/JNK pathway and the endothelial inflammatory protein VAP-1 may be novel therapeutic targets for vasculitis.
A SNP profiling panel for sample tracking in whole-exome sequencing studies
Authors: Reuben J Pengelly, Jane Gibson, Gaia Andreoletti, Andrew Collins, Christopher J Mattocks, Sarah Ennis
Journal: Genome Medicine (2013)

Whole-exome sequencing provides a cost-effective means to sequence protein coding regions within the genome, which are significantly enriched for etiological variants. We describe a panel of single nucleotide polymorphisms (SNPs) to facilitate the validation of data provenance in whole-exome sequencing studies. This is particularly significant where multiple processing steps necessitate transfer of sample custody between clinical, laboratory and bioinformatics facilities. SNPs captured by all commonly used exome enrichment kits were identified, and filtered for possible confounding properties. The optimised panel provides a simple, yet powerful, method for the assignment of intrinsic, highly discriminatory identifiers to genetic samples.
Analysis of the interpolation phenomenon in man evaluated by premature atrial stimulation
Authors: G. MASINI, R. DIANDA
Journal: Cardiovascular Research (1977)

After early premature atrial stimulations, returning cycles shorter than the basic cycle were observed in 25 patients. In 4 of them sinus echoes were seen to occur after premature atrial stimulation coupling intervals shorter than those able to induce completely interpolated beats. Such a sequence is unexpected if we suggest a sino-atrial entrance block for explaining the interpolation phenomenon. An alternative explanation can be postulated assuming that all these early premature beats are sinus node re-entries and that the completely interpolated beat is only a sinus re-entry fortuitously occurring at an appropriate interval.
Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study
Authors: Karim Fizazi, Howard I Scher, Arturo Molina, Christopher J Logothetis, Kim N Chi, Robert J Jones, John N Staffurth, Scott North, Nicholas J Vogelzang, Fred Saad, Paul Mainwaring, Stephen Harland, Oscar B Goodman, Cora N Sternberg, Jin Hui Li, Thian Kheoh, Christopher M Haqq, Johann S de Bono
Journal: The Lancet Oncology (2012)
Attempted Suicide and Alcoholism in Bipolar Disorder: Clinical and Familial Relationships
Authors: J B Potash, H S Kane, Y F Chiu, S G Simpson, D F MacKinnon, M G McInnis, F J McMahon, J R DePaulo
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: This study examined the clinical and familial relationships between comorbid alcoholism and attempted suicide in affectively ill relatives of probands with bipolar I disorder. METHOD: In 71 families ascertained for a genetic linkage study, 337 subjects with major affective disorder were assessed by using the Schedule for Affective Disorders and Schizophrenia—Lifetime Version. RESULTS: Subjects with bipolar disorder and alcoholism had a 38.4% lifetime rate of attempted suicide, whereas those without alcoholism had a 21.7% rate. Attempted suicide among subjects with bipolar disorder and alcoholism clustered in a subset of seven families. Families with alcoholic and suicidal probands had a 40.7% rate of attempted suicide in first-degree relatives with bipolar disorder, whereas other families had a 19.0% rate. CONCLUSIONS: Comorbid alcoholism was associated with a higher rate of attempted suicide among family members with bipolar disorder. Attempted suicide and alcoholism clustered in a subset of families. These relationships may have a genetic origin and may be mediated by intoxication, mixed states, and/or temperamental instability.
Neuropharmacology of Phencyclidine: Basic Mechanisms and Therapeutic Potential
Authors: K M Johnson, S M Jones
Journal: The Annual Review of Pharmacology and Toxicology (1990)

Neuropharmacology of Phencyclidine: Basic Mechanisms and Therapeutic Potential, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/pharmtox/30/1/annurev.pa.30.040190.003423-1.gif
The ShcA PTB Domain Functions as a Biological Sensor of Phosphotyrosine Signaling during Breast Cancer Progression
Authors: Ryuhjin Ahn, Valerie Sabourin, Jacqueline R. Ha, Sean Cory, Gordana Maric, Young Kyuen Im, W. Rod Hardy, Hong Zhao, Morag Park, Michael Hallett, Peter M. Siegel, Tony Pawson, Josie Ursini-Siegel
Journal: Cancer Research (2013)

ShcA (SHC1) is an adapter protein that possesses an SH2 and a PTB phosphotyrosine-binding motif. ShcA generally uses its PTB domain to engage activated receptor tyrosine kinases (RTK), but there has not been a definitive determination of the role of this domain in tumorigenesis. To address this question, we employed a ShcA mutant (R175Q) that no longer binds phosphotyrosine residues via its PTB domain. Here, we report that transgenic expression of this mutant delays onset of mammary tumors in the MMTV-PyMT mouse model of breast cancer. Paradoxically, we observed a robust increase in the growth and angiogenesis of mammary tumors expressing ShcR175Q, which displayed increased secretion of fibronectin and expression of integrin α5/β1, the principal fibronectin receptor. Sustained integrin engagement activated Src, which in turn phosphorylated proangiogenic RTKs, including platelet-derived growth factor receptor, fibroblast growth factor receptor, and Met, leading to increased VEGF secretion from ShcR175Q-expressing breast cancer cells. We defined a ShcR175Q-dependent gene signature that could stratify breast cancer patients with a high microvessel density. This study offers the first in vivo evidence of a critical role for intracellular signaling pathways downstream of the ShcA PTB domain, which both positively and negatively regulate tumorigenesis during various stages of breast cancer progression.
Prehospital Use of Magnesium Sulfate as Neuroprotection in Acute Stroke
Authors: Jeffrey L. Saver, Sidney Starkman, Marc Eckstein, Samuel J. Stratton, Franklin D. Pratt, Scott Hamilton, Robin Conwit, David S. Liebeskind, Gene Sung, Ian Kramer, Gary Moreau, Robert Goldweber, Nerses Sanossian
Journal: New England Journal of Medicine (2015)

Magnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. Delayed initiation of neuroprotective agents has hindered earlier phase 3 trials of neuroprotective agents.We randomly assigned patients with suspected stroke to receive either intravenous magnesium sulfate or placebo, beginning within 2 hours after symptom onset. A loading dose was initiated by paramedics before the patient arrived at the hospital, and a 24-hour maintenance infusion was started on the patient's arrival at the hospital. The primary outcome was the degree of disability at 90 days, as measured by scores on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability).Among the 1700 enrolled patients (857 in the magnesium group and 843 in the placebo group), the mean (±SD) age was 69±13 years, 42.6% were women, and the mean pretreatment score on the Los Angeles Motor Scale of stroke severity (range, 0 to 10, with higher scores indicating greater motor deficits) was 3.7±1.3. The final diagnosis of the qualifying event was cerebral ischemia in 73.3% of patients, intracranial hemorrhage in 22.8%, and a stroke-mimicking condition in 3.9%. The median interval between the time the patient was last known to be free of stroke symptoms and the start of the study-drug infusion was 45 minutes (interquartile range, 35 to 62), and 74.3% of patients received the study-drug infusion within the first hour after symptom onset. There was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the magnesium group and those in the placebo group (P=0.28 by the Cochran-Mantel-Haenszel test); mean scores at 90 days did not differ between the magnesium group and the placebo group (2.7 in each group, P=1.00). No significant between-group differences were noted with respect to mortality (15.4% in the magnesium group and 15.5% in the placebo group, P=0.95) or all serious adverse events.Prehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 hours after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days. (Funded by the National Institute of Neurological Disorders and Stroke; FAST-MAG ClinicalTrials.gov number, NCT00059332.).
Acute Pressure Overload Could Induce Hypertrophic Responses in the Heart of Angiotensin II Type 1a Knockout Mice
Authors: Koichiro Harada, Issei Komuro, Yunzeng Zou, Sumiyo Kudoh, Kazuhisa Kijima, Hiroaki Matsubara, Takeshi Sugaya, Kazuo Murakami, Yoshio Yazaki
Journal: Circulation Research (1998)

Abstract —Increasing evidence has suggested that locally produced angiotensin II (Ang II) plays an important role in the development of cardiac hypertrophy through the Ang II type 1 receptor (AT1). We and others have recently reported that Ang II is critical for mechanical stress–induced hypertrophic responses in vitro. Using AT1a knockout (KO) mice, we examined whether Ang II is indispensable for pressure overload–induced cardiac hypertrophy in the present study. Reverse-transcriptase polymerase chain reaction analysis revealed that AT1 mRNA levels were &lt;10% in the heart of KO mice compared with wild-type (WT) mice, but the Ang II type 2 receptor gene was expressed at almost the same levels in the hearts of both mice. Intravenous infusion of subpressor dose of Ang II induced c- fos gene expression in the hearts of WT mice but not KO mice. Acute pressure overload, however, induced expressions of immediate-early response genes and activations of mitogen-activated protein kinases in the hearts of KO mice as well as WT mice. Both basal and activated levels of all these responses were significantly higher in KO mice than in WT mice. Pressure overload markedly increased the heart weight–to–body weight ratio in both mice strains at 14 days after aortic banding. These results suggest that acute hypertrophic responses could be induced by pressure overload in the in vivo heart without AT1 signaling.
Exploring the Social Brain in Schizophrenia: Left Prefrontal Underactivation During Mental State Attribution
Authors: T A Russell, K Rubia, E T Bullmore, W Soni, J Suckling, M J Brammer, A Simmons, S C Williams, T Sharma
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Evidence suggests that patients with schizophrenia have a deficit in "theory of mind," i.e., interpretation of the mental state of others. The authors used functional magnetic resonance imaging (MRI) to investigate the hypothesis that patients with schizophrenia have a dysfunction in brain regions responsible for mental state attribution. METHOD: Mean brain activation in five male patients with schizophrenia was compared to that in seven comparison subjects during performance of a task involving attribution of mental state. RESULTS: During performance of the mental state attribution task, the patients made more errors and showed less blood-oxygen-level-dependent signal in the left inferior frontal gyrus. CONCLUSIONS: To the authors' knowledge, this is the first functional MRI study to show a deficit in the left prefrontal cortex in schizophrenia during a socioemotional task.
Pulmonary fibrosis: cytokines in the balance
Authors: RK Coker, GJ Laurent
Journal: European Respiratory Journal (1998)

Pulmonary fibrosis can complicate diverse pulmonary and systemic pathologies. In many cases the underlying cause remains unidentified. Mortality from the disease is increasing steadily in the UK and USA. The clinical features are well-described, but patients frequently present at an advanced stage, and current treatments have not improved the poor prognosis. There is a compelling need to identify the fibrotic process earlier and to develop new therapeutic agents. Increased collagen deposition is central to the pathology and interest over the last decade has focused on the role of cytokines in this process. These polypeptide mediators are believed to be released from both circulating inflammatory and resident lung cells in response to endothelial and epithelial injury. Key cytokines currently implicated in the fibrotic process are transforming growth factor-beta, tumour necrosis factor-alpha and endothelin-1. This article outlines the evidence implicating these mediators in the pathogenesis of pulmonary fibrosis and also considers the possible role of cytokines with antifibrotic effects, such as interferon-gamma. The "balance" of positively and negatively regulating cytokines is discussed, and the potential for interaction with other factors including viruses, hormones and altered antioxidant status is also considered. Finally, potential novel therapeutic approaches are discussed, together with suggestions for future studies and clinical trials. As the outcomes of different avenues of research over the last ten years are brought together, it is clear that there is now a hitherto unrivalled opportunity to begin to tackle the treatment of this devastating disease.
Role for TGF-β in Cyclosporine-Induced Modulation of Renal Epithelial Barrier Function
Authors: Gemma Feldman, Breda Kiely, Natalia Martin, Gavin Ryan, Tara McMorrow, Michael P. Ryan
Journal: Journal of the American Society of Nephrology (2007)

It was previously shown that cyclosporine A (CsA) increases transepithelial resistance in MDCK cells. Activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) cascade seems to be pivotal to the CsA-induced increase in transepithelial electrical resistance (TER). This study examined the role played by TGF-beta in mediating the CsA-induced activation of ERK1/2 and the resulting increase in TER in MDCK cells. Paracellular permeability across MDCK monolayers after various treatments was assessed by measurement of TER. TGF-beta secretion was measured by Western blot and ELISA. Activation of the ERK1/2 pathway and tight junction protein expression were also assessed by Western blot analysis. CsA increased production and secretion of TGF-beta and expression of the TGF-beta receptor II. Exogenous addition of TGF-beta1 activated ERK1/2 and increased TER across MDCK monolayers, both of which were attenuated by the MEK inhibitor U0126. Neutralizing antibodies against TGF-beta1 and the TGF-beta receptor II significantly reduced the CsA-induced increase in TER. Both CsA and TGF-beta1 increased expression of tight junction proteins claudin-1 and zonula occludens 2. Inhibition of the p38 MAPK pathway also attenuated the TGF-beta1-induced increase in TER. The results presented here suggest that the CsA-induced modulation of paracellular permeability may be mediated, at least in part, by an increase in TGF-beta production.