tbuckley/cabot-search huggingface dataset:
PAK1 Mediates Resistance to PI3K Inhibition in Lymphomas
Authors: Katherine Walsh, Matthew S. McKinney, Cassandra Love, Qingquan Liu, Alice Fan, Amee Patel, Jason Smith, Anne Beaven, Dereje D. Jima, Sandeep S. Dave
Journal: Clinical Cancer Research (2013)

The phosphoinositide 3-kinase (PI3K) pathway is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B-cell lymphomas.We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs.We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference-mediated knockdown of the PAK1 gene, we showed a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small-molecule inhibitor of PAK1 and found significant synergy between PI3K and PAK1 inhibition.Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.
Combination Analysis of Hypermethylated Wnt-Antagonist Family Genes as a Novel Epigenetic Biomarker Panel for Bladder Cancer Detection
Authors: Shinji Urakami, Hiroaki Shiina, Hideki Enokida, Toshifumi Kawakami, Ken Kawamoto, Hiroshi Hirata, Yuichiro Tanaka, Nobuyuki Kikuno, Masayuki Nakagawa, Mikio Igawa, Rajvir Dahiya
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Aberrant promoter hypermethylation of Wnt-antagonist genes contributes to the pathogenesis of several cancers. We hypothesized that combined methylation analysis of Wnt-antagonist genes could improve their use as a panel of biomarkers for diagnosing and staging of bladder cancers. Experimental Design: Samples (54 total) of bladder tumor and corresponding normal bladder mucosa were analyzed for the methylation and expression levels of six Wnt-antagonist genes (sFRP-1, sFRP-2, sFRP-4, and sFRP-5, Wif-1, and Dkk-3). To increase the sensitivity/specificity of bladder tumor detection, the methylation score (M score), a new method for multigene methylation analysis, was developed. The M score of each sample was calculated as the sum of the corresponding log hazard ratio coefficients derived from multivariate logistic regression analysis of the methylation status for each Wnt-antagonist gene. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal sensitivity/specificity of the M score. Urine DNA from 24 matched patients with bladder tumor and 20 cancer-free volunteers was also used to investigate the methylation status of Wnt-antagonist genes. Results: The methylation levels of Wnt-antagonists were significantly higher and mRNA levels were significantly lower in bladder tumor than in bladder mucosa. Each methylation level was inversely correlated with the corresponding mRNA level. In multivariate regression analysis, the methylation levels of sFRP-2 and Dkk-3 were significant independent predictors of bladder tumor (P &amp;lt; 0.05 and P &amp;lt; 0.01, respectively), whereas with sFRP-1, sFRP-5, and Wif-1 there was a trend towards significance as independent predictors. The M score of Wnt-antagonist genes was significantly higher in bladder tumor than in bladder mucosa (P &amp;lt; 0.05). Overall, the M score had a sensitivity of 77.2% and a specificity of 66.7% as a diagnostic biomarker (areas under the curve, 0.763). The M score could distinguish superficial from invasive bladder tumors with a sensitivity of 72.2% and a specificity of 61.1% as a staging biomarker (areas under the curve, 0.671). In patients with bladder tumor, 80.6% of the methylation-specific PCR results had identical methylation in samples of tumor- and urine-derived DNA. Most urine DNA in normal controls showed no aberrant methylation of the Wnt-antagonist genes. Conclusions: Hypermethylation of Wnt-antagonist genes plays an important role in the pathogenesis of bladder tumor and can be detected using cellular DNA extracted from urine samples. This is the first report demonstrating that M score analysis of Wnt-antagonist genes could serve as an excellent epigenetic biomarker panel for bladder tumors.
P273 Outcome after prolonged invasive mechanical ventilation in myotonic dystrophy
Authors: S. K. Banerjee, V. Licence, N. Oscroft, M. G. Davies, T. Quinnell, J. Shneerson, I. E. Smith
Journal: Thorax (2011)

<h3>Introduction</h3> Patients with myotonic dystrophy (MD) may present acutely with respiratory failure due to muscle weakness and aspiration pneumonia. We are not aware of published data regarding the outcome of intubation and ventilation in these circumstances. <h3>Method</h3> We performed a retrospective case notes review of patients referred to a specialist respiratory support centre with a diagnosis of MD. In this abstract we present the outcomes of patients who had received invasive mechanical ventilation and were transferred as in-patients to our unit. <h3>Results</h3> Between 1996 and 2010, 22 patients (seven men), mean age 39 years, who had all been intubated and ventilated for a minimum of 2 weeks, were referred. At transfer, 16 patients were tracheostomy ventilated, two were on non-invasive ventilation (NIV) and five were self-ventilating but had on-going CO<sub>2</sub> retention. Where specified, admission to ICU was precipitated by pneumonia (16), sudden collapse (2) and cardiac failure (2). The mean duration of invasive ventilatory support was 67 (range 17–196) days. One patient died in our unit. Of those discharged, 11 were on NIV, five still required tracheostomy ventilation and six were ventilator independent. Five patients required a mini-trach tube for access to secretions. The mean length of stay in the weaning unit was 35 (range 2–95) days. Mean survival post discharge was 44 (range 1–102) months. In the same period 53 patients with MD who had not been intubated and ventilated were initiated on NIV for ventilatory failure in our unit. Mean survival in this group was 56 (range 1–144) months. <h3>Conclusion</h3> Patients with MD may require prolonged invasive ventilation when presenting with acute ventilatory decompensation. In this series the majority weaned from invasive mechanical ventilation and treatment including NIV was associated with survival on average of over 3.5 years. The prognosis may not be as good as for those patients with MD starting NIV who have not required prior intubation.
Low bone mineral density in adults with cystic fibrosis
Authors: C S Haworth, P L Selby, A K Webb, M E Dodd, H Musson, R M. Niven, G Economou, A W Horrocks, A J Freemont, E B Mawer, J E Adams
Journal: Thorax (1999)

<h3>BACKGROUND</h3> Patients with cystic fibrosis have several risk factors for the development of low bone mineral density (BMD). To identify the prevalence and clinical correlates of low BMD in adult patients with cystic fibrosis, densitometry was performed in 151 patients (83 men) aged 15–52 years. <h3>METHODS</h3> BMD was measured in the lumbar spine (L1–4) using dual energy<i>x</i> ray absorptiometry (DXA) and quantitative computed tomography (QCT). It was also measured in the proximal femur (total hip and femoral neck) using DXA, and in the distal and ultra distal forearm using single energy <i>x</i> ray absorptiometry (SXA). Biochemical markers of bone turnover, vitamin D levels, parathyroid hormone levels, and a variety of anthropometric variables were also assessed. <h3>RESULTS</h3> The mean (SD) BMD Z score was –0.73 (0.85) in the distal forearm, –0.31 (0.92) in the ultra distal forearm, –1.21 (1.18) in the lumbar spine using DXA, –0.56 (1.36) in the lumbar spine using QCT, –1.25 (1.30) in the femoral neck, and –1.01 (1.14) in the total hip. 34% of patients had a BMD Z score of –2 or less at one or more skeletal sites. Body mass index (0.527, p = 0.01), percentage predicted forced expiratory volume in one second (0.388, p = 0.01), and physical activity (0.249, p = 0.05) were positively related to the mean BMD Z score. Levels of C reactive protein (–0.328, p = 0.01), parathyroid hormone (–0.311, p = 0.01) and biochemical markers of bone turnover (osteocalcin –0.261 and bone specific alkaline phosphatase –0.249, p = 0.05) were negatively related to the mean BMD Z score. Vitamin D insufficiency (25-hydroxyvitamin D &lt;15 ng/ml) was prevalent (53/139 patients, 38%) despite supplementation with 900 IU vitamin D per day. <h3>CONCLUSIONS</h3> Low bone density is prevalent in adult patients with cystic fibrosis. Current levels of vitamin D supplementation appear to be inadequate.
Human Leukocyte Antigen Class I-Restricted Activation of CD8+ T Cells Provides the Immunogenetic Basis of a Systemic Drug Hypersensitivity
Authors: Diana Chessman, Lyudmila Kostenko, Tessa Lethborg, Anthony W. Purcell, Nicholas A. Williamson, Zhenjun Chen, Lars Kjer-Nielsen, Nicole A. Mifsud, Brian D Tait, Rhonda Holdsworth, Coral Ann Almeida, David Nolan, Whitney A. Macdonald, Julia K. Archbold, Anthony D. Kellerher, Debbie Marriott, Simon Mallal, Mandvi Bharadwaj, Jamie Rossjohn, James McCluskey
Journal: Immunity (2008)
Pregnenolone in the Treatment of Rheumatoid Arthritis
Authors: G. Norman Myers
Journal: Annals of the Rheumatic Diseases (1951)

Since Hench, Kendall, Slocumb, and Polley (1949) described their results from the administration of cortisone (17-hydroxy-1 1-dehydrocorticosterone) and of the anterior pituitary adrenocorticotrophic hormone in the treatment of rheumatoid arthritis, there has been much speculation regarding the possible use of other substances which might produce similar effects.The search for such substances has been confined primarily to tWo main groups:(a) those, like adrenaline, which are known to stimulate the production of the anterior pituitary corticotrophic hormone, (b) those which ,may be precursors of more active steroid hormones.From the chemical standpoint A-5-pregnenolone has been suggested as a precursor and has attracted the attention of a number of workers.Davison and others (1950) treated thirty arthritis patients with pregnenolone acetate, fourteen of whom were suffering from rheumatoid arthritis.Solutions in oil, as well as aqueous suspensions, were administered by the intramuscular route.Daily injections, up to 200 and 300 mg.respectively, were given over a period of 3 to 8 weeks.They reported results which appear to be definitely favourable.Pain and stiffness in joints was diminished, muscle strength was increased, and fatigue was less evident.A feeling of " well-being " was established, usually within a few days.Reduction in joint swelling was slow, and reduction in the erythrocyte sedimentation rate, if any, did not run parallel with the clinical improvement, but followed it.No toxic effects were observed; the menstrual cycle and sexual potency were unaffected.None of the subjects under test experienced euphoria, but one patient suffered from insomnia while, receiving the maximum dosage.When the injections were discontinued, the arthritic symptoms returned within a few days.No beneficial effects were observed in cases of rheumatoid arthritis with psoriasis, severe gout, or disseminated lupus.Ishmael and others (1949) employed pregnenolone in doses up to a maximum of 100 mg.daily, as well as in combination with high-dosage androgen and oestrogen theiapy.They reported that when pregnenolone was administered alone, about 50 per cent. of the patients with rheumatoid arthritis responded favourably.One patient, however, developed mental depression and a feeling of weakness.32
Aberrant Stat3 Signaling by Interleukin-4 in Malignant Glioma Cells: Involvement of IL-13Rα2
Authors: Shaik Ohidar Rahaman, Michael A. Vogelbaum, S. Jaharul Haque
Journal: Cancer Research (2005)

Interleukin (IL)-4 exhibits antitumor activity in rodent experimental gliomas, which is likely mediated by the actions of IL-4 on a variety of immune cells present in and around the tumor masses. Here, we show that IL-4, which activates Stat6 in normal human astrocytes and in a variety of other cells, induces an aberrant activation of Stat3 in glioblastoma multiforme (GBM) cells but not in normal human astrocytes. Previously, we have shown that autocrine IL-6 signaling induces a persistent activation of Stat3. Now, we show that Stat3 is further activated by IL-4 stimulation of GBM cells. Expression of IL-13Ralpha2, a decoy receptor for IL-13 that partly blocks IL-4-mediated activation of Stat6 in GBM cells, up-regulates the activation of Stat3 as shown by a small interfering RNA-mediated inhibition of IL-13Ralpha2 expression. In addition, transient expression of the IL-13Ralpha2 transgene in 293T cells increases the IL-4-mediated activation of Stat3 and subsequent expression of Stat3-targeted gene. Coimmunoprecipitation results reveal that IL-13Ralpha2-mediated activation of Stat3 does not require a direct physical interaction between Stat3 and IL-13Ralpha2. Chromatin immunoprecipitation assay employing anti-Stat3 antibody confirms the in vivo binding of activated Stat3 to the promoters of genes that encode antiapoptotic proteins Bcl-2, Bcl-x(L), and Mcl-1. IL-4 significantly up-regulates of the steady-state levels of Bcl-2, Bcl-x(L), and Mcl-1 in GBM cells. These results indicate that IL-4/IL-13 receptor-mediated Stat3 signaling may contribute to the pathogenesis of GBM cells by modulating the expression of the Bcl-2 family of antiapoptotic proteins.
Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia
Authors: Jessica Nordlund, Christofer L Bäcklin, Per Wahlberg, Stephan Busche, Eva C Berglund, Maija-Leena Eloranta, Trond Flaegstad, Erik Forestier, Britt-Marie Frost, Arja Harila-Saari, Mats Heyman, Ólafur G Jónsson, Rolf Larsson, Josefine Palle, Lars Rönnblom, Kjeld Schmiegelow, Daniel Sinnett, Stefan Söderhäll, Tomi Pastinen, Mats G Gustafsson, Gudmar Lönnerholm, Ann-Christine Syvänen
Journal: Genome biology (2013)

Abstract Background Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood. Results We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status. Conclusions Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.
Apoptosis Antagonizing Transcription Factor Protects Renal Tubule Cells against Oxidative Damage and Apoptosis Induced by Ischemia-Reperfusion
Authors: Jun Xie, Qing Guo
Journal: Journal of the American Society of Nephrology (2006)

Apoptosis antagonizing transcription factor (AATF) is a leucine zipper domain-containing protein that has antiapoptotic properties. AATF is expressed in several organs and tissues, including the kidney. AATF may participate in inhibition of proapoptotic pathways and/or activation of antiapoptotic pathways. Ischemia/reperfusion-induced renal injury (IRI) is clinically important because it typically damages renal tubular epithelial cells and glomerular cells and is the most common cause of acute renal failure. It now is reported that AATF is expressed in human kidney proximal tubule (HK-2) cells and in mouse primary renal tubule epithelial cells. Levels of AATF expression were altered significantly in these cells in a well-established in vitro model of renal IRI. In transfected HK-2 cells, RNA interference-mediated silencing of AATF exacerbated whereas overexpression of the full-length AATF ameliorated mitochondrial dysfunction, accumulation of superoxide and peroxynitrite, lipid peroxidation, caspase-3 activation, and apoptotic death that were induced by IRI. In primary renal tubule epithelial cells, overexpression of AATF mediated by recombinant adeno-associated virus (AAV) vectors resulted in significant antiapoptotic activity, whereas knockdown of AATF by small interference RNA led to exacerbated cell death after IRI. These results identify AATF as a novel cytoprotective factor against oxidative and apoptotic damage in renal tubular cells. AATF may represent a potential candidate for therapeutic application in IRI.
The Dispensatory of the United States of America.
Authors: Horatio Charles Wood
Journal: JAMA (1894)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer
Authors: Gunjal Garg, Suwanna Vangveravong, Chenbo Zeng, Lynne Collins, Mary Hornick, Yassar Hashim, David Piwnica-Worms, Matthew A Powell, David G Mutch, Robert H Mach, William G Hawkins, Dirk Spitzer
Journal: Molecular Cancer (2014)

Drug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms. Inhibition of apoptosis by the inhibitor of apoptosis proteins (IAPs) represents one such mechanism, and can be overcome by a mitochondrial protein called second mitochondria-derived activator of caspases (SMAC). We have previously shown that the ligands of sigma-2 receptors effectively induce tumor cell death. Additionally, because sigma-2 receptors are preferentially expressed in tumor cells, their ligands provide an effective mechanism for selective anti-cancer therapy. In the current work, we have improved upon the previously described sigma-2 ligand SW43 by conjugating it to a pro-apoptotic small molecule SMAC mimetic SW IV-52, thus generating the novel cancer therapeutic SW IV-134. The new cancer drug was tested for receptor selectivity and tumor cell killing activity in vitro and in vivo. We have shown that SW IV-134 retained adequate sigma-2 receptor binding affinity in the context of the conjugate and potently induced cell death in ovarian cancer cells. The cell death induced by SW IV-134 was significantly greater than that observed with either SW43 or SW IV-52 alone and in combination. Furthermore, the intraperitoneal administration of SW IV-134 significantly reduced tumor burden and improved overall survival in a mouse xenograft model of ovarian cancer without causing significant adverse effects to normal tissues. Mechanistically, SW IV-134 induced degradation of cIAP-1 and cIAP-2 leading to NF-қB activation and TNFα-dependent cell death. Our findings suggest that coupling sigma-2 ligands to SMAC peptidomimetics enhances their effectiveness while maintaining the cancer selectivity. This encouraging proof-of-principle preclinical study supports further development of tumor-targeted small peptide mimetics via ligands to the sigma-2 receptor for future clinical applications.
Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis
Authors: Volker Teichgräber, Martina Ulrich, Nicole Endlich, Joachim Riethmüller, Barbara Wilker, Cheyla Conceição De Oliveira–Munding, Anna M van Heeckeren, Mark L Barr, Gabriele von Kürthy, Kurt W Schmid, Michael Weller, Burkhard Tümmler, Florian Lang, Heike Grassme, Gerd Döring, Erich Gulbins
Journal: Nature Medicine (2008)
Paternally biased X inactivation in mouse neonatal brain
Authors: Xu Wang, Paul D Soloway, Andrew G Clark
Journal: Genome biology (2010)

X inactivation in female eutherian mammals has long been considered to occur at random in embryonic and postnatal tissues. Methods for scoring allele-specific differential expression with a high degree of accuracy have recently motivated a quantitative reassessment of the randomness of X inactivation. After RNA-seq data revealed what appeared to be a chromosome-wide bias toward under-expression of paternal alleles in mouse tissue, we applied pyrosequencing to mouse brain cDNA samples from reciprocal cross F1 progeny of divergent strains and found a small but consistent and highly statistically significant excess tendency to under-express the paternal X chromosome. The bias toward paternal X inactivation is reminiscent of marsupials (and extraembryonic tissues in eutherians), suggesting that there may be retained an evolutionarily conserved epigenetic mark driving the bias. Allelic bias in expression is also influenced by the sampling effect of X inactivation and by cis-acting regulatory variation (eQTL), and for each gene we quantify the contributions of these effects in two different mouse strain combinations while controlling for variability in Xce alleles. In addition, we propose an efficient method to identify and confirm genes that escape X inactivation in normal mice by directly comparing the allele-specific expression ratio profile of multiple X-linked genes in multiple individuals.
Note on the Effects of the Local Application of Caffeine to the Conjunctiva
Authors: D. A. Robertson
Journal: BMJ (1885)

THE following observations made on myself were undertaken at the suggestion of Dr. Mlurrell, with the view of ascertaining whether cuca or its alkaloid possessed any toxic action.The first series was made with valoid of cuca, a fluid extract, each part of which corresponds to an equal weight of the leaves of the cuca-plant.On December 9th,