tbuckley/cabot-search huggingface dataset:
Gender, Cytidine Deaminase, and 5-Aza/Decitabine—Response
Authors: Reda Z. Mahfouz, Lip Seng Koh, Marissa Teo, Chit Lai Chee, Han Chong Toh, Yogen Saunthararajah
Journal: Clinical Cancer Research (2013)

We thank Ciccoline and colleagues for their attention and comments regarding "Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy" (1). Ciccoline and colleagues have not found a sex difference in CDA activity using high-performance liquid chromatography (HPLC)–based measurements of CDA enzyme activity in red blood cell (RBC) lysates (2). In addition to use of gemcitabine as a substrate, which has a more than 10-fold higher Km for CDA than cytidine (3), this methodology is limited by its analysis of RBC lysates, which may not be representative of CDA activity in pharmacologically more relevant tissues, for example, the liver. Also, pharmacologically relevant are the cancer tissues that are the therapeutic targets of therapy. In contrast to the use of a single methodology (2), we evaluated sex differences in CDA using HPLC-based enzyme activity analysis of heparinized plasma, quantitative real-time PCR (qRT-PCR) quantification of CDA expression in murine liver, mass spectrometric measurement of decitabine levels (a CDA–drug substrate) in murine plasma, and Western blot evaluation of decitabine pharmacodynamic effect. We had consistent results across these model systems and methods, and furthermore, observed sex differences in CDA expression in various target cancer tissues analyzed by microarray. Here, we provide additional verification: CDA was expressed at significantly higher levels in noncancerous human liver from human males compared with females (Fig. 1A). That expression levels of CDA can be more important than CDA-genotype in determining CDA enzyme activity (1) is also illustrated by substantially greater CDA enzyme activity in U937 cells, that express higher levels of the enzymatically less active "CC" CDA variant, compared with cell lines that contain more active "AA" and "AC" CDA variants expressed at lower levels (Fig. 1B and C).We agree that our evaluation of clinical impact was limited by its retrospective nature (1), and sex-based dosage adjustment would be premature. Even so, the clear difference in MDS treatment outcomes despite similar disease biology (cytogenetics and myeloblasts) in the 2 sexes was highly provocative and consistent with epigenetic therapeutic effects that by being S-phase dependent must interact with brief drug half-lives that are further abbreviated by higher CDA enzyme activity in males. Furthermore, clinical trial results and mathematical modeling indicate that the negative impact of lower drug exposure time is exacerbated in low S-phase fraction malignant disease (e.g., MDS; ref. 1). Given that marginal differences in exposure time can determine treatment success or failure with 5-azacytidine or decitabine (4–5), pharmacodynamic or other dosage guidance is clearly a worthy goal.See the original Letter to the Editor, p. 3105No potential conflicts of interest were disclosed.
Fate of herpes simplex virus in lymphocytes from inflammatory joint effusions. i. Failure of the virus to grow in cultured lymphocytes.
Authors: D J Appleford, A M Denman
Journal: Annals of the Rheumatic Diseases (1979)

The ability of lymphocytes isolated from the blood and synovial effusions of patients with rheumatoid arthritis to support the growth of herpex simplex virus (HSV) was studied. Whereas blood lymphocytes supported virus growth, effusion lymphocytes were usually non-permissive. Lymphocytes obtained from the effusions of patients with other forms of inflammatory arthritis or suspected viral arthritis commonly failed to support the growth of HSV, but the virus grew in effusion lymphocytes from patients with noninflammatory joint disease. Several nonspecific factors which might have accounted for this non-permissiveness were excluded.
Trends in High-Risk HLA Susceptibility Genes Among Colorado Youth With Type 1 Diabetes
Authors: Kendra Vehik, Richard F. Hamman, Dennis Lezotte, Jill M. Norris, Georgeanna J. Klingensmith, Marian Rewers, Dana Dabelea
Journal: Diabetes Care (2008)

Type 1 diabetes is associated with a wide spectrum of susceptibility and protective genotypes within the HLA class II system. It has been reported that adults diagnosed with youth-onset type 1 diabetes more recently have been found to have fewer classical high-risk HLA class II genotypes than those diagnosed several decades ago. We hypothesized that such temporal trends in the distribution of HLA-DR, DQ genotypes would be evident, and perhaps even stronger, among 5- to 17-year-old Hispanic and non-Hispanic white (NHW) youth diagnosed with type 1 diabetes in Colorado between 1978 and 2004.HLA-DR, DQ was typed using PCR and sequence-specific oligonucleotide hybridization in 100 youth diagnosed during the period of 1978-1988 and 264 diagnosed during 2002-2004. Logistic regression was used to adjust for confounders and assess temporal trends.The frequency of the highest-risk genotype (DRB1*03-DQB1*02/DRB1*04-DQB1*03) was higher (39%) in children diagnosed during the period 1978-1988 than in those diagnosed during 2002-2004 (28%). A similar pattern was observed in NHWs and Hispanics.We found that high-risk HLA genotypes are becoming less frequent over time in youth with type 1 diabetes of NHW and Hispanic origin. This temporal trend may suggest that increasing environmental exposure is now able to trigger type 1 diabetes in subjects who are less genetically susceptible.
Quantitative assessment of lymph vascular space invasion (LVSI) provides important prognostic information in node-negative breast cancer
Authors: T.J.A. Dekker, C.J.H. van de Velde, D. van Bruggen, W.E. Mesker, J.J.M. van der Hoeven, J.R. Kroep, R.A.E.M. Tollenaar, V.T.H.B.M. Smit
Journal: Annals of Oncology (2013)
Effect of chronic administration of cisapride on gastric emptying of a solid meal and on dyspeptic symptoms in patients with idiopathic gastroparesis.
Authors: R Corinaldesi, V Stanghellini, C Raiti, E Rea, R Salgemini, L Barbara
Journal: Gut (1987)

In a double blind crossover comparison with placebo, the effects of cisapride (10 mg tid for two weeks), a non-antidopaminergic gastrointestinal prokinetic drug, on gastric emptying times and on symptoms were evaluated in 12 patients with chronic idiopathic dyspepsia and gastroparesis. Gastric emptying was studied by a radioisotopic gamma camera technique. The test meal was labelled in the solid component (99mTc-sulphur colloid infiltrated chicken liver). Nine symptoms (nausea, belching, regurgitations, vomiting, postprandial drowsiness, early satiety, epigastric pain or burning, heartburn) were graded weekly on a questionnaire. Cisapride was significantly more effective than placebo in shortening the t1/2 of gastric emptying (p2 = 0.04), but no significant difference was observed between the two treatments with regard to the improvement of total symptom score (p2 = 0.09). No side effects were reported during the study.
Discovery of tissue-specific exons using comprehensive human exon microarrays
Authors: Tyson A Clark, Anthony C Schweitzer, Tina X Chen, Michelle K Staples, Gang Lu, Hui Wang, Alan Williams, John E Blume
Journal: Genome biology (2007)

Higher eukaryotes express a diverse population of messenger RNAs generated by alternative splicing. Large-scale methods for monitoring gene expression must adapt in order to accurately detect the transcript variation generated by this splicing.We have designed a high-density oligonucleotide microarray with probesets for more than one million annotated and predicted exons in the human genome. Using these arrays and a simple algorithm that normalizes exon signal to signal from the gene as a whole, we have identified tissue-specific exons from a panel of 16 different normal adult tissues. RT-PCR validation confirms approximately 86% of the predicted tissue-enriched probesets. Pair-wise comparisons between the tissues suggest that as many as 73% of detected genes are differentially alternatively spliced. We also demonstrate how an inclusive exon microarray can be used to discover novel alternative splicing events. As examples, 17 new tissue-specific exons from 11 genes were validated by RT-PCR and sequencing.In conjunction with a conceptually simple algorithm, comprehensive exon microarrays can detect tissue-specific alternative splicing events. Our data suggest significant expression outside of known exons and well annotated genes and a high frequency of alternative splicing events. In addition, we identified and validated a number of novel exons with tissue-specific splicing patterns. The tissue map data will likely serve as a valuable source of information on the regulation of alternative splicing.
Knee arthroscopy: influence of systems for delivering healthcare on procedure rates
Authors: David F Hamilton, Colin R Howie
Journal: BMJ (2015)

The "correct" rates of discretional interventions are difficult to define. However, <b>David Hamilton</b> and <b>Colin Howie</b> point out that discrepancies in usage of knee arthroscopy within the UK suggest the organisation of the care pathway may be an important determinant
Integrated Genome-Wide Association Study Findings: Identification of a Neurodevelopmental Network for Attention Deficit Hyperactivity Disorder
Authors: Geert Poelmans, David L. Pauls, Jan K. Buitelaar, Barbara Franke
Journal: American Journal of Psychiatry (2011)

Objective: Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder. In the present study, the authors investigated the presence of genomic convergence in the top findings of the five published genome-wide association studies (GWASs) of ADHD. Method: The authors carried out bioinformatics pathway analyses, using the Ingenuity and BiNGO tools, as well as a systematic literature analysis of 85 genes from the five published GWASs containing single nucleotide polymorphisms associated with ADHD at a p value <0.0001. Results: Findings revealed that 45 of the 85 top-ranked ADHD candidate genes encode proteins that fit into a neurodevelopmental network involved in directed neurite outgrowth. Data on copy number variations in patients with ADHD and data from animal studies provide further support for the involvement of this network in ADHD etiology. Several network proteins are also directly modulated by stimulants, the most commonly used psychopharmacological treatment for ADHD. Conclusions: The authors have identified a protein network for ADHD that contributes to our understanding of the molecular basis of the disorder. In addition, the data suggest new candidate genes for ADHD and provide clues to future research into psychopharmacological ADHD treatments.
Hyperpolarized [1-13C] Glutamate: A Metabolic Imaging Biomarker of IDH1 Mutational Status in Glioma
Authors: Myriam M. Chaumeil, Peder E.Z. Larson, Sarah M. Woods, Larry Cai, Pia Eriksson, Aaron E. Robinson, Janine M. Lupo, Daniel B. Vigneron, Sarah J. Nelson, Russell O. Pieper, Joanna J. Phillips, Sabrina M. Ronen
Journal: Cancer Research (2014)

Abstract Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use 13C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-13C] α-KG to hyperpolarized [1-13C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-13C] α-KG, hyperpolarized [1-13C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-13C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-13C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-13C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production. Cancer Res; 74(16); 4247–57. ©2014 AACR.
Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer
Authors: L. Allan
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objectives:</b> To compare patients9 preference for transdermal fentanyl or sustained release oral morphine, their level of pain control, and their quality of life after treatment. <b>Design:</b> Randomised, multicentre, international, open label, crossover trial. <b>Setting:</b> 35 centres in Belgium, Canada, Denmark, Finland, the United Kingdom, the Netherlands, and South Africa. <b>Participants:</b> 256 patients (aged 26-82 years) with chronic non-cancer pain who had been treated with opioids. <b>Main outcome measures:</b> Patients9 preference for transdermal fentanyl or sustained release oral morphine, pain control, quality of life, and safety assessments. <b>Results:</b> Of 212 patients, 138 (65%) preferred transdermal fentanyl, whereas 59 (28%) preferred sustained release oral morphine and 15 (7%) expressed no preference. Better pain relief was the main reason for preference for fentanyl given by 35% of patients. More patients considered pain control as being "good" or "very good" with fentanyl than with morphine (35% <i>v</i> 23%, P=0.002). These results were reflected in both patients9 and investigators9 opinions on the global efficacy of transdermal fentanyl. Patients receiving fentanyl had on average higher quality of life scores than those receiving morphine. The incidence of adverse events was similar in both treatment groups; however, more patients experienced constipation with morphine than with fentanyl (48% <i>v</i> 29%, P&lt;0.001). Overall, 41% of patients experienced mild or moderate cutaneous problems associated with wearing the transdermal fentanyl patch, and more patients withdrew because of adverse events during treatment with fentanyl than with morphine (10% <i>v</i> 5%). However, within the subgroup of patients naive to both fentanyl and morphine, similar numbers of patients withdrew owing to adverse effects (11% <i>v</i> 10%, respectively). <b>Conclusion:</b> Transdermal fentanyl was preferred to sustained release oral morphine by patients with chronic non-cancer pain previously treated with opioids. The main reason for preference was better pain relief, achieved with less constipation and an enhanced quality of life. <h3>What is already known on this topic</h3> The clinical use of potent opioids in the treatment of chronic non-cancer pain is supported by retrospective, survey data and small randomised controlled trials showing efficacy and safety Studies with transdermal fentanyl have shown efficacy and preference over sustained release oral morphine in the treatment of cancer pain <h3>What this study adds</h3> This is the first study to provide comparative data supporting treatment options with potent opioids for chronic non-cancer pain Both transdermal fentanyl and sustained release oral morphine provided effective and well tolerated pain relief During fentanyl treatment patients experienced superior pain relief, higher quality of life, and less constipation; fentanyl was preferred to morphine by 65% of patients
Twizzlers as a Cost-Effective and Equivalent Alternative to the Glucola Beverage in Diabetes Screening
Authors: Diana A. Racusin, Nellie S. Crawford, Sara Andrabi, Melissa A. Suter, Haleh Sangi-Haghpeykar, Lori Showalter, Susan Sharma, Morey Haymond, Kjersti M. Aagaard
Journal: Diabetes Care (2013)

Screening for gestational diabetes mellitus requires an oral glucose challenge test with a 50-g glucola beverage and venous blood sample after 1 h. A “positive screen” is defined as a venous blood glucose of either >130 mg/dL or 140 mg/dL (1,2), and the patient then undergoes a diagnostic fasting 3-h glucose tolerance test (GTT) with a 100-g glucola (1). However, up to 30% of pregnant women cannot tolerate the traditional 50-g glucola beverage (3,4). There are few reports demonstrating viable and cost-effective alternatives, such as commercially available candy. For example, jelly beans have been shown to be better tolerated but with demonstrated lower sensitivity, potentially related to their variability in size and resultant difficulty in calculating glucose load (3,4). We therefore sought to identify whether other forms of candy (such as …
microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer
Authors: Lijing Zhang, Yujuan Dong, Nana Zhu, Ho Tsoi, Zengren Zhao, Chung Wah Wu, Kunning Wang, Shu Zheng, Simon SM Ng, Francis KL Chan, Joseph JY Sung, Jun Yu
Journal: Molecular Cancer (2014)

miR-139-5p was identified to be significantly down-regulated in colon tumor tissues by miRNA array. We aimed to clarify its biological function, molecular mechanisms and direct target gene in colorectal cancer (CRC). The biological function of miR-139-5p was examined by cell growth, cell cycle and apoptosis analysis in vitro and in vivo. miR-139-5p target gene and signaling pathway was identified by luciferase activity assay and western blot. miR-139-5p was significantly down-regulated in primary tumor tissues (P < 0.0001). Ectopic expression of miR-139-5p in colon cancer cell lines significantly suppressed cell growth as evidenced by cell viability assay (P < 0.001) and colony formation assay (P < 0.01) and in xenograft tumor growth in nude mice (P < 0.01). miR-139-5p induced apoptosis (P < 0.01), concomitantly with up-regulation of key apoptosis genes including cleaved caspase-8, caspase-3, caspase-7 and PARP. miR-139-5p also caused cell cycle arrest in G0/G1 phase (P < 0.01), with upregulation of key G0/G1 phase regulators p21Cip1/Waf1 and p27Kip1. Moreover, miR-139-5p inhibited cellular migration (P < 0.001) and invasiveness (P < 0.001) through the inhibition of matrix metalloproteinases (MMP)7 and MMP9. Oncogene NOTCH1 was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression (r = -0.3862, P = 0.0002). miR-139-5p plays a pivotal role in colon cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis and cell cycle arrest by targeting oncogenic NOTCH1.
Four-in-One Antibodies Have Superior Cancer Inhibitory Activity against EGFR, HER2, HER3, and VEGF through Disruption of HER/MET Crosstalk
Authors: Shi Hu, Wenyan Fu, Weihao Xu, Yang Yang, Melissa Cruz, Sandra D. Berezov, Daniel Jorissen, Hiroaki Takeda, Wangdong Zhu
Journal: Cancer Research (2014)

The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti-HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody.
Cardiac-Specific Overexpression of Diacylglycerol Kinase ζ Prevents Gq Protein-Coupled Receptor Agonist-Induced Cardiac Hypertrophy in Transgenic Mice
Authors: Takanori Arimoto, Yasuchika Takeishi, Hiroki Takahashi, Tetsuro Shishido, Takeshi Niizeki, Yo Koyama, Ryoko Shiga, Naoki Nozaki, Osamu Nakajima, Kazuhide Nishimaru, Jun-ichi Abe, Masao Endoh, Richard A. Walsh, Kaoru Goto, Isao Kubota
Journal: Circulation (2005)

Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gqalpha protein-coupled receptor (GPCR) agonists such as angiotensin II, phenylephrine, and others. Diacylglycerol functions as a potent activator of protein kinase C (PKC) and is catalyzed by diacylglycerol kinase (DGK) to form phosphatidic acid and inactivated. However, the functional roles of DGK have not been previously examined in the heart. We hypothesized that DGK might prevent GPCR agonist-induced activation of diacylglycerol downstream signaling cascades and subsequent cardiac hypertrophy.To test this hypothesis, we generated transgenic (DGKzeta-TG) mice with cardiac-specific overexpression of DGKzeta. There were no differences in heart size and heart weight between DGKzeta-TG and wild-type littermate mice. The left ventricular function was normal in DGKzeta-TG mice. Continuous administration of subpressor doses of angiotensin II and phenylephrine caused PKC translocation, gene induction of atrial natriuretic factor, and subsequent cardiac hypertrophy in WT mice. However, in DGKzeta-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGKzeta-TG mice, angiotensin II and phenylephrine failed to increase cross-sectional cardiomyocyte areas and heart to body weight ratios. Phenylephrine-induced increases in myocardial diacylglycerol levels were completely blocked in DGKzeta-TG mouse hearts, suggesting that DGKzeta regulated PKC activity by controlling cellular diacylglycerol levels.These results demonstrated the first evidence that DGKzeta negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.