tbuckley/cabot-search huggingface dataset:
Switching to Sulphonylureas in Children With iDEND Syndrome Caused by <i>KCNJ11</i> Mutations Results in Improved Cerebellar Perfusion
Authors: Wojciech Fendler, Iwona Pietrzak, Melissa F. Brereton, Carolina Lahmann, Mariusz Gadzicki, Malgorzata Bienkiewicz, Izabela Drozdz, Maciej Borowiec, Maciej T. Malecki, Frances M. Ashcroft, Wojciech M. Mlynarski
Journal: Diabetes Care (2013)

Activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the KATP channel, result in permanent neonatal diabetes mellitus. They also may cause neurologic symptoms such as mental retardation and motor problems (iDEND syndrome) and epilepsy (DEND syndrome). Sulphonylurea (SU) treatment is reported to alleviate both the neurologic symptoms and diabetes in such cases. The study aimed to establish the magnitude and functional basis of the effect of SUs on the neurologic phenotype in children with iDEND using neuroimaging before and after insulin replacement with glibenclamide.To localize and quantify the effect of glibenclamide administration, we performed single-photon emission computed tomography in seven patients with different mutations in KCNJ11. In five patients, measurements before and after initiation of SU treatment were performed. RESULTS Significant changes in single-photon emission computed tomography signal intensity after transfer to SU therapy were restricted to the cerebellum, consistent with previous data showing high Kir6.2 expression in this brain region. Cerebellar perfusion improved for both left (P = 0.006) and right (P = 0.01) hemispheres, with the mean improvement being 26.7 ± 7.1% (n = 5). No patients showed deterioration of cerebellar perfusion on SU therapy. Electrophysiological studies revealed a good correlation between the magnitude of KATP channel dysfunction and the clinical phenotype; mutant channels with the greatest reduction in adenosine 5'-triphosphate inhibition were associated with the most severe neurologic symptoms.We conclude it is likely that at least some of the beneficial effects of SU treatment on neurodevelopment in iDEND patients result from improved cerebellar perfusion.
Communicating Evidence-Based Information on Cancer Prevention to State-Level Policy Makers
Authors: Ross C. Brownson, Elizabeth A. Dodson, Katherine A. Stamatakis, Christopher M. Casey, Michael B. Elliott, Douglas A. Luke, Christopher G. Wintrode, Matthew W. Kreuter
Journal: JNCI Journal of the National Cancer Institute (2011)

Opportunities exist to disseminate evidence-based cancer control strategies to state-level policy makers in both the legislative and executive branches. We explored factors that influence the likelihood that state-level policy makers will find a policy brief understandable, credible, and useful. A systematic approach was used to develop four types of policy briefs on the topic of mammography screening to reduce breast cancer mortality: data-focused brief with state-level data, data-focused brief with local-level data, story-focused brief with state-level data, and story-focused brief with local-level data. Participants were recruited from three groups of state-level policy makers—legislative staff, legislators, and executive branch administrators— in six states that were randomly chosen after stratifying all 50 states by population size and dominant political party in state legislature. Participants from each of the three policy groups were randomly assigned to receive one of the four types of policy briefs and completed a questionnaire that included a series of Likert scale items. Primary outcomes—whether the brief was understandable, credible, likely to be used, and likely to be shared—were measured by a 5-point Likert scale according to the degree of agreement (1 = strongly disagree, 5 = strongly agree). Data were analyzed with analysis of variance and with classification trees. All statistical tests were two-sided. Data on response to the policy briefs (n = 291) were collected from February through December 2009 (overall response rate = 35%). All three policy groups found the briefs to be understandable and credible, with mean ratings that ranged from 4.3 to 4.5. The likelihood of using the brief (the dependent variable) differed statistically significantly by study condition for staffers (P = .041) and for legislators (P = .018). Staffers found the story-focused brief containing state-level data most useful, whereas legislators found the data-focused brief containing state-level data most useful. Exploratory classification trees showed distinctive patterns for brief usefulness across the three policy groups. Our results suggest that taking a "one-size-fits-all" approach when delivering information to policy makers may be less effective than communicating information based on the type of policy maker.
Long-term effect of nadolol or nadolol plus isosorbide-5-mononitrate on renal function and ascites formation in patients with cirrhosis
Authors: Carlo Merkel, Angelo Gatta, Carlo Donada, Edda Enzo, Renato Marin, Piero Amodio, Pierluigi Torboli, Paolo Angeli, Giorgio Cavallarin, Giuliana Sebastianelli, Sara Susanna, Cesare Mazzaro, Pietro Beltrame
Journal: Hepatology (1995)

The association beta-blockers plus nitrates has been reported to impair renal function and renal sodium handling, leading to increased risk of development of ascites, or worsening of a preexisting ascites, or increase in the requirements of diuretic agents. In 81 patients with cirrhosis and esophageal varices, participating in a multicenter controlled clinical trial of prophylaxis of variceal bleeding comparing nadolol (NAD) plus isosorbide-5-mononitrate (15M) with NAD alone, renal function, presence of ascites, and diuretic requirements were assessed at inclusion and after 6 months of follow-up. No significant variation in s-urea or s-creatinine was observed in either group. Three patients in the nadolol group and two in the NAD plus 15M developed ascites at 6 months (P = .70), and a need to increase diuretic regimen was observed in four and three patients, respectively (P = .76). Decrease in heart rate and in mean arterial pressure was similar in the two groups. There was a significant correlation between increase in s-creatinine and decrease in mean arterial pressure in the whole series (P = .015). Only in patients treated with the association was there a significant larger proportion of patients ascitic who became anascitic, than of patients anascitic who became ascitic (P = .03). In patients treated with the association, there was a significantly larger decrease in hepatic venous pressure gradient (P = .05). It is concluded that patients treated with the association NAD plus 15M are not at increased risk of developing renal dysfunction or worsening of ascites compared with patients treated with NAD alone. Therefore, the presence of ascites should not be considered a contraindication to the use of this association in patients with cirrhosis and portal hypertension. (Hepatology 1995; 22:808–813.)
Identification of a <i>cis</i> -Acting Glucocorticoid Responsive Element in the Rat Angiotensin II Type 1A Promoter
Authors: Deng-Fu Guo, Shusei Uno, Akira Ishihata, Norifumi Nakamura, Tadashi Inagami
Journal: Circulation Research (1995)

Abstract Enhanced vascular responsiveness to angiotensin II at the AT 1 receptor has been considered one of the major contributing factors to vascular hypertrophy and high blood pressure. The transcription of the rat angiotensin II type 1A receptor gene is stimulated by glucocorticoids. To clarify the molecular mechanism for glucocorticoid action in rat vascular smooth muscle cells, we investigated the effects of dexamethasone on the promoter activity of the angiotensin II type 1A receptor by using promoter/luciferase reporter gene constructs and heterologous context constructs (containing the thymidine kinase promoter) in transfected vascular smooth muscle cells (&lt;12 passages). There are three putative glucocorticoid responsive elements (GREs) in the promoter. However, only one GRE was found to respond to dexamethasone (1 μmol/L) and was located at positions −756 to −770 bp upstream from the transcription initiation site. When compared with the consensus sequence of GRE, 9 of 12 bases were identical. RU38486, a glucocorticoid antagonist, completely blocked the induction by dexamethasone, suggesting that the GRE was functional through a specific glucocorticoid receptor. The response to dexamethasone was lost in vascular smooth muscle cells at higher passage numbers (&gt;8 passages) but was restored when the cells were transfected with a glucocorticoid-receptor expression construct. This finding provided additional support that the response to dexamethasone was mediated by the glucocorticoid receptor. The gel mobility supershift assay showed that the GRE binds in vitro–translated rat glucocorticoid receptors in a specific manner. Compared with the angiotensin II type 1A receptor promoter, no effect by dexamethasone was observed in vascular smooth muscle cells transfected with the angiotensin II type 1B receptor promoter/luciferase reporter gene constructs. We conclude from these experiments that the dexamethasone-induced increase in the transcription of the angiotensin II type 1A receptor gene occurred through the binding of GRE to the glucocorticoid-specific receptor.
Use of Dipeptidyl Peptidase-4 Inhibitors and the Reporting of Infections: A Disproportionality Analysis in the World Health Organization VigiBase
Authors: Marjolein J. Willemen, Aukje K. Mantel-Teeuwisse, Sabine M. Straus, Ron H. Meyboom, Toine C. Egberts, Hubert G. Leufkens
Journal: Diabetes Care (2011)

OBJECTIVE Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. They inactivate incretin hormones but also have many other effects throughout the body, among which are effects on the immune system. This might result in an increased infection risk. This study assessed the association between use of DPP-4 inhibitors and the reporting of infections. RESEARCH DESIGN AND METHODS A nested case-control was conducted using VigiBase, the World Health Organization-Adverse Drug Reactions (WHO-ADR) database. The base cohort consisted of ADRs for antidiabetic drugs (Anatomical Therapeutic Chemical code A10). Cases were defined as ADRs of infection according to the Medical Dictionary for Regulatory Activities (MedDRA) classification system. All other ADRs were considered controls. Reporting odds ratios (RORs) were calculated to estimate the strength of the association between different classes of antidiabetic drugs and the reporting of infections. RESULTS We identified 305,415 suspected ADRs involving antidiabetic drugs in 106,469 case reports, of which 8,083 involved DPP-4 inhibitors monotherapy. Overall, the reporting of infections was higher for patients using DPP-4 inhibitors compared with users of biguanides (ROR 2.3 [95% CI 1.9–2.7]). Reporting of upper respiratory tract infections (ROR 12.3 [95% CI 8.6–17.5]) was significantly associated with use of DPP-4 inhibitors. CONCLUSIONS This study indicates an increased reporting of infections, in particular upper respiratory tract infections, for users of DPP-4 inhibitors compared with users of other antidiabetic drugs. However, the limitations of spontaneous reporting systems (e.g., underreporting, the Weber-effect, reporting bias) should be taken into account. Therefore, further research is needed to evaluate this suspicion and the underlying mechanism.
Atopic dermatitis keratinocytes exhibit normal TH17 cytokine responses
Authors: Kristine E. Nograles, Mayte Suárez-Fariñas, Avner Shemer, Judilyn Fuentes-Duculan, Andrea Chiricozzi, Irma Cardinale, Lisa C. Zaba, Toyoko Kikuchi, Michal Ramon, Reuven Bergman, James G. Krueger, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2010)
Phosphorylation and Activation of Cell Division Cycle Associated 5 by Mitogen-Activated Protein Kinase Play a Crucial Role in Human Lung Carcinogenesis
Authors: Minh-Hue Nguyen, Junkichi Koinuma, Koji Ueda, Tomoo Ito, Eiju Tsuchiya, Yusuke Nakamura, Yataro Daigo
Journal: Cancer Research (2010)

We analyzed the gene expression profiles of clinical lung carcinomas using a cDNA microarray containing 27,648 genes or expressed sequence tags, and identified CDCA5 (cell division cycle associated 5) to be upregulated in the majority of lung cancers. Tumor tissue microarray analysis of 262 non-small cell lung cancer patients revealed that CDCA5 positivity was an independent prognostic factor for lung cancer patients. Suppression of CDCA5 expression with siRNAs inhibited the growth of lung cancer cells; concordantly, induction of exogenous expression of CDCA5 conferred growth-promoting activity in mammalian cells. We also found that extracellular signal-regulated kinase (ERK) kinase phosphorylated CDCA5 at Ser79 and Ser209 in vivo. Exogenous expression of phospho-mimicking CDCA5 protein whose Ser209 residue was replaced with glutamine acid further enhanced the growth of cancer cells. In addition, functional inhibition of the interaction between CDCA5 and ERK kinase by a cell-permeable peptide corresponding to a 20-amino-acid sequence part of CDCA5, which included the Ser209 phosphorylation site by ERK, significantly reduced phosphorylation of CDCA5 and resulted in growth suppression of lung cancer cells. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy.
Immunogenicity and safety profile of the monovalent A/H1N1 MF59-adjuvanted vaccine in patients affected by cystic fibrosis
Authors: F. Alghisi, P. Palma, E. Montemitro, S. Bernardi, G. Pontrelli, P. Rossi, V. Lucidi
Journal: Thorax (2011)

Viral respiratory tract infections may determine lung function deterioration in patients affected by cystic fibrosis (CF). Viruses may have a synergistic action with bacteria to damage the respiratory tract; they may also promote airway bacterial colonisation.1 Influenza virus infection has been described to increase the number of CF pulmonary exacerbations and the incidence of hospitalisation.2 For this reason, vaccination is strongly recommended annually. The immunogenic effect and safety of influenza vaccines in CF children are comparable with that of healthy individuals.3 The reported adverse events after vaccination are mild and not persisting. In 2009, a novel swine pandemic influenza A virus (A/H1N1) was identified. To date, the …
Crosstalk between Keratinocytes and Adaptive Immune Cells in an IκBα Protein-Mediated Inflammatory Disease of the Skin
Authors: Bernd Rebholz, Ingo Haase, Birgit Eckelt, Stephan Paxian, Michael J. Flaig, Kamran Ghoreschi, Sergei A. Nedospasov, Reinhard Mailhammer, Svenja Debey-Pascher, Joachim L. Schultze, Günther Weindl, Irmgard Förster, Ralf Huss, Athanasios Stratis, Thomas Ruzicka, Martin Röcken, Klaus Pfeffer, Roland M. Schmid, Rudolf A. Rupec
Journal: Immunity (2007)
The <i>Telomerase Reverse Transcriptase</i> (<i>hTERT</i>) Gene Is a Direct Target of the Histone Methyltransferase SMYD3
Authors: Cheng Liu, Xiaolei Fang, Zheng Ge, Marit Jalink, Satoru Kyo, Magnus Björkholm, Astrid Gruber, Jan Sjöberg, Dawei Xu
Journal: Cancer Research (2007)

Abstract Recent evidence has accumulated that the dynamic histone methylation mediated by histone methyltransferases and demethylases plays key roles in regulation of chromatin structure and transcription. In the present study, we show that SET and MYND domain-containing protein 3 (SMYD3), a histone methyltransferase implicated in oncogenesis, directly trans-activates the telomerase reverse transcriptase (hTERT) gene that is essential for cellular immortalization and transformation. SMYD3 occupies its binding motifs on the hTERT promoter and is required for maintenance of histone H3-K4 trimethylation, thereby contributing to inducible and constitutive hTERT expression in normal and malignant human cells. Knocking down SMYD3 in tumor cells abolished trimethylation of H3-K4, attenuated the occupancy by the trans-activators c-MYC and Sp1, and led to diminished histone H3 acetylation in the hTERT promoter region, which was coupled with down-regulation of hTERT mRNA and telomerase activity. These results suggest that SMYD3-mediated trimethylation of H3-K4 functions as a licensing element for subsequent transcription factor binding to the hTERT promoter. The present findings provide significant insights into regulatory mechanisms of hTERT/telomerase expression; moreover, identification of the hTERT gene as a direct target of SMYD3 contributes to a better understanding of SMYD3-mediated cellular transformation. [Cancer Res 2007;67(6):2626–31]
<i>JEM</i>'s 2009 Tune-up
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2009)

Scientific journals, like cars, require periodic tune-ups to keep them running smoothly. Effective immediately, several changes to the JEM publication policies will take effect. Our aim is to address policy issues that have arisen over the past several years and, more broadly, to maintain the quality and integrity of the research we publish. The upcoming changes to JEM policies and the impetus behind them are outlined here.
Evolution of arthropod hemocyanins and insect storage proteins (hexamerins).
Authors: J J Beintema, W T Stam, B Hazes, M P Smidt
Journal: Molecular Biology and Evolution (1994)

Crustacean and cheliceratan hemocyanins (oxygen-transport proteins) and insect hexamerins (storage proteins) are homologous gene products, although the latter do not bind oxygen and do not possess the copper-binding histidines present in the hemocyanins. An alignment of 19 amino acid sequences of hemocyanin subunits and insect hexamerins was made, based on the conservation of elements of secondary structure observed in X-ray structures of two hemocyanin subunits. The alignment was analyzed using parsimony and neighbor-joining methods. Results provide strong indications for grouping together the sequences of the 2 crustacean hemocyanin subunits, the 5 cheliceratan hemocyanin subunits, and the 12 insect hexamerins. Within the insect clade, four methionine-rich proteins, four arylphorins, and two juvenile hormone-suppressible proteins from Lepidoptera, as well as two dipteran proteins, form four separate groups. In the absence of an outgroup sequence, it is not possible to present information about the ancestral state from which these proteins are derived. Although this family of proteins clearly consists of homologous gene products, there remain striking differences in gene organization and site of biosynthesis of the proteins within the cell. Because studies on 18S and 12S rRNA sequences indicate a rather close relationship between insects and crustaceans, we propose that hemocyanin is the ancestral arthropod protein and that insect hexamerins lost their copper-binding capability after divergence of the insects from the crustaceans.
Further Evaluation of Intensified and Increased Total Dose of Cyclophosphamide for the Treatment of Primary Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-25
Authors: Bernard Fisher, Stewart Anderson, Arthur DeCillis, Nikolay Dimitrov, James N. Atkins, Louis Fehrenbacher, Patrick H. Henry, Edward H. Romond, Keith S. Lanier, Enrique Davila, Carl G. Kardinal, Leslie Laufman, H. Irving Pierce, Neil Abramson, Alan M. Keller, John T. Hamm, D.L. Wickerham, Mirsada Begovic, Elizabeth Tan-Chiu, Wei Tian, Norman Wolmark
Journal: Journal of Clinical Oncology (1999)

In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results.Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival.No significant difference was observed in DFS (P =.20), distant DFS (P =.31), or survival (P =.76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P =. 29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P =.71) and 3 (78% v 79%, respectively; P =.86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups.Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.
AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model
Authors: H Yao, E Ashihara, J W Strovel, Y Nakagawa, J Kuroda, R Nagao, R Tanaka, A Yokota, M Takeuchi, Y Hayashi, C Shimazaki, M Taniwaki, K Strand, J Padia, H Hirai, S Kimura, T Maekawa
Journal: Blood Cancer Journal (2011)

Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.