tbuckley/cabot-search huggingface dataset:
A Risk Variant in an miR-125b Binding Site in <i>BMPR1B</i> Is Associated with Breast Cancer Pathogenesis
Authors: Pål Sætrom, Jacob Biesinger, Sierra M. Li, David Smith, Laurent F. Thomas, Karim Majzoub, Guillermo E. Rivas, Jessica Alluin, John J. Rossi, Theodore G. Krontiris, Jeffrey Weitzel, Mary B. Daly, Al B. Benson, John M. Kirkwood, Peter J. O'Dwyer, Rebecca Sutphen, James A. Stewart, David Johnson, Garrett P. Larson
Journal: Cancer Research (2009)

MicroRNAs regulate diverse cellular processes and play an integral role in cancer pathogenesis. Genomic variation within miRNA target sites may therefore be important sources for genetic differences in cancer risk. To investigate this possibility, we mapped HapMap single nucleotide polymorphisms (SNP) to putative miRNA recognition sites within genes dysregulated in estrogen receptor-stratified breast tumors and used local linkage disequilibrium patterns to identify high-ranking SNPs in the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer genome-wide association study for further testing. Two SNPs, rs1970801 and rs11097457, scoring in the top 100 from the CGEMS study, were in strong linkage disequilibrium with rs1434536, an SNP that resides within a miR-125b target site in the 3' untranslated region of the bone morphogenic receptor type 1B (BMPR1B) gene encoding a transmembrane serine/threonine kinase. We validated the CGEMS association findings for rs1970801 in an independent cohort of admixture-corrected cases identified from families with multiple case histories. Subsequent association testing of rs1434536 for these cases and CGEMS controls with imputed genotypes supported the association. Furthermore, luciferase reporter assays and overexpression of miR-125b-mimics combined with quantitative reverse transcription-PCR showed that BMPR1B transcript is a direct target of miR-125b and that miR-125b differentially regulates the C and T alleles of rs1434536. These results suggest that allele-specific regulation of BMPR1B by miR-125b explains the observed disease risk. Our approach is general and can help identify and explain the mechanisms behind disease association for alleles that affect miRNA regulation.
The feasibility of classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for pre- and post-menopausal node-positive breast cancer patients in a Belgian multicentric trial: a study of consistency in relative dose intensity (RDI) and cumulative doses across institutions
Authors: A.F. Ferreira Filho, A. Di Leo, M. Paesmans, M. Beauduin, A. Vindevoghel, J. Michel, C. Focan, A. Awada, F. Cardoso, S. Dolci, S. Bartholomeus, M.J. Piccart
Journal: Annals of Oncology (2002)
Risk of serious toxicity in 1181 patients treated in phase I clinical trials of predominantly targeted anticancer drugs: the M. D. Anderson Cancer Center experience
Authors: J.J. Wheler, A.M. Tsimberidou, D.S. Hong, A. Naing, G.S. Falchook, S. Fu, S. Moulder, B. Stephen, S. Wen, R. Kurzrock
Journal: Annals of Oncology (2012)
Quod erat demonstrandum?The mystery of experimental validation of apparently erroneous computational analyses of protein sequences
Authors: Lakshminarayan M Iyer, L Aravind, Peer Bork, Kay Hofmann, Arcady R Mushegian, Igor B Zhulin, Eugene V Koonin
Journal: Genome biology (2001)

Computational predictions are critical for directing the experimental study of protein functions. Therefore it is paradoxical when an apparently erroneous computational prediction seems to be supported by experiment.We analyzed six cases where application of novel or conventional computational methods for protein sequence and structure analysis led to non-trivial predictions that were subsequently supported by direct experiments. We show that, on all six occasions, the original prediction was unjustified, and in at least three cases, an alternative, well-supported computational prediction, incompatible with the original one, could be derived. The most unusual cases involved the identification of an archaeal cysteinyl-tRNA synthetase, a dihydropteroate synthase and a thymidylate synthase, for which experimental verifications of apparently erroneous computational predictions were reported. Using sequence-profile analysis, multiple alignment and secondary-structure prediction, we have identified the unique archaeal 'cysteinyl-tRNA synthetase' as a homolog of extracellular polygalactosaminidases, and the 'dihydropteroate synthase' as a member of the beta-lactamase-like superfamily of metal-dependent hydrolases.In each of the analyzed cases, the original computational predictions could be refuted and, in some instances, alternative strongly supported predictions were obtained. The nature of the experimental evidence that appears to support these predictions remains an open question. Some of these experiments might signify discovery of extremely unusual forms of the respective enzymes, whereas the results of others could be due to artifacts.
Understanding P values
Authors: P. Sedgwick
Journal: BMJ (2014)

Researchers investigated whether a low glycaemic index diet in pregnancy reduced the incidence of macrosomic (large for gestational age) infants in an at risk group. A randomised controlled trial study design was used. Participants were 800 women without diabetes, all in their second pregnancy, who had previously delivered an infant weighing more than 4000 g. The intervention consisted of a low glycaemic index diet from early pregnancy. The control treatment was no dietary intervention. The primary outcome was birth weight.1

Treatment groups were compared in mean birth weight using the independent samples t test. Hypothesis testing was two tailed, with a critical level of significance of 0.05 (5%). The mean birth weight in the intervention group was greater than in the control group, although the difference was not significant (4034 g (standard deviation 510) v 4006 (497); mean difference 28.6 g; 95% confidence interval −45.6 to 102.8; P=0.449). The researchers concluded that a low glycaemic index diet in pregnancy did not reduce the incidence of large for gestational age infants in a group at risk of fetal macrosomia.

Which of the following statements, if any, are true?

Statement a is true, whereas b and c are false.

The aim of the trial was to investigate the effects of a low glycaemic index diet in pregnancy. The treatment groups were compared in the primary outcome of birth weight using traditional statistical hypothesis testing, described in a previous question.2 The sample estimate of the population parameter of the difference between the …
Physiology in respiratory medicine
Authors: Robert Naeije, Denis Chemla, Anh Tuan Dinh-Xuan, Anton Vonk Noordegraaf
Journal: European Respiratory Journal (2012)

Par ma foi! il y a plus de quarante ans que je dis de la prose sans que j’en susse rien… 

Monsieur Jourdain, Moliere, Le Bourgeois Gentilhomme , Act II, Scene IV

Physiological reasoning has always been essential to the practice of respiratory medicine. Yet the teaching of physiology has been on the decline in many universities. Meanwhile, advances in molecular biology, genetics and systems biology have deeply modified biomedical research with renewed demands for bedside translation. Not uncommonly now, the question is raised about the very meaning of the word “physiology”. Is it nothing more than a constant …
Blood Pool SPECT and Planar Imaging in Hepatic Hemangioma
Authors: M H MALIK
Journal: Clinical Nuclear Medicine (1987)

To determine the role of blood pool SPECT in hepatic hemangioma, 13 patients with suspected biliary disease but no prior history of neoplasm, in whom ultrasound examinations revealed one or more hepatic lesions, had blood pool SPECT followed by planar imaging of the liver. All 13 patients also had hepatic flow studies and early planar images. The 13 patients had 18 hemangiomas. The sensitivity for planar and SPECT for all hemangiomas was 12/18 (67%) and 17/18 (94%), respectively. All lesions greater than 3 cm were seen in the planar and SPECT images. For lesions 3 cm or smaller the sensitivity was 6/12 (50%) for planar and 11/ 12 (92%) for SPECT. This study suggests that blood pool SPECT of the liver may be the nuclear medicine study of choice in the diagnosis of hepatic hemangioma and that it has a considerably higher sensitivity than planar imaging in the detection of hemangiomas 3 cm or less in size.
Biased distribution of recombination sites within S regions upon immunoglobulin class switch recombination induced by transforming growth factor beta and lipopolysaccharide.
Authors: T Iwasato, H Arakawa, A Shimizu, T Honjo, H Yamagishi
Journal: The Journal of Experimental Medicine (1992)

We have characterized extrachromosomal circular DNAs from adult mouse spleen cells that were induced to switch to immunoglobulin A (IgA) with bacterial lipopolysaccharide (LPS) and transforming growth factor beta (TGF-beta), and identified breakpoints of S mu/S gamma 3, S mu/S gamma 2, S mu/S alpha, S gamma 3/S alpha, and S gamma 2/S alpha recombinants. The S mu recombination donor sites clustered in the 3' half of the S mu region, while the S alpha recombination acceptor sites clustered in the 5' half of the S alpha region. In addition, donor and acceptor sites of S gamma regions also clustered in the 3' and 5' parts, respectively. These site preferences are in sharp contrast to the dispersed distribution of S mu/S gamma 1 breakpoints within both S mu and S gamma 1 regions upon IgG1 switch induced by LPS and interleukin 4. Our results support the hypotheses that TGF-beta increases the frequency of switch recombination events to IgA and that the switch recombination to IgA often proceeds by successive recombination of S mu/S gamma and S gamma/S alpha.
Lipopolysaccharide and Pristane-Induced Peritoneal Exudate Requirements for Plasma Tumor Cell Colony Formation&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: M Platica, C Bojko, R Clincea, V Hollander
Journal: JNCI Journal of the National Cancer Institute (1982)

The role for lipopolysaccharide (LPS) and a pristaneinduced peritoneal exudate (PIPE) on the in vitro development of murine plasmacytoma was studied. MOPC-315 cell suspensions showed little tendency for colony formation in a soft agar culture medium. Additions of LPS and PIPE were required for maximal colony formation. The LPS effect was dose-dependent down to nanogram quantities. PIPE prepared from inbred strains of mice not susceptible to pristane-induced plasmacytoma (DBA/2) or from normal peritoneal washings was ineffective. PIPE activity was radioresistant and not transferable by cell-free conditioned medium. Three strains of transplantable plasmacytomas showed colony formation stimulation by LPS plus PIPE, but LPS and PIPE were ineffective with lymphosarcoma P1798.
Selective acceptance of MHC class I-deficient tumor grafts in the brain.
Authors: H G Ljunggren, T Yamasaki, P Collins, G Klein, K Kärre
Journal: The Journal of Experimental Medicine (1988)

H-2-deficient (H-2-) tumor variants were accepted equally well compared with H-2+ wild-type cells in the brain of syngeneic mice, while the H-2- cells were selectively eliminated when inoculated extracranially. This indicates a specific absence or suppression of the defense against MHC class I-deficient cells in the brain, suggested to be mediated by NK cells. In contrast, T cell-mediated immune reactions could clearly be detected in the brain under the same experimental conditions. This was shown in control experiments where H-2+ tumor cells were rejected from the brain of preimmunized or allogeneic mice. The present findings may be important for the understanding of neurotropic virus infections, immunology and immunotherapy of brain tumors, as well as for the growing interest in tissue grafting within the central nervous system.
Pulmonary gas exchange and educational level: a community study
Authors: I. Welle, G.E. Eide, A. Gulsvik, P.S. Bakke
Journal: European Respiratory Journal (2004)

Socio-economic status (SES) is related to increased risk of airway disease in terms of forced expiratory volume in one second (FEV 1 ) and forced vital capacity. No data are available as to what extent SES predicts alveolar function in a general population. In this cross-sectional study, 1,275 subjects aged 18–73 yrs underwent pulmonary testing, including the single-breath carbon monoxide transfer capacity of the lungs ( T L,CO ). Educational level was used as an index for SES. Mean±sd T L,CO % predicted was 97% among those with primary school education, 99% among those with secondary school education and 104% among those with a university degree. In a multiple linear regression analysis, adjusting for age, height, haemoglobin, carboxyhaemoglobin, smoking habits, occupational exposure, FEV 1 and body mass index, T L,CO was significantly related to educational level in males but not in females. Occupational exposure was not significant. In this study, socio-economic status was found to be an independent determinant of T L,CO . Even in an affluent country such as Norway, socio-environmental risk factors may differ based on individuals' SES. Such risk factors may, for instance, be higher exposure to airborne pollutants, poorer housing conditions, or lower consumption of fruit and vegetables. Further exploration is called for.
Tobacco companies want more government cooperation
Authors: Linda Beecham
Journal: BMJ (2000)

Tobacco companies want to cooperate more with the UK government and the public health authorities to develop what British American Tobacco (BAT) calls “rational smoking and health policies based on a proper understanding of the science and the lessons to be drawn from the past.”

Martin Broughton, chairman of BAT, said that he wanted to resolve the stalemate between those who took the “social engineering approach” of wanting to eradicate smoking and those who adopted a laissez faire approach.

He was one of five witnesses giving evidence last week to the House of Commons health …
Roadmap for Developing and Validating Therapeutically Relevant Genomic Classifiers
Authors: Richard Simon
Journal: Journal of Clinical Oncology (2005)

Oncologists need improved tools for selecting treatments for individual patients. The development of therapeutically relevant prognostic markers has traditionally been slowed by poor study design, inconsistent findings, and lack of proper validation studies. Microarray expression profiling provides an exciting new technology for relating tumor gene expression to patient outcome, but it also provides increased challenges for translating initial research findings into robust diagnostics that benefit patients and physicians in therapeutic decision making. This article attempts to clarify some of the misconceptions about the development and validation of multigene expression signature classifiers and highlights the steps needed to move genomic signatures into clinical application as therapeutically relevant and robust diagnostics.
Flow cytometric immunobead assay for fast and easy detection of PML–RARA fusion proteins for the diagnosis of acute promyelocytic leukemia
Authors: E H A Dekking, V H J van der Velden, R Varro, H Wai, S Böttcher, M Kneba, E Sonneveld, A Koning, N Boeckx, N Van Poecke, P Lucio, A Mendonça, L Sedek, T Szczepański, T Kalina, V Kanderová, P Hoogeveen, J Flores-Montero, M C Chillón, A Orfao, J Almeida, P Evans, M Cullen, A L Noordijk, P M Vermeulen, M T de Man, E P Dixon, W M Comans-Bitter, J J M van Dongen
Journal: Leukemia (2012)

The PML-RARA fusion protein is found in approximately 97% of patients with acute promyelocytic leukemia (APL). APL can be associated with life-threatening bleeding complications when undiagnosed and not treated expeditiously. The PML-RARA fusion protein arrests maturation of myeloid cells at the promyelocytic stage, leading to the accumulation of neoplastic promyelocytes. Complete remission can be obtained by treatment with all-trans-retinoic acid (ATRA) in combination with chemotherapy. Diagnosis of APL is based on the detection of t(15;17) by karyotyping, fluorescence in situ hybridization or PCR. These techniques are laborious and demand specialized laboratories. We developed a fast (performed within 4-5 h) and sensitive (detection of at least 10% malignant cells in normal background) flow cytometric immunobead assay for the detection of PML-RARA fusion proteins in cell lysates using a bead-bound anti-RARA capture antibody and a phycoerythrin-conjugated anti-PML detection antibody. Testing of 163 newly diagnosed patients (including 46 APL cases) with the PML-RARA immunobead assay showed full concordance with the PML-RARA PCR results. As the applied antibodies recognize outer domains of the fusion protein, the assay appeared to work independently of the PML gene break point region. Importantly, the assay can be used in parallel with routine immunophenotyping for fast and easy diagnosis of APL.
Endobronchial presentation of Hodgkin's disease: a report of nine cases and review of the literature
Authors: J Tredaniel, I Peillon, C Ferme, P Brice, C Gisselbrecht, A Hirsch
Journal: European Respiratory Journal (1994)

Although mediastinal involvement by Hodgkin's disease is frequent, the initial presentation of the lymphoma by an endobronchial lesion is rare. Therefore, the question of whether patients with Hodgkin's disease should undergo fibreoptic bronchoscopy as a staging procedure remains unresolved. In a series of 469 patients with newly diagnosed Hodgkin's disease during a 10 year period, we reviewed the clinical features of nine patients who presented with an endobronchial tumour. They were compared to 34 previously published cases. The major presenting symptoms were cough, wheezing and haemoptysis. Bulky mediastinum was seen in six cases. The three other patients presented respiratory symptoms evocative of endoluminal invasion. All but one of the patients received combined modality therapy, as currently accepted for patients with poor prognostic factors. The overall actuarial survival was 74% after 4 yrs of follow-up. A selective subgroup of patients with stage I-II supradiaphragmatic and endobronchial Hodgkin's disease may, thus, present without poor prognostic factors (but generally with respiratory symptoms), and might be undertreated if this localization is not recognized. We propose that these patients should undergo fibreoptic bronchoscopy.
Crisis in Drug Testing
Authors: Hugh J. Hansen
Journal: JAMA (1985)

In response to questions about the reliability of the results of screening urine for drugs, we evaluated the performance of 13 laboratories, which serve a total of 262 methadone treatment facilities, by submitting prereferenced samples through the treatment facilities as patient samples (blind testing). Error rates for the 13 laboratories on samples containing barbiturates, amphetamines, methadone, cocaine, codeine, and morphine ranged from 11% to 94%, 19% to 100%, 0% to 33%, 0% to 100%, 0% to 100%, and 5% to 100%, respectively. Similarly, error rates on samples not containing these drugs (false-positives) ranged from 0% to 6%, 0% to 37% 0% to 66%, 0% to 6%, 0% to 7% and 0% to 10%, respectively. These blind tests indicate that (1) greater care is taken with known evaluation samples than with routine samples, (2) laboratories are often unable to detect drugs at concentrations called for by their contracts, and (3) the observed underreporting of drugs may threaten the treatment process. Drug treatment facilities should monitor the performance of their contract laboratories with quality-control samples, preferably through blind testing. (<i>JAMA</i>1985;253:2382-2387)
Enhanced Plasma Levels of LIGHT in Unstable Angina
Authors: Hanne Scholz, Wiggo Sandberg, Jan Kristian Damås, Camilla Smith, Arne K. Andreassen, Lars Gullestad, Stig S. Frøland, Arne Yndestad, Pål Aukrust, Bente Halvorsen
Journal: Circulation (2005)

Numerous studies have demonstrated the ability of oxidized LDL [(ox)LDL] to promote an inflammatory response in macrophages. Several inflammatory mediators have been reported to increase after oxLDL stimulation of such cells, but their relative importance is still unknown. In the present study, we used microarrays to identify genes in THP-1 macrophages that were upregulated by oxLDL.Our main findings were as follows. In a microarray screening experiment, we identified LIGHT, a ligand in the tumor necrosis factor superfamily, as one of the genes that were markedly upregulated in oxLDL-stimulated THP-1 macrophages. We showed significantly raised plasma levels of LIGHT in patients with stable angina (n=40) and particularly in those with unstable angina (n=40) compared with healthy controls (n=20), which underscores the clinical relevance of the in vitro finding. We also showed that LIGHT enhanced lipid accumulation in oxLDL-stimulated THP-1 macrophages, possibly through upregulation of class A scavenger receptor (SR-A). This increased lipid accumulation was accompanied by enhanced expression of tissue factor and plasminogen activator inhibitor-1, as well as enhanced thrombin formation, transforming macrophages into a prothrombotic phenotype. The LIGHT-mediated increase in SR-A, tissue factor, and plasminogen activator inhibitor-1 was also seen in human monocyte-derived macrophages. Finally, the LIGHT-mediated enhancement of SR-A and TF expression appears to involve nuclear factor-kappaB activation.These findings suggest that LIGHT could serve as a molecular link between lipid metabolism, inflammation, and thrombus formation, which are all features of atherosclerotic plaques.
Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts
Authors: Dong Chen, Scott Reierstad, Zhihong Lin, Meiling Lu, Chris Brooks, Newton Li, Joy Innes, Serdar E. Bulun
Journal: Cancer Research (2007)

Abstract Aromatase is the key enzyme for estrogen biosynthesis. A distal promoter, PI.4, maintains baseline levels of aromatase in normal breast adipose tissue. In contrast, malignant breast epithelial cells secrete prostaglandin E2 (PGE2), which stimulates aromatase expression via proximal promoters PI.3/PII in a cyclic AMP (cAMP)– and protein kinase C (PKC)–dependent manner in adjacent breast adipose fibroblasts (BAF), leading to increased local concentrations of estrogen. Although an effective treatment for breast cancer, aromatase inhibitors indiscriminately abolish estrogen synthesis in all tissues, causing major side effects. To identify drug targets to selectively block aromatase and estrogen production in breast cancer, we investigated PGE2-stimulated signaling pathways essential for aromatase induction downstream of cAMP and PKC in human BAFs. Here, we show that PGE2 or its surrogate hormonal mixture dibutyryl cAMP (Bt2cAMP) + phorbol diacetate (PDA) stimulated the p38, c-jun NH2-terminal kinase (JNK)-1, and extracellular signal–regulated kinase (ERK) mitogen-activated protein kinase pathways. Inhibition or small interfering RNA–mediated knockdown of p38 or JNK1, but not ERK, inhibited PGE2- or Bt2cAMP + PDA–induced aromatase activity and expression via PI.3/PII. Conversely, overexpression of wild-type p38α or JNK1 enhanced PGE2-stimulated aromatase expression via PII. PGE2 or Bt2cAMP + PDA stimulated c-Jun and activating transcription factor-2 (ATF2) phosphorylation and binding to the PI.3/PII region. Specific activation of protein kinase A (PKA) or EPAC with cAMP analogues stimulated p38 and JNK1; however, only PKA-activating cAMP analogues induced aromatase expression. The PKC activator PDA effectively stimulated p38 and JNK1 phosphorylation but not aromatase expression. Taken together, PGE2 activation of p38 and JNK1 via PKA and PKC is necessary for aromatase induction in BAFs, and p38 and JNK1 are potential new drug targets for tissue-specific ablation of aromatase expression in breast cancer. [Cancer Res 2007;67(18):8914–22]