tbuckley/cabot-search huggingface dataset:
Abstract 3904: Pyridylthiazole-based ureas as inhibitors of Rho-associated protein kinases
Authors: Roberta Pireddu, Kara Forinash, Nan N. Sun, Mathew P. Martin, Shen-Shu Sung, Brian Alexander, Jin-Yi Zhu, Wayne C. Guida, Ernst Schönbrunn, Saïd M. Sebti, Nicholas J. Lawrence
Journal: Cancer Research (2012)

Abstract Rho GTPase is a small G-protein which plays a critical role in signaling pathways and controls cell growth and division. Rho-associated protein kinase (known as ROCK or Rho kinase) is a Ser/Thr protein kinase activated by GTP-bound Rho and phosphorylates target proteins involved in various signal transduction pathways. Rho and the Rho-kinase signalling pathways are implicated in cell morphology, motility, smooth muscle contraction, formation of stress fibres, focal adhesion and cell transformation. ROCKs have been subject to growing attention, having been implicated in a range of therapeutic areas including cardiovascular diseases, CNS disorders, and cancer. Further, the pharmacological inhibition of ROCKs has been suggested as a promising strategy in the prevention of cell invasion, a central event in the process of metastasis. Potent ROCK inhibitors of a new class of 1-benzyl-3-(4-pyridylthiazol-2-yl)ureas have been identified. Remarkable differences in activity were observed for ureas bearing a benzylic stereogenic center. Derivatives with hydroxy, methoxy and amino groups at the meta position of the phenyl ring give rise to the most potent inhibitors (low nM). Substitutions at the para position result in substantial loss of potency. Changes at the benzylic position are tolerated resulting in significant potency in the case of methyl and methylenehydroxy groups. X-ray crystallography was used to establish the binding mode of this class of inhibitors and provides an explanation for the observed differences of the enantiomer series. Potent inhibition of ROCK in human lung cancer cells was shown by suppression of the phosphorylation levels of the ROCK substrate MYPT-1. One of the series, RKI-1447 inhibits migration, invasion and anchorage-independent tumor growth of breast cancer cells and is discussed in an accompanying poster. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3904. doi:1538-7445.AM2012-3904
Case 37-2012
Authors: Lisa Christopher-Stine, Dwight R. Robinson, Carol C. Wu, Eugene J. Mark
Journal: New England Journal of Medicine (2012)

A 21-year-old man presented with fever, arthralgias, dyspnea, and periorbital swelling. Examination revealed periorbital edema and erythema. Chest CT revealed bilateral subpleural reticular and ground-glass opacities. Diagnostic tests and a diagnostic procedure were performed.
Hypervitaminosis D Associated with Drinking Milk
Authors: Claire H. Jacobus, Michael F. Holick, Qing Shao, Tai C. Chen, Ingrid A. Holm, Jonathan M. Kolodny, Ghada El-Hajj Fuleihan, Ellen W. Seely
Journal: New England Journal of Medicine (1992)

Vitamin D has been added to milk in the United States since the 1930s to prevent rickets. We report the unusual occurrence of eight cases of vitamin D intoxication that appear to have been caused by excessive vitamin D fortification of dairy milk. Methods. Medical records were reviewed and a dietary questionnaire was sent to eight patients who had unexplained hypervitaminosis D. Vitamin D analyses with high-performance liquid chromatography were performed on samples of the patients' serum, the dairy milk they drank, and the vitamin D concentrate added to the milk.
Hoopla Competes With Science at the International AIDS Conference
Authors: F. X. Mahaney
Journal: JNCI Journal of the National Cancer Institute (1989)

Hoopla Competes With Science at the International AIDS Conference Francis X. Mahaney, Jr. Francis X. Mahaney, Jr. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 14, 19 July 1989, Pages 1056–1057, https://doi.org/10.1093/jnci/81.14.1056 Published: 19 July 1989
FRI0410 Adult pompe’s disease: screening in patients with myopathies of unknown etiology
Authors: J. Perez-Lopez, A. Selva-O’Callaghan, J. C. Milisenda, L. Gallego, E. Trallero-Araguas, M. Juanos-Iborra, I. Pinal, J. M. Grau-Junyent, M. Vilardell-Tarrés
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Pompe´s disease is an inherited metabolic myopathy caused by deficiency of the lysosomal enzyme acid α-glucosidase. In adults, it may be misdiagnosed as other chronic muscle disease such as limb girdle muscular dystrophy or polymyositis (PM), among others. Until now diagnosis was difficult and substitutive treatment not available, but recently the development of enzymatic methods using dried blood spots (DBS) on filter paper as a simple, quick and inexpensive first test, as well as the approval of enzyme replacement therapy, have substantially changed the patients perspectives. <h3>Objectives</h3> To check for Pompe’s disease in a series of adult patients diagnosed with myopathy of unknown etiology (MUE), PM or with asymptomatic hyperCKemia. <h3>Methods</h3> Patients with high values or creatin kinase (&gt;1000 UI/L) recruited from a general routine laboratory and patients diagnosed with PM or MUE attended in a specialized myopathies outpatient clinic from 2 tertiary University Hospitals in Barcelona during the period of 1 year (from january 2012 to january 2013) were evaluated. The diagnosis of both PM and MUE was reached after a full pathologic analysis including histochemistry and immunohistochemistry on muscle biopsies was performed. We included another group of patients with well-known myopathy as a control group. In all patients, acid α-glucosidase activity in DBS was the method employed for screening and positive cases were then confirmed by enzymatic activity in purified lymphocytes and genetic testing. <h3>Results</h3> One-hundred twenty-four patients (78 female), with a median age (SD) of 53.6 yrs (17.6) were analysed. Polymyositis was diagnosed in 25 patients, hyper CK in 9, and MUE in 50. Other well-known myopathies such as mitochondrial myopathies, dystrophinopathies, dysferlinopathies, and McArdle disease were diagnosed in the remaining 40 (control group). Eight patients (3 with polymyositis, 2 with hyperCKemia and 3 with MUE tested positive for DBS to Pompe´s disease. Only one patient from the group of MUE was confirmed to be positive for Pompe´s disease by enzymatic and genetic testing. <h3>Conclusions</h3> Pompe’s disease may be an underdiagnosed disease in patients with myopathy of uncertain origin and it should be included in the differential diagnosis in these patients. Positivity to DBS required enzymatic and genetic confirmation. <h3>References</h3> Van der Ploeg AT, Reuser AJ. Lysosomal Storage Diseases 2. Pompe´s diseases. Lancet 2008;372:1342-53. van der Beek NA, de Vries JM, Hagemans ML, et al. Clinical features and predictor for disease natural progression in adults with Pompe disease: a nationwide prospective observational study. Orphanet Journal of Rare Diseases 2012, doi: 10.1186/1750-1172-7-88. <h3>Disclosure of Interest</h3> None Declared
Abstract 4275: BMI-1 promotes drug resistance and cellular invasion in head and neck cancer stem cells
Authors: Daniel Lew, David Yi, Jessica Wang-Rodriguez, Zana K. Ahmad, Alan Kiang, Eric L. Abhold, Martin Haas, Kevin Brumund, Robert A. Weisman, Weg M. Ongkeko
Journal: Cancer Research (2010)

Abstract Recently, the growth and metastasis of tumors, including head and neck squamous cell carcinomas (HNSCC), have been attributed to a subpopulation within tumors known as cancer stem cells (CSC). Studies have shown that HNSCC cells that are CD44+ are putative CSC and have the capability to self-renew, differentiate and preferentially express BMI-1. The polycomb group protein BMI-1 is a transcriptional repressor that silences the genes responsible for the expression of the cell cycle inhibitor genes p16 and p19. The gene is essential for maintaining the self-renewal capability of both normal and CSC. Very recent studies have shown that BMI-1 may also be implicated in other critical roles in cancer cell behavior including its role in the invasiveness of cancer cells. In this study, we demonstrate that in HNSCC CSC, BMI-1 is critical for cellular invasion. Knockdown of BMI-1 in CD44+ cells results in significant inhibition of invasion while overexpression of BMI-1 in CD44- cells promotes invasion. Furthermore, we show that this enhaced invasion conferred by BMI-1 is through induction of epithelial-to-mesenchymal transition (EMT) genes and the down-regulation of E-cadherin. In addition, we present evidence that the proteinases MMP2 and MMP9 are induced upon overexpression of BMI-1. CSC are also characterized by being chemoresistant, in part through their enhanced ability to extrude drugs because of their high expression of drug transporters. In this study, we demonstrate another mechanism for the resistance of CSC to DNA-damaging agents. We present evidence that another function of BMI-1 in CSC is its ability to regulate apoptosis. Knockdown of BMI1-1 in CSC using siRNA resulted in increased levels of cisplatin-induced apoptosis compared to cells transfected with scrambled siRNA. Our findings lend support to previous studies that have implicated BMI-1 in the regulation of pro-survival genes as well as the DNA damage response pathway. Our findings have revealed that BMI-1 is not only essential for self-renewal and tumorigenesis, but also that it has critical functions in cancer stem cell drug resistance and invasion, and most likely, metastasis. Since BMI-1 controls many of the properties of CSC and is preferentially expressed in HNSCC CSC, this oncogene may serve not only as a tumor marker, but also as an ideal therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4275.
1112RALOXIFENE HYDROCHLORIDE AS A NOVEL ANTIVIRAL AGENT: INHIBITION OF HEPATITIS C VIRUS (HCV) REPLICATION
Authors: N. Furusyo, E. Ogawa, M. Sudoh, M. Murata, T. Ihara, H. Ikezaki, T. Hayashi, S. Hiramine, J. Hayashi
Journal: Journal of Hepatology (2012)
Young women most at risk are least likely to be offered HPV vaccine
Authors: Jacqui Wise
Journal: BMJ (2014)

Young women most at risk of developing cervical cancer are the least likely to have been offered the human papillomavirus (HPV) vaccine or to have completed the course, according to a survey of women attending sexual health services in England.

In the journal Sexually Transmitted Infections the researchers said that higher risk individuals need to be better targeted to boost uptake of the vaccine, which is below the 80% level needed to make a significant difference to cervical cancer rates. …
Detection of Renal Cortical Defects
Authors: Kimberly Applegate, Len Connolly, S. T. Treves
Journal: Clinical Nuclear Medicine (1998)

Section of Pediatric Radiology; Cleveland Clinic Children's Hospital; Cleveland, OH (Applegate) Department of Radiology; Children's Hospital; Boston, MA (Connolly) Department of Radiology; Children's Hospital; Boston, MA (Treves)
S39 Whole Exome Sequencing in Chronic Thromboembolic Pulmonary Hypertension Reveals Biologically Plausible Novel Genetic Variation
Authors: C McCabe, K Sheares, S Graf, J Pepke-Zaba, N Morrell
Journal: Thorax (2012)

<h3></h3> Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease with no known heritability, the cumulative incidence of which has been placed at between 0.5 and 9.1% following acute pulmonary embolism [1,2]. A majority consensus on its development has emerged predicated on the theory of disordered thrombus resolution following venous thromboembolism. This in part stems from epidemiological data but is also based on studies implicating established clinical and laboratory factors, a central theorem being that individuals respond differently to acute thrombotic insult. Given traditional prothrombotic factors explain less than 10% of reported cases of CTEPH, we hypothesised a significant burden of disease is accounted for by unidentified genetic factors. Using an unbiased approach of exome capture, we selected 20, deeply phenotyped, young individuals (11 female) who had suffered large PE that subsequently developed haemodynamically confirmed CTEPH despite anticoagulation. Individuals with known prothrombotic tendency and significant comorbidity were excluded. Selected patients were White Caucasian origin. Following ethical approval, DNA was extracted from 20 whole blood samples and libraries prepared. Whole exome sequencing was undertaken using Agilent’s Sure Select Exome capture kit on the Hiseq 2000 platform prior to bioinformatic analysis. 75 bp paired-end reads were aligned to the H19 Reference genome and the pipeline annotated for SNPs and indels. Intergenic, intronic and UTR variants were removed from the dataset with minimum mapping quality score and 20x read-depth coverage stipulated for variant calls. Consecutive filtres were applied, firstly retaining those predicted to be pathogenic flagged as splice-site, essential splice-site, missense, frameshift-coding, non-synonymous coding, NMD-transcript, within-mature-miRNA, STOP-gained and STOP-lost. Variants also present in twenty locally sourced normal controls were discarded. Additional filtres were subsequently applied to exclude variants already listed in dbSNP/1000 genomes data with remaining variants split into heterozygous and homozygous groups (Table 1). Our final candidate list contains novel DNA variants lying within pathways known to mediate both inflammation and endothelial dysfunction in the pulmonary vasculature. Detailed downstream biological analysis of our variant effects following validation measures may lead to the uncovering of novel mechanisms in this difficult disease. <h3>References</h3> Surie S, Gibson NS, Gerdes VE, Bouma BJ, van Eck-Smit BL, Buller HR, Bresser P. Active search for chronic thromboembolic pulmonary hypertension does not appear indicated after acute pulmonary embolism. <i>Thromb Res</i>. 2010; 125: 202–5. Becattini C, Agnelli G, Pesavento R, Silingardi M, Poggio R, Taliani MR, Ageno W. Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism. <i>Chest</i>. 2006; 130:172–5.
Abstract 2999: Assessment of microRNA expression in two-dimensional histopathological fields of breast cancer
Authors: Alex M. Rosenberg, Christine K. Zoon, Elizabeth S. Clark, Michael D. Armani, Benjamin Shapiro, Elisabeth Smela, Jeffrey C. Hanson, Jaime Rodriguez-Canales, Michael R. Emmert-Buck, Michael A. Tangrea
Journal: Cancer Research (2010)

Abstract Breast cancer is the second most common type of cancer among women with an expected ∼192,000 newly diagnosed cases in the United States this year alone. Early detection methods are becoming increasingly important for guiding treatment options and decisions. Currently, standard molecular diagnostic tests of breast cancer characterize patient cases by estrogen receptor (ER), progesterone receptor (PR) and Her2neu status. The recently discovered biomolecule, microRNA (miRNA), is being assessed as a novel diagnostic tool; however, since miRNA is a regulatory molecule it is likely that expression is cell-type and location specific, thus studies that don't specifically study malignant and normal cells may mask miRNA patterns within tissue. The goal of our study was to evaluate miRNA expression within sub-regions of formalin-fixed paraffin-embedded breast cancer tissue. Utilizing a combination of laser-based and manual microdissection techniques, we evaluated the expression of several breast cancer associated miRNA via TaqMan chemistry. We dissected selected areas of tumor and normal cells, as well as a grid-like pattern over entire tissue sections to separately evaluate each histopathological region. The data suggest there is heterogeneity of miRNA expression within the tumor and the surrounding normal tissue. In order study this phenomenon in more detail, we are now adapting a new two-dimensional amplification (2D-PCR) device to measure miRNA levels across tissue specimens with fine resolution. This approach to examining miRNA profiles in tissue sections may lead to novel findings with diagnostic or prognostic implications for breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2999.
Abstract LB-186: Somatic Y641 mutations in EZH2 alter the balance of di- and tri-methylation of H3K27 in diffuse large B-cell lymphomas
Authors: Elsie Diaz, Michael T. McCabe, Yong Jiang, Stephanie Chen, Melissa Pappalardi, Kimberly Smitheman, Anthony Della Pietra, Alan Graves, Ryan Kruger, Martin Brandt, Sharon Sweitzer, Benjamin Schwartz, Peter J. Tummino, Caretha L. Creasy
Journal: Cancer Research (2011)

Abstract EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) responsible for methylating histone H3 on lysine 27 (H3K27) and repressing transcription of target genes. PRC2 activity is essential for maintaining the self-renewal capacity of embryonic and adult stem cells and the dynamic regulation of this activity is critical for proper development and differentiation. Dysregulation of H3K27 methylation is implicated in tumorigenesis and occurs through multiple mechanisms. Elevated levels of EZH2 are known to correlate with poor prognosis in a number of solid tumors including prostate and breast. Inactivating mutations in UTX, an H3K27 demethylase which acts in opposition to EZH2, have been described in several tumor types including multiple myeloma, esophageal squamous cell carcinoma, and renal cell carcinoma. More recently, somatic mutations in EZH2 were identified in myelodysplastic syndrome (MDS), follicular lymphoma (FL), and GCB diffuse large B cell lymphoma (DLBCL). While the mutations in MDS are often homozygous and encompass missense, nonsense, and frame shift mutations at multiple regions of the protein, the mutations in DLBCL and FL are heterozygous and occur at a single residue (Y641) suggesting that the effect of these mutations on PRC2 activity could be quite different between MDS and lymphoma. Utilizing a biochemical approach with recombinant PRC2 containing either wild-type or mutant EZH2, we demonstrate that Y641 mutants exhibit an altered substrate preference. In contrast to wild-type EZH2 which prefers an unmodified or mono-methylated K27 residue, Y641 mutants act primarily on a di-methylated H3K27 with little activity for unmodified or mono-methylated K27. Consistent with these biochemical data, we find that when compared to wild-type lymphoma cell lines those harboring Y641 mutations have elevated levels of H3K27me3 and reduced H3K27me2. To further characterize the substrate specificity of PRC2 complexes containing either WT or mutant EZH2, we utilized an epigenetic peptide library which contained unmodified and modified peptides from histone H2A, H2B, H3 and H4. In addition, we have conducted cell-based studies to understand the effect of these mutations on H3 methylation and the regulation of EZH2 target genes. These data and the implications of these findings for the treatment of FL and DLBCL will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-186. doi:10.1158/1538-7445.AM2011-LB-186
AB0575 Prevalence of hla-cw * 06 and * 07 and its relationship with psoriatic arthritis in northwestern spain.
Authors: E. A. Blanco, C. Bejerano, J. Pinto-Tasende, S. Pértega, I. Rego, C. Fernandez, M. Freire, J. De Toro, F. J. Blanco, J. L. Fernández-Sueiro
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Psoriatic arthritis (PsA) is a disease developed in 10-20% of psoriasis patients. <i>HLA–Cw*06</i> has been identified as the major genetic determinant of susceptibility to psoriasis. <h3>Objectives</h3> To estimate the prevalence of HLA-Cw6 and Cw7 in healthy population, patients with psoriasis without joint disease and patients with PsA and to analyze the influence of both alleles in the characteristics of PsA. <h3>Methods</h3> Genotyping of HLA-Cw * 06 and * 07 was performed on DNA samples of 390 Caucasian subjects by PCR-SSP (Sequence specific primer). The allele frequencies of HLA-Cw * 06 and * 07 were determined in patients with psoriasis (n = 117), PsA (n = 172), and compared with those of healthy controls (n = 101), and we calculated the odds ratio and confidence interval of 95% (OR, 95% CI). We determined the association of alleles with clinical-radiological forms of PsA (peripheral and axial / mixed). We used the chi-square test, Fisher's exact test and t Student. We consider to be significant at p &lt;0.05. <h3>Results</h3> The frequencies of HLA-Cw * 06 were higher in type 1 psoriasis (OR 7.1, 95% CI 1.8-27.9, P &lt;0.0001) and PsA (OR 3.5, 95% CI 1.7-7.3, P 0.001) relative to healthy controls, thus, in HLA-Cw * 06 positive patients with psoriasis, the diagnosis was at younger ages, 19.4 years (SD 12.5) vs 34.8 (18.8), p &lt;0.0001) but not in PsA (p 0.941<b>);</b> although PsA patients with type I psoriasis had been diagnosed before patients with type II psoriasis (40.0 years (12.2) vs 57.6 (9.7), p &lt;0.0001) regardless of the alleles. HLA-Cw * 0602 was associated with type I psoriasis (OR 3.3, 95% CI 1.5-7.1, p 0003) and PsA (OR 3.5, 95% CI 1.7-7.3, p 0.001) compared to healthy controls, but there were no differences in the HLA-Cw * 0602 prevalence between clinical-radiological forms of APs neither in clinical and laboratory features, metrology and radiological damage. PsA patients with type I psoriasis had a higher prevalence of HLA-Cw * 0602 than PsA patients with type II psoriasis (p 0.001). No differences were observed for the HLA-Cw * 07 and its subtypes relative to healthy controls or patients with psoriasis. <h3>Conclusions</h3> HLA-Cw * 06 and its main subtype * 0602, are more prevalent in our patients with cutaneous psoriasis and psoriatic arthritis compared with healthy controls, and are more frequent in patients with a diagnosis of an earlier age. There was no influence on other features analyzed in PsA patients We found no difference in HLA-Cw * 07. <h3>Acknowledgements</h3> The authors thank José Luis Fernández-Sueiro for him hard work and dedication. Rest in peace. <h3>Disclosure of Interest</h3> None Declared