tbuckley/cabot-search huggingface dataset:
P262 Skeletal tuberculosis – a retrospective review at two inner City UK Hospitals: Abstract P262 Table 1
Authors: GC Hagan, J Piper, H Bagnall, I Ahmed, N Nathani
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Skeletal tuberculosis (TB) accounts for about 10% of extrapulmonary tuberculosis in Europe and the USA.<sup>1</sup> Outcomes and duration of treatment are less well described than pulmonary TB. We sought to identify characteristics and outcomes for patients diagnosed with skeletal TB in the two hospitals in our trust. <h3>Methods</h3> Cases of TB treated in our NHS trust from 1/1/2011 to 31/12/2013 with site of disease including bone and/or spine were included. Data was obtained from the Enhanced TB Surveillance Database and case note review. Patients with a positive alternative diagnosis were excluded. TB affecting other body systems was defined as imaging abnormalities with exclusion of alternative diagnoses. <h3>Results</h3> 34 patients (20 males), mean age 42.7 years, were identified. 29(85%) were born outside the UK. No patients were HIV positive (test not offered/refused in 11%). Sites of disease are shown in Table 1. 13(38%) of patients had the diagnosis made via non-surgical biopsy (either radiological or bedside), 6(18%) through surgical biopsy, and 5(15%) of patients having the diagnosis made through sampling from another site (usually pulmonary). The remainder of patients (10) either had a clinico-radiological diagnosis or the diagnosis made overseas, with 4 of those patients undergoing a non-diagnostic biopsy. Mean length of treatment was 10 months. At end of treatment 9(40%) of spinal TB patients had ongoing back pain and 4(33%) of patients with appendicular joint involvement had residual stiffness. <h3>Conclusions</h3> Bedside or image guided procedures have a role in diagnosis of skeletal TB; about 30% will also have pulmonary TB which may be more accessible for diagnosis. Sending for TB culture during surgery is important. After appropriate treatment a proportion of patients have residual pain and stiffness. <h3>Reference</h3> 1 Pigrau-Serrallach C, Rodríguez-Pardo D. Bone and joint tuberculosis.<i> Eur Spine J</i>. 2013;<b>22</b>(Suppl 4):556–566
P53 Inactivation and Genomic Aberrations in Relation to Imatinib Resistance in Chronic Myeloid Leukemia.
Authors: Jitka Malcikova, Jana Smardova, Daniela Zackova, Tomas Jurcek, Ludmila Rocnova, Martin Trbusek, Alexandra Oltova, Michael Doubek, Zdenek Racil, Sarka Pospisilova, Jiri Mayer
Journal: Blood (2009)
Abstract 4906: The selective class I HDAC inhibitor entinostat enhances the antitumor effect of PD-1 inhibition in a syngeneic orthotopic murine model of renal cell carcinoma
Authors: Ashley R. Orillion, Li Shen, Remi Adelaiye-Ogala, May Elbanna, Sreenivasulu Chintala, Sreevani Arisa, Roberto Pili
Journal: Cancer Research (2016)

Abstract Background: Recent advances in immunotherapy have highlighted the antitumor effects of immune checkpoint inhibition. Novel anti-PD-1/PD-L1 immunotherapies have been shown to effectively overcome tumor avoidance of immune surveillance in several tumor types including renal cell carcinoma. Our group has recently shown that the selective class I HDAC inhibitor entinostat is effective in suppressing regulatory T cells and enhancing immunotherapies in murine renal and prostate models, RENCA and Myc-Cap respectively. In this study we have evaluated the combination of entinostat with an anti-PD-1 antibody in the RENCA renal cell carcinoma model. Methods: 32 BALB/c female mice were implanted with the syngenic, orthotopic, renal cell carcinoma mouse model, RENCA - luciferase tagged - at day -8. Treatment (8 mice /group) with anti-mouse-PD-1 (aPD-1; 10mg/kg twice a week, I.P.), entinostat (5mg/kg 5 days a week), or combination of the two was begun at day 1. Bioluminescence imaging was performed at days -1, 9 and 19 to assess the orthotopic tumor growth. End point tumor weights were taken to assess the effect of combination treatment. Results: Analysis of tumor growth showed a reduction of bioluminescence across the three time points in the combination group as compared to the vehicle and single agent treatments. Additionally, end point analysis of tumor weights revealed an overall reduction in the size of the tumors in the entinostat/anti-mPD-1 combination group (88% inhibition) as compared to the vehicle (p = 0.0002), aPD-1 alone (25% inhibition)(p = 0.0181), and entinostat alone (63% inhibition)(p = 0.0481) groups. Examination of the status of the infiltrating immune cells of the tumor microenvironment via flow cytometry, qRT-PCR, immunohistochemistry, and/or immunofluorescence analysis is ongoing. Conclusions: Our preliminary results suggest that the immunomodulatory activity of the selective class I HDAC inhibitor entinostat may enhance the antitumor effect of PD-1/PD-L1 inhibition and provide the rationale for the clinical testing of this novel combination in patients with RCC. Citation Format: Ashley R. Orillion, Li Shen, Remi Adelaiye-Ogala, May Elbanna, Sreenivasulu Chintala, Sreevani Arisa, Roberto Pili. The selective class I HDAC inhibitor entinostat enhances the antitumor effect of PD-1 inhibition in a syngeneic orthotopic murine model of renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4906.
ECG Response: May 17, 2016
Journal: Circulation (2016)

ECG Challenge: A 70-year-old man with a history of coronary artery disease and an ischemic cardiomyopathy with a left ventricular ejection fraction of 38% presents to the emergency room with complaints of lightheadedness. His medications include a β-blocker, an angiotensin-converting enzyme inhibitor, and Imdur. His pulse is noted to be slow, and a 12-lead ECG is obtained.



The rhythm is regular at a …
Abstract 4860: The BTK inhibitor ibrutinib modulates T cell immunity in mouse models and in differentiated human T cells
Authors: Yujun Huang, Jeff Hsu, Mint Sirisawad, Hsu-Ping Kuo, Betty Y. Chang
Journal: Cancer Research (2016)

Abstract Ibrutinib inhibits Bruton's tyrosine kinase (BTK) and effectively treats B-cell malignancies. Ibrutinib also targets IL-2-inducible T-cell kinase (ITK) and modulates the T-cell receptor signaling pathway. Because ibrutinib enhanced antitumor immunity when combined with anti-PD-L1 in various syngeneic solid tumor and lymphoma models (Sajiv-Barfi, PNAS 2015), we sought to determine the effect of ibrutinib on T-cell function and activation. Using in vitro human primary T-cell activation assays, we found that ibrutinib did not suppress T-cell proliferation but slightly inhibited IFNã production in CD4 and CD8 effector T cells when human peripheral blood mononuclear cells (PBMCs) were stimulated with anti-CD3 and anti-CD28 antibodies. Ibrutinib also inhibited PD-1 expression on human CD8 effector T cells. More strikingly, ibrutinib significantly suppressed naïve murine CD4 T-cell differentiation in vitro into Foxp3+ regulatory T cells (Treg) in the presence of TGF-â. Further, we evaluated the immunomodulatory effect of ibrutinib in tumor-bearing mice. In pancreatic (Pan02) and renal cell carcinoma (Renca) models, we found that single-agent ibrutinib, as well as in combination with standard-of-care agents, effectively inhibited tumor growth. In the syngeneic Renca tumor model, combination ibrutinib treatment significantly reduced CD4+Foxp3+ Treg cells both in the spleen (P &amp;lt; 0.001) and tumor microenvironment (P &amp;lt; 0.05), compared with everolimus alone. Ibrutinib also significantly reduced the percentage of PD-1hi cells among CD8 tumor-infiltrating lymphocytes in A20 lymphoma-bearing mice (P &amp;lt; 0.05). These data demonstrate that ibrutinib, a BTK inhibitor, can suppress immune-inhibitory factors and enhance antitumor immunity in vivo. Ibrutinib may serve as a promising immunomodulatory agent in potentiating current cancer immunotherapy in solid tumors. Citation Format: Yujun Huang, Jeff Hsu, Mint Sirisawad, Hsu-Ping Kuo, Betty Y. Chang. The BTK inhibitor ibrutinib modulates T cell immunity in mouse models and in differentiated human T cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4860.
Relapsed Marginal Zone B-Cell Lymphoma: Clinical Features and Treatment Outcome.
Authors: Sung Yong Oh, Won Seog Kim, Seok Jin Kim, Jin Seok Kim, Sung Hyun Kim, Dae Ho Lee, Jong Ho Won, In Gyu Hwang, Min Kyoung Kim, Soon Il Lee, Jong Gwang Kim, Deok-Hwan Yang, Hye Jin Kang, Chul Won Choi, Jinny Park, Young Jin Choi, Hyo Jung Kim, Jung Hye Kwon, Cheolwon Suh, Hyo-Jin Kim
Journal: Blood (2009)
Abstract 3648: Resolving copy number variations from existing exome SNP data without the need for sophisticated software
Authors: Marcus C. Hansen, Laura L. Herborg, Anne S. Roug, Sadudee Chotirat, Chirayu U. Auewarakul, Eigil Kjeldsen, Peter Hokland
Journal: Cancer Research (2016)

Abstract Several tools exists to evaluate copy-number variation (CNV) from sequencing read data. Here, the aim is to investigate whether larger CNVs in leukemia can be extracted directly from already called variants - without specialized algorithms. Methods: 12 cases of leukemia, with 6 paired and 6 unpaired, were included (Table 1). Following exome sequencing and reference alignment variants were called with GATK to produce recalibrated sets in variant call format (VCF). Passed single nucleotide polymorphisms (SNPs) were limited to depth of coverage &amp;gt; 29x. Each chromosome were visualized as frequency scatter plot and smoothened histograms of frequency distribution in order to inspect frequency bands and number of peaks in histograms. Kolmogorov-Smirnov test was employed to compare distributions between paired samples. Results: None of the AML cases with normal karyotype displayed CNVs and no significant changes in frequency distributions were detected. In the relapse of paired T-ALL a Chr 4 trisomy and a 33×10−6 bp copy-number neutral loss of heterozygosity (CN-LOH) on Chr 9 were detected. Collectively, 7 aberrations confirmed standard cytogenetics, 8 new aberrations were added to the cytogenetical profile and 5 could not be detected as shown in Table 1. The aberrations not detected were, as expected, balanced translocations (3) and microdeletions (2). Discussion: No previously found large aberrations escaped detection, when disregarding translocations. In addition, other CNVs not detected by conventional cytogenetics were found by SNP analysis. Moreover, the added information is in agreement with the literature: 5% of T-ALL patients display del(11)(p12p13) and +12 is one of the most common cytogenetic changes of CLL, e.g. Thus, we suggest that CNV profiling can be initiated by directly evaluating frequencies from existing variant calls. This may ease implementation of “closed toolboxes”, enable analysis of single unpaired samples and function as a direct complement to array-CGH or FISH to detect CN-LOH. Table 1SamplesPairedCytogeneticsCNV detectedNK-AML5YesNormal karyotypeNoneT-ALL relapse1Yes4+, 3p26.2 and Xp22.2 micro-deletions+4, partial del(9p)AML M01YesNormal karyotypePartial del(11p)AML M31Not(15;17)NoneCML1Not(9;22)NoneT-ALLNodel(5) t(7;14)Partial del(5q), +4q, +9p, del(11p), del(12q)CLL1NoNot analyzed+12AML M01NoNormal karyotypePartial +11 Citation Format: Marcus C. Hansen, Laura L. Herborg, Anne S. Roug, Sadudee Chotirat, Chirayu U. Auewarakul, Eigil Kjeldsen, Peter Hokland. Resolving copy number variations from existing exome SNP data without the need for sophisticated software. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3648.
P0893 : Resistance analysis of treatment-experienced genotype 1 and 3 HCV infected patients treated with sofosbuvir in combination with GS-5816 +/− ribavirin for 12 weeks
Authors: B.P. Doehle, E.S. Svarovskaia, K. Chodavarapu, J. McNally, S. Pianko, S.K. Roberts, D.M. Brainard, M.D. Miller, H. Mo
Journal: Journal of Hepatology (2015)
Abstract 4131: Blocking endogenous TBX2 abrogates prostate cancer bone metastasis through WNT signaling
Authors: Srinivas Nandana, Manisha Tripathi, Peng Duan, Gina Chu, Haiyen E. Zhau, Robert J. Matusik, Leland W.K. Chung
Journal: Cancer Research (2016)

Abstract Bone metastasis is a crucial turning point in the progression of PCa and is seen in &amp;gt; 90% of the lethal cases. Identifying factors that mediate the metastatic spread and subsequent remodeling of the bone is highly relevant to successful therapeutic intervention in advanced human prostate cancer (PCa). TBX2, a transcription factor that belongs to the T-box family negatively regulates p21 cell cycle inhibitor and is known to play critical roles during embryonic development and cancer progression. Interestingly, a recent report found TBX2 over-expression in the bone metastases from patients with castrate resistant prostate cancer. We found TBX2 over-expression in human prostate cancer specimens and in aggressive androgen independent human PCa cell lines. Further, we found TBX2 over-expression in bone metastases in multiple xenograft mouse models of human PCa progression. Blocking endogenous TBX2 in PC3 and ARCaPM PCa cells through the use of a dominant negative construct resulted in decreased proliferation, colony formation and invasion in vitro. Utilizing various pre-clinical xenograft mouse models, we found that blocking endogenous TBX2 in PCa cells leads to decreased invasion and abrogation of bone and soft tissue metastasis in vivo. Further, utilizing the intra-tibial mouse model of growth in the bone microenvironment, we found that blocking endogenous TBX2 in PCa cells dramatically reduces bone remodeling. Additionally we found that TBX2 acts upstream of the canonical WNT (WNT3A) signaling in PCa and positively regulates its transcription by binding to its promoter. Further, rescue of WNT3A levels in PCa cells in the context of blocking endogenous TBX2 rescues the metastatic ability of the cells in vivo. Taken together, our findings highlight a novel and critical role of TBX2 in PCa progression, metastasis and the subsequent bone remodeling, and that TBX2 function in PCa is mediated through the canonical WNT signaling. Citation Format: Srinivas Nandana, Manisha Tripathi, Peng Duan, Gina Chu, Haiyen E. Zhau, Robert J. Matusik, Leland W.K. Chung. Blocking endogenous TBX2 abrogates prostate cancer bone metastasis through WNT signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4131.
Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice
Authors: Xi-Ling Jiang, Hong-Wu Shen, Donald E. Mager, Stephan Schmidt, Ai-Ming Yu
Journal: Acta Pharmaceutica Sinica B (2016)

We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT-elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1A receptor and thermogenesis via the stimulation of 5-HT2A receptor, respectively. Thus serotonergic 5-MeO-DMT-induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SC50 value (1.88-0.496 µmol/L) for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT-induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.
Une épidémie d'oreillons dans la Province de León, Espagne, 1995-1996
Authors: L. E. Visser, K. C. González Perez, J Ramos Tejera, A C Berjón Barrientos, Y Vergara Guerrero, J. F. Martinez Navarro
Journal: Eurosurveillance (1998)

Les oreillons sont une maladie virale aigue dont le symptome le plus courant est une tumefaction douloureuse d'une ou des deux glandes salivaires. Dans l'enfance, les manifestations cliniques des oreillons sont generalement legeres et environ 30% des infections sont asymptomatiques (1,2). L'infection systemique, touchant les gonades, le pancreas et le systeme nerveux central, est plus frequente chez les patients postpubertaires.
Abstract 2060: Polymer mediated RNAi-based combination therapy for treating prostate cancer
Authors: Michael Danquah
Journal: Cancer Research (2016)

Abstract Purpose. To determine whether RNAi-based combination therapy targeting androgen receptor (AR) and XIAP signaling pathways using polymeric micelles can treat prostate cancer. Methods. Potency of siRNAs targeting AR and XIAP genes was assessed using real time RT-PCR, Western Blot and ELISA. Cell viability was determined by MTT assay. A library of polymers designed to degrade via hydrolysis and enhance siRNA delivery was synthesized by conjugating hexylamine, pentaethylenehexamine and 3-morpholinopropylamine to poly(ethylene glycol)-block-poly(5-methyl-5-carboxyl-propylene carbonate) backbone using EDC/HOBT coupling chemistry. Polymer structure and molecular weight were verified with proton NMR and Gel Permeation Chromatography, respectively. Results. Three siRNA sequences targeting different regions of the AR and XIAP genes were designed, blasted against the human genome database to eliminate cross-silencing of nontarget genes and their potency screened in LNCaP and C4-2 cells following transfection. All siRNAs targeting AR (start site: 1172, 1648 and 1768) used in this study silenced AR mRNA and protein expression in both cell lines. Furthermore, 1172 was identified as the most potent sequence resulting in approximately 75% knockdown regardless of cell type. Also, the three siRNAs targeting XIAP (start site: 264, 297 and 458) down-regulated XIAP mRNA and protein levels in both cells and were generally more potent in C4-2 cells compared to LNCaP cells. C4-2 cells transfected with siRNA targeting AR (start site: 1172) and XIAP (start site: 264) alone or in combination and assayed after 96 hours revealed XIAP and AR down-regulation resulted in approximately 20% and 50% growth inhibition in C4-2 cells, respectively, compared to control. However, combined silencing of XIAP and AR genes decreased cell growth by 62% and was more potent in inhibiting cell proliferation compared to monotherapy. Additionally, combination of siRNA targeting AR (start site: 1172) and XIAP (start site: 264) significantly increased percentage of cells undergoing apoptosis (85%) compared to control or monotherapy. Poly(ethylene glycol)-block-poly(5-methyl-5-carboxyl-propylene carbonate) copolymer was synthesized by ring opening polymerization and conjugated with various ratios of hexylamine, pentaethylenehexamine and 3-morpholinopropylamine moieties. The resulting copolymer (PEG-b-P(CC-g-PHEXYL-g-PMORPH-g-PPHEA) were non-toxic even at concentration of 1500 μg/mL and successfully condensed siRNA at N/P of 25 with average hydrodynamic diameter of approximately 175 nm. Conclusions. Combination based therapy using siRNA targeting AR and XIAP can potentially treat prostate cancer. Citation Format: Michael Danquah. Polymer mediated RNAi-based combination therapy for treating prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2060.
The Monocyte Genomic Response is Conserved Between Mice and Humans Following Acute Myocardial Infarction
Authors: N Ruparelia, R Lee, E Dall'Armellina, J Godec, D Medway, C Forfar, B Prendergast, R K Kharbanda, A P Banning, S Neubauer, C A Lygate, K M Channon, W N Haining, R P Choudhury
Journal: Circulation (2013)
Abstract 869: Meditope enablement and structural analysis of anti-CD33 antibodies
Authors: Calin D. Dumitru, Michael Matho, Elisabeth Gardiner, John C. Williams, Krzysztof Bzymek
Journal: Cancer Research (2016)

Abstract Meditope Biosciences’ SnAP (Site-specific novel Antibody Platform) technology provides a novel and specific way to create antibody drug conjugates (ADCs). Cyclic peptides, termed ‘meditopes’, have been designed to selectively bind to a ‘meditope binding site’ engineered into the Fab of an antibody. The process of conferring meditope binding is referred to as “meditope enablement”. Enabling antibodies for meditope binding does not interfere with antigen recognition or antibody integrity due to the unique location of the binding site. Meditope peptide binding can be utilized to attach cytotoxic payloads to an enabled antibody in a specific and consistent manner, and has the potential to dramatically improve the consistency of ADC production. For advanced hematological cancers such as CD33 positive acute myeloid leukemia (AML), using an anti-CD33 monoclonal antibody conjugated to a potent cytotoxic agent may be a useful tumor reduction strategy, especially when patients have failed other treatments. To this end, meditope enablement of lintuzumab and gentuzumab permits a consistent, site-specific attachment of cytotoxins with a highly controllable drug antibody ratio (DAR). Structural and biophysical characterization of the meditope enabled anti CD33 antibodies has provided key insight to the meditope enablement process. Experiments confirm that payload conjugation and meditope peptide binding does not interfere with antibody integrity or antigen recognition. The meditope peptide drug complexes were tested in cell-based assays for CD33-targeted cell killing. Using X-ray crystallographic analysis and guided docking, we propose modifications to further enhance affinity of the meditope peptide conjugate : CD33 antibody interaction. Citation Format: Calin D. Dumitru, Michael Matho, Elisabeth Gardiner, John C. Williams, Krzysztof Bzymek. Meditope enablement and structural analysis of anti-CD33 antibodies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 869.