tbuckley/cabot-search huggingface dataset:
Abstract 2371: Multi-cell phylogenetic inference of copy number evolution in breast cancer
Authors: Alexander J. Davis, Ruli Gao, Emi Sei, Pei-Ching Tsai, Anna Casasent, Amy Zhang, Xiuqing Shi, Yong Wang, Jill Waters, Funda Meric-Bernstam, Mary Edgerton, Nicholas Navin
Journal: Cancer Research (2016)

Abstract Aneuploidy is a hallmark of breast cancer, but little is known about how these complex genomic rearrangements evolve during tumor growth. To investigate this question, we developed a Highly-Multiplexed Single Nucleus Sequencing (HM-SMS) method to profile genome-wide copy number in individual tumor cells and compared multiple cells to infer evolutionary lineages. We applied this method to analyze thousands of single cells from 12 triple-negative breast cancer patients and 10 ductal-carcinoma-in-situ (DCIS) patients. Integer copy number profiles were calculated from a combination of sequencing data and ploidy estimation using flow cytometry. A multi-cell segmentation algorithm was used to identify common CNA events that are shared between tumor cells in each patient. Trinary event matrices were calculated for each patient to determine the presence or absence of individual copy number aberrations (CNAs) in individual cells. Using the maximum parsimony criterion, we inferred a phylogenetic tree for each tumor and estimated the temporal order of the CNAs.. Our data suggest that most tumors consisted of 1-4 major clonal subpopulations that shared a common evolutionary lineage, suggesting that they evolved from a single normal cell in the breast tissue. Furthermore our data support a punctuated model of copy number evolution, which which the majority of CNAs were acquired in a short evolutionary burst, followed by one or more stable clonal expansions to form the tumor mass. Citation Format: Alexander J. Davis, Ruli Gao, Emi Sei, Pei-Ching Tsai, Anna Casasent, Amy Zhang, Xiuqing Shi, Yong Wang, Jill Waters, Funda Meric-Bernstam, Mary Edgerton, Nicholas Navin. Multi-cell phylogenetic inference of copy number evolution in breast 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 2371.
Abstract A46: Real time niche tracking of cancer stem cell cycle kinetics using a novel bi-cistronic lentiviral reporter.
Authors: Gabriel Pineda, Kathleen M. Lennon, Florence Lambert-Fliszar, Gennarina L. Riso, Catriona Jamieson
Journal: Clinical Cancer Research (2015)

Abstract Human leukemia stem cells (LSC) are quiescent self-renewing cells that drive leukemic transformation of myeloproliferative neoplasms and myelodysplastic syndromes. Currently, there are few methods to quantitatively visualize cell cycle progression in (LSC) and to interrogate stem cell cycle gene regulatory networks in live cells. Human LSC are characterized as quiescent self-renewing cells and current methods require sequential transduction and clonal selection. These methods and conditions are not feasible for studying primary patient samples and LSC, which are generally limited in cell numbers. To alleviate this challenge, we generated a lentiviral biscistronic vector encoding FUCCI2 (fluorescent ubiquitination-based cell-cycle indicator) probes. We characterized the fidelity of the cell cycle by confirming normal cell division and distinct nuclear staining of either green or red fluorescence in both transiently and stably transduced 293 cells. Further, analysis by flow cytometry of 293 cell confirmed that S/G2/M and G1/G0 phases of cell cycle correlate with expression of fluorescent reporters expressed from the bicistronic lentiviral vector and recapitulate FACS based analysis using traditional Ki67 and 7AAD staining. Recently, using this lentiviral biscistronic reporter we succeeded in tracking cell cycle progression in CD34+ cells from CML primary patient samples co-cultured with SL/M2 cells. Time-lapse confocal imaging of these samples reveals distinct differences within the population of CML cells. In summary using this new Dual FUCCI2 lentiviral reporter makes it possible to track real time cell cycle kinetics in cancer stem cells. Future studies will include measuring LSC, cell cycle gene regulatory networks in live cells at different stages of the cell cycle. Citation Format: Gabriel Pineda, Kathleen M. Lennon, Florence Lambert-Fliszar, Gennarina L. Riso, Catriona Jamieson. Real time niche tracking of cancer stem cell cycle kinetics using a novel bi-cistronic lentiviral reporter. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A46.
Efficacy of Ruxolitinib in Chronic Eosinophilic Leukemia Associated with t(8;9)(p22;p24) and PCM1-JAK2 Fusion Gene.
Authors: Ilaria Casetti, Elisa Rumi, Jelena D. Milosevic, Irene Dambruoso, Daniela Pietra, Emanuela Boveri, Marina Boni, Paolo Bernasconi, Francesco Passamonti, Robert Kralovics, Mario Cazzola
Journal: Blood (2012)
A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency
Authors: Soesma A Jankipersadsing, Fatemeh Hadizadeh, Marc Jan Bonder, Ettje F Tigchelaar, Patrick Deelen, Jingyuan Fu, Anna Andreasson, Lars Agreus, Susanna Walter, Cisca Wijmenga, Pirro Hysi, Mauro D'Amato, Alexandra Zhernakova
Journal: Gut (2016)

A GWAS meta-analysis suggests roles for xenobiotic metabolism and ion channel activity in the biology of stool frequency Stool consistency and frequency patterns are complex traits that are often altered in GI disease, and recent studies published in Gut highlight the importance of stool frequency in relation to gut microbiota composition and the efficacy of pharmacological and dietary treatments in IBS. [1]][3] Despite reported heritability in invertebrates 4 and similar evidence from open-field defaecation models in rats, 5 the genetics of stool frequency has not been explored in humans.We undertook a genome-wide association study (GWAS) in two well-characterised population-based cohorts with genotype and defaecation data available: LifeLines-Deep (LLD) from the Netherlands (N=1546; 58% females; mean age 44 years (range 18-86)) and PopCol (PC) from Sweden (N=284; 60% females; mean age 54 years (range 22-71)). 6 7The average number of bowel movements per day (BM/d) was extracted from daily records kept by both populations and did not differ between cohorts (LLD=1.39±0.64SD; PC=1.42±0.74SD).Available CytoChip+Immunochip (LLD) and HumanOmniExpressExome (PC) Illumina single-nucleotide polymorphism (SNP) genotype data were imputed using IMPUTE2 (https://mathgen.stats.ox.ac.uk/ impute/impute_v2.html)with the Genome of the Netherlands (http://www.nlgenome.nl/) as reference.SNPs were filtered on minor allele frequency >0.05 and Hardy-Weinberg equilibrium p>1E-04, samples were filtered on infoscore ≥0.8 and population outliers were excluded using principal component analysis.In total, high-quality genotype data for 5 390 800 common SNPs and BM/d information were obtained for 1022 LLD and 259 PC individuals.Genotype-BM/d association tests were performed in SNPTEST (https://mathgen.stats.ox.ac.uk/genetics_software/snptest/ snptest.html)using logistic regression under an additive model correcting for age and sex, followed by a fixed-effect model meta-analysis with META (https:// mathgen.stats.ox.ac.uk/genetics_software/ meta/meta.html).Summary statistics for the top-10 loci from the meta-analysis and the corresponding effect of associated alleles on the frequency (increased/decreased) of defaecation are given in figure 1.Although none of these associations achieved genome-wide significance
Disease activity states of the DAPSA, a psoriatic arthritis specific instrument, are valid against functional status and structural progression
Authors: D Aletaha, F Alasti, JS Smolen
Journal: Annals of the Rheumatic Diseases (2016)

Recently, disease activity states were developed for the Disease Activity index for PSoriatic Arthritis (DAPSA). Here, we assess if different DAPSA disease activity states are associated with different degrees of functional impairment and different extents of joint damage progression in patients with psoriatic arthritis (PsA).We used data from two pivotal trials of tumour necrosis factor (TNF) inhibitors in PsA (IMPACT II and GO-REVEAL) and identified patients in DAPSA remission (REM, ≤4), and low, moderate or high disease activity (LDA, ≤14; MDA, ≤28; HDA, >28) at 6 months. Across these groups we compared the functional scores (Health Assessment Questionnaire Disability Index, HAQ and physical component scale of the Short Form-36, PCS), and 1-year structural progression (PsA-modified Sharp/van der Heijde Score).We identified 310 from GO-REVEAL and 130 from IMPACT II, with a mean (SD) baseline DAPSA of 48.8 (26.4) and 44.6 (17.9), respectively. HAQ scores increased across patients groups in the four DAPSA disease activity states, while PCS decreased (p<0.001 for both). The mean progression in the combined cohort was -0.47 for REM, -0.28 for LDA, -0.14 for MDA and 0.51 for HDA (p<0.001). This association was also significant in the individual trial cohorts, and in the subgroups of patients treated with TNF inhibitors or placebo. Higher DAPSA scores were significantly and independently associated with probability of structural progression in multiple analyses.Disease activity states of the PsA specific DAPSA score are highly valid for future use as endpoints in clinical trials or as targets in clinical practice.IMPACT 2: NCT02152254; GO-REVEAL: NCT00265096.
Psychosomatic Medicine in Germany: More Timely than Ever
Authors: Stephan Zipfel, Wolfgang Herzog, Johannes Kruse, Peter Henningsen
Journal: Psychotherapy and Psychosomatics (2016)

In Germany, psychosomatic medicine is not a subspecialty of psychiatry, although it has clear connections in terms of shared models, methods, and overlapping care for patients.At some places, most prominently in Heidelberg and Tübingen, departments of psychosomatic medicine are part of overarching departments for internal medicine.The institutional independence of psychosomatic medicine in Germany is largely due to German psychiatry resisting the integration of psychotherapy as a core method.Hence, psychosomatic medicine developed independently as an institutional and academic basis for psychotherapy in medicine and later for integrated care models.The clinical core competency of German psychosomatic medicine is centered on integrated care for the following disorders: somatoform/functional disorders, eating disorders, somatopsychic disorders (including psycho-oncology, psychocardiology, neuropsychosomatics, and psychodiabetology), and psychotraumatology.An overlap with psychiatry exists in the fields of depressive, anxiety, and personality disorders.The following presents a brief overview of the current state of institutionalization, research, and teaching in the field of German psychosomatic medicine.
Abstract 2066: Albumin-binding doxorubicin prodrug selectively activated by radiation-induced apoptotic tumor cells
Authors: Seung Woo Chung, Kwangmeyung Kim, Seong Who Kim, In-San Kim, Sang Yoon Kim, Youngro Byun
Journal: Cancer Research (2016)

Abstract Despite the well-recognized potent anticancer effect of doxorubicin, the clinical use of doxorubicin is limited due to its dose-dependent toxicity. In this study, a novel drug delivery technology fundamentally different from the conventional tumor-targeting approaches was employed to improve the therapeutic index of doxorubicin. The prepared doxorubicin prodrug, EMC-DEVD-S-DOX, has two distinct features for effective tumor targeting: EPR effect-mediated passive targeting of tumor and extended plasma half-life by in situ albumin binding, and radiation-induced apoptosis targeting. The prodrug comprises of two important functional molecules: first, a maleimide group that allows in situ binding of the prodrug to the circulating albumin after intravenous administration; second, a DEVD motif that plays a crucial role in the activation of the prodrug through caspase-3-mediated cleavage in the apoptotic tumor cells that are exposed to radiation. As a result, EMC-DEVD-S-DOX showed a prolonged plasma half-life with selective accumulation within the tumor tissue, and was only activated and released free doxorubicin when combined with radiotherapy, thereby showing excellent synergistic effect. Our suggested drug delivery strategy completely relies on the anatomical feature of tumor vasculatures and the upregulated caspase-3 after exposure to radiation. In this reason, the genomic variations of tumor cells are unlikely to influence the efficacy of the prodrug. Considering that the conventional active tumor targeting approach is seriously challenged by the intratumor heterogeneity, EMC-DEVD-S-DOX could be an outstanding alternative for an effective cancer treatment. Citation Format: Seung Woo Chung, Kwangmeyung Kim, Seong Who Kim, In-San Kim, Sang Yoon Kim, Youngro Byun. Albumin-binding doxorubicin prodrug selectively activated by radiation-induced apoptotic tumor 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 2066.
S89 Epithelial Mesenchymal Transition (EMT) in Chronic Obstructive Pulmonary Disease (COPD) Airways is Attenuated by Inhaled Corticosteroids (ICS): Abstract S89 Table 1
Authors: Sukhwinder Singh Sohal, Amir Soltani, David Reid, Chris Ward, Steven Weston, Hans Konrad Muller, Richard Wood-Baker, Eugene Haydn Walters
Journal: Thorax (2012)

<h3>Introduction and Objectives</h3> We recently reported<sup>1, 2</sup> that EMT is active in the airways of COPD patients; in this process epithelial cells change shape and become motile, then digest through the reticular basement membrane (Rbm) which becomes fragmented and transition to a mesenchymal fibroblast-like cell. We also demonstrated that the Rbm is hyper-vascular, a combined picture specifically suggesting active EMT-type-III, which is a dangerous, pre-malignant condition. This may well be the link between COPD and lung cancer. In this study, we have assessed the effects of ICS on markers of EMT in endobronchial biopsies (ebb) in COPD. <h3>Methods</h3> A double-blinded, randomised, placebo-controlled study assessed the effects of inhaled fluticasone propionate (FP: 500µg twice daily) on EMT in 34 COPD patients. Ebb were assessed for EMT related Rbm fragmentation (core structural marker) and immunostained for the EMT signatures S100A4 (a fibroblast epitope), matrix-metalloproteinase-9 (MMP-9) and the epithelial activation marker, epidermal growth factor receptor (EGFR). <h3>Results</h3> Table 1. <h3>Conclusions</h3> This is the first study to report the positive effects of ICS on EMT markers in COPD. This may be the mechanistic link between ICS and its reported preventive action against smoking-related lung cancer in COPD. <h3>References</h3> Sohal SS, et al. <i>Respirology</i> 2010, <b>15</b>(6):930–938. Sohal SS, et al. <i>Respir Res</i> 2011, <b>12</b>(1):130.
Abstract 2963: VB7-756: a Her2-specific diabody armed with deBouganin, a plant toxin with a distinct MOA
Authors: Shilpa Chooniedass, Rachelle L. Dillon, Arjune Premsukh, Joycelyn Entwistle, Gregory P. Adams, Peter J. Hudson, Glen C. MacDonald, Jeannick Cizeau
Journal: Cancer Research (2016)

Abstract VB7-756 is Targeted Protein Therapeutic (TPT) comprised of a de-immunized form of bouganin (deBouganin), a potent, plant-derived, type I ribosome-inactivating protein (RIP), genetically linked to the C6.5 anti-Her2 diabody via a furin protease sensitive linker. To engineer the optimal diabody TPT format, several constructs were generated to assess the best diabody-deBouganin orientation. All constructs were expressed as a soluble protein in E. coli supernatant and compared with respect to expression level, stability and potency. The optimal configuration consisted of deBouganin genetically linked to the N-terminus of the VH-VL diabody via a furin protease-sensitive linker and was termed VB7-756. VB7-756 potency was analyzed against a panel of breast cancer cell lines with disparate levels of Her-2 expression and compared to that of Trastuzumab chemically linked to either DM1 (T-DM1) or MMAE (T-MMAE). Overall, VB7-756 was more potent than T-DM1 and T-MMAE with high Her-2 expressing tumor cell lines. In contrast to T-DM1, VB7-756 potency was unaffected by the Her2-Her3 dimerization mediated by heregulin. As opposed to T-DM1 and T-MMAE, which showed only minimal cytoxicity, VB7-756 was highly potent in vitro against tumor cells with cancer stem cell properties. To further differentiate the RIP mechanism of action of deBouganin from tubulin inhibitor reagents, tumor cells that escaped T-DM1 and T-MMAE treatment were incubated in the presence of VB7-756. Results revealed that, VB7-756 was cytotoxic against cancer cells surviving T-DM1 or T-MMAE treatment suggesting that deBouganin can overcome mechanisms of resistance developed by small molecule agents. Moreover, VB7-756 was also cytotoxic against tumor initiating cancer cells evading T-DM1 or T-MMAE toxicity by preventing tumorosphere formation. Overall these results demonstrate that deBouganin's distinct MOA could overcome mechanisms of resistance affecting the efficacy of small molecule drugs. Citation Format: Shilpa Chooniedass, Rachelle L. Dillon, Arjune Premsukh, Joycelyn Entwistle, Gregory P. Adams, Peter J. Hudson, Glen C. MacDonald, Jeannick Cizeau. VB7-756: a Her2-specific diabody armed with deBouganin, a plant toxin with a distinct MOA. [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 2963.
Abstract 690: Functional characterization of RPS6KA3 (RSK2) and identification of its naturally occurring mutants in hepatocellular carcinoma
Authors: Lo-Kong Chan, Daniel Wai-Hung Ho, Yung-Tuen Chiu, Alan Ka-Lun Kai, Chun-Ming Wong, Irene Oi-Lin Ng.
Journal: Cancer Research (2016)

Abstract RPS6KA3 encodes the p90 ribosomal S6 kinase 2 (p90RSK2 or RSK2), a protein kinase to relay the upstream transduction signal of the mitogen-activated protein kinase (MAPK) pathway. Currently, no characterization on RSK2 in human HCC has been performed. We determined the RSK2 mRNA expression in paired human HCC samples and their corresponding non-tumorous livers (n = 22) by real time PCR. RSK2 over-expression (≥2 folds) was found in 38% of the human HCCs and this over-expression was associated with tumor microsatellite formation, a feature of HCC metastasis. The oncogenic and pro-metastatic roles of RSK2 were further assessed and demonstrated in vivo by an orthotopic liver injection model in nude mice with stable shRSK2 knockdown HCC cells. Stable shRSK2 knockdown cells showed a significant reduction in tumor incidence in liver and lung metastasis. By exome-sequencing and targeted sequencing in a cohort of HBV-associated HCC patient samples (n = 111), we found that RSK2 was recurrently mutated in 6.3% of the samples being screened (n = 7). All the RSK2 mutants were confirmed by independent Sanger sequencing. Intriguingly, among the identified somatic RSK2 mutants, half of them introduced pre-mature stop gain to the transcript, which leads to the loss-of function of RSK2 through various mechanisms. Taken together, our data suggested that RSK2 may play differential roles in different subsets of HCC patients. Further characterization will definitely derive novel insights on the functional role of mutant RSK2 and its potential use to stratify HCC patients into different molecular subgroups. (This study was supported by a RGC GRF fund (17116414), SK Yee Medical Research Fund 2011 and University Development Fund of The University of Hong Kong. Ng is Loke Yew Professor in Pathology) Citation Format: Lo-Kong Chan, Daniel Wai-Hung Ho, Yung-Tuen Chiu, Alan Ka-Lun Kai, Chun-Ming Wong, Irene Oi-Lin Ng. Functional characterization of RPS6KA3 (RSK2) and identification of its naturally occurring mutants in hepatocellular 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 690.
ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult—Summary Article
Authors: Sharon Ann Hunt, William T. Abraham, Marshall H. Chin, Arthur M. Feldman, Gary S. Francis, Theodore G. Ganiats, Mariell Jessup, Marvin A. Konstam, Donna M. Mancini, Keith Michl, John A. Oates, Peter S. Rahko, Marc A. Silver, Lynne Warner Stevenson, Clyde W. Yancy, Elliott M. Antman, Sidney C. Smith, Cynthia D. Adams, Jeffrey L. Anderson, David P. Faxon, Valentin Fuster, Jonathan L. Halperin, Loren F. Hiratzka, Sharon Ann Hunt, Alice K. Jacobs, Rick Nishimura, Joseph P. Ornato, Richard L. Page, Barbara Riegel
Journal: Circulation (2005)

The writing committee intended BNP to indicate B-type natriuretic peptide rather than a specific type of assay.Assessment can be made using assays for BNP or N-terminal proBNP.The two types of assays yield clinically similar information.
Potent preclinical antitumor activity of MGCD265, an oral Met/VEGFR kinase inhibitor in phase II clinical development, in combination with taxanes or erlotinib.
Authors: J. M. Besterman, M. Fournel, I. Dupont, C. Bonfils, M. Dubay, H. Ste-Croix, C. R. Maroun
Journal: Journal of Clinical Oncology (2010)

e13595 Background: Therapeutics used to treat patients with NSCLC include cytotoxic agents such as taxanes, and targeted agents such as EGFR inhibitors. Although these treatments provide some clinical benefit, there is a need for improved therapies in advanced NSCLC. MGCD265 targets Met, VEGFR1/2/3, Tie-2 and Ron. Met is overexpressed and phosphorylated in NSCLC, and Met activation is identified as a molecular mechanism through which tumors evade specific inhibition of EGFR. In support of the clinical development of MGCD265, the studies described here provide a rationale for combining MGCD265 with a taxane or an EGFR inhibitor. Methods: The in vivo anti-tumor activity of MGCD265 (10 or 20mg/kg orally, daily) in combination with either docetaxel (5 or 10mg/kg, iv weekly), paclitaxel (30mg/kg iv, on days 0, 1, 13, 14),or an EGFR inhibitor, erlotinib (25 or 50 mg/kg orally, daily), was analyzed in multiple xenograft models including NSCLC models. The anti-angiogenic activity of MGCD265 with docetaxel was evaluated by immunohistochemistry following CD31 labeling of tumor sections from treated animals. Results: We demonstrate that the combination of MGCD265 with docetaxel or paclitaxel achieves greater anti-tumor responses than treating with either agent alone and this occurs in the absence of overt toxicity. The combination of MGCD265 with docetaxel also results in greater reduction of tumor vasculature. Good anti-tumor activity in the absence of overt toxicity is also demonstrated when MGCD265 is combined with erlotinib in NSCLC xenografts including a model that expresses an EGFR mutant resistant to erlotinib (T790M). PK analyses demonstrate that the combination of MGCD265 with either docetaxel, paclitaxel or erlotinib does not result in drug-drug interactions. Conclusions: The combination of MGCD265 with either a taxane or erlotinib results in improved antitumor activities when compared to treatments with either agent alone. In addition, these combinations are well tolerated and do not show drug-drug interactions. These preclinical studies support the clinical development of MGCD265 in combination with docetaxel or erlotinib in patients with NSCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MethylGene MethylGene