tbuckley/cabot-search huggingface dataset:
Abstract 4466: Characterization of the pan class I PI3K inhibitor NVP-BKM120 mechanism of action across a broad range of concentrations
Authors: Saskia M. Brachmann, Julia Kleylein-Sohn, Swann Gaulis, Frederic Stauffer, Johannes Voshol, Daniel Guthy, Christopher Wilson, Alan Huang, Markus Wartmann, Thomas Bruemmendorf, Patrick Chene, Christine Fritsch, Wolfgang Hackl, Jan Cosaert, Christian Schnell, Francesco Hofmann, Michel Maira
Journal: Cancer Research (2011)

Abstract NVP-BKM120 is a pan class I PI3K inhibitor that has recently entered phase II clinical trials. The compound was shown to inhibit cell proliferation and survival of cancer models displaying PI3K pathway dependency, in a dose-dependent manner, and proportionally to the extent of pathway inhibition. To further characterize NVP-BKM120, we have investigated its mechanism of action across a broad range of relevant models and concentrations of the molecule and compared it to other PI3K inhibitors (e.g. GDC0941 and ZSTK474). The effects observed on phenotypical read-outs were similar for all compounds, when tested up to concentrations necessary to achieve near complete pathway inhibition (IC90 for Akt-S473P). More profound effects were however observed with NVP-BKM120, at higher concentrations (&amp;gt;2 micromolar), in PI3K-independent models, suggesting that at these dose levels, NVP-BKM120 might display inhibitory activities other than PI3K. In order to determine this potential off-target activity, a gene expression profiling study was performed in a PI3K insensitive model, comparing effects of GDC0941 and NVP-BKM120 at equipotent concentrations. Gene-Set Enrichment Analysis (GSEA) revealed that NVP-BKM120 at the highest dose only (3.6 micromolar, 2 fold above the S473-Akt IC90 of PI3K sensitive models), led to increased expression of genes involved in G2 and mitotic (M) phases. Subsequent FACS analysis showed that in contrast to the other pan-PI3K inhibitors, NVP-BKM120 was indeed able to induce a strong G2/M arrest in several PI3K non addicted cell lines when used at concentrations higher than 2 micromolar. DAPI and tubulin immuno-histochemistry studies showed that the NVP-BKM120 induced block was phenotypically similar to that of Nocodazole, suggesting effects on spindle dynamics in prometaphase. Indeed, in cellular or in in vitro purified systems, NVP-BKM120 greatly reduced microtubule polymerization.Based on analysis the antitumor activity observed in vivo in PI3K-dependent animal models, it appears that efficacy is solely due to pure PI3K inhibition, as these off-target activities are generally observed at concentrations (corrected for free fraction) that could not be achieved in animals. Based on modeling of human PK data, a similar conclusion can be reached for patients, as the exposure currently observed in plasma does predict sole coverage of PI3K inhibitory activities. 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 4466. doi:10.1158/1538-7445.AM2011-4466
Patterns of storage, use, and disposal of opioids among cancer patients presenting to the emergency center.
Authors: Akhila Sunkepally Reddy, Julio Silvestre, Maxine Grace De la Cruz, Jimin Wu, Diane D Liu, Eduardo Bruera, Knox H. Todd
Journal: Journal of Clinical Oncology (2015)

184 Background: Approximately 75% of prescription opioid abusers obtain the drug from an acquaintance. Improper opioid storage, use, and disposal along with lack of patient education may lead to increased availability of the drug for abuse by others. Our aim was to determine the opioid storage, use, and disposal patterns in patients presenting to the emergency center (EC) of a comprehensive cancer center. Methods: We surveyed 113 cancer patients receiving opioids for at least 2 months and collected information regarding opioid use, storage, and disposal. Unsafe storage was defined as storing the opioids in plain sight and sharing or losing their opioids was defined as unsafe use. Results: The median age was 53 years, 55% were female, and 64% were white and 86% had advanced cancer. 19% of the patients had history of illicit drug use and 24% reported that drug abuse is prevalent in their neighborhood. 59% obtained the opioid from their oncologist and 6% believed they were prescribed more medication than required. Of the 113 respondents, 36% stored opioids in plain sight, 53% kept them hidden but unlocked, and only 15% locked their opioids. 73% agreed that they would use a lockbox to store their opioids if given one, 78% were unaware of proper opioid disposal methods, and 67% had unused opioids at home. Only 13% previously received education about safe disposal of opioids. Patients who reported that others have asked them for their pain medications (P = .004) and those who would use a lockbox if given one (P = .019) were more likely to keep them locked. 13 patients (12%) used opioids unsafely by either sharing (5%) or losing (8%) them. Patients who reported to being prescribed more pain pills than required (P = .032), others having asked them for their pain pills (P = .06), being unemployed (P = .07), and those who were unaware of drug take-back programs (P = .06) were more likely to participate in unsafe use. Overall, 77% (87) of the patients reported unsafe storage, unsafe use, or possessed unused opioids at home. Conclusions: A large number of cancer patients improperly and unsafely store, use, or dispose of opioids. More research is needed to determine whether patient education has an effect on minimizing prescription opioid abuse.
Abstract 4985: Identification of PARP-1 as a novel KLF8 interacting and regulating protein
Authors: Heng Lu, Xianhui Wang, Alison M. Urvalek, Tianshu Li, Lin Yu, Jinhua Zhu, Qishan Lin, Jihe Zhao
Journal: Cancer Research (2010)

Abstract KLF8 transcription factor regulates important genes including cyclin D1 and E-cadherin and plays a critical role in cell cycle progression, oncogenic transformation and EMT. Transcription factors need to interact with both DNA and other proteins in order to regulate transcription. However, little is known about KLF8-protein interaction. Using mass spectrometry and co-immunoprecipitation (co-IP), we identified PARP-1, a chromatin-associated enzyme that catalyzes protein poly(ADP-ribosyl)ation (PARylation), as one of novel proteins that interact with KLF8. Co-IP and western blotting indicated that KLF8 is a PARylation substrate. Mutation of the cystein residues in the first and second zinc-finger motifs of KLF8 abolishes its interation with PARP1. Luciferase assays showed KLF8 activation on the cyclin D1 promoter was significantly reduced when PARP1 was physically deleted or functionally inhibited or when KLF8-PARP-1 interation was disrupted. Surprisingly, immunofluorescent staining demonstrated that KLF8 was localized in the nuclei of the wild-type mouse embryonic fibroblasts (MEF), but was mislocalized in the perinuclear cytoplasm of the PARP-1−/− MEFs, which could be rescued by re-expression of PARP1. Interestingly, while the PARP1-interation deficient KLF8 mutant was also mislocalized in the cytoplasm of the wild-type MEFs, inhibition of PARP1 activity in the MEFs did not affect the nuclear localization of wild-type KLF8. Cychloheximade (CHX)-chase assay revealed the stability of KLF8 dramatically reduced by loss of PARP-1 or when KLF8-PARP-1 interaction was disrupted. Ubiquitination assay showed heavier ubiquitin chains in PARP-1−/− MEFs or when KLF8-PARP-1 interaction was disrupted. Furthermore, DNA damage assay under Doxorubin treatment indicated KLF8 involved in PARP-1-dependent DNA damage repair pathway. Those results suggest that PARP-1 work as a co-activator in KLF8's transcriptional activity on Cyclin D1 promoter, keep KLF8's nuclear localization, inhibit KLF8's ubiquitination and contribute to KLF8's stability. This work has identified PARP1 as a novel binding partner and post-translational modifier of KLF8 and a critical regulator of KLF8 localization, function and stability in the cells. 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 4985.
SWOG S0509: A phase II study of novel oral antiangiogenic agent AZD2171 (NSC-732208) in malignant pleural mesothelioma
Authors: L. L. Garland, K. Chansky, A. Wozniak, A. Tsao, S. Gadgeel, C. Vershraegen, M. Da Silva, M. Redman, D. Gandara
Journal: Journal of Clinical Oncology (2009)

7511 Background: Preclinical studies suggest the autocrine growth loop involving VEGF and its receptors is a relevant therapeutic target for malignant pleural mesothelioma (MPM). We evaluated AZD2171, a potent tyrosine kinase inhibitor (TKI) of VEGFR1/2 in MPM. Methods: MPM patients (pts) after platinum-based chemotherapy, with PS 0–2, measurable disease and adequate organ function were treated with oral daily dosing of AZD2171 45 mg. Study endpoints were response rate, progression free survival (PFS), overall survival (OS), frequency/severity of toxicities, and correlation of clinical outcomes with tumor and serum biomarkers. Results: 54 pts were registered between November 2005 and April 2008; 45 pts are eligible for response and 46 for toxicity analysis. Median age was 66.8 yrs; M/F: 37/9. Tumor response by RECIST was seen in 4/45 (9%) of pts; of these responders, 2 pts with bulky disease had 56% and 91% tumor shrinkage, respectively. 15/45 (33%) had SD; 21/45 (47%) had PD; 1/45 (2%) had early death. Thirty-five pts have died. For 46 pts, median PFS is estimated at 3 months; median OS is estimated at 10 months. For 46 pts, frequent grade 1–3 toxicities included anorexia (30%), diarrhea (63%), fatigue (60%), hypertension (67%), and proteinuria (28%). There were 8 grade 4 events: Cognitive disturbance, colitis, confusion, ileal perforation, hypertension, hyponatremia, hypotension, and renal failure. Conclusions: AZD2171 has antitumor activity in MPM, with a DCR (CR/PR/SD) of 42% by RECIST, which has limitations in measuring response in pleural tumors. Notably, 2 pt tumors were exquisitely sensitive to this drug. Toxicities were consistent with those of the anti-angiogenic TKI class of drugs. Studies correlating outcome measures with tumor hypoxia- and angiogenesis-related gene expression and circulating endothelial cells are underway. Based on these data, we are proceeding in SWOG with a study of pemetrexed/cisplatin ± AZD2171 (S0905). This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA14028, CA46441, CA105409, CA13612, CA45808, CA20319, CA86780, CA35090, CA67663, CA46282, CA42777, CA76448, CA04919, CA35176, CA63848, CA27057, CA16385. [Table: see text]
FREQUENT ASSOCIATION OF LATE REVERSIBLE SPECT THALLIUM-201 STRESS DEFECTS WITH RESTING MYOCARDIAL ISCHEMIA AND SEVERE CORONARY STENOSIS.
Authors: Hosen Kiat, Daniel S. Berman, Ling De Yang, Lynne Roy, John Friedman, Alan Rozanski, Jamshid Maddahi
Journal: Clinical Nuclear Medicine (1988)

Kiat, Hosen; Berman, Daniel S.; De Yang, Ling; Roy, Lynne; Friedman, John; Rozanski, Alan; Maddahi, Jamshid Author Information
Targeting autoreactive plasma cells in autoimmunity: a new treatment approach combining plasma cell and B cell depletion
Authors: A Taddeo, B F Hoyer, H-D Chang, A Radbruch, F Hiepe
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background and objectives</h3> Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease. Compelling evidence suggests that autoreactive memory plasma cells (PC) contribute to the maintenance of autoimmunity and inflammatory processes secreting pathogenic autoantibodies. These cells reside in specific survival niches in the bone marrow (BM) and inflamed tissues where they are resistant to immunosuppression and cytotoxic drugs. In this study the authors tested a new treatment approach aimed at depleting PC and, at the same time, preventing the generation of new autoreactive plasmablasts/PC that results from B cell-hyperreactivity. To this aimed the authors combined the PC-depleting drug bortezomib with an anti-CD20 antibody and analysed the PC-B cells dynamics in BM and spleen. <h3>Materials and methods</h3> Lupus-prone NZB/W mice were treated or not with a murine anti-CD20 antibody. After 1 week the mice were injected twice whit bortezomib to deplete short- and long-lived PC. To assess the grade of PC and B cell depletion (BCD) and to explore the dynamics of repopulation of the PC pool, the mice were killed at different time points after the treatment, and PC and B cells subsets were characterised by FACS and ELISPOT. <h3>Results</h3> Our results showed that after depleting short and long-lived PC with bortezomib these cells, including the autoreactive ones, were early regenerated. These results confirmed the hypothesis that new autoreactive PC can be generated from chronically activated B cells. Therefore, the authors treated NZB/W mice with bortezomib in combination with a murine anti-CD20 antibody. The group treated with the combination-therapy showed a heterogeneous grade of BCD more efficient in lymph nodes and spleen respect to BM. The mature, transitional and follicular B cells were efficiently depleted instead marginal zone, germinal center and prepro B cells were particularly resistant. Moreover, although in the mice treated with the combination therapy the repopulation of the PC pool was slower respect to bortezomib-treatment, the supply of newly generated autoreactive PC from hyperreactive-B cells was not completely suppressed. <h3>Conclusions</h3> Our data showed that PC are regenerated early after bortezomib mediated depletion. Moreover, anti-CD20 therapy was not able to completely prevent the differentiation of autoreactive B cells in long-lived autoreactive PC after depletion, maybe due to the incomplete BCD in NZB/W mice. These results shed new light on the dynamics and relationship between PC and B cells and emphasise a rationale for developing a combination therapy able to efficiently target both the compartment in autoimmune diseases.
Consensus classification criteria for paediatric Behçet's disease from a prospective observational cohort: PEDBD
Authors: Isabelle Koné-Paut, Fahrad Shahram, Martha Darce-Bello, Luca Cantarini, Rolando Cimaz, Marco Gattorno, Jordi Anton, Michael Hofer, Bouchra Chkirate, Kenza Bouayed, Ilknur Tugal-Tutkun, Jasmin Kuemmerle-Deschner, Hélène Agostini, Sylvia Federici, Armelle Arnoux, Celine Piedvache, Seza Ozen
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> We aimed to describe the main features of Behçet9s disease (BD) in children in the largest prospective cohort to date and to propose a classification. <h3>Methods</h3> An international expert consensus group was formed to define a data set of minimal symptoms for the inclusion of patients. Patients were entered prospectively during 66 months. Experts classified patients on a consensus basis. The concordance of two international classifications was analysed in confirmed patients with BD. Comparisons of subgroups of patients helped define consensus criteria. BD-associated clinical manifestations were also investigated in three control diseases extracted from an independent data set (Eurofever). <h3>Findings</h3> In total, 42 centres from 12 countries included 230 patients; data for 219 (M/F ratio=1) could be analysed. The experts classified 156 patients (71.2%) as having confirmed BD. Males more often than females showed cutaneous, ocular and vascular symptoms and females more often genital aphthosis. Age at disease onset and skin and vascular involvement were lower for European than non-European children. Oral aphthosis was the presenting sign for 81% (179/219) of patients. The mean delay to the second symptom was 2.9±2.2 years. International classifications were not concordant with the expert classification. Our paediatric classification contains six categories, a minimum of three signs (each in a distinct category) defining paediatric BD. Three clinical signs discriminated our cohort from the Eurofever cohorts. <h3>Interpretation</h3> We present a comprehensive description of a large cohort of patients from both European and non-European countries and propose the first classification of paediatric BD for future therapeutic trials.
Repositioning Dislocated Temporomandibular Joints
Authors: Daniel F. Zweifel, Giorgio Pietramaggiori, Martin Broome
Journal: New England Journal of Medicine (2014)

Common causes of temporomandibular joint dislocation include extreme opening of the mouth, as may occur with yawning, prolonged dental treatment or intubation, and trauma. This video demonstrates the repositioning of these joints after dislocation.
Life Expectancy and Causes of Death in the Marfan Syndrome
Authors: J. Lamont Murdoch, Bryan A. Walker, Barry L. Halpern, Jan W. Kuzma, Victor A. McKusick
Journal: New England Journal of Medicine (1972)

Abstract The Marfan syndrome is a dominantly inherited disorder of connective tissue with multisystem involvement. The cardiac complications, particularly aortic dilatation, dissection and rupture and involvement of the aortic and mitral valves, lead to a greatly reduced life expectancy. This poor survival was demonstrated in a series of 257 patients with the Marfan syndrome. The average age at death for the 72 deceased patients was 32 years. Cardiac problems led to 52 of the 56 deaths of known cause, with aortic dilatation and its complications accounting for 80 per cent of these. Congestive heart failure, myocardial infarction and bacterial endocarditis were other cardiac causes of death. In patients with early aortic changes treatment with propranolol or reserpine is suggested. These agents decrease myocardial contractility and diminish the pulsatile flow stress on the weakened aorta.
Abstract 4981: ICI182,780 induces P-cadherin upregulation in breast cancer cells through histone modifications at the promoter level: The role of C/EBPbeta in <i>CDH3</i> gene activation
Authors: André Albergaria, Ana Sofia Ribeiro, Sandra Pinho, Fernanda Milanezi, Vítor Carneiro, Bárbara Sousa, Sónia Sousa, Carla Oliveira, José Carlos Machado, Raquel Seruca, Joana Paredes, Fernando Schmitt
Journal: Cancer Research (2010)

Abstract P-cadherin is a classical cadherin which has been extensively studied concerning its functions and its prognostic value in breast cancer. Moderate to intense expression of P-cadherin has been identified in 30% - 50% of invasive ductal carcinomas of the breast, being reported to be strongly associated with proliferative and high histological grade, decreased patient survival and as a marker of the aggressive behaviour of basal-like and HER-2 tumour subtypes. In vitro, P-cadherin overexpression is also able to induce increased cell invasion and migration. However, only a few works have been published in order to decipher the regulatory mechanisms behind P-cadherin overexpression in breast cancer. P-cadherin is up-regulated by the antiestrogen ICI 182,780, suggesting that the lack of ERalpha signalling may be responsible for the aberrant P-cadherin expression in breast cancer, but the mechanisms underlying this ICI-induced aggressive behaviour are completely unknown. The aim of this study was to determine whether the induction of the CDH3 gene is a direct effect of ICI 182,780 at CDH3 promoter level or would require the prior induction of other genes/proteins or epigenetic mechanisms. We found that ICI 182,780 increases CDH3 promoter activity as well as induces an epigenetic mechanism that lead to activating histone modifications at putative C/EBPbeta binding sites in at the CDH3 promoter. We also demonstrate that this transcription factor is able to directly activate P-cadherin transcription in breast cancer cells and that these two proteins are highly associated in human breast carcinomas, being both significantly related with high grade and proliferative invasive breast carcinomas. This study brings forward the characterization of putative intracellular pathways and epigenetic mechanisms that are able to induce P-cadherin overexpression in breast cancer cells and, in general, contribute to clarify the ability of ICI 182,780 to induce expression of signal transduction genes normally repressed by oestrogen/ER signalling. In addition, we showed for the first time that the transcription factor C/EBPbeta is able to regulate P-cadherin overexpression in breast cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 4981.
Abstract 2142: Multifaceted genomic analyses reveal novel glioblastoma candidate genes and microbial DNAs
Authors: Christopher G. Duncan, Patrick J. Killela, Hai Yan
Journal: Cancer Research (2010)

Abstract The glioblastoma (GBM) genome displays remarkable chromosomal aberrations, which harbor critical GBM specific genes contributing to several oncogenetic pathways. However, deciphering further driver genomic changes from passenger gene alterations remains a daunting challenge. In attempt to identify novel GBM genes, we carried out a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in GBM patients. First, we performed copy number analysis using Digital Karyotyping (DK) and Illumina BeadChip technologies and identify genomic loci which consistently present as focal copy number alterations. Next, we overlaid copy number altered loci with the somatic mutation data from our genome-wide coding sequencing analysis. Upon expression analyses of these genes, we identify several previously unrecognized genes which are dysregulated in GBM. Most significantly, we identify grade-specific activation of set of genes potentially involved in chromosomal instability of the GBM genome. Finally, we evaluated the contribution of microbial DNA to the GBM genome using an approach, called DK-MICROBE, which we developed to identify genomic DNA of bacteria and viruses in human disease tissues. Our multifaceted genomic evaluation of GBM establishes several candidate oncogenes, tumor suppressors and caretaker genes and provides insight on the molecular mechanisms and pathways to this deadly disease. 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 2142.