tbuckley/cabot-search huggingface dataset:
Abstract 3077: Potent inhibition of bromodomain-containing BET family with ABBV-075 induces robust antitumor efficacy in preclinical models of breast cancer and exhibits <i>in vitro</i> synergy with doxorubicin
Authors: Emily J. Faivre, Xiaoyu Lin, Denise M. Wilcox, Xiaoli Huang, Aparna Sarthy, Terry Magoc, Daniel H. Albert, Guowei Fang, Saul H. Rosenberg, Keith F. McDaniel, Warren M. Kati, Yu Shen
Journal: Cancer Research (2016)

Abstract Breast cancer diagnosisis highly prevalent in the US, with an estimated 231,840 new cases occurring in 2015. Targeted therapies, such as tamoxifen or Trastuzumab (herceptin) are available to woman whose tumors are estrogen receptor (ER) positive or HER2 positive, respectively. However, women with triple negative breast cancer or relapsed metastatic disease have limited treatment options. ABBV-075 is a novel BET family bromodomain inhibitor currently under phase I clinical investigation for a wide spectrum of cancer indications. Here we show that ABBV-075 exhibits broad anti-proliferative activity across cell lines representing ER positive, HER2+, and triple negative breast cancer. Notably, ABBV-075 induced G1 arrest and growth inhibition of breast cancer cell lines regardless of ER or RB status. This result suggests that ABBV-075 may provide therapeutic benefit to a broader patient population relative to the recently approved cdk4/6 inhibitor, palbociclib. The G1 arrest mechanism of ABBV-075 was efficacious in breast cancer xenograft studies, where significant tumor growth inhibition was observed. Additionally, ABBV-075 exhibited synergy in ER positive cell lines with doxorubicin, a TOPO2 inhibitor and DNA intercalating agent prescribed to ER positive patients refractory to hormone therapies. Intriguingly, the mechanism by which ABBV-075 and doxorubicin interact was independent of the TOP2-trapping activity of doxorubicin and instead required DNA intercalation. Together, these results demonstrate the potential of ABBV-075 as a treatment option across the different subtypes of breast cancer and in combination with doxorubicin in patients with ER positive disease Citation Format: Emily J. Faivre, Xiaoyu Lin, Denise M. Wilcox, Xiaoli Huang, Aparna Sarthy, Terry Magoc, Daniel H. Albert, Guowei Fang, Saul H. Rosenberg, Keith F. McDaniel, Warren M. Kati, Yu Shen. Potent inhibition of bromodomain-containing BET family with ABBV-075 induces robust antitumor efficacy in preclinical models of breast cancer and exhibits in vitro synergy with doxorubicin. [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 3077.
Cancer clinical trial accessibility in the United States: An analysis of travel distance.
Authors: Asma Latif, Kristian D Stensland, Ryan Hendricks, Erin L. Moshier, James H. Godbold, William K. Oh, Matt D. Galsky
Journal: Journal of Clinical Oncology (2013)

6540 Background: Accessibility of cancer clinical trials has been cited as a barrier to participation. While there are several dimensions to accessibility, travel distance may represent an important measure with potential socio-demographic implications. We sought to identify the driving distance from each ZIP-code in the United States to the nearest clinical trial site for four common solid tumors, and correlate ZIP-code level demographics with travel distance. Methods: The ClinicalTrials.gov database was queried on September 12, 2012 to identify all open, actively recruiting phase II and phase III therapeutic interventional trials in first-line metastatic disease for the four most common solid tumor types in the United States (prostate, breast, lung, and colorectal). Driving distance from each ZIP-code in the continental United States to the nearest trial site for each tumor type was calculated. Trial sites located within the ZIP-code were set at a travel distance of 0 miles. ZIP-code level demographics, derived from the 2010 Census, were correlated with driving distance. Results: We identified 42 prostate cancer trials with 958 sites, 81 breast cancer trials with 1,345 sites, 83 lung cancer trials with 2,249 sites, and 32 colorectal cancer trials with 566 sites which met inclusion criteria. The travel distances for each tumor type are shown in the Table. Analyses correlating driving distance with ZIP-code level demographics are ongoing. Conclusions: Substantial heterogeneity exists regarding accessibility of cancer trials in the United States as measured by driving distance. The optimal geographic distribution of trials, the burden imposed by travel, and the degree to which travel distance contributes to poor cancer clinical trial enrollment all warrant further investigation. [Table: see text]
Abstract LB-181: KLF4 suppresses T-cell acute lymphoblastic leukemia by inhibiting the stress kinase MAP2K7 pathway
Authors: Ye Shen, Chun Shik Park, Koramit Suppipat, Toni-Ann Mistretta, Monica Puppi, Terzah Horton, Karen Rabin, Daniel Lacorazza
Journal: Cancer Research (2016)

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with the highest incidence of relapse of any pediatric ALL. A minimal two-hit model of leukemogenesis suggests that an initial genetic driver transforms hematopoietic progenitor cells into LICs, whereas a secondary genetic alteration would endow LICs with proliferative and survival advantages. Although most T-ALL patients exhibit activating mutations in NOTCH1, the cooperating genetic events required to accelerate onset of leukemia and worsen disease progression are largely unknown. Here, we show that low levels of the transcription factor KLF4 in children with T-ALL were associated with methylation of its promoter. Consistent with a tumor suppressor function, loss of KLF4 accelerated the development of NOTCH1-induced T-ALL in mice by enhancing the G1-to-S transition and promoting the expansion of leukemia-initiating cells that are responsible for chemoresistance and relapses. Mechanistically, KLF4 represses the gene encoding the kinase MAP2K7, and thus loss of KLF4 activates MAP2K7 and downstream effector JNK both in murine model of T-ALL and lymphoblasts from pediatric patients with T-ALL. Furthermore, pharmacological inhibition of JNK reduced leukemia burden in a xenograft model of human T-ALL and small molecule inhibitors exhibited anti-leukemic properties in patient-derived xenograft cells. In summary, our findings demonstrate a novel tumor suppressor function of KLF4 in a T-ALL mouse model and in pediatric T-ALL and support a model of leukemia inhibition by repression of the stress kinase MAP2K7 and its downstream targets JNK, c-JUN, and ATF2. In addition, our study provides proof-of-principle pre-clinical data supporting JNK inhibition as a potential targeted therapy for T-ALL and prompts future studies in high-risk T-ALL patients with refractory and relapsed disease. Citation Format: Ye Shen, Chun Shik Park, Koramit Suppipat, Toni-Ann Mistretta, Monica Puppi, Terzah Horton, Karen Rabin, Daniel Lacorazza. KLF4 suppresses T-cell acute lymphoblastic leukemia by inhibiting the stress kinase MAP2K7 pathway. [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 LB-181.
Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence?
Authors: Molly Stanley, Shannon L. Macauley, David M. Holtzman
Journal: The Journal of Experimental Medicine (2016)

Individuals with type 2 diabetes have an increased risk for developing Alzheimer’s disease (AD), although the causal relationship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils of amyloid-β (Aβ) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aβ levels and tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause or consequence of AD.
Case 31-1969
Authors: J. Gordon Scannell, Benjamin Castleman
Journal: New England Journal of Medicine (1969)

Presentation of Case First admission. A fifty-six-year-old man was admitted to the hospital because of a tender mass in the epigastrium.For several years he had experienced indigestion, and gastrointestinal series three and two years before admission showed thickened folds in the gastric fundus. Several months before entry he noticed a tender mass in the left side of the epigastrium; a gastrointestinal series revealed a gastric tumor. His father had died as a result of carcinoma of the stomach.On physical examination the lungs and heart were normal, and the liver and spleen were not palpable. A firm mass, . . .
Personalized Computer Simulation of Diastolic Function in Heart Failure
Authors: Ali Amr, Elham Kayvanpour, Farbod Sedaghat-Hamedani, Tiziano Passerini, Viorel Mihalef, Alan Lai, Dominik Neumann, Bogdan Georgescu, Sebastian Buss, Derliz Mereles, Edgar Zitron, Andreas E. Posch, Maximilian Würstle, Tommaso Mansi, Hugo A. Katus, Benjamin Meder
Journal: Genomics Proteomics & Bioinformatics (2016)

The search for a parameter representing left ventricular relaxation from non-invasive and invasive diagnostic tools has been extensive, since heart failure (HF) with preserved ejection fraction (HF-pEF) is a global health problem. We explore here the feasibility using patient-specific cardiac computer modeling to capture diastolic parameters in patients suffering from different degrees of systolic HF. Fifty eight patients with idiopathic dilated cardiomyopathy have undergone thorough clinical evaluation, including cardiac magnetic resonance imaging (MRI), heart catheterization, echocardiography, and cardiac biomarker assessment. A previously-introduced framework for creating multi-scale patient-specific cardiac models has been applied on all these patients. Novel parameters, such as global stiffness factor and maximum left ventricular active stress, representing cardiac active and passive tissue properties have been computed for all patients. Invasive pressure measurements from heart catheterization were then used to evaluate ventricular relaxation using the time constant of isovolumic relaxation Tau (τ). Parameters from heart catheterization and the multi-scale model have been evaluated and compared to patient clinical presentation. The model parameter global stiffness factor, representing diastolic passive tissue properties, is correlated significantly across the patient population with τ. This study shows that multi-modal cardiac models can successfully capture diastolic (dys) function, a prerequisite for future clinical trials on HF-pEF.
Minimal Residual Disease and Normalization of the Bone Marrow after Long-Term Treatment with Alpha-Interferon2b in Polycythemia Vera. A Report on Seven Patients in Sustained Complete Hematological Remission with Major Molecular Responses.
Authors: Thomas Stauffer Larsen, Michael Boe Møller, Karin de Stricker, Peter Nørgaard, Jan Samuelsson, Claus Marcher, Ole Weis Bjerrum, Morten T Andersen, Hans Carl Hasselbalch
Journal: Blood (2008)
Abstract 2326: LTX-315, an oncolytic peptide, increases anticancer immunity mediated by CTLA4 blockade in an interleukin-2 receptor beta-chain-dependent manner
Authors: Takahiro Yamazaki, Marie Vetizou, Camila Flores, Aurelien Marabelle, Baldur Sveinbjørnsson, Øystein Rekdal, Guido Kroemer, Laurence Zitvogel
Journal: Cancer Research (2016)

Abstract Intratumoral immunotherapies aim at reducing local immunosuppression as well as reinstating and enhancing systemic anticancer T cell functions without inducing side effects. LTX-315 is a first-in-class oncolytic peptide -based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumour microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid derived-suppressor cells and by increasing the frequency of polyfunctional TH1/TC1 cells with a concomitant raise in their expression of CTLA4 and a drop in PD-1 expression. Logically, in tumours that were resistant to intratumoural or systemic CTLA4 blockade, subsequent local inoculation of LTX-315 cured the animals or caused tumour regressions with abscopal effects(meaning that even malignant lesions that were established in the opposite flank and were not treated by LTX-315 responded to the therapy). This synergistic interaction between CTLA4 blockade and LTX-315 was reduced upon blockade of the β-chain of the interleukin-2 receptor (CD122) which is required for signalling in response to IL-2 and IL-15. This preclinical study provides a strong rationale for administering the oncolytic peptide LTX-315 to patients who are receiving treatment with the CTLA4 blocking antibody ipilimumab. Citation Format: Takahiro Yamazaki, Marie Vetizou, Camila Flores, Aurelien Marabelle, Baldur Sveinbjørnsson, Øystein Rekdal, Guido Kroemer, Laurence Zitvogel. LTX-315, an oncolytic peptide, increases anticancer immunity mediated by CTLA4 blockade in an interleukin-2 receptor beta-chain-dependent manner. [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 2326.
Abstract 4647: BET protein inhibition blocks growth of triple-negative breast cancer by inducing mitotic and cytokinetic dysfunction
Authors: Jennifer M. Brancato, Sylvia Gayle, Kristen Weber-Bonk, Matthew Summers, Gurkan Bebek, Ruth Keri
Journal: Cancer Research (2016)

Abstract Bromodomain and Extra Terminal (BET) proteins are epigenetic “readers” that recognize acetylated histones and mark areas of the genome for transcription. BRD4, a BET family member protein, has been implicated in a number of types of cancer. It has been recently found to associate with super-enhancers, and elevated levels of BRD4 have been linked to increased expression of MYC as well as other oncogenes. BET protein inhibitors are currently being tested for their potential use in the treatment of HIV, heart failure, and cancer, all of which are diseases of aberrant transcription. However, little is known regarding their efficacy in triple-negative breast cancer (TNBC). We found JQ1, a prototypical BET inhibitor, impedes growth of seven TNBC cell lines in a dose-dependent manner within 72 hours of treatment. JQ1 also suppresses growth of three different TNBC xenografts, including a patient-derived model of basal-like breast cancer. Growth arrest, in vitro, is followed by either apoptosis or senescence. However, prior to the induction of these two terminal responses, prolonged treatment results in polyploidy in many of the cell lines, suggesting BETi disrupts mitosis/cytokinesis. Live-cell imaging revealed JQ1 significantly increased the duration of mitosis, and microarray analyses showed a significant JQ1-mediated downregulation of genes critical for cell cycle progression, mitosis, and cytokinesis. In all TNBC cell lines tested, Aurora kinases, proteins critical for proper progression through mitosis and cytokinesis, are suppressed in response to JQ1. Treatment with AZD1152, an Aurora kinase B inhibitor, elicits the same cellular responses as BET inhibition, indicating that the suppression of Aurora kinases plays a key role in the response of TNBC cells to BET inhibitors. These findings reveal that BET inhibitors block the growth of highly aggressive TNBC cells by inducing mitotic dysfunction and that these drugs are promising potential therapeutics for the treatment of TNBC. Citation Format: Jennifer M. Brancato, Sylvia Gayle, Kristen Weber-Bonk, Matthew Summers, Gurkan Bebek, Ruth Keri. BET protein inhibition blocks growth of triple-negative breast cancer by inducing mitotic and cytokinetic dysfunction. [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 4647.
Abstract 2663: Insights into the oncogenic basis of long non-coding RNA PVT1 in human cancer
Authors: Kojiro Tashiro, Robert Klink, Jon Zetterval, Veronica Diedrich, Yuen-Yi Tseng, Anindya Bagchi
Journal: Cancer Research (2016)

Abstract Though gain of 8q24.21 is a common mutation in human cancers, its functional annotation is limited to studying myelocytomatosis (MYC), the prominent oncogene in the amplicon. However, MYC is co-gained with an adjacent long non-coding RNA gene plasmacytoma variant translocation 1 (PVT1), the CCDC26 gene candidate and gasdermin C GSDMC. Whether copy number gain of one or more of these genes drives neoplasia is not known. We developed chromosome engineered mouse strains with an extra copy of 1) Myc, 2) Pvt1, Ccdc26, Gsdmc, and 3) Myc, Pvt1, Ccdc26, Gsdmc. When rat Neu was introduced to test the change in the latency in mammary tumor development, only the mice with an extra copy of Myc, Pvt1, Ccdc26, Gsdmc (but not with an extra copy of Myc or Pvt1, Ccdc26, Gsdmc) developed adenocarcinomas with reduced latency, suggesting that while an extra copy of Myc gene failed to measurably advance cancer, it may co-operate with Pvt1, Ccdc26 or Gsdmc to promote cancer. Si-RNA mediated knockdown of Pvt1/PVT1 reduced the proliferation rates in the tumors, and in SK-BR-3 and MDA-MB-231, two human breast cancer cell lines with 8q24 amplification. Ablation of PVT1 markedly decreased MYC protein levels, suggesting a PVT1-dependence of MYC protein in MYC amplified cancer cells. Analysis of the cancer genome atlas suggested 99% of tumors with increased MYC copy-number also harbor co-gain of PVT1. Tissue microarray analysis revealed that PVT1 RNA and MYC protein expression are correlated in primary human tumors. These data suggests that PVT1 can potentiate MYC in human cancers. CRISPR mediated deletion of PVT1 in colorectal cell line HCT116 impaired tumor formation in xenografts, and significantly reduced MYC levels. We further confirmed the oncogenic potential of PVT1 in cancers even without supernumerary 8q24. Additionally, we have identified the putative functional domain of PVT1 which confers its oncogenic potential. We propose that the dependence of high levels of MYC on lncRNA PVT1 provides a much-needed therapeutic window against MYC protein, known to be refractory to small molecule inhibition. Citation Format: Kojiro Tashiro, Robert Klink, Jon Zetterval, Veronica Diedrich, Yuen-Yi Tseng, Anindya Bagchi. Insights into the oncogenic basis of long non-coding RNA PVT1 in human 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 2663.
Abstract 103: Gene expression based subtypes of colorectal cancer
Authors: Kaja G. Berg, Ina A. Eilertsen, Sharmini Alagaratnam, Stine A. Danielsen, Arild Nesbakken, Anita Sveen, Ragnhild A. Lothe
Journal: Cancer Research (2016)

Abstract Colorectal cancer is a heterogeneous disease and improved molecular stratification of patients is warranted for precise treatment. Several gene expression classification systems are reported in the literature, albeit many have shown low reproducibility in external validation. A robust random forest classification system based on gene expression profiles was recently proposed, suggesting the existence of four biologically different subtypes with associations to prognosis (CMS1, CMS2, CMS3 and CMS4) (Guinney,J., et al., Nat Med, 2015). By applying the CMS classifier to high-quality gene expression profiles from a consecutive series of &amp;gt;400 stage I-IV primary colorectal cancers we are able to reproduce results from Guinney et al in an independent cohort. Analyses of mutational hotspots in BRAF / KRAS and the complete coding sequence of TP53 confirms enrichment of BRAF mutations in CMS1 (p&amp;lt;0.001), TP53 mutations in CMS2 and KRAS mutations in CMS4 (p&amp;lt;0.001). We further validate high levels of somatic copy number aberrations (SCNAs) in CMS2 and CMS4 compared to CMS1 and CMS3 (pair-wise comparisons, fraction of genome affected by SCNAs: CMS1 vs CMS2: p&amp;lt;0.001; CMS1 vs CMS4: p&amp;lt;0.01; CMS2 vs CMS3: p&amp;lt;0.001; CMS3 vs CMS4: p&amp;lt;0.01). Additionally we explore within-subtype variations with respect to SCNAs in the CMS2 and CMS4 subtypes. Altogether our results validate the CMS system as a robust classification system for colorectal cancer. Citation Format: Kaja G. Berg, Ina A. Eilertsen, Sharmini Alagaratnam, Stine A. Danielsen, Arild Nesbakken, Anita Sveen, Ragnhild A. Lothe. Gene expression based subtypes of colorectal 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 103.
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: Executive Summary
Authors: Stephan D. Fihn, Julius M. Gardin, Jonathan Abrams, Kathleen Berra, James C. Blankenship, Apostolos P. Dallas, Pamela S. Douglas, JoAnne M. Foody, Thomas C. Gerber, Alan L. Hinderliter, Spencer B. King, Paul D. Kligfield, Harlan M. Krumholz, Raymond Y.K. Kwong, Michael J. Lim, Jane A. Linderbaum, Michael J. Mack, Mark A. Munger, Richard L. Prager, Joseph F. Sabik, Leslee J. Shaw, Joanna D. Sikkema, Craig R. Smith, Sidney C. Smith, John A. Spertus, Sankey V. Williams
Journal: Journal of the American College of Cardiology (2012)
Abstract 3094: Identification of mimotopes of the epithelial mucin-1 (MUC1) in non-small cell lung cancer
Authors: Yu Qiu, Wang Jianfei, Cao Ruoqiong, Zhang Yi, Sun Yangyang, Li Zhong
Journal: Cancer Research (2016)

Abstract Background Mimotope analysis has been widely used in mapping epitopes for drug target, and also used in the development of new diagnostics, therapeutics and vaccines. The epithelial mucin-1 (MUC1) is a glycoprotein in human endometrium and has been found highly expressed in tumor tissues of NSCLC patients. Mimotopes of MUC1 has great potentials to be immunotherapy targets for NSCLC. In this study, we use phage display technology to screen a T7 NSCLC phage library to identify mimotope peptides of MUC1 proteins. Method A T7 NSCLC phage library was screened by 3-round of biopanning with anti-MUC1 monoclonal antibody acting as a molecular target. Forty positive clones were picked for ELISA confirmation using anti-MUC1 antibody. In addition, these clones were then amplified and coated with ELISA plates. Forty NSCLC patient and 40 control serum samples were used to test the ELISA plates. Statistical analysis was preformed, and the most significant clones were picked and PCR amplified for sequencing. Result Two peptide sequences, AAPDFRP and SAPDDRP, were identified and the competitive inhibitory rates of MUC1 were more than 50%. The intensity between MUC1 monoclonal antibody and the positive clones of these two sequences had positive correlation. In addition, in serum binding specificity detection, these two amino acid sequences showed higher tumor binding specificity with lung cancer patients serum than that of healthy human serum(P&amp;lt;0.05). Conclusion Peptides of AAPDFRP and SAPDDRP showed a high homology in the mimic epitopes of the epithelial mucin-1 (MUC1) glycoprotein in NSCLC. These may be potential immunotherapy targets which could also act as candidates of tumor vaccines Citation Format: Yu Qiu, Wang Jianfei, Cao Ruoqiong, Zhang Yi, Sun Yangyang, Li Zhong. Identification of mimotopes of the epithelial mucin-1 (MUC1) in non-small cell lung 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 3094.