tbuckley/cabot-search huggingface dataset:
Abstract 1358: Structure-based drug design of 3-site binding, high affinity inhibitors of S100B in malignant melanoma
Authors: Michael C. Cavalier, Paul T. Wilder, Diane Luci, David J. Maloney, Lei Fang, Mohd. Imran Ansari, Alexander D. MacKerell, Andrew Coop, Ajit Jadhav, David J. Weber
Journal: Cancer Research (2016)

Abstract An especially predictive biomarker when used in combination with other diagnostic indicators, S100B is elevated in &amp;gt;90% of malignant melanoma (MM) patients and its protein level correlates directly with poor survival (&amp;lt;1 yr.) and relapse. For patients with low levels of S100B (5-10%), MM vaccines are uniquely effective. While this correlation is not fully understood, mechanistic studies show that S100B is capable of blocking p53 oligomerization, promoting p53 phosphorylation in its C-terminus, and contributing to p53 degradation in concert with hdm2. Correspondingly, lowering S100B levels via siRNA or via small molecule inhibitors restore p53 levels and its tumor suppressor activities including UV-activated apoptosis pathways found in normal melanocytes. Additionally, elevated S100B and overexpression of the receptor for advanced glycation end products (RAGE) confers a metastatic phenotype. Studies into how S100B affects tumor progression and metastasis are ongoing, novel S100B inhibitors (termed SBiXs) to ablate S100B-dependent effects in cancer are in development. Structure-activity relationship (SAR) studies are ongoing to improve the affinity and selectivity of SBiXs. These studies reveal that the binding surface of S100B can be divided into “hot spots” or “persistent sites” that contribute more energetically to the protein-protein interactions (PPI) than the surrounding protein surface. Described here are descriptions of SBiXs which bind these Sites (1, 2, and 3), details to the SAR studies involved in the chemical optimization of these ligands, and information into the tethering of these SBiXs into a single-molecule capable of binding all 3 sites simultaneously. Also provided is a discussion regarding how protein dynamics affect the on/off rates of SBiXs and the resulting apparent binding affinity. The results described here represent a Structure-based drug design approach to the development of PPI inhibitors nearing the threshold required for a useful therapeutic window. Citation Format: Michael C. Cavalier, Paul T. Wilder, Diane Luci, David J. Maloney, Lei Fang, Mohd. Imran Ansari, Alexander D. MacKerell, Andrew Coop, Ajit Jadhav, David J. Weber. Structure-based drug design of 3-site binding, high affinity inhibitors of S100B in malignant melanoma. [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 1358.
Use of Eltrombopag after Romiplostim in Primary ITP Patients
Authors: Tomás José González-López, Cristina Pascual, María Teresa Álvarez-Román, Fernando Fernández-Fuentes, Blanca Sánchez-González, Isabel Caparrós, Isidro Jarque, María Eva Mingot, José Angel Hernández-Rivas, Mónica Martín-Salces, Laura Solán, Paola Beneit, Reyes Jiménez, Silvia Bernat, Marcio M. Andrade, Montserrat Cortés, María José Cortti, Susana Pérez-Crespo, Marta Gómez-Núñez, Pavel E. Olivera, Gloria Pérez-Rus, Violeta Martínez-Robles, Rafael Alonso, Angeles Fernández-Rodríguez, María Carmen Arratibel, María Perera, Carmen Fernández-Miñano, Miguel Angel Fuertes-Palacio, Juan Andrés Vázquez-Paganini, Luis Miguel Juárez-Salcedo, Inés Valcarce, Francisco Javier Díaz-Gálvez, Adriana Sainz, Rosa Fisac, Carlos Aguilar, María Paz Martínez-Badas, María Jesús Peñarrubia, Javier García-Frade, Maria Calbacho, Carmen de Cos, Manuel González-Silva, Erika Coria, Arancha Alonso, Alberto Casaus, Armando Luaña, Pilar Galán, Cristina Fernández-Canal, José Ramón González-Porras
Journal: Blood (2014)
Abstract LB-022: The E3-ligase CHIP negatively regulates the expression and function of the tumor suppressor TAp63 through ubiquitination and subsequent proteasome-mediated degradation
Authors: Stephen R. Armstrong, Benfan Wang, Yasser Abuetabh, Roger Leng
Journal: Cancer Research (2016)

Abstract The p53 tumor suppressor family is comprised of three members: p53, p63, and p73. These transcription factors can negatively regulate cell proliferation by inducing the expression of proteins related to apoptosis (ex. bax) and cell cycle arrest (ex. p21). Isoforms of the p63 protein can be divided into two major groups, the transcriptionally active TAp63 variants, and the dominant-negative ΔNp63 variants. The TAp63 variants are considered to be tumor suppressor proteins that can cooperate with p53 and p73 to prevent cancer development. Unlike p53, which is frequently mutated in cancer, TAp63 is rarely mutated, and its transcription function is primarily regulated at the protein level. One such method of regulation at this level is proteasome-mediated degradation, initiated by tagging the substrate protein with a poly-ubiquitin chain recognized by the proteasome. This ubiquitination is mediated by E-3 ligases such as Mdm2 and AIP4, two previously characterized regulators of the p53 family. In this study, we report that CHIP, an E-3 ligase involved in protein chaperoning during the heat shock response is a negative regulator of TAp63. The purpose of this study was to characterize CHIP as a TAp63-interacting protein that negatively regulates TAp63 expression and function. Using transient transfection assays, we found that CHIP can bind to, ubiquitinate, and reduce the expression of TAp63 in H1299 lung carcinoma cells. Stably knocking down CHIP expression in these cells using anti-CHIP shRNA restores endogenous p63 expression. This negative regulation of TAp63 by CHIP is associated with a decrease in p21 promoter transcription (measured by a luciferase reporter assay), cell cycle arrest and cellular apoptosis (measured by flow cytometry), and accompanied by an increase in cell survival (measured by colony forming assay) and invasive capacity (measured by a cell scattering assay). An immunoblot analysis of carcinoma cell lines and invasive prostate cancer tissue samples also demonstrates a negative correlation between CHIP and TAp63 expression levels. We conclude that CHIP is a negative regulator of TAp63 expression and function, and, therefore, has an oncogenic role in context with TAp63. Citation Format: Stephen R. Armstrong, Benfan Wang, Yasser Abuetabh, Roger Leng. The E3-ligase CHIP negatively regulates the expression and function of the tumor suppressor TAp63 through ubiquitination and subsequent proteasome-mediated degradation. [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-022.
Visceral Vistas: Basil Hirschowitz and the Birth of Fiberoptic Endoscopy
Authors: Ian S. Campbell, Joel D. Howell, H. Hughes Evans
Journal: Annals of Internal Medicine (2016)

Fiberoptic endoscopy was developed at the University of Michigan in the 1950s by gastroenterology fellow Basil Hirschowitz and 2 physicists. Previous methods to visualize the gastrointestinal lumen used rigid instruments that relied on rudimentary optical systems. They were limited in reach and caused patients considerable discomfort. Fiberoptic technology dramatically changed endoscopic practice. The fiberoptic endoscope, or fiberscope, was a flexible instrument that allowed direct inspection of the gastrointestinal lumen. Although many practicing endoscopists initially resisted its adoption, the fiberscope ultimately held sway. Studying the period from the fiberscope's first introduction in the late 1950s to its more widespread acceptance in the late 1960s may help us understand how a new technology makes its way into routine clinical practice.
Re: Mark W. Ball, Nathaniel Readal, Phillip M. Pierorazio, Mohamad E. Allaf. Splitting One Kidney into Two: Robotic Partial Kidney Transplant in a Porcine Model. Eur Urol 2016;69:968–9
Authors: Valerian Ciprian Lucan, Salvatore Butticè, Rosa Pappalardo, Carlo Magno
Journal: European Urology (2016)
Abstract 3924: AIRE is expressed and associated with good prognosis in breast cancer
Authors: Francesca Bianchi, Loris De Cecco, Tiziana Triulzi, Sandra Romero-Cordoba, Michele Sommariva, Chiara Storti, Piera Aiello, Elda Tagliabue, Andrea Balsari, Lucia Sfondrini
Journal: Cancer Research (2016)

Abstract The transcription factor Autoimmune Regulator (AIRE) gene plays a fundamental role in tolerance process by promoting the ectopic expression of thousands of genes encoding for tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs). Beside the high expression of AIRE in mTECs, there are few evidences of AIRE expression in other lymphoid organs and very recently, AIRE was described to be expressed in human and mouse keratinocytes and in tumors originating in stratified and pseudostratified epithelia. Therefore, we evaluated the hypothesis that AIRE could be expressed by epithelial tumors and we focused on breast cancer, for which large public datasets are available. Our analysis on the TCGA, the largest public breast cancer RNA-seq dataset, revealed that AIRE is expressed in 33% of the cases, and Aire protein expression was confirmed in 26% of 115 human primary breast cancer specimens by immunohistochemistry analysis. AIRE expression was revealed associated to a better relapse-free survival in the TCGA patients and also in two public gene expression microarray-based dataset developed on Agilent and Illumina platform (NKI-295 and KM-plotter). In all the datasets analyzed, AIRE expression resulted an independent strong prognostic factor for relapse-free survival, particularly in ER-positive tumors. Ingenuity Pathway Analysis (IPA) showed that AIRE-expressing tumors were enriched in translation-related pathways, accordingly with AIRE's described function in mTECs. Moreover, in breast cancer luminal cell lines MCF-7 and MDA-MB-361 transfected with AIRE-expressing vector, a significant increase of cell in G1 phase and activation of caspases cascade were observed, supporting the hypothesis that genotoxic stress, induced by AIRE-mediated proteins over-translation, leads to cycle arrest and apoptosis. These data highlight for the first time AIRE expression in breast cancer and an association with a better prognosis was revealed. Imbalance of cellular homeostasis, caused by AIRE transcriptional function, is a new unusual mechanisms to trigger apoptosis in breast cancer cells. Citation Format: Francesca Bianchi, Loris De Cecco, Tiziana Triulzi, Sandra Romero-Cordoba, Michele Sommariva, Chiara Storti, Piera Aiello, Elda Tagliabue, Andrea Balsari, Lucia Sfondrini. AIRE is expressed and associated with good prognosis 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 3924.
Outcomes in patients with multiple myeloma with TP53 deletion after autologous hematopoietic stem cell transplant
Authors: Sameh Gaballa, Rima M. Saliba, Samer Srour, Gary Lu, Jonathan E. Brammer, Nina Shah, Qaiser Bashir, Krina Patel, Fabian Bock, Simrit Parmar, Chitra Hosing, Uday Popat, Ruby Delgado, Gabriela Rondon, Jatin J. Shah, Elisabet E. Manasanch, Robert Z. Orlowski, Richard Champlin, Muzaffar H. Qazilbash
Journal: American Journal of Hematology (2016)

TP53 gene deletion is associated with poor outcomes in multiple myeloma (MM). We report the outcomes of patients with MM with and without TP53 deletion who underwent immunomodulatory drug (IMiD) and/or proteasome inhibitor (PI) induction followed by autologous hematopoietic stem cell transplant (auto-HCT). We identified 34 patients with MM and TP53 deletion who underwent IMiD and/or PI induction followed by auto-HCT at our institution during 2008-2014. We compared their outcomes with those of control patients (n = 111) with MM without TP53 deletion. Median age at auto-HCT was 59 years in the TP53-deletion group and 58 years in the control group (P = 0.4). Twenty-one patients (62%) with TP53 deletion and 69 controls (62%) achieved at least partial remission before auto-HCT (P = 0.97). Twenty-three patients (68%) with TP53 deletion and 47 controls (42%) had relapsed disease at auto-HCT (P = 0.01). Median progression-free survival was 8 months for patients with TP53 deletion and 28 months for controls (P < 0.001). Median overall survival was 21 months for patients with TP53 deletion and 56 months for controls (P < 0.001). On multivariate analysis of both groups, TP53 deletion (hazard ratio 3.4, 95% confidence interval 1.9-5.8, P < 0.001) and relapsed disease at auto-HCT (hazard ratio 2.0, 95% confidence interval 1.2-3.4, P = 0.008) were associated with a higher risk of earlier progression. In MM patients treated with PI and/or IMiD drugs, and auto-HCT, TP53 deletion and relapsed disease at the time of auto-HCT are independent predictors of progression. Novel approaches should be evaluated in this high-risk population. Am. J. Hematol. 91:E442-E447, 2016. © 2016 Wiley Periodicals, Inc.
Fatty liver diseases, bile acids, and FXR
Authors: Yan Zhu, Hongxia Liu, Min Zhang, Grace L. Guo
Journal: Acta Pharmaceutica Sinica B (2016)

The prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide has increased at an alarming rate, which will likely result in enormous medical and economic burden. NAFLD presents as a spectrum of liver diseases ranging from simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even to hepatocellular carcinoma (HCC). A comprehensive understanding of the mechanism(s) of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved. An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH. Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury. The bile acid homeostasis is critically regulated by the farnesoid X receptor (FXR) that is activated by bile acids. FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport. Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver. Therefore, the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD.
Abstract 1675: Activation of phosphatase toward the retinoblastoma protein inhibits invasion in MDA-MB-231 breast cancer cells
Authors: Jacklynn Egger, Maria Lane, Brixhilda Dedi, Nancy A. Krucher
Journal: Cancer Research (2016)

Abstract Excessive phosphorylation of the Retinoblastoma protein (Rb) is found in most cancer tumor types. Several cyclin dependent kinase (cdk) inhibitors are in development or in clinical trials at the present time. Our previous studies have focused on the regulation of Rb phosphorylation by the phosphatase, PP1. In proliferating cells, PP1 is regulated by a protein called PNUTS (Phosphatase Nuclear Targeting Subunit). PNUTS is a competitive inhibitor of Rb binding to PP1 and siRNA mediated knockdown of PNUTS in several cancer cell types (breast, colon, ovarian) leads to an increase in Rb directed PP1 activity, Rb dephosphorylation on several sites, and a dramatic induction of apoptosis. In this study we have used MDA-MB-231 breast cancer cells grown in Matrigel. By lentiviral-mediated doxycycline inducible expression of PNUTS siRNA, expression of PNUTS protein is blocked and phosphorylation of Rb cells is reduced. Cells become less invasive and expression of mesenchymal markers N-cadherin, Zeb and Slug is lost. A reversion to the epithelial phenotype is suggested by an increase in E-cadherin expression. PNUTS knockdown has no effect on cells that do not contain highly phosphorylated Rb such as non-transformed MCF-10A cells or Rb-negative MDA-MB-468 cells. Further experiments using highly invasive HT-1080 cells show that reduction of Rb phosphorylation appears to reduce invasiveness in this cell model, supporting the idea that Rb phosphorylation plays a critical role in the regulation of invasion. Citation Format: Jacklynn Egger, Maria Lane, Brixhilda Dedi, Nancy A. Krucher. Activation of phosphatase toward the retinoblastoma protein inhibits invasion in MDA-MB-231 breast cancer 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 1675.
Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN): Findings related to the oropharynx.
Authors: S. J. Wong, A. Y. Chen, W. J. Curran, A. S. Garden, P. M. Harari, B. A. Murphy, L. A. Bellm, M. Schwartz, K. Ang
Journal: Journal of Clinical Oncology (2010)

5585 Background: We present the first report of findings focused on the oropharynx (OP) from LORHAN, a prospective, observational national registry of head and neck carcinoma (HNC) patients (pts). The Registry is now sufficiently large to perform site-specific analyses. Methods: Pts with newly diagnosed HNC, scheduled to receive radiotherapy (RT) or chemotherapy (CT), ≥18 years of age and who have provided written informed consent are eligible for enrollment. Electronic records are locked once they have been reviewed and signed off by the investigator. Results: As of Jan. 3, 2010, 3525 pts have been enrolled in LORHAN. Nearly 100 community (Comm) and academic (Acad) sites from 35 states have enrolled pts in the registry. Of principal investigators participating in LORHAN, 22% designated their setting as Acad, 78% as Comm. Acad centers accrued 65% of pts. Of pts enrolled, there are 941 locked baseline and treatment records for pts with the primary diagnosis of OP cancer, representing 44% of locked records for all diagnoses of HNC. Compared to Acad centers, Comm sites treated pts with OP cancer who were older (59 years of age vs. 56; p=0.0002), had less advanced disease (stage IV: 71% vs. 85%; p<0.0001) and had a better performance status (most differences due to more Zubrod 0 pts and fewer Zubrod 2 pts; p=0.002); other clinical features were similar. 80% of all pts presented with stage IV disease. HPV testing was done in 12% of OP cancer pts; in 56% of pts the test was not performed, and in 32% of pts, HPV testing was unknown. Of pts with an HPV test performed, 82% had a positive finding; P16 was the most common test method (82% for P16 vs. 19% for FISH/ISH). The three most common initial therapies for OP pts were concurrent CT/RT (428 pts; 46%), induction CT before curative surgery or RT (155 pts; 17%), and curative surgery followed by CT/RT (143 pts; 15%). The 1- and 2-yr rates for LRC were 88% and 80% and for OS were 89% and 79%, respectively. Conclusions: This report from LORHAN provides the first analysis of pt characteristics, treatment patterns and outcomes for OP cancer pts. As the sample size grows, LORHAN will be increasingly suited to look at factors affecting differences in treatment and outcome for HNC pts by primary tumor site. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MedNet Solutions Bristol-Myers Squibb, ImClone Systems, Lilly, MedNet Solutions Bristol-Myers Squibb, Merck, sanofi-aventis, Serano Amgen, Cellectar, Genentech, ImClone Systems
Abstract LB-237: BMS-986012, a fully human anti-fucosyl-GM1 antibody has potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer
Authors: Bing Chen, Chin Pan, Paul Ponath, Miho Oyasu, Daniel Menezes, Pina Cardarelli
Journal: Cancer Research (2016)

Abstract Fucosyl-GM1, is a sphingolipid monosialoganglioside and tumor-associated antigen with a high prevalence in human small cell lung cancer (SCLC), while its expression is minimal in most normal tissue. Here, we report results of our preclinical studies with BMS-986012, a novel fully human, non-fucosylated, IgG1 monoclonal antibody that specifically binds to FucGM1. The binding affinity of BMS-986012 was evaluated in Biacore® and cell-based assays. BMS-986012 binds with a high affinity to FucGM1 and demonstrates no significant binding to other closely related gangliosides. The antibody was engineered in a non-fucosylated IgG1 format, resulting in a 40-fold increased affinity for FcγRIIIa (CD16). In in vitro assays, BMS-986012 binds to FucGM1 on cancer cells and activates antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-mediated phagocytosis (ADCP). The antitumor activity of BMS-986012 was profiled in a panel of SCLC lung cancer models in immunodeficient mice with varying FucGM1 target expression levels qualified using immunohistochemistry. Dose-dependent antitumor activity was observed in a panel of SCLC xenograft models with tumor regressions occurring at BMS-986012 doses greater than 0.3 mg/kg against DMS79 tumors. BMS-986012 efficacy generally correlated with FucGM1 target expression in tumor models. In mice, the antibody was well tolerated, with no adverse events observed in long term efficacy studies. Preclinical studies also explored combinations of BMS-986012 with standard-of-care (SOC) chemotherapeutics, including cisplatin, etoposide, topotecan and irinotecan. Combination therapy of BMS-986012 with SOC resulted in significantly enhanced antitumor activity compared to monotherapy. Finally, studies conducted with BMS-986012 in combination with anti-CD137 antibody resulted in significant improvement in efficacy. These data provide preclinical support for evaluation of BMS-986012 in SCLC. BMS-986012 is currently in a phase I trial. Citation Format: Bing Chen, Chin Pan, Paul Ponath, Miho Oyasu, Daniel Menezes, Pina Cardarelli. BMS-986012, a fully human anti-fucosyl-GM1 antibody has potent in vitro and in vivo antitumor activity in preclinical models of 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 LB-237.