tbuckley/cabot-search huggingface dataset:
Abstract LB-003: Novel multi-functional chemoprobes for the characterization of the mechanism of action of histone lysine demethylases inhibitors in cancer
Authors: Serena Lunardi, Filippo Ciceri, Cristina Mascaró Crusat, Raquel Ruiz, Elena Carceller, Alberto Ortega, Natalia Sacilotto, Paola Dessanti, Jordi Salas, Michele Lufino, Tamara Maes
Journal: Cancer Research (2018)

Abstract Histone Lysine demethylases (KDMs) are emerging clinical targets in cancer. However, a characterization of the mechanism of action of KDMs small molecule inhibitors is limited by the fact that these targets act at multiple levels, having several substrates, different scaffolding roles and regulating gene expression in a cell-specific manner. We developed biotinylated chemoprobes capable of binding to the active site of different KDMs and demonstrated their versatility in target engagement and chemoproteomics analysis. First, we synthetized a biotinylated chemoprobe capable of binding selectively and irreversibly to the active form of KDM1A. By coupling the chemoprobe to an immune-based assay, we can quantify the levels of free KDM1A relative to total levels of KDM1A in a dose-dependent manner in vitro and in vivo. Using this assay, we measured the KDM1A target engagement in models for AML and SCLC. These data were used to perform quantitative pharmacological modeling of SCLC xenograft models treated with ORY-1001 (see Medhi et al, AACR 2018 submitted abstract). The technique can be readily applied to clinical samples and has been used to characterize the pharmacokinetic / pharmacodynamic relationship of KDM1A inhibitors in Phase I trials. In addition, we show that the proteomic profile of the chemoprobe pulldown mirrors the binding partners of inhibited KDM1A. Our proteomic analysis using the KDM1A specific chemoprobe in AML cells identified several ZNF transcription factors but SNAG domain proteins, known to bind to the inhibitor binding site, were not retrieved, providing insight in the interaction changes induced by a KDM1A inhibitor. The strategy was also applied to other targets such as Jumonji C (JmjC) domain-containing proteins like the KDM5 demethylase family, reported to play a role in the emergence of drug tolerance. Overall, this study offers important insights and tools for investigating the role of KDM inhibitors in cancer and their further development into the clinical setting. Citation Format: Serena Lunardi, Filippo Ciceri, Cristina Mascaró Crusat, Raquel Ruiz, Elena Carceller, Alberto Ortega, Natalia Sacilotto, Paola Dessanti, Jordi Salas, Michele Lufino, Tamara Maes. Novel multi-functional chemoprobes for the characterization of the mechanism of action of histone lysine demethylases inhibitors in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-003.
Abstract 2083: Innate immunity polymorphisms and risk of pediatric cancer
Authors: Gabriela E. Mercado, Gabriela A. Rosales-Bravo, David Velazquez-Fernandez, Marta Zapata-Tarres, Luis E. Juarez-Villegas
Journal: Cancer Research (2018)

Abstract In Mexico, cancer represents the second leading cause of death in the pediatric population. The identification of susceptibility genes associated with cancer has been one of the main challenges of human genomics. Several studies have proposed that genetic variation in immune-related genes could be a determinant of susceptibility in different types of cancer. In the present study we evaluated the possible association between 10 polymorphisms in genes that participate in innate immunity and the risk of pediatric cancer. We analyzed genotyping data from 101 patients from Hospital Infantil de México “Federico Gómez” (HIM) with confirmed diagnosis of pediatric cancer. The genotypes were compared with 274 healthy adults without a medical history of pediatric cancer. For each polymorphism we calculated allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE). The association between cancer and pediatric cancer was analyzed using Pearson chi-square and odds ratio (OR); survival analyses were performed by the log rank test and Kaplan-Meier curves. Our results show that risk of pediatric cancer in our sample is significantly associated with the genetic variants IL8-251 (p= 0.04327, OR= 0.701, IC 95% = 0.496-0.990), IL6-174 (p= 0.0037, OR= 2.413, IC 95% = 1.310-4.445), and IL10-592 (p= 0.0062, OR= 0.670, IC 95% = 0.502-0.894). However, we did not find any significant association between selected polymorphisms and overall or disease-free survival. Citation Format: Gabriela E. Mercado, Gabriela A. Rosales-Bravo, David Velazquez-Fernandez, Marta Zapata-Tarres, Luis E. Juarez-Villegas. Innate immunity polymorphisms and risk of pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2083.
Pulmonary Artery Aneurysms
Authors: Brianblades, Williamford, Patrickclark
Journal: Circulation (1950)

The successful surgical treatment of an aneurysm of the left main pulmonary artery is reported. It appears that, after ligation of the main pulmonary artery, it is desirable not to remove the lung but preserve it as a space occupying organ which will retain some function. Literature on the subject of pulmonary aneurysms is reviewed.
Abstract 13739: Short-term Lanthanum Carbonate Safely Inhibits Aortic Allograft Calcification and Intimal Hyperplasia in a Rabbit Circulatory Transplant Model
Authors: Kenichi Okamura, Haruo Yamauchi, Osamu Kinoshita, Minoru Ono
Journal: Circulation (2017)

Introduction: Aortic allografts tend to lack durability due to calcification and this remains a major issue, particularly in young recipients. In this study, we evaluated the efficacy of administering a phosphate binder, lanthanum carbonate (LC) in order to prevent calcification. Methods: Seven-week-old male New Zealand White (NZW) rabbits and Japanese White (JW) rabbits were used as donors and recipients, respectively. The descending aorta harvested from a NZW rabbit was transplanted into the carotid artery of a JW rabbit in a circulatory transplant model. The N8 group were fed a normal diet (ND) for 8 weeks, the L1N7 group were fed a one-week LC diet and a seven-week ND, the L2N6 group: a 2-week LC diet and a 6-week ND, the L4N4 group: a 4-week LC diet and a 4-week ND, and the L8 group: an 8-week LC diet. Results: The calcium content in the allografts decreased as the length of the LC diet increased, and especially the L8 group demonstrated significantly lower calcium levels than the N8 group. The degre...
Abstract 3428: Development and validation of the plasma monitor test system
Authors: Kevin J. Kelly, Jasmina Uvalic, Daniel Bergeron, Shelbi Burns, Melissa Soucy, Guruprasad Ananda, Andrew Hesse, Pavalan Panneer Selvam, Honey V. Reddi
Journal: Cancer Research (2018)

Abstract Introduction: Non-invasive monitoring of variants in a cancer patient for minimal residual disease, recurrence and/or resistance has tremendous clinical utility and warrants the development of a cell-free circulating tumor DNA panel, which involves the use of a simple blood draw. Towards this end, JAX has validated a new liquid biopsy assay called the Plasma MonitorTM that focuses on 84 clinically significant hotspots across 14 genes to complement our current clinical test menu, with a focus on comprehensive profiling of cancer. Methods: Post development and optimization of a custom amplicon panel, which included running multiple batches of samples through the assay to determine appropriate extraction methods, input DNA QC metrics, sequencing batch size, and sequencing loading concentrations, clinical validation of The Plasma MonitorTM was initiated. Validation included the evaluation of 20 uncharacterized plasma samples and 14 known controls and was executed in 5 phases: (1) Sample Processing for Validation Parameter determination; (2) LOD, sensitivity, specificity and accuracy (3) inter-assay concordance; (4) intra-assay concordance; (5) clinical validity in terms of interpretation and reporting of variants identified. Results: The final clinical protocol was developed using an input of 10ng of ctcfDNA quantified and qualified by a custom qPCR assay. Wet lab results of the first validation batch can be seen in Table 1. Using samples containing variants with known allele frequencies and a droplet digital PCR (ddPCR) based confirmation of novel variants identified by our assay, we established the assay's limit of detection (LOD) to be 0.9%. At this LOD, sensitivity, specificity, and accuracy were found to be 96.6%, 100%, and 98% respectively. Conclusion: Based on the results of this validation, the Plasma Monitor assay will be incorporated into the JAX clinical test menu. This new assay allows for comprehensive profiling and monitoring of cancer progression, response to therapy and minimal residual disease, and a significant benefit to both patients and clinicians. Citation Format: Kevin J. Kelly, Jasmina Uvalic, Daniel Bergeron, Shelbi Burns, Melissa Soucy, Guruprasad Ananda, Andrew Hesse, Pavalan Panneer Selvam, Honey V. Reddi. Development and validation of the plasma monitor test system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3428.
Abstract 5216: Exosome as a vehicle for delivery of membrane protein therapeutics, PH20 for enhanced tumor penetration and anti-tumor efficacy
Authors: yoosoo yang, Yeonsun Hong, Gi Beom Kim, Gihoon Nam, In-san Kim
Journal: Cancer Research (2018)

Abstract As biochemical and functional studies of membrane protein remain a challenge, there is growing interest in the application of nanotechnology to solve the difficulties of developing membrane protein therapeutics. Exosome, composed of lipid bilayer enclosed nano-sized extracellular vesicles, is a successful platform for providing a native membrane composition. Here, we report an enzymatic exosome, which harbors native PH20 hyaluronidase (Exo-PH20), was able to penetrate deeply into tumor foci via hyaluronan degradation, allowing tumor growth inhibition and increased T cell infiltration into the tumor. This exosome-based strategy was developed to overcome the immunosuppressive and anti-cancer therapy-resistant tumor microenvironment, which is characterized by an overly accumulated extracellular matrix. Notably, our engineered exosome with the native GPI-anchored form of hyaluronidase had a higher enzymatic activity than a truncated form of the recombinant protein. In addition, the exosome-mediated co-delivery of PH20 hyaluronidase and a chemotherapeutic (doxorubicin) efficiently inhibited tumor growth. This exosome is designed to degrade hyaluronan along the path of its movement, thereby augmenting nanoparticle penetration and drug diffusion. Our results thus show that this is a promising exosome-based platform that harbors not only a membrane-associated enzyme with high activity but also therapeutic payloads. Citation Format: yoosoo yang, Yeonsun Hong, Gi Beom Kim, Gihoon Nam, In-san Kim. Exosome as a vehicle for delivery of membrane protein therapeutics, PH20 for enhanced tumor penetration and anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5216.
Molecular Determinants of Altered Ca2+ Handling in Human Chronic Atrial Fibrillation
Authors: AliEl-Armouche, PeterBoknik, ThomasEschenhagen, LucieCarrier, MichaelKnaut, UrsulaRavens, DobromirDobrev
Journal: Circulation (2006)

Background— Abnormal Ca2+ handling may contribute to impaired atrial contractility and arrhythmogenesis in human chronic atrial fibrillation (cAF). Here, we assessed the phosphorylation levels of key proteins involved in altered Ca2+ handling and contractility in cAF patients. Methods and Results— Total and phosphorylation levels of Ca2+-handling and myofilament proteins were analyzed by Western blotting in right atrial appendages of 49 patients in sinus rhythm and 52 cAF patients. We found a higher total activity of type 1 (PP1) and type 2A phosphatases in cAF, which was associated with inhomogeneous changes of protein phosphorylation in the cellular compartments, ie, lower protein kinase A (PKA) phosphorylation of myosin binding protein-C (Ser-282 site) at the thick myofilaments but preserved PKA phosphorylation of troponin I at the thin myofilaments and enhanced PKA (Ser-16 site) and Ca2+-calmodulin protein kinase (Thr-17 site) phosphorylation of phospholamban. PP1 activity at sarcoplasmic reticulum is...
Effects of In Vivo Administration of Anti–B7-1/B7-2 Monoclonal Antibodies on Murine Acute Myocarditis Caused by Coxsackievirus B3
Authors: YoshinoriSeko, NaoyukiTakahashi, MiyukiAzuma, HideoYagita, KoOkumura, YoshioYazaki
Journal: Circulation Research (1998)

Abstract—In viral myocarditis, we previously reported that antigen-specific T cells infiltrate the heart and play an important role in the pathogenesis of myocardial damage. For antigen-specific T-cell activation to occur, it is necessary for T cells to receive costimulatory signals provided by costimulatory molecules expressed on antigen-presenting cells as well as main signals provided by binding of T-cell receptors to antigens. To investigate the roles of costimulatory molecules B7-1 and B7-2 in the development of acute viral myocarditis, we first analyzed the expression of B7-1/B7-2 in the hearts of mice with acute viral myocarditis induced by coxsackievirus B3 (CVB3). Second, we evaluated the induction of B7-1/B7-2 in cultured cardiac myocytes treated with interferon gamma (IFN-γ). Third, we examined the effects of in vivo administration of anti–B7-1/B7-2 monoclonal antibodies (mAbs) on the development of acute viral myocarditis. We found that CVB3-induced murine acute myocarditis resulted in enhance...
Abstract 3091: Functional screening of genes involved in carcinogenesis using a cDNA expression library of ovarian clear cell carcinoma cells
Authors: Tsutomu Miyamoto, Yasushi Yamada, Koichi Ida, Ryoichi Asaka, Hisanori Kobara, Hirofumi Ando, Hiroyasu Kashima, Akihisa Suzuki, Tanri Shiozawa
Journal: Cancer Research (2018)

Abstract Background: Ovarian clear cell carcinoma (OCCC) is one of the 4 major histological types of ovarian carcinoma (OVC) and is frequently arising from ovarian endometriotic cysts. OCCC is rare in the United States and western countries, but it is more frequent in Japan and may be seen in almost 25% of OVC. OCCC commonly shows chemo-resistance which makes difficult to treat OCCC. In order to develop the new therapeutics for OCCC, genetic abnormalities that lead to the development of OCCC need to be elucidated in detail. The comprehensive analysis using next-generation sequencing has rapidly revealed the accumulation of genetic abnormalities in many cancers. However, the significance of each abnormality has not been elucidated. Therefore, functional screening using a cDNA expression library was performed in order to identify genes involved in the pathogenesis of OCCC. Methods: The mRNA was extracted from an OCCC cell line, RMG-1, and a cDNA library was established using a retroviral vector. This cDNA library was transfected into mouse NIH3T3 cells, and then the transformed foci which formed multilayered growth were picked up and the inserted DNAs of those foci were detected by sequencing. The mRNA and protein expression and the transforming ability of the identified genes were confirmed by immunohistochemistry and focus-formation assay. Result: Seven genes were isolated; Dishevelled 1(DVL1), beta subunit of Sec61 (SEC61B), K-specific demethylase 4A (KDM4A), chromosome 1 open reading frame 38 (C1ORF38), splicing factor 1 (SF1), ribosomal protein S2 (RPS2), and ribosomal protein S3A (RPS3A). Of these genes, RT-PCR and immunostaining revealed that the expression of SEC61B and C1ORF38 was stronger than that in other histological types of ovarian cancer. A mutational analysis of the DVL1 c-terminal region detected 3 point-mutations in RMG1 cells, whereas no mutation was found in 24 cases of OCCC. Focus formation was confirmed by the transfection of SEC61B, C1ORF38, and DVL1 into NIH3T3 cells. Conclusion: These results suggest that SEC61B, C1ORF38, and DVL1 may be involved in the pathogenesis of OCCC. Citation Format: Tsutomu Miyamoto, Yasushi Yamada, Koichi Ida, Ryoichi Asaka, Hisanori Kobara, Hirofumi Ando, Hiroyasu Kashima, Akihisa Suzuki, Tanri Shiozawa. Functional screening of genes involved in carcinogenesis using a cDNA expression library of ovarian clear cell carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3091.
Abstract 3851: Novel small-molecule inhibitor of PD1/PDL1 pathway demonstrated single agent and drug combo effectiveness in cancer immunotherapy
Authors: Yuguang Wang, He Zhou, Nong Zhang, Feilan Wang, Qiang Zhao, Tianzhi Wu, Haiyan Zhu, Yuzhi Liu
Journal: Cancer Research (2018)

Abstract With 5 antibodies approved for cancer treatments, PD-1/PD-L1 pathway has been the most successful target in cancer Immuno-therapy. Small molecules that inhibit PD-1/PD-L1 interaction are also attractive because their better tissue penetration may lead to stronger and broader anti-tumor efficacy in addition to more convenient dosing regimen. A series of such small molecule inhibitors have been developed by Maxinovel. Among them, Max 10043 and its 2nd generation compound MAX-10129 potently inhibited PD-1/PD-L1 interaction, reversed PD-L1 suppression of anti-CD3 mediated activation of human T cells, and was well tolerated in animal studies. MAX-10043 also demonstrated anti-tumor efficacy in CT26 murine colorectal carcinoma model. MAX-10129, with improved oral bioavailability, displayed significant inhibition of tumor progression with dose dependency in murine colorectal carcinoma MC-38 model. MAX-10129 also demonstrated synergistic anti-tumor efficacy in different combinations with an anti-CTLA4 antibody, an IDO inhibitor Epacadostat, a COX-2 inhibitor Celebrex and a chemo drug Cisplatin, respectively. The p value of the combo treatment group relative to the vehicle group is less than 0.01 for the Epacadostat combo, the Celebrex Combo and the Cisplatin combo while it is less than 0.05 for the anti-CTLA4 combo. More studies are on-going to illustrate mechanism of action as well as the possibility of all oral triple and quadruple combinations . These data suggest the MAX-10129, a small molecule inhibitor of PD-1/PDL-1 interaction, may represent a novel, orally administrated, safe and effective immunotherapy agent. Citation Format: Yuguang Wang, He Zhou, Nong Zhang, Feilan Wang, Qiang Zhao, Tianzhi Wu, Haiyan Zhu, Yuzhi Liu. Novel small-molecule inhibitor of PD1/PDL1 pathway demonstrated single agent and drug combo effectiveness in cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3851.
Abstract 4485: VGLL3 is a novel outlier in African American prostate tumors and its expression is associated with a tumor suppressor phenotype in prostate cancer
Authors: Hongjun Kang
Journal: Cancer Research (2018)

Abstract Higher incidence, progression and mortality of prostate cancer (PCa) have been noted in African American (AA) men compared with Caucasian (CA) men. In fact AA race is an independent predictor of biochemical recurrence for all stage of PCa (Dr. Schaeffer's data analysis, n=1634 of AA patients). The etiology of PCa racial disparities is likely multi-factorial with increasing support of biologic contributors to these differences. By analyzing large cohort of PCa, we have demonstrated that AA PCa exhibits a unique spectrum of molecular subtypes. For example, AA men presented with PCa have a significant decrease in fusion proteins such as ERG, ETS and SPINK, with an enrichment of fusion unknown (FU; triple negative) cases. Given the increased mortality of PCa in AA populations and the enrichment of FU cases among AA tumors, there is an urgent need to define and explore individual outlier as race-based modifiers of disease aggressiveness. By utilizing a large multi-institutional cohort of prostate cancer cases of mixed racial composition, we have identified novel outliers enriched in AA among FU group by COPA outlier analysis.VGLL3 is one of the top outliers enriched in AA. VGLL3 positive cases are associated with low stage (less LNI, p=0.001; SVI, p&amp;lt;0.001; and EPE, p=0.009) and low grade disease (less Gleason &amp;gt;7, p=0.012) of higher protective phenotype of adverse cancer grade and stage. This preliminary work on VGLL3 expression suggests it may be associated with a tumor suppressor-like phenotype with reductions in expression with increasingly aggressive PCa. Studies of VGLL3 in cancer are limited and the role of VGLL3 in prostate has not been explored at all. The goal of this study is to investigate the role of VGLL3 as a novel outlier in AA prostate cancer that modulates disease aggressiveness. We found that mRNA expression levels of VGLL3 were lower in prostate cancer epithelial cells than in normal epithelial cells or stromal cells. By establishing and characterizing PCa models overexpressing VGLL3 in vitro and in vivo, our data demonstrate that VGLL3 significantly reduced migration and invasion of PCa cells and inhibited primary tumor cell growth. Our preliminary data also indicate VGLL3 inhibits PCa metastasis. Furthermore, VGLL3 seems to negatively affect both hippo and AR activity in PCa cells and these might be the mechanisms that VGLL3 inhibits tumor cell growth. These data is consistent with our clinical data suggesting tumor suppressive role of VGLL3 in advanced PCa. Citation Format: Hongjun Kang. VGLL3 is a novel outlier in African American prostate tumors and its expression is associated with a tumor suppressor phenotype in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4485.