tbuckley/cabot-search huggingface dataset:
Abstract 6311: An enabling technology to detect low abundance targets in cells and tissues
Authors: Deven Patel, Jixiang Liu, Pengfei Dong, Shu Kan, Haiyan Wu, Qin Zhao, Zhenjun Diwu
Journal: Cancer Research (2020)

Abstract The rapid advances in sequencing, genomics and bioinformatics have generated a huge amount of genomic data available at our disposal. However, some proteins, the products of those genes, are expressed in cells or tissues at extremely low levels, making the identification and characterization of proteins the bottle neck for biomedical research field. Approximately, 65% of the human proteome is expressed at less than a few thousand copies. Thus, the availability of protein detection probes and tools becomes a critical element to measure lower abundance protein targets in the cells and tissues to identify clinical significance of the particular target proteins. There are several common signal amplification methods available for detecting low abundance protein targets. However, in some cases, their sensitivities are still not satisfactory. Biotin/avidin amplification system has been predominantly used to enhance detection sensitivity but it is still sometimes not sufficient, leading to extremely challenging to accurately measure the low expressed protein targets. There is urgently unmet need to develop a new signal amplification system with enhanced detection sensitivity. We develop the Power Styramide Signal Amplification (PSA) system that can detect extremely low-abundance targets in cells and tissues. The PSA technique is much more sensitive than the traditionally used biotin/avidin and TSA amplification methods. PSA uses a concept that utilizes the catalytic activity of horseradish peroxide (HRP) for covalent deposition of Styramide in situ. The radicals generated from the Styramide based substrates have much higher reactivity towards the target, thus producing a more robust signal and achieve much higher sensitivity towards lower expressed targets. When this technique was compared to directly conjugated antibody, we saw a significant increase in the signal and improved detection limit by 10-100 folds. Another advantage using Styramide-based substrates is that the need of either primary or secondary antibodies gets significantly reduced. You can get robust signal just by using very little antibodies without sacrificing the quality of the fluorescent images. Overall, this new technology enables us to detect low expressed targets in cells or tissues using lower antibody concentration with high detection limit. Citation Format: Deven Patel, Jixiang Liu, Pengfei Dong, Shu Kan, Haiyan Wu, Qin Zhao, Zhenjun Diwu. An enabling technology to detect low abundance targets in cells and tissues [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6311.
“When Will <i>We</i> Have a Vaccine?” — Understanding Questions and Answers about Covid-19 Vaccination
Authors: Barry R. Bloom, Glen J. Nowak, Walter Orenstein
Journal: New England Journal of Medicine (2020)

“When Will We Have a Vaccine?” People inquiring about Covid-19 vaccines often want to know when the public can be confident that available vaccines are safe and effective, when a vaccine will be av...
Abstract LB-145: Immunomodulatory activity of selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC)
Authors: Rohinton S. Tarapore, Varun V. Prabhu, Samuel C. Mok, Chilam Au Yeung, Lorna Rodriguez, Eugenia Girda, Gina Mantia-Smaldone, Victoria Bae-Jump, Guangrong Lu, Wolfgang Oster, Joshua E. Allen
Journal: Cancer Research (2020)

Abstract ONC201 is a small molecule DRD2 antagonist and ClpP agonist that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The enhanced immune modulatory nature of ONC201 was observed in a Phase I study that revealed increased infiltration of granzyme B+ and CD56+ cells, corroborating preclinical reports of NK cell intratumoral infiltration in response to ONC201. A broad induction of immune cytokines and effector molecules was observed in patients treated with ONC201, in particular among patients who experienced at least stable disease by RECIST for 12 or more weeks. Patients who had a &amp;gt; 50% induction in serum perforin, a cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and NK cells, upon ONC201 administration had better outcomes. Regressions in individual metastatic lesions were noted in a small number of EC patients. A multi-center Phase 2 study to explore the efficacy of weekly ONC201 in recurrent or metastatic Type II EC enrolled 5 patients with recurrent EC who underwent paired tumor biopsies before and 9 days after ONC201 initiation. Four of the 5 patients exhibited a 2-5-fold increase in CD4+ Thelper cells in their tumors and the majority of these patients also had CD4+FoxP3+ cells, indicating a significant population of Tregulatory cells (Treg). One patient exhibited an 80% increase in CD8+ T-cells in their tumor 8 days after initiating ONC201. Two of the patients had &amp;gt;2 fold induction of intratumoral granzyme B expression that was surprisingly not accompanied by NK cell infiltration, as assessed by CD56 staining. These results may be consistent with innate immune system activation by ONC201 that results in T-cell modulation. The multi-fold increase in Treg expression could be suppressing tumor cell death. As such, ONC201 dose intensification or combination with immunotherapy are being evaluated for ONC201 in the context of endometrial cancer. Citation Format: Rohinton S. Tarapore, Varun V. Prabhu, Samuel C. Mok, Chilam Au Yeung, Lorna Rodriguez, Eugenia Girda, Gina Mantia-Smaldone, Victoria Bae-Jump, Guangrong Lu, Wolfgang Oster, Joshua E. Allen. Immunomodulatory activity of selective DRD2 antagonist ONC201, an imipridone, in metastatic endometrial cancer (mEC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-145.
DPP4/CD32b/NF-κB Circuit: A Novel Druggable Target for Inhibiting CRP-Driven Diabetic Nephropathy
Authors: Patrick Ming-Kuen Tang, Ying-Ying Zhang, Jessica Shuk-Chun Hung, Jeff Yat-Fai Chung, Xiao-Ru Huang, Ka-Fai To, Hui-Yao Lan
Journal: Molecular Therapy (2020)

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, but treatment remains ineffective. C-reactive protein (CRP) is pathogenic in DN, which significantly correlated with dipeptidyl peptidase-4 (DPP4) expression in diabetic patients with unknown reason. Here, using our unique CRPtg-db/db mice, we observed human CRP markedly induced renal DPP4 associated with enhanced kidney injury compared with db/db mice. Interestingly, linagliptin, a US Food and Drug Administration (FDA)-approved specific DPP4 inhibitor, effectively blocked this CRP-driven DN in the CRPtg-db/db mice. Mechanistically, CRP evoked DPP4 in cultured renal tubular epithelial cells, where CD32b/nuclear factor κB (NF-κB) signaling markedly enriched p65 binding on the DPP4 promoter region to increase its transcription. Unexpectedly, we further discovered that CRP triggers dimerization of DPP4 with CD32b at protein level, forming a novel DPP4/CD32b/NF-κB signaling circuit for promoting CRP-mediated DN. More importantly, linagliptin effectively blocked the circuit, thereby inhibiting the CRP/CD32b/NF-κB-driven renal inflammation and fibrosis. Thus, DPP4 may represent a precise druggable target for CRP-driven DN.
Abstract 3525: Epidemiology and clinicopathology prognostic factors of TFEB translocation renal cell carcinoma (TBRCC): Analysis of updated pooled database
Authors: Philip A. Haddad, Dalia Hammoud, Kevin Gallagher
Journal: Cancer Research (2020)

Abstract Renal cell carcinomas harboring the t(6;11) (p21;q12) translocation with a specific Alpha(MALAT1)-TFEB gene fusion is a recognized rare subtype of the Microphthalmia Transcription factor (MiT) family of translocation RCC. TBRCC is an indolent disease that occurs at a younger age. Though it may take on a wide spectrum of morphology, TBRCC has been classically characterized by distinctive biphasic morphology with larger epithelioid cells and smaller cells clustered around eosinophilic spheres formed by basement membrane material. This analysis was conducted to update and expand our existing knowledge of this rare disease. In order to study the demographic characteristics, cytogenetic and molecular signatures, survival, and prognostic factors, we compiled a pooled database of 140 cases. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on survival. The median age was 32 (3-78) years with a peak incidence between ages 17 and 30 years. Males and females were afflicted equally. The median overall survival (OS) of the whole group was not reached with more than 78% alive at 10 years. The group's median disease-free survival (DFS) was 96 months. Six percent of this cohort recurred. Among patients who recurred, the median time to recurrence was 24(6-75) months. Sex did not impact OS or DFS. Similarly, the molecular partner of the TFEB gene fusion, Alpha (MALAT1) versus others, did not seem to impact OS or DFS. The presence of necrosis seemed to adversely impact OS (HR:14.3, p&amp;lt;0.0001) and DFS (HR:14.4, p&amp;lt;0.0001). Nuclear grade negatively impacted DFS, the higher the grade the worse the DFS. The presence of eosinophilia, psammoma bodies, and pigmentation did not affect OS or DFS. Similarly, the histologic morphology, biphasic vs others, did not affect OS or DFS. Multivariate analysis revealed older age (HR:1.08, p=0.01) and larger tumor size (HR:10.12, p=0.002) adversely impacted OS. This study presents an updated epidemiologic and clinicopathologic data from a pooled cohort of patients with TBRCC. Age, size, and necrosis were found to adversely impact the OS. However, higher nuclear grade only adversely impacted the cohort's DFS. Citation Format: Philip A. Haddad, Dalia Hammoud, Kevin Gallagher. Epidemiology and clinicopathology prognostic factors of TFEB translocation renal cell carcinoma (TBRCC): Analysis of updated pooled database [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3525.
Abstract 6566: Defining the effects of inhibiting the beta-catenin-CBP signaling axis with the small molecule E7386 by integrative analysis of omics data
Authors: Anthony Federico, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Maria Kukuruzinksa, Stefano Monti
Journal: Cancer Research (2020)

Abstract Head and neck squamous cell carcinoma (HNSCC) is associated with high morbidity, poor survival rates, and limited treatment options. We previously reported that aberrant activation of nuclear β-catenin/cAMP-responsive element binding (CREB)-binding protein (CBP) signaling in primary HNSCC tumors was associated with progression to advanced disease and poor patient survival. Further, inhibition of β-catenin-CBP interaction with the first-generation inhibitor, ICG-001, greatly attenuated aggressive properties of HNSCC cells and tumor growth and metastases in murine and zebrafish models. Our recent findings show that a novel β-catenin/CBP modulator, E7386, displays an activity profile that closely overlaps with that of ICG-001, but exhibits ~50-100-fold lower EC50 values. In this study, we used a novel method for gene regulatory network (GRN) reconstruction which analyzes publicly available high-throughput transcriptomics data from HNSCC to further elucidate the mechanisms of β-catenin-CBP inhibition by E7386. A Bayesian framework was used to reconstruct high-dimensional GRNs using constraint-based and shared structure learning from bulk RNA-seq data from TCGA. HNSCC patients were grouped into two subtypes, based on their “high” vs. “low” response to E7386 inhibition as predicted by the activation - or enrichment by Gene Set Variation Analysis (GSVA) - of the transcriptional signature we derived. GRNs for the two subtypes were built, and their comparison highlighted new interactions in the “high” responders network between the β-catenin/CBP network and genes associated with histone modifications (ASH1L) and amino acid metabolism (MTR) concomitant with loss of interactions with regulators of cell cycle (ERCC6L) and protein secretion (SCAMP1) identified in the “low” responders network. Additionally, Kaplan-Meier survival plots showed that HNSCC patients with high activation of the E7386 signature had a significantly lower probability of survival. These results suggest that our GRN-based approach represents an important novel tool for assessing changes in regulatory network interactions in HNSCC and cancer. Citation Format: Anthony Federico, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Maria Kukuruzinksa, Stefano Monti. Defining the effects of inhibiting the beta-catenin-CBP signaling axis with the small molecule E7386 by integrative analysis of omics data [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6566.
Abstract 3506: African-specific improvement of a polygenic hazard score to predict age of onset of prostate cancer
Authors: Roshan Karunamuni, Minh-Phuong C. Huynh-Le, Chun C. Fan, Ian G. Mills, Ole A. Andreassen, Anders M. Dale, Tyler M. Seibert
Journal: Cancer Research (2020)

Abstract Introduction: Polygenic hazard models can be used in predicting age of onset of prostate cancer. A recently published model, PHS46, showed reduced performance in men with African genetic ancestry - the hazard ratio for aggressive prostate cancer in individuals with high values of PHS46 was approximately half as large for those with African genetic ancestry (2.4) as it was for those with European (5.6) or Asian (5.2) ancestry. We used a cross-validated search to identify SNPs that would add statistical value to a base model of PHS46 among African men and help bridge the performance gap in this population. Material and Methods: Anonymized genotypic data were obtained from 6,253 men with African genetic ancestry from the PRACTICAL consortium. Ten iterations of a ten-fold cross-validation search were conducted, where SNPs were added greedily and stepwise to the PHS46 Cox proportional hazards model using age of onset of any prostate cancer as the dependent variable. Individuals without prostate cancer were censored at age of last follow-up. SNPs were selected for the final, enhanced-PHS46 model if they were selected in more than 50% of the folds. The predictive performances of PHS46 and enhanced-PHS46 were compared using the same cross-validated approach. Results: Three SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in enhanced-PHS46 model. All three SNPs are located on chromosome 8q.24. Enhanced-PHS46 model showed substantial improvements in all performance metrics measured, including a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53), a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 95% increase in the relative hazard of those in the upper 2% compared to the middle 40% (2.1 to 4.1). Similar improvements were demonstrated using the age of onset of aggressive prostate cancer. Conclusions: We identified three SNPs (rs76229939, rs74421890, and rs5013678) that substantially improved the performance of PHS46 in a dataset of men with African genetic ancestry. A strategy of building on established models might be applied to other groups generally under-represented in genome-wide association studies. Citation Format: Roshan Karunamuni, Minh-Phuong C. Huynh-Le, Chun C. Fan, Ian G. Mills, Ole A. Andreassen, Anders M. Dale, Tyler M. Seibert, The PRACTICAL Consortium. African-specific improvement of a polygenic hazard score to predict age of onset of prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3506.
Abstract 3173: Predictive biomarker evaluation for the anti-cancer imipridone ONC201
Authors: Sara Morrow, Varun Vijay Prabhu, Joshua E. Allen, Wolfgang Oster
Journal: Cancer Research (2020)

Abstract Small molecule imipridone ONC201 is a selective, mixed competitive and non-competitive antagonist of dopamine receptor D2 (DRD2), a GPCR that is overexpressed in a broad range of malignancies (Madhukar et al, Nature Communications, 2019). ONC201 was recently found to also act as an allosteric agonist of the mitochondrial protease ClpP that degrades members of the electron transport chain and other mitochondrial substrates (Ishizawa et al, Cancer Cell 2019). ONC201 is currently being tested in several Phase II clinical trials with evidence of clinical activity in DRD2-dysregulated tumor types, including high-grade glioma, endometrial cancer, mantle cell lymphoma and adrenal tumors. Previously, we reported that DRD2 and DRD5 expression correlates with ONC201 efficacy in the NCI60 and GDSC panels (&amp;gt;1000 cancer cell lines) (Prabhu et al, Clinical Cancer Research, 2019). In this study, we explored additional predictive biomarkers of response for ONC201, including ClpP and known downstream effects of ONC201 across the NCI60 and GDSC cancer cell line panels. Elevated ClpP expression emerged as a top predictive biomarker for ONC201 anti-cancer efficacy (low IC50) in the NCI60 and GDSC (p = 0.0066 and p = 0.00071, respectively) panels. Upregulation of HIF1 expression is known to drive cancer cells toward glycolysis; conversely, its loss shunts cellular energetics toward oxidative phosphorylation as the primary mechanism of ATP generation (Clark et al, Cell, 2019) that is inhibited by ONC201 via ClpP activation. Accordingly, decreased HIF1a expression correlated with increased anti-cancer efficacy in the NCI60 (p = 0.058) and GDSC (p = 0.0021) panels. ONC201 is known to cause downstream activation of the integrated stress response pathway, triggering induction of ATF4 (Ishizawa et al, Science signaling, 2016). High baseline ATF4 expression correlated with lower ONC201 IC50s in the GDSC panel (p = 0.027). Proteasomal degradation of c-myc by ONC201 has been reported in association with DRD2 antagonism and inhibition of oxidative phosphorylation in GBM (Ishida et al Clinical Cancer Research, 2018). High c-myc expression correlated with lower ONC201 IC50s in the GDSC panel (p = 2.5e-6). Ongoing studies are investigating biomarker combinations and identifying tumor types that are enriched for these predictive biomarkers. In conclusion, a series of target and downstream signaling biomarkers can be used to predict innate ONC201 tumor cell sensitivity that may provide guidance for patient and tumor type selection in future ONC201 clinical trials. Citation Format: Sara Morrow, Varun Vijay Prabhu, Joshua E. Allen, Wolfgang Oster. Predictive biomarker evaluation for the anti-cancer imipridone ONC201 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3173.
Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats
Authors: Kimberly M. Alonge, Zaman Mirzadeh, Jarrad M. Scarlett, Aric F. Logsdon, Jenny M. Brown, Elaine Cabrales, Christina K. Chan, Karl J. Kaiyala, Marie A. Bentsen, William A. Banks, Miklos Guttman, Thomas N. Wight, Gregory J. Morton, Michael W. Schwartz
Journal: Nature Metabolism (2020)
Abstract 1317: <i>RET</i> aberrations in Chinese solid tumor patients: Next-generation sequencing of 10194 patients
Authors: Chengzhi Zhou, Junhang Zhang, Zhuojian Shen, Hongbiao Wang, Yun Li, Minghui Wang, Qin Fu, Lin Zhang, Angen Liu
Journal: Cancer Research (2020)

Abstract Purpose: RET is an emerging oncogenic target showing promise in phase I/II clinical trials, but the comprehensive genomic landscape of RET aberrations across multiple cancers has had limited exploration. Experimental Design: We interrogated the molecular portfolio of 10194 patients with diverse cancers for the presence of RET aberrations using targeted next-generation sequencing (NGS) of 450 genes panel (OrigiMed, Shanghai). Results: Among various cancer types, RET aberrations were identified in 234 cases (2.3%, 234/10 194), with mutations being the most common alteration (62.4%, 146/234), followed by fusions (19.2%, 45/234), amplifications (13.2%, 31/234), and rearrangements (5.1%, 12/234). The proportion of RET mutations in papillary thyroid carcinoma, lung adenocarcinoma, colorectal adenocarcinoma, small cell lung cancer, and other subtypes was 28.6%, 4.2%, 3.6%, 3.0%, and 16.5% respectively. Most patients had coexisting aberrations in addition to RET anomalies (73.5%, 172/234), with the most common being in TP53-associated genes (40.2%, 94/234), the Wnt signaling pathway (39.3%, 92/234), the HR signaling pathway (19.2%, 45/234), the PI3K signaling pathway (17.5%, 41/234), and MAPK effectors (16.2%, 38/234). All 172 patients harboring coexisting aberrations had distinct genomic portfolios. Conclusions: This study revealed RET aberrations in 2.3% of Chinese solid tumor patients. RET aberrations were detected more in papillary thyroid carcinoma, lung adenocarcinoma, colorectal adenocarcinoma, and small cell lung cancer. Most cases harbored actionable, albeit distinct, coexisting alterations, all of which may potentially contribute to more effective treatment options in the future. Citation Format: Chengzhi Zhou, Junhang Zhang, Zhuojian Shen, Hongbiao Wang, Yun Li, Minghui Wang, Qin Fu, Lin Zhang, Angen Liu. RET aberrations in Chinese solid tumor patients: Next-generation sequencing of 10194 patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1317.