tbuckley/cabot-search huggingface dataset:
Development and validation of a model to predict survival in colorectal cancer using a gradient-boosted machine
Authors: Jean-Emmanuel Bibault, Daniel T Chang, Lei Xing
Journal: Gut (2020)

Objective The success of treatment planning relies critically on our ability to predict the potential benefit of a therapy. In colorectal cancer (CRC), several nomograms are available to predict different outcomes based on the use of tumour specific features. Our objective is to provide an accurate and explainable prediction of the risk to die within 10 years after CRC diagnosis, by incorporating the tumour features and the patient medical and demographic information. Design In the prostate, lung, colorectal and ovarian cancer screening (PLCO) Trial, participants (n=154 900) were randomised to screening with flexible sigmoidoscopy, with a repeat screening at 3 or 5 years, or to usual care. We selected patients who were diagnosed with CRC during the follow-up to train a gradient-boosted model to predict the risk to die within 10 years after CRC diagnosis. Using Shapley values, we determined the 20 most relevant features and provided explanation to prediction. Results During the follow-up, 2359 patients were diagnosed with CRC. Median follow-up was 16.8 years (14.4–18.9) for mortality. In total, 686 patients (29%) died from CRC during the follow-up. The dataset was randomly split into a training (n=1887) and a testing (n=472) dataset. The area under the receiver operating characteristic was 0.84 (±0.04) and accuracy was 0.83 (±0.04) with a 0.5 classification threshold. The model is available online for research use. Conclusions We trained and validated a model with prospective data from a large multicentre cohort of patients. The model has high predictive performances at the individual scale. It could be used to discuss treatment strategies.
Abstract 671: mTORC1 suppression in Paneth cells prevents tumors in a mouse model of intestinal cancer
Authors: Manish Parihar, Sherry G. Dodds, Paul Hasty, Zelton Dave Sharp
Journal: Cancer Research (2020)

Abstract The mechanistic (or mammalian) target of rapamycin, mTOR, is a highly conserved PI3K-related kinase that regulates cell growth, proliferation, survival, transcription, and protein synthesis. It forms two different complexes, mTOR complex-1 (mTORC1) and -2 (mTORC2). Rapamycin is an allosteric inhibitor specific to mTORC1 and extends life and health span with chronic use. Previous research from our lab shows that an enteric release formulation of rapamycin, eRapa, enhances the lifespan of mice mutated for adenomatous polyposis coli (Apc) tumor suppressor (ApcMin/+ mice), which normally develop intestinal cancer. These mice model familial adenomatous polyposis (FAP) in humans. eRapa restored a normal (and in 60% of the mice longer) life span in female ApcMin/+ mice. Mutations in Apc, a part of the Wnt/β-catenin pathway, accelerate the initiation of the adeno-carcinoma in FAP, resulting in numerous colorectal polyps at a young age, and if left untreated these polyps progress to colorectal cancer.eRapa treatment prevents polyposis in ApcMin/+ mice but the precise mechanism of action remains to be determined. We used a cross sectional and survival approach to test the preventive effects of eRapa and gain mechanistic insights. Four-week-old male and female animals were put on a diet containing either 42 ppm of eRapa or empty microcapsules. A subset of the animals was sacrificed to harvest tissue for analysis at 16 weeks of age and the rest were allowed to live out their lifespans.eRapa prevented polyposis in the small intestine of ApcMin/+ mice with only a few to no tumors in both males and females. In addition to adenomas in the intestine, ApcMin/+ mice also suffer from severe anemia. Hematocrits from the animals showed anemia in the control mice, however, eRapa treated animals did not have anemia. There was a reduction in phosphorylation of ribosomal protein S6 in the small intestine tissue, showing suppression of mTORC1 activity with eRapa. Histological analysis revealed that this suppression occurred in the Paneth cells of the small intestinal crypt. The Paneth cells, along with the stem cells at the base of the crypt form a niche and signaling between this niche maintains homeostasis in the crypt. Although the polyps are believed to originate from stem cells, our results suggest involvement of Paneth cells in tumor prevention perhaps by signaling changes in the niche. These are novel effects of rapamycin and help define its mechanisms of cancer prevention. Citation Format: Manish Parihar, Sherry G. Dodds, Paul Hasty, Zelton Dave Sharp. mTORC1 suppression in Paneth cells prevents tumors in a mouse model of intestinal 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 671.
Abstract 5079: Immuno-competent 3d in vitro tumor models as novel platform to assess combinatorial biologics therapy
Authors: Irina Agarkova, Nicole Buschmann, Silvan Strebel, Armin Wolf, Francesca Chiovaro
Journal: Cancer Research (2020)

Abstract Background: Immunotherapy has revolutionized cancer treatment, but clinical success is still limited to a subset of patients, underlining the need for novel therapeutic targets. Available ex vivo animal platforms for drug screening show limitations due to only partial recapitulation of tumor-intrinsic features and of the interactions of tumors with stromal/immune cells. Here, we review our 3D InSightTM tumor models, a complex in-vitro platform allowing to study the efficacy of immune-targeting agents on tumor infiltration and killing by peripheral blood mononuclear cells (PBMCs) and to acquire insights on the modulatory capacity of immune checkpoint inhibitors. Aim: In the present study we have developed a 3D tumor - immune cell coculture model and evaluated its application to study the effect of immune checkpoint inhibitors on tumor viability, cytokine secretion, and immune cell infiltration. Material and Methods: Lung carcinoma GFP-A549 cells were cultured with dermal fibroblasts and PBMCs in Akura 96/384-well plates. Immune cells were pre-treated using different activation protocols to induce priming and pT-cell exhaustion. We assessed the effect of PD-1 inhibitors in combination with cytokines for potential synergistic anti-cancer effects. Killing activity and effector function of T cells were evaluated by measuring tumor microtissue size by automatic stage fluorescence microscopy and measuring release of IL-6, TNF, IFNγ and GM-CSF with a MAGPIXTM Luminex system over time. Immune tumor infiltration was quantified using fluorescent staining of CD3+ cells and the effect of the immune cell attack on the tumor cells was assessed by IHC staining. Results: Combination treatment with cytokines and anti-PD-1 led to higher release of IL-6/TNF/IFNγ/GM-CSF and increased tumor microtissue infiltration by CD3+ lymphocytes, stronger expression of Granzyme B, resulting in enhanced tumor killing and apoptosis. Conclusion: Our 3D InSightTM tumor models can be successfully employed for optimal high throughput screening of biologics to unveil the efficacy and anti-tumor efficacy of immune-targeting therapeutic agents. Citation Format: Irina Agarkova, Nicole Buschmann, Silvan Strebel, Armin Wolf, Francesca Chiovaro. Immuno-competent 3d in vitro tumor models as novel platform to assess combinatorial biologics therapy [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 5079.
Abstract 2129: Proteogenomic analysis points to relationship between LINE-1 retrotransposon expression and copy number variation
Authors: Wilson H. McKerrow, Xuya Wang, Mark Grivainis, David Fenyö
Journal: Cancer Research (2020)

Abstract Changes in the DNA copy number of genes (copy number variation/CNV) are widespread in many cancers and affect the expression of tumor suppressors and oncogenes. Many of these CNVs arise from chromosomal aberrations that are the result of improperly repaired DNA damage. LINE-1 retrotransposons - genomic elements that cut DNA and then reverse transcribe themselves into the gap - are expressed in many cancers and likely contribute to DNA damage and CNV in cancer cells. Using multi-omic data from CPTAC, we developed cloud-based tools on the NCI funded Cancer Genomics Cloud to measure LINE-1 RNA, protein, phosphoprotein and insertion in five cancer types - breast, ovarian, endometrial, kidney and colon - and identified mutation, expression and phosphorylation correlates of LINE-1 expression. We found significant LINE-1 expression in all, but kidney cancer. LINE-1 expression was significantly correlated with global copy number variation in breast, endometrial and ovarian cancer, a trend that was reflected in the fact that we observed the highest LINE-1 expression in ovarian cancer, which is characterized by very high CNV, and the lowest LINE-1 expression in kidney cancer, which has less overall CNV. This correlation is mirrored in our finding that, in breast, ovarian and endometrial cancer, p53 mutants express more LINE-1, indicating that high LINE-1 expression occurs in a background that is tolerant of DNA damage and CNV. We also observed an association between LINE-1 expression and phosphorylation of 53BP1 in breast, colon and endometrial cancers. ATM phosphorylated 53BP1 localizes to double strand breaks and promotes repair by non-homologous end-joining (NHEJ). Taken together, this analysis supports the hypothesis that in many cancers LINE-1 contributes to DNA damage and copy number variation, perhaps involving mismatched repair by NHEJ. Funded by NCI Contract No. HHSN261200800001E Citation Format: Wilson H. McKerrow, Xuya Wang, Mark Grivainis, David Fenyö. Proteogenomic analysis points to relationship between LINE-1 retrotransposon expression and copy number variation [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 2129.
COCOA: coordinate covariation analysis of epigenetic heterogeneity
Authors: John T. Lawson, Jason P. Smith, Stefan Bekiranov, Francine E. Garrett-Bakelman, Nathan C. Sheffield
Journal: Genome biology (2020)

Abstract A key challenge in epigenetics is to determine the biological significance of epigenetic variation among individuals. We present Coordinate Covariation Analysis (COCOA), a computational framework that uses covariation of epigenetic signals across individuals and a database of region sets to annotate epigenetic heterogeneity. COCOA is the first such tool for DNA methylation data and can also analyze any epigenetic signal with genomic coordinates. We demonstrate COCOA’s utility by analyzing DNA methylation, ATAC-seq, and multi-omic data in supervised and unsupervised analyses, showing that COCOA provides new understanding of inter-sample epigenetic variation. COCOA is available on Bioconductor ( http://bioconductor.org/packages/COCOA ).
Abstract 2616: RhoC decreases tight junction stabilization in breast cancer cells, revealing a potential therapeutic target
Authors: Hannah Abraham, Laura Goo, Andrew Little, Joel Yates, Zhifen Wu, Sofia D. Merajver
Journal: Cancer Research (2020)

Abstract RhoC, a member of the Rho GTPase family, has been shown to have a role specifically in facilitating metastasis of breast cancer cells via influencing motility, invasion, and chemokine secretion, but as yet there is no integrated model of the precise mechanism of how RhoC promotes metastasis. As these processes require disruptions in cell-cell junctions, we use wild-type and CRISPR RhoC and RhoA knockout lines of the breast cancer cell lines SUM-149 (inflammatory breast cancer, IBC) and MDA-MB-231 (triple-negative breast cancer, TNBC) in order to assess the influence of RhoC and RhoA on their cell-cell junctions. Protein lysates from these cell lines were blotted for the adherens junction markers E-cadherin and β-catenin, as well as the tight junction markers ZO-1 and Occludin. Cells were also fixed and stained for these junction markers to further assess expression and localization. In order to measure junction stability, we conducted FITC-Dextran assays, wherein cells were grown to confluency on Transwell plates, the apical chambers were incubated with FITC-Dextran solution for 24 hours, and the fluorescence of the basal chambers was subsequently measured. We demonstrate that CRISPR-Cas9 knockout of RhoC in SUM-149 IBC and MDA-MB-231 TNBC cells results in increased epithelial morphology, cell-cell connections, and tight junction marker colocalization, as measured via immunofluorescent staining. Furthermore, RhoC knockout cells have increased junctional proteins compared to wild-type cells, as measured by Western blot. In functional assessments of junction stability, RhoC knockout cells have increased barrier integrity compared to wild-type cells, by the FITC-Dextran leakage assay. These results suggest that high expression of RhoC in cancer cells destabilizes tight junctions, although loose clusters of cells are observed depending on cell type; taken together, upregulation of RhoC activation may contribute to increased metastatic potential, in part through destabilization of tight junctions. We will report on further invasion functional assays and RNA-seq data on the RhoC knockout cell lines. Taken together, these data support an important role for RhoC in tight junction modulation, thereby advancing the evidence for a potential highly specific new therapeutic target in RhoC-driven metastases control. Citation Format: Hannah Abraham, Laura Goo, Andrew Little, Joel Yates, Zhifen Wu, Sofia D. Merajver. RhoC decreases tight junction stabilization in breast cancer cells, revealing a potential therapeutic target [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 2616.
Development of the Concussion Recovery Questionnaire: a self-report outcome measure of functional status following concussion (PhD Academy Award)
Authors: Jacqueline Josee van Ierssel
Journal: British Journal of Sports Medicine (2020)

I employed an iterative, patient-centred approach to develop a concussion-specific functional status measure.

While most adults fully recover from concussion, at least 15% exhibit ongoing symptoms including headache, fatigue and difficulty concentrating for years resulting in high degrees of disability.1 Since no objective biomarker exists for concussion, self-reported symptom burden is the most commonly reported recovery measure, along with cognitive function, balance and exercise tolerance in terms of frequency, duration, difficulty or agreement level. Clinical tests of cognition and balance often appear normal beyond the acute phase. Symptoms are non-specific and commonly present in other conditions such as depression, anxiety and post-traumatic stress disorder.1 Persons with concussion often manage their symptoms by limiting provocative activities and social participation. A low symptom score may thus reflect reduced life activities rather than functional recovery. Prior to my research, no concussion-specific measure of functional status existed. I conducted this research to address a gap in clinical tools within …
Rare APC promoter 1B variants in gastric cancer kindreds unselected for fundic gland polyposis
Authors: Katherine Dixon, Janine Senz, Pardeep Kaurah, David G Huntsman, Kasmintan A Schrader
Journal: Gut (2020)

Table 1 Personal and family GC history in index cases assessed for germline variants in the APC promoter 1B Personal cancer history No of index cases Family history of GC, no of index cases
Apalutamide and Overall Survival in Prostate Cancer
Authors: Matthew R. Smith, Fred Saad, Simon Chowdhury, Stéphane Oudard, Boris A. Hadaschik, Julie N. Graff, David Olmos, Paul N. Mainwaring, Ji Youl Lee, Hiroji Uemura, Peter De Porre, Andressa A. Smith, Sabine D. Brookman-May, Susan Li, Ke Zhang, Brendan Rooney, Angela Lopez-Gitlitz, Eric J. Small
Journal: European Urology (2020)

The phase 3 SPARTAN study evaluated apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and prostate-specific antigen doubling time of ≤10 mo. At primary analysis, apalutamide improved median metastasis-free survival (MFS) by 2 yr and overall survival (OS) data were immature. We report the prespecified event-driven final analysis for OS. A total of 1207 patients with nmCRPC (diagnosed by conventional imaging) were randomised 2:1 to apalutamide (240 mg/d) or placebo, plus on-going androgen deprivation therapy. After MFS was met and the study was unblinded, 76 (19%) patients still receiving placebo crossed over to apalutamide. OS and time to cytotoxic chemotherapy (TTChemo) were analysed by group-sequential testing with O'Brien-Fleming-type alpha spending function. At median 52-mo follow-up, 428 deaths had occurred. The median treatment duration was 32.9 mo for apalutamide group and 11.5 mo for placebo group. Median OS was markedly longer with apalutamide versus placebo, reaching prespecified statistical significance (73.9 vs 59.9 mo, hazard ratio [HR]: 0.78 [95% confidence interval {CI}, 0.64–0.96]; p = 0.016). Apalutamide also lengthened TTChemo versus placebo (HR: 0.63 [95% CI, 0.49–0.81]; p = 0.0002). Discontinuation rates in apalutamide and placebo groups due to progressive disease were 43% and 74%, and due to adverse events 15% and 8.4%, respectively. Subsequent life-prolonging therapy was received by 371 (46%) patients in the apalutamide arm and by 338 (84%) patients in the placebo arm including 59 patients who received apalutamide after crossover. Safety was consistent with previous reports; when adverse events were adjusted for treatment exposure, rash had the greatest difference of incidence between the apalutamide and placebo groups. Extension of OS with apalutamide compared with placebo conferred impactful benefit in patients with nmCRPC. There was a 22% reduction in the hazard of death in the apalutamide group despite 19% crossover (placebo to apalutamide) and higher rates of subsequent therapy in the placebo group. With data presented herein, all primary and secondary study end points of SPARTAN were met; findings demonstrate the value of apalutamide as a treatment option for nonmetastatic castration-resistant prostate cancer.
Abstract 4729: Identifying genomic drivers of lung adenocarcinoma brain metastases
Authors: Naema Nayyar, David J. Shih, Ivanna Bihun, Ibiayi Dagogo-Jack, Corey M. Gill, Elisa Aquilanti, Mia Bertalan, Alexander Kaplan, Megan R. D'Andrea, Ugonma Chukwueke, Christopher Alvarez-Breckenridge, Matthew Lastrapes, Ben Kuter, Matthew R. Strickland, Juan Carlos Martinez-Gutierrez, Deepika Nagabhushan, Magali De Sauvage, Michael D. White, Brandyn A. Castro, Kaitlin Hoang, Sun Ha Paek, Sun Hye Park, Maria Martinez-Lage, Anna S. Berghoff, Parker Merrill, Elizabeth R. Gerstner, Tracy T. Batchelor, Matthew P. Frosch, Ryan P. Frazier, Darrell R. Borger, A John Iafrate, Sandro Santagata, Matthias Preusser, Daniel P. Cahill, Scott L. Carter, Priscilla K. Brastianos
Journal: Cancer Research (2020)

Abstract Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases (BM-LUAD) are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 BM-LUAD to a control cohort of 503 primary lung adenocarcinomas. We identified MYC, YAP1 and MMP13 as genomic regions with significantly more frequent amplifications in BM-LUAD compared to control cohort. We validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model, where incidence of brain metastases was higher in mice injected with tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. These candidate drivers may serve as therapeutic targets in patients with brain metastatic lung adenocarcinomas. Citation Format: Naema Nayyar, David J. Shih, Ivanna Bihun, Ibiayi Dagogo-Jack, Corey M. Gill, Elisa Aquilanti, Mia Bertalan, Alexander Kaplan, Megan R. D'Andrea, Ugonma Chukwueke, Christopher Alvarez-Breckenridge, Matthew Lastrapes, Ben Kuter, Matthew R. Strickland, Juan Carlos Martinez-Gutierrez, Deepika Nagabhushan, Magali De Sauvage, Michael D. White, Brandyn A. Castro, Kaitlin Hoang, Sun Ha Paek, Sun Hye Park, Maria Martinez-Lage, Anna S. Berghoff, Parker Merrill, Elizabeth R. Gerstner, Tracy T. Batchelor, Matthew P. Frosch, Ryan P. Frazier, Darrell R. Borger, A John Iafrate, Sandro Santagata, Matthias Preusser, Daniel P. Cahill, Scott L. Carter, Priscilla K. Brastianos. Identifying genomic drivers of lung adenocarcinoma brain metastases [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 4729.
Abstract 5866: SCAR (Selective CRISPR Antigen Removal) vector system expands cancer immunology discovery with in vivo functional genomics
Authors: Juan Dubrot, Sarah Kate Lane-Reticker, Emily Kessler, Clara Wolfe, Animesh Mahapatra, Peter Du, Robert T. Manguso
Journal: Cancer Research (2020)

Abstract The ability to make rapid genetic alterations to tumor cells with CRISPR for screens and single-gene studies has been transformative for studying cancer biology. Recently, we and others have used CRISPR in murine tumor models in vivo to identify targets and resistance mechanisms for immunotherapy. However, the use of these techniques in immunocompetent mice is limited by endogenous immune recognition of CRISPR components such as Cas9. Here we report the design of a screening-compatible lentiviral vector system which allows selective CRISPR antigen removal (SCAR) from tumor cells before they are implanted in vivo. The SCAR system enables highly efficient genome engineering and reverses CD8+ T cell-mediated rejection of CRISPR modified tumor cells in vivo. Using this technology, we conducted a pooled, in vivo screen designed to probe tumor-immune interactions in the highly immunogenic CT26 colon carcinoma model and discovered that these tumors require intact interferon signaling to evade immune destruction. The SCAR system enables the study of tumor-immune interactions in any cancer model and can be more broadly applied to generate non-immunogenic lentivirally-engineered cells. Citation Format: Juan Dubrot, Sarah Kate Lane-Reticker, Emily Kessler, Clara Wolfe, Animesh Mahapatra, Peter Du, Robert T. Manguso. SCAR (Selective CRISPR Antigen Removal) vector system expands cancer immunology discovery with in vivo functional genomics [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 5866.