tbuckley/cabot-search huggingface dataset:
<i>CoreCruncher</i>: Fast and Robust Construction of Core Genomes in Large Prokaryotic Data Sets
Authors: Connor D Harris, Ellis L Torrance, Kasie Raymann, Louis-Marie Bobay
Journal: Molecular Biology and Evolution (2020)

Abstract The core genome represents the set of genes shared by all, or nearly all, strains of a given population or species of prokaryotes. Inferring the core genome is integral to many genomic analyses, however, most methods rely on the comparison of all the pairs of genomes; a step that is becoming increasingly difficult given the massive accumulation of genomic data. Here, we present CoreCruncher; a program that robustly and rapidly constructs core genomes across hundreds or thousands of genomes. CoreCruncher does not compute all pairwise genome comparisons and uses a heuristic based on the distributions of identity scores to classify sequences as orthologs or paralogs/xenologs. Although it is much faster than current methods, our results indicate that our approach is more conservative than other tools and less sensitive to the presence of paralogs and xenologs. CoreCruncher is freely available from: https://github.com/lbobay/CoreCruncher. CoreCruncher is written in Python 3.7 and can also run on Python 2.7 without modification. It requires the python library Numpy and either Usearch or Blast. Certain options require the programs muscle or mafft.
Abstract 4: Choking cancer: Developing a pathway of Withaferin A for the prevention of angiogenesis
Authors: Rishab Rajeev Samant, Rajeev S. Samant
Journal: Cancer Research (2020)

Abstract Cancer is arguably the most perplexing medical issue of today and manifests in many forms. Most cancers grow as solid tumors, and if they receive enough nutrients, they can metastasize. These tumors receive their nutrients from new blood vessels that grow in the direction of the tumor when the tumor sends bio-chemical signals such as VEGF (vascular endothelial growth factor). Stopping angiogenesis – new blood vessel formation – can cause the tumors to choke and die, which prevents metastasis. One-way of stopping angiogenesis is by using nutraceuticals: foods with a medical benefit. One well-recognized nutraceutical that stops angiogenesis is turmeric. However, not all nutraceuticals possess this property. This project determines if there exist any other easily accessible nutraceuticals possessing effective antiangiogenic properties. I used three different nutraceuticals: basil, ashwagandha, and valerian. Basil was my positive control because there are several published accounts of basil possessing antiangiogenic qualities. My negative control was saline. My hypothesis is that ashwagandha would have a strong antiangiogenic property. Although no study showed that ashwagandha possesses this property, several review articles stated that ashwagandha stopped cancer growth. I used CAMs (chick chorioallantoic membrane) as a to model study angiogenesis. I kept the CAMs, ex-ovo, in individual ceramic bowls lined with plastic wrap and incubated them for a certain number of days. I then took photos of my results and used Powerpoint to analyze them. My conclusion supported my hypothesis because ashwagandha blocked angiogenesis by 67%. This was almost identical to holy basil's rate of stopping angiogenesis. To obtain clues as to how ashwagandha stopped angiogenesis, I used a previously published study by Szarc et.al. (PLoS One. 2014;9(2):e87850) and analyzed the results using Gene Expression Omnibus (Geo Database: GEO2R-GSE53O49) to obtain the top 250 changes in gene expression upon treatment of breast cancer cells (MCF7 and MDA-MB-231) with ashwaghanda. Examination of the list for angiogenesis related gene expression changes, revealed 19 significantly changing genes following ashwagandha treatment. I used the Search Tool for the Retrieval of Interacting Genes/Proteins: STRING- analysis, to reveal the interaction network between these 19 genes. I found that these genes were influencing DNA replication and cell cycle machinery. Thus, my findings suggest that ashwaghanda can inhibit the cell cycle of cancer cells to stop tumor growth. It possibly affects proliferation of endothelial cells to block angiogenesis. Citation Format: Rishab Rajeev Samant, Rajeev S. Samant. Choking cancer: Developing a pathway of Withaferin A for the prevention of angiogenesis [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 4.
Early Description of Coronavirus 2019 Disease in Kidney Transplant Recipients in New York
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Currently, the clinical presentation, optimal management strategy, and outcomes for patients with kidney transplants who develop COVID-19 infection remain unknown. The description of our cohort represents the first cohort of patients with kidney transplants and COVID-19 infection and includes clinical features, markers of inflammation, and a strategy for management that includes both immunosuppression reduction and the use of adjuvant therapy, including hydroxychloroquine, azithromycin, and tocilizumab. This approach appears to have resulted in favorable outcomes in our cohort of hospitalized kidney transplant patients and provides an effective treatment strategy for the management of these patients Background The novel SARS-CoV-2 virus has caused a global pandemic of coronavirus disease 2019 (COVID-19). Although immunosuppressed individuals are thought to be at an increased risk of severe disease, little is known about their clinical presentation, disease course, or outcomes. Methods We report 15 kidney transplant recipients from the Columbia University kidney transplant program who required hospitalization for confirmed COVID-19, and describe their management, clinical course, and outcomes. Results Patients presented most often with a fever (87%) and/or cough (67%). Initial chest x-ray most commonly showed bilateral infiltrates, but 33% had no acute radiographic findings. Patients were managed with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin. Although 27% of our patients needed mechanical ventilation, over half were discharged home by the end of follow-up. Conclusions Kidney transplant recipients with COVID-19 have presentations that are similar to that of the general population. Our current treatment protocol appears to be associated with favorable outcomes, but longer follow-up of a larger cohort of patients is needed.
Abstract 5235: <i>In vitro</i> validation of drug-target interactions revealed <i>in silico</i> by Comprehensive Resource of Biomedical Relations with Network Representations and Deep Learning (CROssBAR) in HCC
Authors: Esra Nalbat, Ahmet Sureyya Rifaioglu, Tunca Dogan, Maria Jesus Martin, Rengul Cetin-Atalay, Volkan Atalay
Journal: Cancer Research (2020)

Abstract Computational methods are more commonly employed for our understanding of cellular signaling mechanisms with the aim to develop cures for diseases including cancer. Identification of disease specific targeted drugs requires systems level analysis of cellular networks. Our research group developed a comprehensive resource, called CROssBAR, which connects various biological data sources in order to provide a well-connected resource with a focus on drug discovery and precision medicine. CROssBAR aims to predict and reveal novel drug-target interactions using deep learning algorithms. CROssBAR predictions were validated on hepatocellular carcinoma cells which is the 5th most prevalent and 3th deadliest cancer worldwide. We have selected 2 new small molecule kinase inhibitors Lenvatinib, Sunitinib along with Sorafenib and Regorafenib which are currently used in clinics. CROssBAR identifies novel and known gene targets for Lenvatinib, Sunitinib in comparison with Sorafenib and Regorafenib. Genes from SAPK/JNK and PI3K/Akt pathway that were not previously associated with hepatocellular carcinoma therapeutics were determined. All selected small molecules were bioactive on Huh7 and Mahlavu cells by SRB assay. Cell death was characterized by Annexin V which was due to G1/S cell cycle arrest. Further analysis of proteins involved in the SAPK/JNK, PI3K/Akt pathways and apoptotic markers such as PARP and Caspases were examined with immunoblotting upon treatment. As a result, cellular stress mechanisms activated PI3K/Akt and SAPK/JNK pathways which caused programmed cell death in HCC. With our deep learning approach, we were able to demonstrate a correlation between Lenvatinib and Sunitinib and their novel targets in HCC. Our validation results have illustrated that the comprehensive CROssBAR tool developed by our research group achieved in vitro significant predictions of new drugs and their targets against HCC that were not previously reported. Hence with this study we were able to demonstrate the use and validity of the CROssBAR tool along with new targets for primary liver cancer therapeutics. Citation Format: Esra Nalbat, Ahmet Sureyya Rifaioglu, Tunca Dogan, Maria Jesus Martin, Rengul Cetin-Atalay, Volkan Atalay. In vitro validation of drug-target interactions revealed in silico by Comprehensive Resource of Biomedical Relations with Network Representations and Deep Learning (CROssBAR) in HCC [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 5235.
Correspondence on ‘Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry’ by Gianfrancesco<i>et al</i>. Disease activity, rather than glucocorticoid therapy, may be associated with COVID-19 severity in patients with rheumatic musculoskeletal diseases
Authors: Alessandro Giollo, Eugenia Bertoldo, Giovanni Adami, Adam J Cybulski, Angelo Fassio, Giovanni Orsolini, Luca Idolazzi, Davide Gatti, Ombretta viapiana, Maurizio Rossini
Journal: Annals of the Rheumatic Diseases (2020)

Table 1 Clinical characteristics of patients with rheumatic musculoskeletal disease according to their disease status Clinical characteristics Active disease (n=5) Remission (n=6) Age (years) 61±10 59±12 Female sex, n (%) 3 (60) 2 (33) Body mass index (kg/m 2 ) 26±8 24±4 Ever used tobacco, n (%) 2 (40) 1 (16) Disease duration (years) 10±11 13±10 Cardiovascular disease, n (%) 2 (40) 4 (67) Biologic DMARD, n (%) 2 (40) 4 (67) Conventional synthetic DMARD, n (%) 3 (60) 1 (16) Glucocorticoid therapy, n (%) 3 (60) 2 (33) Interstitial infiltrates, n (%) 4 (80) 2 (33) Abnormal ECG, n (%) 4 (80) 2 (33) Respiratory rate ≥22, n (%) 3 (60) 3 (50) Heart rate ≥100 beat/min, n (%) 3 (60) 0 (0) Temperature at admission (°C) 37.9 (0.9) 37.3 (1.0) Continuous data are reported as mean±SDs.DMARD, disease-modifying antirheumatic drug; ECG, electrocardiography.;à
Abstract 5981: CAP70 suppresses the development of triple-negative breast cancer by inhibiting EGFR pathway activation
Authors: Junfang Zheng, Yuanzhen Ma, Yijun Qi
Journal: Cancer Research (2020)

Abstract Background: Among all major subtypes of breast cancer, triple-negative breast cancer (TNBC) carries the worst prognosis for the patients. The poor clinical outcome of TNBC is further exacerbated by the lack of effective targeted therapies. Therefore, the identification of functional molecular targets for TNBC therapy is urgently needed. The goal of this study was to determine the role of CFTR-associated protein of 70 kDa (CAP70, also called PDZK1) in the development of TNBC and assess its value as a target for TNBC therapy. Methods: Bioinformatics analysis and immunohistochemistry were performed to determine the expression of CAP70 in TNBC. The functions of CAP70 were demonstrated in a series of in vitro and in vivo experiments. GST Pull-down, mass spectrometry, co-immunoprecipitation, bioinformatics analysis, pharmacologic treatment, and western blotting were performed to elucidate the potential mechanisms of CAP70 activities. Results: CAP70 was specifically downregulated in TNBC tissues and was related to tumor stage, lymph node metastasis, and patient survival. Functional assays showed that CAP70 suppressed TNBC carcinogenesis, progression, and metastasis by inhibiting EGFR signaling. Moreover, inhibition of EGFR signaling by CAP70 enhanced the sensitivity of TNBC to EGFR inhibitor erlotinib. Conclusions: CAP70 suppresses TNBC development and enhances its sensitivity to erlotinib by inhibiting EGFR signaling. CAP70 is a significant prognostic factor of TNBC and a potential molecular therapeutic target for the treatment of this subtype of breast cancer. Citation Format: Junfang Zheng, Yuanzhen Ma, Yijun Qi. CAP70 suppresses the development of triple-negative breast cancer by inhibiting EGFR pathway activation [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 5981.
Abstract 688: Targeting tumor associated host cells by modifiers of integrated endoplasmic reticulum stress response
Authors: Berin Upcin, Daniel Szi-Marton, Erik Henke, Süleyman Ergün, Bertal Huseyin Aktas
Journal: Cancer Research (2020)

Abstract Solid tumors are composed of cancer cells, tumor associated host cells (TAHCs) and extracellular matrix components. TAHCs form tumor vasculature, secrete extracellular matrix components, provide protection from host immune-defense, and contribute to therapy resistance. Agents that can abrogate the survival and/or proliferation of both cancer cells and TAHCs would be more potent and less vulnerable to acquired resistance. Solid tumors are under stress due to host immune surveillance, lagging vascularization, and an unstable nascent vasculature that results in nutrients and oxygen restriction. Tumors utilize adaptive pathways including hypoxia activated signaling, integrated endoplasmic reticulum (ER) stress response (IERSR) signaling, and immune evasion for survival and progression. The IERSR is a double-edged sword that is pro-survival if activated transiently but cause cell death if activated in a sustained manner. In particular, sustained activation by eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation (eIF2α-P) arm of the IERSR causes cell death. eIF2α-P reduces overall protein synthesis while inducing expression of some pro-apoptotic and tumor suppressor genes. Because TAHCs actively synthesize proteins in supporting tumor cells, we hypothesized that specific activators of eIF2α kinases will abrogate tumor survival and/or progression by dual effect on TACHs and cancer cells. We tested this hypothesis by evaluating chemical activators of eIF2α kinase heme regulated inhibitor (HRI) in ex-vivo aortic ring angiogenesis assay and against tumor organoids formed by co-culture of macrophages, fibroblasts, endothelial cells, and human breast or melanoma cancer cells. All HRI activators inhibited angiogenesis in the aortic ring assay (ARA) and had profound effects on tumor angiogenesis and macrophages. At sublethal concentration, HRI activators disrupted tumor vasculature and significantly reduced macrophages in the tumor organoids. These agents also significantly inhibited cell migration as measured by wound healing assay and by cell-migration assay of xCELLigence® RTCA DP instrument. These data indicate that HRI activators can target both tumor and TAHCs in a dose dependent manner and support further development of these agents for cancer therapy. Citation Format: Berin Upcin, Daniel Szi-Marton, Erik Henke, Süleyman Ergün, Bertal Huseyin Aktas. Targeting tumor associated host cells by modifiers of integrated endoplasmic reticulum stress response [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 688.
Abstract 3381: Identifying tumor antigen-specific CD4+ T cell dysfunctional states by single cell transcriptomics in immunotherapy-treated cancer patients
Authors: Edgar Kozlova, Shingo Eikawa, Sacha Gnjatic, Bojan Losic
Journal: Cancer Research (2020)

Abstract Dysfunctional T cell states resulting from continuous exposure to self shared tumor antigens or neoantigens are key to understanding immune mechanisms that prevent proper antitumor immunity. We previously showed that repeated administration of recombinant tumor antigen vaccines without immunological adjuvant emulates a tolerized-like immune response that cannot be rescued even after in vivo re-challenge with adjuvant. We used bulk and single-cell RNA-seq of purified antigen-specific CD4+ T-cells (i.e., the orchestrator of immunity) from 12 ovarian and non-small cell lung cancer patients receiving NY-ESO-1 or MAGE-A3 vaccines with or without adjuvant, over a period of 13 weeks. First, using bulk RNA-seq data, we derived novel temporal, tolerization CD4+ T cell expression and clonotype evolution signatures using differential expression and VDJ-deconvolution analyses, highlighting significant association with cell cycle and immune activation. Then, we projected these signatures onto several recently published single-cell RNA-seq data profiling exhausted tumor-infiltrating and peripheral blood lymphocytes, finding reasonable predictive power (AUC~0.8) to classify dysfunctional T-cell states that could distinguish exhaustion from tolerance. Next, we characterized in depth the transcriptional profiles and heterogeneity of our antigen-specific CD4+ T-cells pre- and post-treatment at the single-cell level using combined scRNAseq and scTCRseq. Finally, we computationally inferred the regulatory axis of tolerized T-cells by deriving transcription factor signaling networks upstream of gene expression. In conclusion, we characterized transcriptional signatures of tumor antigen-specific CD4+ T-cells and derived a specific tolerization profile, distinguishable from exhaustion, and conserved across datasets. Through comprehensive identification of genes and pathways in a human experimental setting for induction of tolerization and exhaustion, these findings provide relevant and promising avenues to reverse dysfunctional CD4+ T cell states. Citation Format: Edgar Kozlova, Shingo Eikawa, Sacha Gnjatic, Bojan Losic. Identifying tumor antigen-specific CD4+ T cell dysfunctional states by single cell transcriptomics in immunotherapy-treated cancer 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 3381.
Abstract LB-021: Focal adhesive kinase inhibitor IN10018 sensitizes KRAS mutant cancer and overcomes drug resistance of KRAS G12C inhibition
Authors: Baoyuan Zhang, Yan Zhang, Jiangwei Zhang, Ping Liu, Bo Jiao, Zaiqi Wang, Ruibao Ren
Journal: Cancer Research (2020)

Abstract KRAS mutation is found in around 20-30% of human cancer. Previously, lack of targeting therapy limited the treatment outcomes. Recently, KRAS G12C inhibitors like AMG510, MRTX849, and MRTX1257 were developed and exhibited promising therapeutic outcomes targeting the mutation. However, a considerable amount of cases showed less sensitivity, indicating either intrinsic or adaptive resistance mechanisms. Other reports and our own data exhibited that Focal Adhesive Kinase (FAK) inhibition showed good treatment effects to KRAS mutant cancer. Interestingly, TCGA data analysis reveal that FAK mRNA expression level is significantly higher in KRAS mutant tumors. Considering that FAK is one predominant target for cancer treatment resistance, we hypothesize that FAK is one of mediator leading to resistance mechanism of KRAS G12C inhibition. To explore our hypothesis, we employed high potent FAK inhibitor IN10018, which is being tested in phase I clinical trial for different cancer types. First, we found that IN10018 is active in a series of KRAS mutated cancer xenograft models. The compound sharply decreased the level of phosphoFAK Y397, a direct marker for FAK activity. Then we investigated whether combination of IN10018 with KRAS G12C inhibitors can show synergic effects in vitro and in vivo. IN10018 in combination with either AMG510 or MRTX1257 showed better effects in killing KRAS G12C cancer cells than each single treatment. More importantly a significant synergy between IN10018 with KRAS G12C inhibitors against KRAS mutated cancer cell lines was observed in vivo. Further evidence showed that KRAS G12C inhibition can significantly increase the expression of phosphoFAK Y397, suggesting a possible underlying mechanism of resistance to KRAS G12C inhibitors. IN10018 significantly decreased the upregulated FAK Y397 phosphorylation in the combination treatments, underlying the mechanism of synergy between the two inhibitors. Our results indicate that KRAS G12C cancer patients can be better treated by the combination of IN10018 with KRAS G12C inhibitor. Citation Format: Baoyuan Zhang, Yan Zhang, Jiangwei Zhang, Ping Liu, Bo Jiao, Zaiqi Wang, Ruibao Ren. Focal adhesive kinase inhibitor IN10018 sensitizes KRAS mutant cancer and overcomes drug resistance of KRAS G12C inhibition [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-021.