tbuckley/cabot-search huggingface dataset:
Abstract 2450: A systemic approach to decipher the interactome of RET receptor isoforms
Authors: Samira Kheitan, Annika E. Pedersen, Brandy D. Hyndman, Luka Drecun, Punit Saraon, Igor Stagliar, Lois M. Mulligan
Journal: Cancer Research (2021)

Abstract The REarranged during Transfection (RET) receptor tyrosine kinase is pivotal for normal tissue development, but is also an oncogene driver involved in several human cancers. Alternative splicing at the 3' end of the RET gene leads to expression of two conserved protein isoforms, RET9 and RET51, that differ in their subcellular localization and protein trafficking, as well as their functional roles in tumorigenesis and metastatic processes. Importantly, RET9 and RET51 have unique C-terminal phospho-tyrosine binding sites, suggesting that they may also differ in their interactomes. We used a combination of cell-based screening and in silico approaches to identify novel potential interaction partners of RET isoforms. We performed a Mammalian Membrane Two-Hybrid (MaMTH) screen using a library of SH2 domain-containing adaptor and signaling proteins, to identify interactions with each RET isoform. We complemented these studies by using sequence homology detection models (HMM, PSSM), based on SH2 domain sequences known to interact with RET, to rank the SH2 library members and predict novel interactions. Independently, we compared published consensus binding sequences for each SH2 domain library member with predicted RET phosphotyrosine motifs to identify potential interactors. Predicted interactions were validated in co-immunoprecipitation assays. We confirmed previously known interactions of RET with SH2 domain proteins including SHC1, GRB2 and GRB10, and identified additional novel RET-binding proteins, a subset of which showed differential interactions that were mediated through RET isoform-specific docking sites. Our results suggest that combinations of distinct interaction partners may contribute to RET isoform-specific functions. Together, our research has developed a systematic approach to map and characterize RET isoform interactions. Our data suggest that no single method identified all confirmed RET interactions, and that a combination of multiple approaches improves characterization of growth factor receptor interactomes. Citation Format: Samira Kheitan, Annika E. Pedersen, Brandy D. Hyndman, Luka Drecun, Punit Saraon, Igor Stagliar, Lois M. Mulligan. A systemic approach to decipher the interactome of RET receptor isoforms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2450.
Abstract 1916: Lymph node targeting double stranded CpG act effective adjuvant in cancer peptide vaccine
Authors: Takayuki Nakagawa, Motoyasu Onishi, Soichi Tofukuji, Shinya Omoto, Kazufumi Katayama, Akira Kugimiya, Morio Nagira, Ken J. Ishii
Journal: Cancer Research (2021)

Abstract Background: Adjuvants can enhance immune responses of vaccinated antigen by inducing host innate immune responses. While cancer peptide vaccines were largely studied in recent years, effective cancer peptide vaccines have not been found yet so far because of their poor immunogenicity. Developing an effective vaccine adjuvant suitable for peptide antigen is a promising approach. CpG oligodeoxynucleotides(CpG) are a toll-like receptor 9 agonists and effectively elicit innate immune responses. In order to improve adjuvanticity of CpG, we designed a novel lymph-node targeting CpG, which is composed from a single stranded CpG and a modified complementary strand with amphiphilic chain. Methods: S-540956 is a double stranded oligodeoxynucleotide composed from a single stranded phosphorothioate oligonucleotide and the complementary strand with amphiphilic chain at the 5' end. Accumulating capability to lymph nodes of fluorescent labeled S-540956 was analyzed by flow cytometer, IVIS imaging system, and 2-photon microscopy. Incorporation of S-540956 by antigen-presenting cells in lymph nodes was assessed by Image Stream® imaging cytometer. To test cellular immune responses, three types of MHC class-I epitope peptides were employed as antigenic peptides. Therapeutic effect of S-540956 adjuvanted HPV E7 peptide vaccine was evaluated in TC-1 tumor model. Results:S-540956 exhibited higher accumulating capacity to lymph nodes in mice compared to a typical CpG adjuvant, ODN2006. Systemic proinflammatory cytokine responses were decreased by combining the complementary strand with amphiphilic chain. S-540956 was efficiently incorporated into plasmacytoid DCs and induced the expression of costimulatory molecules. Cellular immune responses induced by S-540956 adjuvanted peptide vaccine were significantly higher than ODN2006 adjuvanted peptide vaccine. And this enhanced adjuvant effect was observed also in protein vaccine. In TC-1 tumor model, therapeutically administered S-540956 adjuvanted HPV-E7 peptide vaccine lead to significant tumor shrinkage compared to ODN2006 adjuvanted peptide vaccine. Conclusion: S-540956 acted as a potent adjuvant for peptide vaccine by inducing cellular immune responses effectively. Accumulating capacity to lymph nodes of S-540956 is a promising adjuvant for not only for peptide but for protein or other biologic antigens. Citation Format: Takayuki Nakagawa, Motoyasu Onishi, Soichi Tofukuji, Shinya Omoto, Kazufumi Katayama, Akira Kugimiya, Morio Nagira, Ken J. Ishii. Lymph node targeting double stranded CpG act effective adjuvant in cancer peptide vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1916.
Abstract 14697: Galectin-3 as a Predictor of Long-Term Survival and Adverse Outcomes After Adult Cardiac Surgery
Authors: Devin M Parker, Sherry L Owens, Donald S Likosky, Niveditta Ramkumar, Richard Berman, Todd A MacKenzie, Anthony W DiScipio, David J Malenka, Jeremiah R Brown
Journal: Circulation (2018)

Introduction: Galectin-3 is a well-established biomarker of adverse clinical outcomes but its prognostic value for long-term survival after cardiac surgery is not well understood. Elevated levels o...
Case 21-2021: A 33-Year-Old Pregnant Woman with Fever, Abdominal Pain, and Headache
Authors: Andrea L. Ciaranello, Kathy M. Tran, Craig R. Audin, Melis N. Anahtar
Journal: New England Journal of Medicine (2021)

A 33-year-old pregnant woman with ulcerative colitis presented at 10 weeks of gestation with fever, nausea, vomiting, abdominal pain, and headache. On hospital day 3, the systolic blood pressure declined to 70 mm Hg. Three weeks earlier, the patient had had an ulcerative colitis flare; methylprednisolone and mesalamine were administered. A diagnosis was made.
Abstract 1885: Potent tumoricidal activity of a FGFR4 CART in rhabdomyosarcoma
Authors: Adam Cheuk, Meijie Tian, Jeetendra Kumar, Peter Azorsa, Nityashree Shivaprasad, Dina Schneider, Berkley Gryder, Jun Wei, Young Song, Xinyu Wen, Sivasish Sindiri, Joon-Yong Chung, Zhongyu Zhu, Dimiter Dimitrov, Stephen Hewitt, Boro Dropulic, Rimas Orentas, Javed Khan
Journal: Cancer Research (2021)

Abstract Despite decades of multi-module therapies, RMS remains incurable once it has metastasized, thus new therapeutic strategies are warranted. FGFR4 is a developmentally regulated cell surface receptor tyrosine kinase, overexpressed in virtually all, mutationally activated in about 10% of RMS, and directly activated by PAX3-FOXO1 fusion protein which makes it a tractable target for immunotherapy. We generated fifteen binders against FGFR4 and characterized them further as candidate molecules for immune therapy. We found that 3A11, a mouse IgG antibody, bound to FGFR4 positive cell lines. The VL and VH domain of 3A11 was cloned and made into scFvFc format (mouse Fv and Human IgG1 Fc). The chimeric form of 3A11 antibody was successfully produced in vitro and retained its FGFR4 specificity with an observed binding affinity at nanomolar range. By ELISA using the extra cellular domain of human FGFR1, FGFR2, FGFR3 or FGFR4, 3A11 scFvFc showed dose dependent binding to FGFR4 only. We then made 3A11 into a second generation CAR. Human T cells transduced with 3A11 CAR construct were found to be highly potent at inducing IFN-γ, TNF-α, IL-2 and cytotoxicity when the FGFR4-CART was co-cultured with RMS cells, but not with RMS cells with FGFR4 knocked out and FGFR4 negative cells. Our in vivo testing also found that 3A11 CART was able to eliminate RMS cells in murine xenograft metastatic models. Here we report the successful generation of binders specific to human FGFR4. FGFR4 CAR developed from 3A11 was able to kill FGFR4 positive target cells both in-vivo and in-vitro. Thus, 3A11 CAR T cells targeting FGFR4 may provide effective immune therapies for rhabdomyosarcoma and other FGFR4 expressing cancers and clinical trials are planned. Citation Format: Adam Cheuk, Meijie Tian, Jeetendra Kumar, Peter Azorsa, Nityashree Shivaprasad, Dina Schneider, Berkley Gryder, Jun Wei, Young Song, Xinyu Wen, Sivasish Sindiri, Joon-Yong Chung, Zhongyu Zhu, Dimiter Dimitrov, Stephen Hewitt, Boro Dropulic, Rimas Orentas, Javed Khan. Potent tumoricidal activity of a FGFR4 CART in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1885.
Abstract 649: Classics to diagnostics: Assessing EMT biomarkers in colorectal cancer prognosis
Authors: Rohin Patel, Angelique Robertson, Anjana Saxena, Mintoo Patel
Journal: Cancer Research (2021)

Abstract Colorectal cancer (CRC) is a second most common cause of cancer death in the United States and exhibits disparities among racial and ethnic minorities. Colon polyps are abnormal growth in the epithelium that can rapidly invade surrounding mesenchyme and metastasize to form multiple secondary tumor sites. Such Epithelial-Mesenchymal Transition (EMT) is the fundamental event that results in lower survival rate for CRC patients. Altered EMT processes are also indicative of health disparity as observed for aggressive nature of prostate cancer in African Americans. In search of potential diagnostic markers that enable us to capture this transition in situ in CRC, we focused on two major biomarkers, E-Cadherin, an epithelial specific surface protein, and Vimentin, a mesenchymal specific cellular filament component. We obtained de-identified biopsy tissues samples of different stages in CRC, classified as precancerous and cancerous, along with the normal tissues, that were collected during colonoscopies for routine histopathological evaluation. In parallel, these formalin fixed paraffin embedded tissues were immunostained for the expression of E-Cadherin and Vimentin. As expected, normal tissue specimens expressed E-Cadherin exclusively in the mucosal epithelial cells while mesenchymal cells in the stroma specifically stained for vimentin expression. Interestingly, in some precancerous and cancerous specimens, we observed vimentin-positive foci within epithelial cells that lack E-Cadherin expression. This suggests a proof-of principal that an initiation of epithelial to mesenchymal transition can be detected at the clinics by performing selective immunofluorescence staining of these markers. More importantly, such detection can be correlated with the stage of the CRC that can be very insightful for the progression of the disease. Early detection in CRC through these biomarkers to supplement histopathological evaluation is promising and would provide more predictive and detailed analysis of cancer progression in tissue samples to aid in the choice of appropriate treatment plan. The accurate pre-treatment patient evaluation is pivotal to the modern push for personalized therapy. The array of early detection biomarkers will also enhance our understanding in health disparity in CRC when a large set of samples are analyzed for these markers. Citation Format: Rohin Patel, Angelique Robertson, Anjana Saxena, Mintoo Patel. Classics to diagnostics: Assessing EMT biomarkers in colorectal cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 649.
The US Preventive Services Task Force Recommendation Statement About Screening Asymptomatic Adults for Carotid Stenosis
Authors: Raffaele Ornello, Francesca Pistoia, Simona Sacco
Journal: JAMA (2021)

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Abstract 2351: Multiomics integration elucidates onco-metabolic modulators of drug resistance in lymphoma
Authors: Satishkumar Singh, Fouad Choueiry, Amber Hart, Anuvrat Sircar, Jiangjiang Zhu, Lalit Sehgal
Journal: Cancer Research (2021)

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Bruton's tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure. Upon reaching drug tolerance, B-cell NHL cells proliferate faster, which suggests increased metabolic activity. In this study, we explored the onco-metabolic regulators of ibrutinib -resistant activated B-cell (ABC) DLBCL using a ‘multi-omics' analysis that integrated metabolomics (using high-resolution mass spectrometry) and transcriptomics (gene expression analysis). We performed unbiased statistical analyses to uncover dysregulated metabolic pathways among the proteomic and transcriptomic datasets. Overlay of the analyses identified two significantly altered metabolic pathways at both the metabolic and transcript level. Gene-metabolite integration revealed interleukin 4 induced 1 (IL4I1) at the crosstalk of two significantly altered metabolic pathways involved in the production of various amino acids. We showed for the first time that a metabolic shift from glycolysis towards oxidative phosphorylation in these lymphomas is activated via the BTK-PI3K-AKT-IL4I1 axis and can be targeted therapeutically. These findings from our unbiased analyses highlight the role of metabolic dysregulation during drug resistance development. Furthermore, our work demonstrates that a multi-omics approach can be a powerful and unbiased strategy to uncover genes and pathways that drive metabolic dysregulation in cancer cells. Citation Format: Satishkumar Singh, Fouad Choueiry, Amber Hart, Anuvrat Sircar, Jiangjiang Zhu, Lalit Sehgal. Multiomics integration elucidates onco-metabolic modulators of drug resistance in lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2351.
Major Adverse Cardiovascular Events (MACE) following partial nephrectomy: PN-A4CH a novel risk index
Authors: A.A. Nasrallah, H. Dakik, N. Abou Heidar, O. Nasrallah, J. Najdi, M. Mansour, H. Tamim, A. El Hajj
Journal: European Urology (2021)
Abstract 526: Novel mechanisms of Neuropilin-1 inhibition result in improved tumor growth inhibition <i>in vivo</i>
Authors: Shalini Sethumadhavan, Eric Zhu, Aaron Fulgham, Mandana Abbassi, Ameya Apte, Tiffany Liao, Chengfeng Merriman, Katherine Molloy, Caitlin Stein, Amber Hanna, James Geoghegan, Bianka Prinz, Hongyue Dai, Jonathan Hurov, Pearl Huang, Daniel Blom
Journal: Cancer Research (2021)

Abstract Background Cygnal Therapeutics, pioneer in exoneuronal biology, has identified the neuronal protein, Neuropilin-1 (NRP1) as a critical regulator of tumor growth and anti-tumor immunity. NRP1 is a co-receptor that complexes with diverse ligands and their cognate receptors. As such, it plays a role in multiple different biological processes, including axon guidance and angiogenesis. NRP1 contains two CUB domains (a1 and a2) involved in binding the ligand Semaphorin3A (SEMA3A), two Factor V/VIII domains (b1 and b2) involved in VEGF ligand binding and one MAM domain (c domain). While functional antibodies with anti-tumor activity have been generated against the SEMA3A and VEGF binding domains, targeting other domains of NRP1 has not been well-studied. For example, the c-domain of NRP1 has been implicated in the dimerization of NRP1, a prerequisite for functionality. Thus c-domain blockers might inhibit multiple signaling pathways required for tumor growth. Alternatively, binders targeting the interface of two different domains might allow for simultaneous blocking of multiple ligands. We therefore hypothesized that these novel binders to alternative regions of NRP1 such as the b1/b2 interface and the c-domain would have improved and significant anti-tumor activity. Methods Antibodies with diverse binding characteristics were tested for in vivo anti-tumor activity in multiple syngeneic models, including anti-PD1 non-responsive models. Ability of these of the anti-NRP1 antibodies to elicit an adaptive immune response was evaluated. Results Novel binders to alternative regions of NRP1 such as domain interfaces and the c-domain resulted in significant tumor growth inhibition in multiple syngeneic models. Additionally, the NRP1 antagonists induced a robust CD8 T cell response, indicating immune-stimulatory role of these antibodies. Conclusions Cygnal has developed fully human monoclonal antibodies against previously untargeted domains of NRP1. These novel domain binders show remarkable inhibition of tumor growth in multiple syngeneic models and offer a novel means of therapeutic intervention in patients. Citation Format: Shalini Sethumadhavan, Eric Zhu, Aaron Fulgham, Mandana Abbassi, Ameya Apte, Tiffany Liao, Chengfeng Merriman, Katherine Molloy, Caitlin Stein, Amber Hanna, James Geoghegan, Bianka Prinz, Hongyue Dai, Jonathan Hurov, Pearl Huang, Daniel Blom. Novel mechanisms of Neuropilin-1 inhibition result in improved tumor growth inhibition in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 526.
Abstract 2138: Whole genome cfDNA profiles reveal common signatures of Immune checkpoint inhibition response in kidney, melanoma, and lung cancers
Authors: Hayley Donnella, Yue Zhang, Irving Wang, Francesco Vallania, Maggie Louie, C. Jimmy Lin
Journal: Cancer Research (2021)

Abstract Immune checkpoint inhibition (ICI) via anti-PD-1/PD-L1 and anti-CTLA4, has improved clinical outcomes for multiple cancers, including non-small cell lung cancer (NSCLC), kidney cancer, and melanoma. Despite this success, response rates remain low, highlighting the need for more robust predictive biomarkers. In this study, we used cell-free DNA (cfDNA) profiles from patients undergoing ICI therapy to identify common signatures associated with responses shared among the three cancers. Whole-genome sequencing (mean coverage=18X) of cfDNA was performed on pre-treatment plasma samples from 126 patients across three cancers (NSCLC, n=91; kidney, n=21; melanoma, n=14). Transcriptional activation for protein-coding genes was then inferred by modeling fragment distribution around each transcription start site (TSS-GAP). Transcription factor binding activity (TFBA) was estimated by measuring binding site accessibility across the genome. To delineate potential signatures of response, we performed a gene set enrichment analysis (GSEA) based on weighted average effect sizes of TSS-GAP levels between response groups across the three cancer types. GSEA results showed an enrichment of DNA repair and cell cycle genes in non-responders and of EMT processing genes in responders. To identify shared signatures of ICI response, we performed a meta-analysis by (1) computing the effect size between response groups for TFBA and TSS-GAP features in each cancer type; (2) calculating a weighted-average effect size across cancer types; (3) performing gene selection based on the degree of heterogeneity among cancer types, followed by false discovery rate correction and assessment of significance through Monte Carlo permutation testing. This analysis identified 13 transcription factors and 269 genes consistently enriched in response groups across these cancer types. Notably, this analysis revealed significantly higher accessibility in STAT5A (p=0.02), JUN (p=0.02) and JUNB (p=0.03) in non-responders, suggesting JAK/STAT-pathway dependency as a common feature in ICI resistance. Using our platform that detects both tumor and non-tumor-derived signals, we identified common signatures of ICI response, revealing a potential pathway of resistance through JAK/STAT signaling and a possible EMT signature of response in kidney, melanoma, and NSCLC. These findings warrant further investigation into using cfDNA signatures for patient stratification and response monitoring. Citation Format: Hayley Donnella, Yue Zhang, Irving Wang, Francesco Vallania, Maggie Louie, C. Jimmy Lin. Whole genome cfDNA profiles reveal common signatures of Immune checkpoint inhibition response in kidney, melanoma, and lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2138.
Non-communicable diseases among Palestinian refugees from Syria: a cross-sectional study on prevalence, case management, access to and utilisation of UNRWA Health Services
Authors: Monique Chaaya, Lilian A Ghandour, Fouad M. Fouad, Aline Germani, Rana Charide, Yousef Shahin, Suha Ismail, Saleh Fahd
Journal: The Lancet (2021)