tbuckley/cabot-search huggingface dataset:
Abstract 5722: Acquired stemness by luminal cells
Authors: Wouter Karthaus, Matan Hofree, Danielle Choi, Eliot L. Linton, Mesruh Turkekul, Alborz Bejnood, Brett Carver, Anuhandra Gopalan, Vincent Laudone, Moshe Biton, Ojasvi Chaudhary, Ignas Masilionis, Linas Mazutis, Dana Pe'er, Aviv Regev, Charles Sawyers
Journal: Cancer Research (2020)

Abstract Rare cell types in the prostate are reported to have stem cell properties based on organ regeneration potential following castration. Here, we use single cell RNA-seq (scRNA-Seq) to characterize these populations from the murine and human prostate in hormonally intact and androgen deprived conditions. Prostate cells from hormonally intact mice partitioned into one large subset of basal epithelial cells, another large subset of luminal epithelial cells, which we designate luminal 1 and two rare luminal populations: luminal 2 and luminal 3. Luminal cells that persist following castration display enhanced organoid regeneration potential, particularly within 1-2 days of androgen addback, and contribute equipotently to prostatic regeneration as revealed by lineage tracing. This regeneration is mediated, in part, through the orchestrated expression of Nrg2, Igf1, Fgf10 and Rspo3 by distinct populations of androgen-responsive mesenchymal and smooth muscle cells. Thus, luminal cells that persist post-castration undergo a cell state change that primes a proliferative response to microenvironment signals, analogous to other models of tissue injury such as liver damage. Citation Format: Wouter Karthaus, Matan Hofree, Danielle Choi, Eliot L. Linton, Mesruh Turkekul, Alborz Bejnood, Brett Carver, Anuhandra Gopalan, Vincent Laudone, Moshe Biton, Ojasvi Chaudhary, Ignas Masilionis, Linas Mazutis, Dana Pe'er, Aviv Regev, Charles Sawyers. Acquired stemness by luminal cells [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 5722.
TCT-695 Elixhauser comorbidity score is the best risk score in predicting survival after MitraClip implantation
Authors: Juliëtte Velu, Stijn Haas, Martijn van Mourik, Karel Koch, M. Marije Vis, Jose PS. Henriques, Renée van den Brink, S. Matthijs Boekholdt, Jan Piek, Berto Bouma, Jan Baan
Journal: Journal of the American College of Cardiology (2017)
Abstract 4678: The role of EGR1 and AP1 in acute myeloid leukemia cell reprogramming toward cell cycle arrest and apoptosis
Authors: Michael Roberts, Lauren Kageler, Kayla Bendinelli, Shannon Bonner, Ashir Borah, Jeffrey Forrester
Journal: Cancer Research (2020)

Abstract EGR and AP1 transcription factors are rapidly upregulated in acute myeloid leukemia cells responding to treatment with phorbol esters. Phorbol ester induced transcriptome changes are accompanied by phenotypic changes including cell cycle arrest, myeloid differentiation, and ultimately apoptosis. Here we present results documenting the transcriptome alterations of the phorbol ester response in HL-60 cells by DNA microarray and RNA-seq analyses, and explore the specific roles of EGR and AP1 in determining the evolving transcriptional program. Overexpression of egr1 or c-fos recapitulates many of the phorbol ester-induced transcriptome alterations and affects cell proliferation, differentiation and survival. Identification of changes in EGR1 and FOS/AP1 target gene expression supports the hypothesis that EGR and AP1 are involved in a genetic reprogramming of AML cells leading to loss of the leukemic phenotype and recovery of apoptotic competency. We also provide a comprehensive bioinformatic analysis of AML patient sample data provided by The Cancer Genome Atlas and the published study from Tyner et al., Nature 562:526-531 (2018) accessible through the Beat AML data viewer (Vizome) regarding expression of egr1. Egr1 high expression correlates with improved overall survival and a particular mutational signature distinct from patients with low egr1 expression. We define a mutational and transcriptional signature for AML patients based on egr1 expression levels that correlates with clinical outcomes. Citation Format: Michael Roberts, Lauren Kageler, Kayla Bendinelli, Shannon Bonner, Ashir Borah, Jeffrey Forrester. The role of EGR1 and AP1 in acute myeloid leukemia cell reprogramming toward cell cycle arrest and apoptosis [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 4678.
Abstract 142: Identification of symmetric methylation and hemimethylation patterns with optimal panel design, library preparation, and error correction
Authors: Hsiao-Yun Huang, Ushati Das Chakravarty, Kevin Lai, Timothy Barnes, Tzu-Chun Chen, Jessica Sheu, Ramses Lopez, Karissa Scott, Lynette Lewis, Anastasia Potts
Journal: Cancer Research (2020)

Abstract DNA methylation patterns are epigenetic modifications with direct implications in gene expression and chromatin structure regulation. Altered DNA methylation has been reported in various human cancers. The methylation profile of cell-free DNA (cfDNA) from plasma can be exploited to detect and diagnose tissue pathologies and is therefore of great diagnostic interest. Due to limitations of existing NGS library preparations, we present a new workflow, that integrates Unique Molecular Identifier (UMI) based error correction and optimizes library preparation and target enrichment. This workflow incorporates an engineered mutant ligase and proprietary methylated adapters that together prevent chimeras, suppress dimer-formation, and maximize conversion. Our library preparation provides &amp;gt;80% unique mapping efficiency and high conversion efficiency which creates superior sensitivity and specificity for detecting epigenetic signatures from a wide range of inputs (1-250 ng) and samples, including genomic DNA, FFPE DNA and cfDNA. This workflow is suitable for both genome-wide and targeted methylation sequencing. We implemented the target methyl-seq workflow to distinguish between fully methylation and hemimethylation on only one strand of the DNA by ligating in-line UMIs prior to target enrichment, followed by bisulfite conversion and PCR. Using a custom panel for targeted methylation sequencing, we detected &amp;gt;60% of CpG methylation in normal human samples and &amp;gt;95% of CpG methylation in in vitro methylated HCT116 samples. Employing ultra-deep sequencing to an average target depth of 10,000X followed by double-stranded consensus building analysis enables accurate low frequency methylation and hemimethylation detection. The studies presented here offer tools to advance epigenetics research. Citation Format: Hsiao-Yun Huang, Ushati Das Chakravarty, Kevin Lai, Timothy Barnes, Tzu-Chun Chen, Jessica Sheu, Ramses Lopez, Karissa Scott, Lynette Lewis, Anastasia Potts. Identification of symmetric methylation and hemimethylation patterns with optimal panel design, library preparation, and error correction [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 142.
Abstract 1535: Identification of novel epithelial-mesenchymal transition inducers and their clinical significance in colorectal cancer
Authors: Satoshi Ishikawa, Naohiro Nishida, Shiki Fujino, Takayuki Ogino, Hidekazu Takahashi, Norikatsu Miyoshi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizusima, Hirofumi Yamamoto, Koshi Mimori, Masaki Mori, Yuichiro Doki, Hidedoshi Eguchi
Journal: Cancer Research (2020)

Abstract Purpose. Cancer tissues contain a substantial amount of stromal tissues, and transcriptome derived from bulk samples originates from a mixture of the cancer epithelium and stroma. Gene signature of epithelial-mesenchymal transition (EMT) cells is similar to that of stromal cells; therefore, gene signature that we considered to be related EMT might be only contamination of stroma. Here, we identify novel EMT inducers by analysis of independent gene expression profiles in the colorectal cancer epithelium and stroma. Materials and Methods. Gene expression data of pure epithelial tissue was obtained using laser microdissection technique from 13 colorectal cancer tissues. Next, the ratio of each gene expression in the stroma to in the epithelium and correlation of each gene expression with a target gene derived from The Cancer Genome Atlas (TCGA) is plotted in two dimensions, and correlation coefficients are calculated. We regard genes with high correlation coefficients but highly expressed in the epithelium as candidates of EMT inducers. We manipulate the expression of some candidate genes in colorectal cancer cell lines to investigate the alterations of EMT markers and migration ability in vitro. Results. We extract 91 new putative EMT-related genes in silico. They are highly expressed in similar cell lines to known EMT markers in a public database. Furthermore, some candidates have reported having a relation to EMT, and that indicates the validity of this procedure. The knockdown of three candidate genes upregulates epithelial gene expression and downregulates mesenchymal gene expression. The knockdown of one of the three genes reduces cell migration. In contrast, overexpression of the gene downregulates epithelial gene expression and leads to cell migration. Conclusion. We identify novel EMT inducers successfully using purified gene expression data. They could be new prognostic markers and therapeutic targets of colorectal cancer. Citation Format: Satoshi Ishikawa, Naohiro Nishida, Shiki Fujino, Takayuki Ogino, Hidekazu Takahashi, Norikatsu Miyoshi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizusima, Hirofumi Yamamoto, Koshi Mimori, Masaki Mori, Yuichiro Doki, Hidedoshi Eguchi. Identification of novel epithelial-mesenchymal transition inducers and their clinical significance in colorectal 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 1535.
Abstract 97: Analysis of Pten-null mouse astrocytes revealed overlapping transcribed genes with human glioblastoma transcriptome
Authors: Tian Liu, Penelope Mei-Yu Or, Chi-Wai Wong, Stanley Kwok-Kuen Cheung, Yubing Wang, Yiwei Wang, Andrew M. Chan
Journal: Cancer Research (2020)

Abstract Glioblastoma is an aggressive form of brain cancer with universally poor prognosis. Even with optimal therapy, the cancer recurs frequently. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene whose mutations are often found in multiple human cancers. PTEN encodes a lipid phosphatase and serves as a negative regulator of the phosphoinositide 3-kinase (PI3K) pathway. Cumulative evidence suggests that PTEN mutations play significant roles in tumorigenesis of glioblastoma as 60% of glioblastoma patients acquired mutations in this gene. Based on our preliminary data, transcriptomic profiling of primary astrocytes derived from Pten knockout mice revealed an overlapping enrichment of mitotic regulators and cell cycle related pathways with human GBM. 4 genes (RCC1, RCC2, NEK2, and CHK2) were validated to be significantly upregulated in PTEN KO astrocytes by qRT-PCR. Regulator of chromatin condensation 2 (RCC2) has been reported to be guanine-nucleotide exchange factor (GEF) for Rac1 and RalA GTPase and act as a regulator of cell cycle progression. Accumulating evidence revealed a pro-tumorigenic role of RCC2 in multiple cancers such as tumor growth and tumor metastasis. Via siRNA inhibition of RCC2, we demonstrated that knocking down of RCC2 in glioblastoma cell lines suppresses cell growth and RCC2 is essential for both G1-S and G2-M progression. Additionally, RCC2 knocking down and a PI3K inhibitor LY294002 inhibit glioblastoma cell viability in a synergistic manner. In summary, PTEN deficiency leads to the upregulation of RCC2, which may promote tumorigenesis of glioblastoma by dysregulating cell cycle progression.To further explore the RCC2 roles, we will find the potential downstream target of RCC2 in dysregulating cell cycle and its potential therapeutic effect in vivo. Funding: General Research Fund Grant #14113519 from The Research Grants Council of Hong Kong Citation Format: Tian Liu, Penelope Mei-Yu Or, Chi-Wai Wong, Stanley Kwok-Kuen Cheung, Yubing Wang, Yiwei Wang, Andrew M. Chan. Analysis of Pten-null mouse astrocytes revealed overlapping transcribed genes with human glioblastoma transcriptome [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 97.
Abstract 6307: <i>In vivo</i> drug screening platform accelerates anti-hCD40 antibody drug discovery
Authors: Yi Yang, Zhihong Li, Yu Zhu, Jingshu Xie, Yunyun Chen
Journal: Cancer Research (2020)

Abstract The CD40 (also known as TNFRSF5) and its ligand CD40L (also known as CD154) belong to the TNF/TNFR family. CD40 is expressed on antigen presenting cells (APCs), including B cell, monocytes, macrophages and dendritic cells. CD40-CD40L is a pair of costimulatory molecules that, after interacting at the cell surface, promotes intracellular signaling by recruiting TNFR-associated factor (TRAF) in the cytosol, thereby activating multiple downstream signaling pathways. Therapeutic targeting of CD40 by agonistic monoclonal antibodies (mAbs) aims to activate CD40+ APCs to effectively boost tumor-specific cytotoxic T cells to eliminate tumor cells. In principle it has the advantage of greater tumor specificity over other T cell activating approaches, such as checkpoint inhibition or indiscriminate T cell activation. We are interested in developing a novel immune checkpoint monoclonal antibody that targets CD40 and can treat cancer patients. Using Biocytogen's antibody research platform, dozens of candidate antibodies were obtained by classical hybridoma technology as well as high-throughput flow cytometry screening. Next, these murine antibodies were screened directly in humanized mouse models (B-hCD40) bearing a syngeneic cancer cell line. We discovered candidates that have potent anti-tumor activity in vivo. These candidate antibodies were further humanized, and we found an antibody called YH003 with potent antitumor activity in the MC38 tumor model. Fortunately, YH003 was able to inhibit tumor growth in combination with Pembrolizumab in the double humanized model of h-CD40 and h-PD1 bearing a syngeneic B16F10 cancer cell line. In vitro studies demonstrated that YH003 bound specifically and potently to human and monkey CD40 proteins, we used cynomolgus monkeys to further explore the safety evaluation. In conclusion, we use Biocytogen's in vivo drug screening platform to obtain more novel CD40 antibodies with anti-tumor activity in addition to YH003, accelerating the progress of preclinical antibody discovery. Citation Format: Yi Yang, Zhihong Li, Yu Zhu, Jingshu Xie, Yunyun Chen. In vivo drug screening platform accelerates anti-hCD40 antibody drug discovery [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 6307.
Abstract 2824: <i>In vitro</i> tumor killing assays for predicting cellular therapeutic efficacy
Authors: Robert Nunan, Michelle Yap, Enrique Garcia-Alvarez, Marie Carkill, Anna Pascoe, Louise Brackenbury, Jezrom Self-Fordham, S. Rhiannon Jenkinson
Journal: Cancer Research (2020)

Abstract Cellular immunotherapy is emerging as a fifth pillar of cancer treatment. Clinical efficacy has been proven for a variety of cancers; however, its true potential has yet to be unlocked. Development of reliable and mechanistically appropriate in vitro screening assays that recapitulate in vivo immune-tumor interactions have been outpaced by in vivo living cell therapy efficacy models. Here we describe a range of in vitro primary human assays to model tumor killing by immune cells. This platform addresses multiple anti-tumor immune effector pathways and has been validated with standard of care therapeutics. Fluorescently labelled target cells (PDX-cell lines, tumor cell lines or human primary/iPSC derived cells) screened for relevant antigen expression were cultured in monolayer or spheroid forms and co-cultured with the cellular therapeutic. On target killing by effectors is driven by binding of the TCR or CAR to its cognate antigen (MHC/peptide or protein, respectively) with readouts of cell killing utilising live cell imaging (IncuCyte) and flow cytometry based approaches to measure target cell growth and apoptosis. Additional analysis of soluble mediators can determine the extent of effector cell activation. To discriminate between ‘on' and ‘off' target killing by cellular therapeutics, primary/iPSC-derived normal cell types representative of different tissue types were screened for expression of an HLA subtype capable of binding exogenously applied tumor-associated antigen (TAA) prior to co-culture. Under these conditions in the case of a TCR based cellular therapeutic, efficacy can be screened for, or in the absence of the putative TAA expression, the extent of off-target killing determined. Enhancement of tumor targeting and killing by immune cells is an attractive therapeutic modality partly due to the clinical success of checkpoint inhibitors which can enhance the activation and effector function of endogenous T/NK cells or cellular therapeutics. The presented data highlight the importance of assays which can recapitulate tumor-immune interactions and include immune effector pathways known to potentiate anti-tumor immune responses. These assays represent valuable screening tools capable of informing cellular therapeutic target selection and refinement before moving to more complex in vivo models. Citation Format: Robert Nunan, Michelle Yap, Enrique Garcia-Alvarez, Marie Carkill, Anna Pascoe, Louise Brackenbury, Jezrom Self-Fordham, S. Rhiannon Jenkinson. In vitro tumor killing assays for predicting cellular therapeutic efficacy [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 2824.
Abstract 584: TGN1412 induces dose and time dependent human cytokines in a humanized PBMC mouse model for cytokine release syndrome
Authors: Hongyuan Yang, Jing Jiao, Danying Cai, Mingshan Cheng, Michael Brehm, Dale Grainer, Leonard Shultz, James Keck
Journal: Cancer Research (2020)

Abstract There have been remarkable progresses in the development of immune therapies for cancer. However, the promise of immune therapy comes with significant challenges of a variety of adverse effects. Due to the lack of predictive preclinical model to evaluate antibody mediated adverse effects, TGN1412, a humanized anti-CD28 monoclonal antibody which acts as a superagonist of CD28 to activate T cells, unfortunately caused life-threatening cytokine release syndrome (CRS) during the first-in-man trial. Therefore there is a critical need for translational protocols that could predict immune toxicity more accurately. We have developed a sensitive and reproducible PBMC-humanized mouse model that can measure cytokine release induced by bispecifics or checkpoint inhibitors in vivo. In this study the utility of this platform was demonstrated using TGN1412 as a model. NSG™ mice or derivative strains such as SGM3 mice were engrafted with human PBMCs for 6 days before being treated with TGN1412 at different concentrations (0.2, 1.0 and 2 mg/kg). Mouse blood was collected at 1, 2, 4, 6, 24 and 48 hours post dose for flow cytometry and cytokine analysis. We observed dose and time dependent increase of human IFN-γ, TNFα, IL-2, IL-4, IL-6 and IL-10 levels in the serum following TGN1412 treatment with TNFα peaking at 1 h and the others peaking at 2-4 h post dose. A significant decrease in hCD45+ cells was observed in the peripheral blood collected at 6h post treatment. TGN1412 was tested in the humanized NSG™ mice with PBMCs from 7 different donors, and a significant decrease in hCD45+ cell population in the peripheral blood was observed in all donors. We have demonstrated that the novel mouse model using PBMC-humanized NSG™ can successfully detect CRS induced by TGN1412 in a dose and time dependent manner, suggesting that indeed CRS could be a strong adverse effect associated with TGN1412 treatment in human. Our data supports that our newly developed mouse model for CRS assessment may be a valuable tool to assess in vivo safety of experimental human therapeutic antibodies including immune checkpoint inhibitors and bispecifics with better reliability than an in vitro assay. Citation Format: Hongyuan Yang, Jing Jiao, Danying Cai, Mingshan Cheng, Michael Brehm, Dale Grainer, Leonard Shultz, James Keck. TGN1412 induces dose and time dependent human cytokines in a humanized PBMC mouse model for cytokine release syndrome [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 584.
Abstract 4093: Drug combinations that can overcome resistance to PARP inhibitor therapy for BRCA1-associated breast cancer
Authors: Dina Mohamed Abd El Aziz Moustafa, Maha Abd Elwahed, Hanaa El Said, Jeffrey Parvin
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) represents approximately 10–15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy. Poly (ADP-ribose) polymerases inhibitors (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Surprisingly, EMI1 downregulation also led to resistance to a MEK inhibitor, though this inhibitor blocks cells in G1 phase of the cell cycle and would not be expected to be sensitive to EMI1 levels. Notably, increasing the RAD51 protein expression can mimic the EMI1 downregulation and lead to resistance to different PARPis and the other cytotoxic drugs. This result suggests that the key downstream effect of EMI1 downregulation is increasing the concentration of RAD51 protein in the cell. We found that combining CHK1 inhibitor with Olaparib results in cell death in a dose specific manner. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells. Citation Format: Dina Mohamed Abd El Aziz Moustafa, Maha Abd Elwahed, Hanaa El Said, Jeffrey Parvin. Drug combinations that can overcome resistance to PARP inhibitor therapy for BRCA1-associated breast 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 4093.
Polygenic architecture informs potential vulnerability to drug-induced liver injury
Authors: Masaru Koido, Eri Kawakami, Junko Fukumura, Yui Noguchi, Momoko Ohori, Yasunori Nio, Paola Nicoletti, Guruprasad P. Aithal, Ann K. Daly, Paul B. Watkins, Hisashi Anayama, Yvonne Dragan, Tadahiro Shinozawa, Takanori Takebe
Journal: Nature Medicine (2020)