tbuckley/cabot-search huggingface dataset:
Abstract 2699: NFATc2 in non-small cell lung cancer mediates inhibition of peripheral blood mononuclear cell proliferation
Authors: Ian K. Lam, Zhi-Jie Xiao, Vicky P. Tin, Fang Ping Huang, Maria P. Wong
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of cancer death worldwide. While genetic mutations that provide growth advantages to cancer cells are fundamental to malignant transformation, ability to evade the immune system is also crucial in tumorigenesis. We have previously shown that human lung cancers with high expression of nuclear factor of activated T cells, cytoplasmic 2, (NFATc2) are associated with reduced recurrence-free and overall survival. NFATc2 is expressed in most immune cells and has been extensively studied in immune cells. However, its function in cancer development is not completely understood. In this study, the role of NFATc2 in lung cancer on immune escape is explored. Lung cancer cell lines with high NFATc2 expression were co-cultured with peripheral blood mononuclear cells (PBMC) and a significant inhibition of PBMC proliferation was observed compared to PBMC only control. However, the inhibitory effect of PBMC proliferation was reversed in co-culture with NFATc2 knockdown cancer cells. When cancer cells and PBMC were separated by a membrane using Transwell inserts, the anti-proliferative effect on PBMC was not observed suggesting that cell-cell contact was required for the NFATc2-mediated inhibition. Moreover, interleukin-2 (IL-2) was produced by PBMC irrespective of the presence or absence of lung cancer cells. These results showed that the inhibition of proliferation was independent of the activation of PBMC. Taken together, we have shown NFATc2 in lung cancer plays a role in immune modulation by inhibiting PBMC proliferation and this could be a novel mechanism of immune evasion in lung cancer. Citation Format: Ian K. Lam, Zhi-Jie Xiao, Vicky P. Tin, Fang Ping Huang, Maria P. Wong. NFATc2 in non-small cell lung cancer mediates inhibition of peripheral blood mononuclear cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2699. doi:10.1158/1538-7445.AM2017-2699
Case 19-1999
Authors: Kwan Kew Lai, Andrew E. Rosenberg
Journal: New England Journal of Medicine (1999)

Presentation of CaseA 55-year-old man was admitted to the hospital because of a painful right tibial lesion.Twenty-one months before admission, the patient had undergone orthotopic liver transplantation at this hospital because of cryptogenic cirrhosis. The donor liver was fatty and suboptimal, and it was replaced with a second liver one month after the first transplantation. Insulin-dependent diabetes mellitus subsequently developed. Sixteen months before the current admission, a biopsy-confirmed acute rejection reaction was managed successfully.Thirteen months before the current admission, the patient was readmitted to the hospital because of Enterobacter cloacae sepsis, which was thought to have originated . . .
Abstract LB-286: ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice
Authors: Radhika Mathur, Burak H. Alver, Adrianna K. San Roman, Boris G. Wilson, Xiaofeng Wang, Agoston T. Agoston, Peter Park, Ramesh Shivdasani, Charles W. Roberts
Journal: Cancer Research (2017)

Abstract Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are collectively mutated in ~20% of all human cancers, but the mechanism by which these mutations promote tumorigenesis is unclear. In this study, we investigate the tumor suppressor role of ARID1A, the subunit of SWI/SNF complexes that is the most frequent target of mutations. We develop an inducible Arid1a-knockout mouse model and find that mice develop invasive ARID1A-deficient colon adenocarcinoma. These cancers show prominent mucinous differentiation and tumor-infiltrating lymphocytes, features associated particularly with microsatellite-instable (MSI) human colorectal cancer - the subtype with the highest frequency of inactivating ARID1A mutations (37-39%). Although deregulation of Wnt signaling components (APC/β-catenin) is commonly utilized to model intestinal tumorigenesis, Arid1a-knockout mice reflect human colorectal cancer with greater accuracy. These mice do not show deregulation of Wnt signaling components, thus demonstrating a novel pathway to colon tumorigenesis that is independent of established models. Chromatin immunoprecipitation sequencing reveals that SWI/SNF complexes are targeted primarily to enhancers, where they function in coordination with transcription factors to activate gene expression. ARID1A loss impairs the targeting of SWI/SNF complexes to thousands of enhancers, which subsequently lose activity - showing reduced levels of H3K27ac and expression of nearest genes. Residual SWI/SNF complexes in ARID1A-deficient cells bind enhancers that remain active; these complexes contain ARID1B, the subunit that is mutually exclusive with ARID1A and has been identified as a therapeutic target in ARID1A-deficient cancers. Enhancers associated with developmental gene expression programs are most affected by ARID1A loss, both in the mouse colonic epithelium and in human colon cancer cells. Collectively, these findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as the principal tumor suppressor function of ARID1A. Citation Format: Radhika Mathur, Burak H. Alver, Adrianna K. San Roman, Boris G. Wilson, Xiaofeng Wang, Agoston T. Agoston, Peter Park, Ramesh Shivdasani, Charles W. Roberts. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-286. doi:10.1158/1538-7445.AM2017-LB-286
Abstract 401: Designing for success: the right CRISPR design strategies for the right experiment
Authors: Leigh Brody, Neil Humphryes-Kirilov, Victor Dillard, Riley Doyle
Journal: Cancer Research (2017)

Abstract CRISPR design is a complex multivariate problem. The weight of each variable differs depending on the experiment under consideration. Current methods of designing CRISPR experiments are based on a single-variable, resulting in poor experimental outcomes. From the numerous experiments enabled by the DESKGEN platform, we can demonstrate key design improvements to maximise experimental outcome. Our current scoring methods were tested and validated using an sgRNA library of over 3,500 sgRNAs in essential genes with a variety of predicted sgRNA activities and specificities. The predicted 'good' sgRNAs achieved significantly higher read depletion for essential genes, with fewer failing sgRNAs, compared to sgRNAs that didn't meet the scoring criteria. Our scoring algorithm incorporates multiple published observations for choosing effective sgRNAs, which differs from other CRISPR tools that tend to focus on one factor such as sgRNA sequence or specificity. We were unable to find correlations for some currently accepted sgRNA selection criteria, such as position within a gene, which demonstrates the need to constantly challenge and improve sgRNA design rules. Citation Format: Leigh Brody, Neil Humphryes-Kirilov, Victor Dillard, Riley Doyle. Designing for success: the right CRISPR design strategies for the right experiment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 401. doi:10.1158/1538-7445.AM2017-401
Abstract 2825: Gene expression profile in genetically engineered mouse model of lung cancer correlates with that in human lung adenocarcinoma
Authors: Imayavaramban Lakshmanan, Satyanarayana Rachagani, Moorthy Ponnusamy, Seema Chugh, Samikshan Dutta, Sakthivel Muniyan, Surinder Batra, Apar Kishore
Journal: Cancer Research (2017)

Abstract Introduction: Despite recent advances in the understanding of the biology of lung cancer, there are no agents that can target Kras, the most common mutation seen in lung adenocarcinoma. Development of genetically engineered mouse (GEM) models with krasG12Dand p53R172H+ will help us to understand the biology of kras mutated lung cancer and develop specific targeted therapeutic agents. Material and Methods: We have developed two GEM models of lung adenocarcinoma harboring the KrasG12D mutation [KrasG12D;AdCre (KA) and KrasG12D; p53R172H;AdCre (KPA)] by conditional activation in the lung. We performed RNA-seq analysis from KA and KPA tumor tissues and compared them to normal lungs from littermate controls. The results were compared with publicly available human data (TCGA, cBioportal). In addition, we have developed two novel syngeneic cell lines from KA and KPA tumors, which will be used to test the efficacy of candidate drugs. Results: Hyaluronan binding protein (Habp2) was top most upregulated gene [LogFC 12.7 (KA) 10.4 (KPA)] in both KA and KPA tumor tissues compared to normal. The TCGA and cBioportal data suggest Habp2 is overexpressed in lung adenocarcinoma as opposed to other histologic subtypes. We then analyzed Habp2 associated gene signature and observed that fibrinogen alpha chain (FGA), fibrinogen gamma chain (FGG), hyaluronan synthase 1 (HES1), serpin peptidase inhibitor, clade E1(Serpine1) were also upregulated in both models. On comparison of KA and KPA tumors, we observed that St6galnac1(ST6 N Acetylgalactosaminide Alpha-2,6 Sialyltransferase 1) was upregulated only in the KPA model, suggesting that p53R175H mutation leads to St6galnac1 overexpression. Conclusion: Hyaluronan binding protein (Habp2) was top most upregulated gene in the KA and KPA models, while St6galnac1expression appeared to be associated with p53R175H mutation. Gene expression data from our GEM models of lung cancer agree with the TCGA and cBioportal analyses. Thus these GEM models seem to replicate human lung cancer and can be used to test drugs for in vivo therapeutic efficacy, prior to use in humans. Citation Format: Imayavaramban Lakshmanan, Satyanarayana Rachagani, Moorthy Ponnusamy, Seema Chugh, Samikshan Dutta, Sakthivel Muniyan, Surinder Batra, Apar Kishore. Gene expression profile in genetically engineered mouse model of lung cancer correlates with that in human lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2825. doi:10.1158/1538-7445.AM2017-2825
Adrenocorticotropic Hormone–Secreting Neuroendocrine Tumor of the Rectum Demonstrated on 68Ga-DOTATATE and 18F-FDG PET Imaging
Authors: Jeremy Szajer, Grace Yung, Roberto Russo, Robert Mansberg
Journal: Clinical Nuclear Medicine (2017)

An 81-year-old man with Cushing syndrome was referred for a 68Ga-DOTATATE PET/CT study to investigate for an ectopic source of adrenocorticotropic hormone. The scan demonstrated mildly increased octreopeptide uptake at a rectal mass and focal uptake at multiple regions throughout the bone marrow of the axial skeleton, consistent with metastases. A subsequent 18F-FDG PET/CT study was performed for further evaluation and demonstrated markedly increased metabolism at the previously identified rectal mass, in addition to the liver and multiple regions throughout the skeleton. Histopathology from biopsy of the rectal mass confirmed a small cell neuroendocrine carcinoma.
Abstract 5162: Oligodendrocytes might up-regulate the invasiveness of glioblastoma cells via Angiopoietin-2 signaling pathway
Authors: Toshiyuki Kawashima
Journal: Cancer Research (2018)

Abstract Background &amp; Aims: Glioblastoma (GBM, WHO Grade IV) is considered as the most lethal neoplasm of all solid cancers due to its inherent intensive invasiveness. GBM may arise de novo, or following progression from lower grade gliomas. Recently, solid tumor progression has been recognized as the product of an evolving crosstalk between the cancer cells and its surrounding glial cells. The intensive invasion activity of GBM cells might be regulated by surrounding normal cells such as oligodendrocytes or fibroblasts. In this study, we evaluated the interactive factors between GBM cells and normal glial cells to determine the role of oligodendrocytes in regulating the invasiveness of glioblastoma cells. Methods: Two GBM cell lines, T98G and U251, were used. Two oligodendrocyte cell lines, ODC1 and ODC2, were derived one each from surgical tissues of patients with low-grade glioma (WHO Grade II). Two fibroblasts cell lines, GF1 and GF2, were derived one each from surgical tissues of patients with GBM. Oligodendrocytes and fibroblasts were confirmed by immuno-histochemical staining. The invasive property of GBM cells was analyzed in the presence or absence of conditioned medium from oligodendrocytes or fibroblasts by wound-healing assay and Boyden chamber invasion assay. The proliferation ability of GBM cells was examined by MTT assay. Subsequently Cytokine array was used to examine the cytokines and growth factors in the conditioned medium from oligodendrocytes or fibroblasts. Results: Oligodendrocyte cells, ODC1 and ODC2 cells, significantly (p&amp;lt;0.01) increased the migration and invasion ability of GBM cells, T98G and U251. In contrast, fibroblasts, GF1 and GF2 cells, did not affect the migration and invasion ability of GBM cells. Cytokine array indicated that Angiopoietin-2 was found in the conditioned medium from oligodendrocytes, but not that from fibroblasts. Angiopoietin-2 significantly (p&amp;lt;0.01) increased the invasiveness of GBM, but not their proliferation ability. Conclusion: Oligodendrocytes might up-regulation of the invasiveness of GBM cells via angiopoietin-2 signaling pathway. Hence, angiopoietin-2 can be considered as a promising target for the treatment of malignant gliomas. Citation Format: Toshiyuki Kawashima. Oligodendrocytes might up-regulate the invasiveness of glioblastoma cells via Angiopoietin-2 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5162.
Abstract LB-157: Association of aflatoxin and gallbladder cancer in Shanghai
Authors: Jill E. Koshiol, Yu-Tang Gao, Michael Dean, Patricia Egner, Chirag Nepal, Kristine Jones, Bingsheng Wang, Asif Rashid, Wen Lou, Alison Van Dyke, Catterina Ferreccio, Michael Malasky, Ming-Chang Shen, Bin zhu, Jesper Andersen, Allan Hildesheim, Ann W. Hsing, John Groopman
Journal: Cancer Research (2017)

Abstract Background: Aflatoxin, which is a risk factor for developing hepatocellular carcinoma, may also cause gallbladder cancer (GBC). We hypothesized that GBC patients have higher aflatoxin exposure than gallstone patients. Methods: We used samples and data from the Shanghai Biliary Tract Cancer Case-control Study conducted from 1997-2001. Of the 267 GBC and 730 gallstone participants with plasma available, 250 GBC patients and 250 controls with gallstones were randomly selected for measurement of aflatoxin B1 (AFB1)-lysine plasma adducts using isotope dilution mass spectrometry. In 54 GBC patients, tumor tissue was examined for the aflatoxin-related R249S TP53 mutation through targeted sequencing. Results: We calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (CIs), as well as the population attributable fraction (PAF). AFB1-lysine adduct detection was nearly 3-fold higher in GBC patients (OR, 2.96; 95% CI, 1.90 to 4.61). Among the 85 GBC patients (34%) with detectable AFB1-lysine adduct levels, the median was 4.6 pg/mg, compared to 1.2 pg/mg among the 37 gallstone-patient controls (15%) with detectable levels, and the OR was 9.97(95% CI, 2.73 to 36.44) for quartile 4 versus 1 in GBC compared to gallstone patients. The PAF for cancer related to aflatoxin was 22% (95% CI: 17%-27%). In 54 GBC patients, tumor tissue was examined for the aflatoxin-related R249S TP53 mutation through targeted sequencing, however, all patients were negative for the mutation. Conclusions: Aflatoxin is significantly associated with GBC, although it does not appear to be correlated with the R249S TP53 mutation in the gallbladder. If aflatoxin is shown to cause GBC, it may have accounted for up to 22% of the gallbladder cancers in Shanghai during the study period and may account for an even higher proportion in high-risk areas. If verified, reducing aflatoxin exposure may reduce GBC incidence. Citation Format: Jill E. Koshiol, Yu-Tang Gao, Michael Dean, Patricia Egner, Chirag Nepal, Kristine Jones, Bingsheng Wang , Asif Rashid, Wen Lou, Alison Van Dyke, Catterina Ferreccio, Michael Malasky, Ming-Chang Shen, Bin zhu, Jesper Andersen, Allan Hildesheim, Ann W. Hsing, John Groopman. Association of aflatoxin and gallbladder cancer in Shanghai [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-157. doi:10.1158/1538-7445.AM2017-LB-157
Abstract 4011: Validation of novel continuous live-cell assays for immune cell activation and killing of blood cell cancers
Authors: Nicola Bevan, Hinnah Campwala, Clare Szybut, Kalpana Patel, Dan Appledorn, Tim Dale, Derek Trezise
Journal: Cancer Research (2017)

Abstract The blood cancers leukaemia, lymphoma and myeloma are expected to cause the deaths of &amp;gt; 55,000 people in the US in 2016. New immunological approaches afford great promise for improved therapies. Here, we describe novel high throughput live-cell image-based assays for immune cell activation and killing of target cells that are geared toward screening for new treatments for these malignancies. Myeloid and lymphoid cells (Jurkats, Raji, Ramos, WIL2-NS, THP-1, PBMCs) were plated on poly-L-ornithine (PLO) or fibronectin coated 96-well flat plates and monitored over time (h to days) using non-invasive live-cell analysis (IncuCyte). The dynamics of proliferation were quantified via phase-contrast image analysis (% confluence), and validated as a robust measure of cell number by correlating to direct cell counts (Scepter, Millipore) and ATP assays (PerkinElmer). Anti-CD3/IL-2 (0.1-100/10 ng/mL) or anti-CD28 activation (1-100 ng/mL) of PBMCs evoked time-dependent proliferation (0-5d) that was sensitive to the initial cell density and concentration of stimulus. L-Kynurenine (4.69 - 300 µM), a metabolite of the amino acid L-tryptophan caused concentration and time-dependent inhibition of proliferation of PBMCs. To quantify immune-cell killing in co-cultures, WIL2Ns and Ramos B-cell myelomas were first transduced with nuclear-targeted RFP (NucLight Red) to enable direct cell counting. PBMCs, either pre-activated or activated in situ (IL-2/CD3), were then added and the time-course of killing quantified through live (RFP) and dead/apoptotic (annexin-V) cell counting. Together, these protocol developments and validation data illustrate non-invasive continuous measurement of proliferation, activation, clustering and immune-cell killing of non-adherent tumour cells at industrial scale. Unlike flow cytometry, this approach follows the full time-course of the biology without perturbing the cells and allows cell-cell interactions to be visualised. These assays are amenable to testing new therapeutic antibodies, small molecules and genetic T-cell modulation such as CAR-T. Citation Format: Nicola Bevan, Hinnah Campwala, Clare Szybut, Kalpana Patel, Dan Appledorn, Tim Dale, Derek Trezise. Validation of novel continuous live-cell assays for immune cell activation and killing of blood cell cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4011. doi:10.1158/1538-7445.AM2017-4011
Abstract LB-217: Microenvironment mediated mechanisms of resistance to HER2 inhibitors differ between HER2+ breast cancer subtypes
Authors: Spencer Watson, Joe Gray, James Korkola, Mark Dane, Laura Hesier, Koei Chin, Gordon Mills
Journal: Cancer Research (2017)

Abstract Clinical responses of HER2+ breast cancers to tyrosine kinase inhibitors (TKIs) are often limited by de novo and acquired resistance. Recent studies have shown that the tumor microenvironment has a substantial capacity to generate signals and create niches that enable otherwise sensitive cells to avoid therapeutic control. We describe here the use of MicroEnvironment MicroArrays (MEMAs) to identify specific signals from the tumor microenvironment that reduce sensitivity to small molecule HER2 targeted TKIs. We show here that responses to these signals differ between HER2+ cells that express transcriptional signatures associated with basal (HER2E) or luminal (L-HER2+) HER2+ subtypes. Specifically, we show that HER2E cell lines are rescued from the TKIs lapatinib and neratinib by hepatocyte growth factor (HGF), while L-HER2+ cell lines are rescued by neuregulin1-β1 (NRG1β). We further show that these divergent responses are due to differential use of the PI3K and MAPK pathways, and expression of receptors HER3 and MET. This is supported by transcriptomics of human tumors performed by The Cancer Genome Atlas. HGF and NRG1β are expressed in the stroma of primary mammary tumors, but can also be highly expressed in common sites of both HER2E and L-HER2+ metastasis. We show that NRG1β mediated resistance in L-HER2+ lines is reversed by inhibiting HER2-HER3 dimers with pertuzumab, while HGF mediated resistance in HER2E lines is reversed with the MET inhibitor crizotinib. These studies suggest that L-HER2+ and HER2E tumors should be treated as separate diseases and that treatments should be tailored to counter microenvironment mediated resistance mechanisms that may differ between metastatic locations based on local production and action of growth factors. Citation Format: Spencer Watson, Joe Gray, James Korkola, Mark Dane, Laura Hesier, Koei Chin, Gordon Mills. Microenvironment mediated mechanisms of resistance to HER2 inhibitors differ between HER2+ breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2017-LB-217