tbuckley/cabot-search huggingface dataset:
Abstract 2948: A distinct CD8+ tumor infiltrating lymphocyte subset is associated with high TIL density, enhanced cytotoxicity and improved survival in patients with lung cancer
Authors: Anusha Preethi Ganesan, Oliver Wood, Eva Garrido-Martin, Serena Chee, Toby Mellows, James Clarke, Daniela Samaniego-Castruita, Divya Singh, Gregory Seumois, Aiman Altezani, Edwin Woo, Peter Friedman, Gareth Thomas, Emma King, Tilman Sanchez-Elsner, Pandurangan Vijayanand, Christian H. Ottensmeier
Journal: Cancer Research (2017)

Abstract High tumor infiltrating lymphocyte (TIL) density predicts for good prognosis in several cancers and therapies that boost the anti-tumor responses of cytotoxic lymphocytes (CTLs) have shown promise in the clinic. However, clinical responses to currently available immunotherapeutic agents vary considerably, the molecular basis of which is unclear. We performed global transcriptional profiling of CTLs in tumors and adjacent non-tumor tissue from 36 patients with early stage lung cancer to define the molecular features associated with robustness and heterogeneity of anti-tumor immune responses. We observed major differences in the transcriptional program of tumor-infiltrating CTLs (CD8+ TILs) that is shared across tumor subtypes. Pathway analysis revealed enrichment of genes in cell cycle, TCR activation and co-stimulation pathways, indicating tumor-driven expansion of presumed tumor antigen-specific CTLs. We also observed marked heterogeneity in the expression of molecules associated with TCR activation and immune checkpoints, and their expression was positively correlated with the density of tumor-infiltrating CTLs. Interestingly, TILhigh tumors were also enriched for a distinct CD8+ tumor infiltrating lymphocyte subset that appeared to have enhanced cytotoxicity and independently predicted improved survival in patients with lung cancer. In summary, we define the molecular fingerprint of tumor-infiltrating CTLs and identify a number of novel targets that may be important in modulating the magnitude and specificity of anti-tumor immune responses in lung cancer. Citation Format: Anusha Preethi Ganesan, Oliver Wood, Eva Garrido-Martin, Serena Chee, Toby Mellows, James Clarke, Daniela Samaniego-Castruita, Divya Singh, Gregory Seumois, Aiman Altezani, Edwin Woo, Peter Friedman, Gareth Thomas, Emma King, Tilman Sanchez-Elsner, Pandurangan Vijayanand, Christian H. Ottensmeier. A distinct CD8+ tumor infiltrating lymphocyte subset is associated with high TIL density, enhanced cytotoxicity and improved survival in patients with lung cancer [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 2948. doi:10.1158/1538-7445.AM2017-2948
Abstract 5773: Automation and miniaturization of 3D tumor models for compound screens
Authors: Michael Kowalski, Kayla Hill, Vipat Raksakulthai, Kristin Prasauckas, Tara Jones-Roe
Journal: Cancer Research (2017)

Abstract Three-dimensional (3D) systems of cell culture can provide a more representative model of solid tumors and more physiologically relevant outputs from drug screens than two-dimensional cell cultures. A diverse array of 3D models have been used to investigate tumor physiology and susceptibility to chemotherapeutics but all of these models present challenges to establish and manipulate at the high throughputs required for screens. Cancer spheroids are large clusters of cells formed in suspension to replicate the gradients of gases, nutrients, and drugs seen by solid tumors. In contrast, Matrigel® or other hydrogel cultures are often used to replicate native cell morphology and polarity or to enable studies of 3D structure formation or cell migration. To overcome manual challenges and improve reliability, we automated the plating, drug treatment, and analysis of these 3D models. We were able to form consistent cancer spheroids in both hanging drop and low attachment plates and used imaging and flow cytometry to gain a more complete understanding of the cytotoxic drug response in this model. Cells were also plated on top of and embedded within Matrigel and cell growth and apoptosis induction was measured with standard and confocal imaging approaches. Both 3D models were miniaturized to 384-well format, thereby enabling the throughput required for large-scale screens to identify novel cancer treatments. Citation Format: Michael Kowalski, Kayla Hill, Vipat Raksakulthai, Kristin Prasauckas, Tara Jones-Roe. Automation and miniaturization of 3D tumor models for compound screens [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 5773. doi:10.1158/1538-7445.AM2017-5773
Abstract 1351: Alternative splicing of neurofibromin 1 is associated with elevated MAPK activity and poor prognosis in glioma
Authors: Robert Siddaway, Arun Ramani, Man Yu, Michael Brudno, Cynthia Hawkins
Journal: Cancer Research (2017)

Abstract High-grade gliomas (HGG) are invasive with poor prognosis regardless of age: diffuse intrinsic pontine gliomas (DIPG), arising in the brainstem, are almost universally fatal and the leading cause of brain-tumor death in children; while adult anaplastic astrocytoma and glioblastoma multiforme (GBM) have median survivals of 1-3 years. The mutational spectra of adult and pediatric HGG differ, with pediatric tumours containing recurrent mutations of H3F3A and HIST1H3B. However, alterations leading to RAS/MAPK/PI3K pathway activation, including PDGFRA amplification, EGFRvIII, BRAF-V600E, NF1 deletion, are frequently found, although not all tumours will have mutations in this pathway. The neurofibromin 1 (NF1) gene negatively regulates RAS signalling by stimulating RAS-GTP turnover, thereby leading to RAS-inactivation. The two major isoforms, NF1-I and NF1-II, differ only by inclusion of the 21 aa exon23a in the GAP-related domain of NF1-II. Exon23a-inclusion has been shown to render NF1 10 times less active towards RAS, leading to elevated MAPK signalling. The brain expresses predominantly NF1-I, while the major isoform elsewhere is NF1-II. Here we used RNA-Seq to identify genes alternatively spliced between DIPG and normal brain, identifying an isoform switch from NF1-I in normal brain to NF1-II; we additionally found the same isoform switch in the TCGA adult GBM and LGG cohorts. For both GBM and LGG, RAS/MAPK/PI3K wild-type tumors with elevated NF1-II conferred significantly reduced patient survival compared to RAS/MAPK/PI3K mutant tumors. NF1-exon23a inclusion is known to be repressed in cell model systems by the CELF and ELAV-like families of splice regulators. We further show that members of these gene families are downregulated in HGG. Together, our results indicate a novel mechanism by which gliomas can activate signaling downstream from RAS independent of mutations and tumor grade, which promotes tumorigenesis by regulating pathways such as proliferation and invasion. Citation Format: Robert Siddaway, Arun Ramani, Man Yu, Michael Brudno, Cynthia Hawkins. Alternative splicing of neurofibromin 1 is associated with elevated MAPK activity and poor prognosis in glioma [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 1351. doi:10.1158/1538-7445.AM2017-1351
Abstract 3926: Is FGD3 a potentially prognostic marker for breast cancer
Authors: Yuliang Sun, Scooter Willis, Xiaoqian Lin, Justin Achua, Casey Williams, Brian Leyland-Jones
Journal: Cancer Research (2017)

Abstract Background: Prognostic factors are capable of providing information on clinical outcomes at the time of diagnosis; they are usually indicators of growth, invasion, and metastatic potential (Gasparini G. et al. 1993; Hayes DF. et al. 1998). Tissue marker is one of the prognostic factors; to date, only a small proportion of markers are ultimately clinically useful, including Ki-67 and HER2. Faciogenital dysplasia 3 protein (FGD3), a putative regulator of cell morphology and motility, has been shown to regulate cell migration. In a study of 3,256 tumors, low expression of FGD3 mRNA indicates poor outcome (Hayakawa M. et al. 2008; Scooter W. et al. 2014). However, an immunohistochemistry (IHC) study to evaluate FGD3 protein expression has not been done. We hypothesize that the expression levels of FGD3 protein by IHC might improve the prediction of patient outcomes, and FGD3 might be a potentially prognostic marker of breast cancer. Materials and Methods: 322 cases of breast cancer Tissue Microarrays (TMA) (BR1504a, BR1505b, HBre-Duc068Bch-01, and BR20837) were purchased from US Biomax, Inc (Rockville, MD). Rabbit polyclonal antibody against FGD3 was purchased from Novus Biologicals, LLC (Littleton, CO). Tissue cores were stained for FGD3 with Dako’s EnVision + Dual Link System. Image acquisition was performed using an Olympus camera and software. FGD3 protein expression by IHC was quantitatively determined in the range of 0-4. Unpaired t-test was used for data analyses. Results: 1) Benign tumor and breast adenocarcinomas in lower stages showed strong expression of FGD3, whereas the breast adenocarcinomas in higher stages showed mild ~ weak expression. 2) Invasive breast cancer in stage IIA showed strong FGD3 expression compared to matched metastatic carcinoma which showed mild expression of FGD3. 3) FGD3 protein levels for tumors (n=135) with N0 indicating no regional lymph node metastasis were compared with tumors with lymph node metastasis (N1-3; n=98) and corresponding matched metastatic tissue (n=103). An unpaired t-test comparing N0 vs. N1-3 showed lymph node metastasis is associated with lower FGD3 protein levels (p&amp;lt;0.0001). Conclusion: FGD3 protein expression levels within breast tumors were different according to metastatic status. Our IHC results suggest the possibility of FGD3 to be a prognostic marker in patients with breast cancer. Citation Format: Yuliang Sun, Scooter Willis, Xiaoqian Lin, Justin Achua, Casey Williams, Brian Leyland-Jones. Is FGD3 a potentially prognostic marker for breast cancer [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 3926. doi:10.1158/1538-7445.AM2017-3926
Abstract 2110: Anti-invasive and antimetastatic actions of omega-3 polyunsaturated fatty acids in glioblastoma cells
Authors: Soyeon Kim, Soyeon Shin, Soyeon Jeong, Seung-Hyeon Han, Yoon-Seon Yoo, Prashanta Silwal, Young-Joo Jeon, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim
Journal: Cancer Research (2017)

Abstract Glioblastoma (GBM) is the most aggressive and deadliest brain malignancy in adults. Despite of surgical techniques, radiotherapy and chemotherapy, GBM has remained an invariably lethal tumor with a median survival less than 15 months. Although the anticancer mechanisms of omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been reported in several cancers, it is still unclear in brain cancer. Here, our data show the anti-invasive and anti-metastatic effects of ω3-PUFAs in GBM. Invasiveness using transwell chamber was inhibited by docosahexaenoic acid (DHA) treatment in D54MG and GL261 cells. In zymography, MMP-2 activity was suppressed by DHA in a dose dependent manner. MMP-2 promoter activity was also decreased. DHA inhibited both p-STAT3 and β-catenin levels that contribute to invasion by stimulating pro-invasion factors such as MMP-2. Additionally, fat-1 (ω3-desaturease) stable D54MG cell was established and the effect of the high level of ω3-PUFAs was investigated endogenously. The invasiveness were significantly inhibited in the fat-1 stable cells compared to control cell. Moreover, the metastasis in vivo was significantly reduced when GL261 mouse glioma cells were injected through tail vein into the fat-1 transgenic mice. In immunohistochemistry, intensity of p-STAT-3 and β-catenin were significantly weak in metastatic lung tumor from Fat-1 mice compared to wild type mice. These results indicate that anti-invasive and anti-metastatic actions of ω3-PUFA may be correlated with inhibition of MMP-2 through decrease of STAT3 and β-catenin in GBM cells. Thus, these findings provide important preclinical evidence and molecular insight for utilization of ω-3 PUFAs for the chemoprevention and treatment of human GBM. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2007-0054932, NRF-2015R1D1A1A01056887) and by the framework of international cooperation program managed by National Research Foundation of Korea (2015K2A2A6002008)]. Citation Format: Soyeon Kim, Soyeon Shin, Soyeon Jeong, Seung-Hyeon Han, Yoon-Seon Yoo, Prashanta Silwal, Young-Joo Jeon, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim. Anti-invasive and antimetastatic actions of omega-3 polyunsaturated fatty acids in glioblastoma cells [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 2110. doi:10.1158/1538-7445.AM2017-2110
Abstract 1316: Germline genetic signals across multiple aggressive prostate cancer phenotypes
Authors: Caroline G. Tai, Nima C. Emami, Thomas J. Hoffmann, Lori C. Sakoda, Eric Jorgenson, Laurel A. Habel, Jun Shan, Dilrini K. Ranatunga, Chun R. Chao, Nirupa R. Ghai, David Aaronson, Joseph Presti, Catherine Schaefer, Neil Risch, Stephen K. Van Den Eeden, John S. Witte
Journal: Cancer Research (2017)

Abstract Prostate cancer (PrCa) is documented to be highly heritable. But many known prostate cancer loci are not associated with aggressive prostate cancer phenotypes such as high-grade cancer or biochemical failure. Previous efforts have been largely underpowered or not replicated. We conducted a study of 6,321 men with PrCa and 5,663 controls of European ancestry recruited from Kaiser Permanente (KP) matched by age and self-reported race. Phenotype data combined patient-level demographic, clinical, and tumor data from KP databases with data from 1994 to 2016. High-grade PrCa was defined using Gleason score: low-grade defined as ≤ 7 (3+4), high-grade defined as ≥ 7 (4+3). Biochemical failure was defined for cases using post-treatment prostate specific antigen (PSA) values: post-surgery failure if PSA ≥ 0.4 ng/mL; post-radiation failure if PSA value ≥ 2 ng/mL + nadir; and no failure if PSA did not reach specified threshold. Early-onset disease was defined as age &amp;lt; 55 years at diagnosis. Men were genotyped for over 650,000 SNPs using an ethnic-specific Affymetrix Axiom array and imputed to 1000 Genomes. We tested genetic associations for multiple aggressive phenotypes (410 early-onset cases, 1324 biochemical failure cases, and 886 high grade cases) in both a case-only (e.g., high vs. low grade) and case-control (e.g., high grade vs. no prostate cancer controls) analysis using logistic regression adjusting for ancestry principal components, age, BMI, and kit for batch effects. PrCa specific mortality was too rare to be evaluated. We identified several known and novel loci. Case-control analyses highlighted known prostate cancer loci at 8q24, 10q11, 11q13, 16q22, and 19q13. Previous reports of case-only analyses also identified 8q24, 20p13 and the gene, KLK3 in 19q13, to be associated with high-grade PrCa; we confirmed these signals in our study. Previous family-based studies identified 15q11 as a familial or early-onset prostate cancer locus. These aggressive-specific variants could perform better in predicting clinically actionable prostate cancers than variants for overall prostate cancer and can improve the predictive ability of pre-diagnostic PSA. Citation Format: Caroline G. Tai, Nima C. Emami, Thomas J. Hoffmann, Lori C. Sakoda, Eric Jorgenson, Laurel A. Habel, Jun Shan, Dilrini K. Ranatunga, Chun R. Chao, Nirupa R. Ghai, David Aaronson, Joseph Presti, Catherine Schaefer, Neil Risch, Stephen K. Van Den Eeden, John S. Witte. Germline genetic signals across multiple aggressive prostate cancer phenotypes [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 1316. doi:10.1158/1538-7445.AM2017-1316
Keratoacanthoma management: results of a survey of U.K. dermatologists and surgeons
Authors: R.E. Watchorn, S. Thomas, C. Miller, R.A. Carr, D. Koch, P. Thomas, S.M. Taibjee
Journal: British Journal of Dermatology (2017)

Distinction of keratoacanthoma (KA) from squamous cell carcinoma (SCC) is challenging. Management is controversial, with some advocating prompt surgical excision and others monitoring to allow for spontaneous resolution(1) . The controversy is compounded by rare reports of metastasis(2) . And yet the benign natural history of KA is supported by various studies, including a systematic review of 455 cases with no cases of metastasis or death(1) , and observational studies confirming spontaneous resolution(1).
Abstract 2012: UVB-induced ULBP1 upregulation in melanocytes depends on HMGB1-mediated activation of NF-κB and IRF3
Authors: Zhaohui Wu, Wei Wang
Journal: Cancer Research (2017)

Abstract Anti-tumor immune surveillance mediated by innate immunity cells such as NK cells plays a critical role in eliminating “damaged” cells at precancerous stage and preventing cancer progression. As a key epidemiological factor associated with melanoma, solar UV radiation also elicit immunosurveillance by upregulating ligands for NK cell activating receptor NKG2D. Nevertheless, how UVR upregulates NKG2DL in melanocytes is not completely understood. We found UVB exposure induced secretion of damage-associated molecular patterns molecule HMGB1 from skin cells. HMGB1 activates transcription factors NF-κB and IRF3 in melanocytes which synergistically enhances NKG2D ligand ULBP1 transcription. Moreover, RAGE is essential for HMGB1-induced activation of NF-κB and IRF3, which serves as the HMGB1 receptor and mediates activation of TBK1. Consistently, HMGB1 deficient melanoma cells are less susceptible to NK cells mediated cytotoxicity. Our study provides a mechanistic link between environmental UV radiation and antitumor immunosurveillance induced in melanocytes, which may play a critical role in the early stages of melanomagenesis. Citation Format: Zhaohui Wu, Wei Wang. UVB-induced ULBP1 upregulation in melanocytes depends on HMGB1-mediated activation of NF-κB and IRF3 [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 2012. doi:10.1158/1538-7445.AM2017-2012
Abstract 5450: Urinary microRNA as diagnostic and prognostic biomarkers for prostate cancer
Authors: Jacob Fredsøe, Anni K. Rasmussen, Anni R. Thomsen, Peter Mouritzen, Søren Høyer, Michael Borre, Torben F. Ørntoft, Karina D. Sørensen
Journal: Cancer Research (2017)

Abstract Widespread use of Prostate Specific Antigen (PSA) testing for prostate cancer (PC) detection has led to extensive overdiagnosis and overtreatment. Thus, we aimed to train and validate urine-based microRNA (miRNA) biomarkers that may assist in the diagnosis and prognosis of PC. To this end, we profiled the expression levels of 92 miRNAs by RT-qPCR in exosome-enriched cell-free urine samples from 20 patients with benign prostatic hyperplasia (BPH) and 188 patients with clinically localized PC (cohort 1). The diagnostic potential of individual miRNAs and multi-miRNA ratio models were assessed by receiver operating characteristic (ROC) curve analysis. Prognostic potential was evaluated by Kaplan-Meier, uni- and multivariate Cox regression analyses using biochemical recurrence (BCR) after radical prostatectomy (RP) as endpoint. Our findings were validated in an independent cohort of 20 BPH patients and 197 patients with clinically localized PC (cohort 2). We identified and validated several deregulated miRNAs in urine samples from PC patients. In addition, we trained a novel diagnostic 3-miRNA model that distinguished BPH and PC patients with an area under the curve (AUC) of 0.95 in cohort 1, and which was successfully validated in cohort 2 (AUC=0.89). Furthermore, we trained a novel prognostic 3-miRNA model that predicted time to BCR after RP independently of routine clinicopathological parameters in cohort 1, and was successfully validated in cohort 2. Citation Format: Jacob Fredsøe, Anni K. Rasmussen, Anni R. Thomsen, Peter Mouritzen, Søren Høyer, Michael Borre, Torben F. Ørntoft, Karina D. Sørensen. Urinary microRNA as diagnostic and prognostic biomarkers for prostate cancer [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 5450. doi:10.1158/1538-7445.AM2017-5450
Abstract LB-220: A microfluidic model for real-time monitoring of tumor-lymphocyte interactions
Authors: Nathan Moore, Daniel Doty, Jose Santos, Louis B. Kratchman, Stephanie Angione, Vienna Mott, Mark Zielstroff, Hongmin Chen, Alla Gimbel, Jeffrey Borenstein
Journal: Cancer Research (2017)

Abstract The emergence of immune checkpoint inhibitors and the promise of increased patient survival reinforces the potential for targeting the tumor microenvironment as a drug development strategy. The tumor microenvironment consists of a heterogeneous composition of cancer cells, vascular cells, fibroblasts, and immune cells that are regulated by both intrinsic and extrinsic chemical and physical stimuli. Within this microenvironment, aberrant blood vessel formation and extra cellular matrix (ECM) restructuring lead to increased interstitial fluid flow and shear stress that stimulate differential gene expression, reorganization of tumor cell structure, and suppression of local cytotoxic T-cell activity. Elevated levels of fluid pressure and shear stress have also been demonstrated to alter cell sensitivity and response to therapeutic agents. Traditional static 2D in vitro models fail to adequately address tumor-immune cell interactions and flow mediated change in sensitivity, contributing to inaccurate predictions of in vivo therapeutic response. The development of 3D microfluidic systems have greatly enhanced the ability to model components of the tumor microenvironment, such as fluid flow, and capture the dynamics of tumor and immune cell responses to emerging therapeutic compounds. Here, we have developed a medium throughput microfluidic device which is constructed using bioinert materials that are also compatible with real-time confocal imaging, to model the effects of therapeutic treatment on tumor viability. In addition to exposing tumors to a dynamic flow environment, this model system enables the introduction of flowing lymphocytes, permitting tracking of tumor-lymphocyte interactions in real-time. As a test case, we demonstrate the ex vivo binding and cytotoxic activity of MC38-derived tumor infiltrating lymphocytes (TILs) on tumor fragments. These results highlight the power of a dynamic microfluidic flow system to model the tumor-lymphocyte microenvironment and the potential of this system to more accurately evaluate novel therapeutic agents. Citation Format: Nathan Moore, Daniel Doty, Jose Santos, Louis B. Kratchman, Stephanie Angione, Vienna Mott, Mark Zielstroff, Hongmin Chen, Alla Gimbel, Jeffrey Borenstein. A microfluidic model for real-time monitoring of tumor-lymphocyte interactions [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-220. doi:10.1158/1538-7445.AM2017-LB-220