tbuckley/cabot-search huggingface dataset:
Abstract 1791: Spatially positioned tumor infiltrating lymphocytes predict survival in metastaticHER2positive breast cancer treated with trastuzumab
Authors: Jussi Pekka Koivunen, Tiia Honkanen, Tiina Moilanen, Peeter Karihtala, Juha Väyrynen, Markus Mäkinen
Journal: Cancer Research (2017)

Abstract Background: Disease outcomes of HER2+ breast cancers have dramatically changed after targeted therapies, such as trastuzumab, came to clinical practice but predictive factors for trastuzumab sensitivity and resistance are frequently unknown. Methods: Metastatic breast cancer patients (n=48), who were treated with trastuzumab and had pre-treatment tumor samples available, were studied. The tumors were immunostained for T-cell (CD3, CD8) and NK-cell (CD56) markers and quantitative analysis of the immune cells was carried out using a computer-assisted image analysis in different tumor locations. Results: High number of CD3 and CD8 positive T-cells was associated with significant survival benefit in the center of the tumor (CT) (p=0.007, p=0.001), but not in the invasive region. NK-cell tumor infiltration was infrequent and they could not be reliably analyzed. In a subgroup analyses, high density of CD8 CT cells was associated with significant survival benefit in non-bone only disease, in TX-3, and in ER+ tumors (p=0.006, p=0.003, p=0.001). Moreover, high CD8 CT cell density was associated with good trastuzumab responses (p=0.042). Conclusion: High number of CD3 and CD8 positive tumor infiltrating lymphocytes in the CT area is associated with survival benefit in some patient groups with HER2+ breast cancer treated with trastuzumab. Furthermore, high number of CD8 CT cells predicts benefit from trastuzumab. Citation Format: Jussi Pekka Koivunen, Tiia Honkanen, Tiina Moilanen, Peeter Karihtala, Juha Väyrynen, Markus Mäkinen. Spatially positioned tumor infiltrating lymphocytes predict survival in metastatic HER2 positive breast cancer treated with trastuzumab [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 1791. doi:10.1158/1538-7445.AM2017-1791
Abstract 5676: Functional pairing of immunomodulatory targets in anaplastic thyroid cancer
Authors: Sanjukta Chakraborty, Rachana R. Maniyar, Neha Y. Tuli, Ghada Ben Rahoma, Cameron Budenz, Sarnath Singh, Jan Geliebter, Raj Tiwari
Journal: Cancer Research (2017)

Abstract Thyroid cancer is the most common type of endocrine malignancy that has an escalating global frequency. Although most well differentiated thyroid cancers (WDTC) are manageable and respond to current therapeutic modalities, undifferentiated anaplastic thyroid cancers (ATC) exhibit a dramatically different clinical behavior and poor prognosis. With the recent development of immunotherapies, targeted, well-defined treatment plans can demonstrate promising treatment outcomes in ATC patients. Precise immunological targets in ATCs with potential clinical relevance are unknown. Major progress has been made in last 5 years toward development of immune checkpoint inhibitors using anti-CTLA-4 and anti-PD-1/PD-L1 antibodies for cancer treatment which has made immunotherapies one of the mainstream treatment choices. Few additional members of the immunoglobulin superfamily of receptors, like LAG3, TIM3 and VISTA have recently been identified as potential checkpoint targets. Interestingly some of these molecules including TIM3 and PD-L1 promote tumor progression and immune escape. Identification of specific immunotherapeutic targets requirs a better understanding of the immune microenvironment in ATC. To this end we evaluated the expression of prominent co-stimulatory and co-inhibitory cell surface molecules by RT-PCR in three thyroid cancer cell lines - TPC-1 (papillary), CGTH-W-1 (follicular) and 8505C (anaplastic). We observed that many co-inhibitory molecules were upregulated in all three tumor cell lines. CTLA4, interestingly, had the highest expression in 8505C. Additionally we observed differential expression of BTLA, LAIR1, TIM3 and VISTA between TPC-1 and 8505C. LAG3, PD-1 and PD-L1 were also upregulated in 8505C compared to TPC-1. Similar pattern was observed with the expression of co-stimulatory molecules, CD40L and GITR . GITR has been shown to have a tumor suppressor function in multiple myeloma. Another co-stimulatory molecule OX40, which has shown promise in tumor recession when targeted, was upregulated in all three cell lines and 8505C showed the highest expression. Our findings suggest that the aggressive and less immunogenic phenotype of ATC might be attributed to the differential expression of these molecules. Targeting these immunomodulatory molecules in ATC warrants a better understanding of the crosstalk between them and it might provide an efficient means for the disease management. Citation Format: Sanjukta Chakraborty, Rachana R. Maniyar, Neha Y. Tuli, Ghada Ben Rahoma, Cameron Budenz, Sarnath Singh, Jan Geliebter, Raj Tiwari. Functional pairing of immunomodulatory targets in anaplastic thyroid 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 5676. doi:10.1158/1538-7445.AM2017-5676
Abstract 3288: Effects of concomitant metformin and statins on overall survival of pancreatic cancer patients: results from SEER-Medicare data analyses
Authors: Jian-Yu E, Shou-En Lu, Yong Lin, Judith M. Graber, David Rotter, Lanjing Zhang, Gloria M. Petersen, Kitaw Demissie, Grace Lu-Yao, Xiang-Lin Tan
Journal: Cancer Research (2017)

Abstract Purpose: Growing mechanistic and epidemiologic evidence suggests that both metformin and statins have anti-cancer effects and are associated with reduced pancreatic cancer mortality. However, the joint effect of combination statin/metformin on pancreatic cancer mortality is unknown. By applying a robust analytic approach, we aim to examine the association between metformin and/or statin use and overall survival in a large cohort of patients with primary pancreatic adenocarcinoma (PDAC). Patients and Methods: 12,572 elderly patients with primary PDAC diagnosed between 2008 and 2012 were identified by using the Surveillance, Epidemiology, and End Results (SEER), and the detailed information on metformin and statin use was extracted from Medicare Part D. A Cox proportional hazard model with time-varying covariate adjusted for the propensity score was applied to assess the association of metformin and /or statin use with overall survival while controlling for potential confounders. Results: Of total 12,572 PDAC patients (median age = 76 years), 11,526 (91.77%) patients died before the study ended with a median follow-up of 3.8 months (interquartile range: 1.4-10.1). By the time-varying covariate analysis, statin use was significantly associated with an improved overall survival [Hazard ratio (HR), 0.938; 95% confidence interval (CI), 0.898 to 0.979], and more pronounced in post-diagnosis statin users (HR, 0.693; 95% CI, 0.555 to 0.864). However, metformin use was not significantly associated with overall survival (HR, 1.011; 95% CI, 0.939 to 1.091), neither in pre-diagnosis users (HR, 1.015; 95% CI, 0.970 to 1.061) nor in post-diagnosis users (HR, 0.990; 95% CI, 0.866 to 1.131). Additionally, no superior beneficial effect was observed for dual users (HR, 0.998; 95% CI, 0.947 to 1.053). Conclusions: Exposures to statin, not metformin, was significantly associated with reduced overall mortality of PDAC, indicating potential benefits of statin use on improving survival among PDAC patients. Further prospective validation is required to confirm these findings. Citation Format: Jian-Yu E, Shou-En Lu, Yong Lin, Judith M. Graber, David Rotter, Lanjing Zhang, Gloria M. Petersen, Kitaw Demissie, Grace Lu-Yao, Xiang-Lin Tan. Effects of concomitant metformin and statins on overall survival of pancreatic cancer patients: results from SEER-Medicare data analyses [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 3288. doi:10.1158/1538-7445.AM2017-3288
Abstract 2935: Sex disparity in the response of the immune microenvironment to colon cancer liver metastases
Authors: Simon Milette, Ni Wang, Stéphanie Perrino, Pnina Brodt
Journal: Cancer Research (2017)

Abstract Background Metastasis remains the most life-threatening aspect of malignant disease and a major clinical challenge. Myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes (Tregs), which are frequently found in the tumor microenvironment, are known to impair immune surveillance and promote a state of immune tolerance that leads to metastatic expansion. Previously, we have shown that the incidence of colon carcinoma liver metastases was reduced in TNF receptor 2 (TNFR2) deficient female mice, as a consequence of reduced recruitment of MDSCs and Tregs into the liver. Intriguingly however, no reduction in liver metastasis or MDSC/Treg accumulation was observed in TNFR2 deficient male mice, suggesting that their recruitment and survival were distinctly regulated. The objective of this study was, therefore, to elucidate the mechanisms underlying the sex disparity observed in the response of the immune microenvironment to liver metastases, in particular the role of sex hormones in immune response regulation in this context. Methods Hormone-ablated female mice were generated using surgical ovariectomy (OVX). Estrogen-deprived mice, sham-operated controls and hormone reconstituted OVX mice were injected with syngeneic murine colon carcinoma MC-38 cells via the intrasplenic/portal route and experimental liver metastases enumerated 2 weeks later. MDSCs and Tregs recruited into the livers of tumor-bearing mice were analyzed 7-10 days post-tumor injection using flow cytometry, as well as IHC performed on liver cryostat sections. Results We found that the number of experimental liver metastases was markedly reduced in ovariectomized female mice, as compared to sham-operated controls but was restored in estradiol supplemented OVX mice. Reduced incidence of hepatic metastases in OVX mice correlated with reduced accumulations of CD11b+Gr-1+ myeloid cells (MDSCs) and CD4+Foxp3+ cells (Tregs) at metastatic sites. IHC also revealed an increased CD8+ : CD4+Foxp3+ (i.e. cytotoxic T cell : Treg) ratio around hepatic metastases in OVX mice as compared to sham-operated controls. Estradiol reconstitution in OVX mice restored MDSC and Treg cell accumulation to the levels observed in control mice. Conclusion Together, our data identify female sex hormones as major players in the regulation of the tumor immune microenvironment and a potential contributing factor in the patients’ response to immune-based cancer therapy. Supported by the Canadian Institute for Health Research, MDEIE and FRSQ. Citation Format: Simon Milette, Ni Wang, Stéphanie Perrino, Pnina Brodt. Sex disparity in the response of the immune microenvironment to colon cancer liver metastases [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 2935. doi:10.1158/1538-7445.AM2017-2935
Abstract 15528: Immunoproteasome Activation During Mouse Adenovirus Type 1 Myocarditis
Authors: Mary K McCarthy, Rachael E Levine, Megan C Procario, Saul R Powell, Sharlene M Day, Jason B Weinberg
Journal: Circulation (2013)

The immunoproteasome (IP) is essential for generation of peptides that are presented by MHC class I molecules to CD8 T cells. IP activity is also critical for IκB degradation, facilitating NF κB-mediated activation of inflammatory responses. As such, the IP is likely to contribute to pathology in viral myocarditis. Adenoviruses (Ad) are common causes of viral myocarditis, but their strict species specificity precludes detailed studies of human Ad myocarditis. We have established mouse adenovirus type 1 (MAV-1) as a novel model to study Ad pathogenesis. We used MAV-1 to test the hypothesis that IP activation contributes to Ad-induced myocarditis. Neonatal C57BL/6 mice were infected intranasally with MAV-1 or mock infected with conditioned media. Routine staining was used to assess cardiac inflammation and myocyte damage. Real-time PCR was used to quantify DNA viral loads and mRNA levels of IFN-γ, a key inducer of IP activity, and IP subunits β5i, and PA28α. Western blot was used to quantify protein levels of IP subunits β5, β5i, PA28Sα, and PA28Sβ. Active β5 and β5i subunits were quantified using PROCISE assay. Peak IFN-γ upregulation and peak viral loads were detected at 10 days post infection (dpi). Cellular inflammation and myocyte necrosis were most pronounced between 10 and 14 dpi. PA28α and β5i mRNA levels were upregulated in infected hearts coincident with peak viral replication and IFN-γ expression. Similarly, there were substantial increases in β5i, PA28α, and PA28β protein and a striking decrease of β5 protein in infected hearts at 11 dpi (Table). We detected a corresponding increase in β5i active subunits and decrease in β5 active subunits, with an overall increase in the β5i:β5 ratio at 11 dpi (Table). MAV-1 infection causes myocarditis characterized by cellular inflammation, IFN-γ upregulation, and IP activation. Inhibition of IP activity may provide a novel approach to decrease cardiac damage induced by Ad or other pathogens.
Abstract 526: NFκB p65 overexpression promotes bladder cancer migration via FBW7-mediated degradation of RhoGDIα protein
Authors: Yang Li, Junlan Zhu, Jingxia Li, Chuanshu Huang
Journal: Cancer Research (2017)

Abstract Since bladder cancer (BC) is one of the most lethal urological malignant tumors worldwide, understanding the molecular mechanisms that trigger the migration, invasion and metastasis of BC has great significance in reducing the mortality of this disease. RelA/p65, a member of the NF-kappa B transcription factor family, is increasingly recognized as a crucial player in many steps of cancer initiation and progression. In this study, we unexpectedly found that p65 protein expression increased in the bladder carcinogen N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced high invasive bladder tumor tissues, and in human bladder cancer cell lines. We also observed that p65 overexpression promoted bladder cancer cell migration by inhibiting RhoGDIα expression. We further demonstrate that the regulatory effect of p65 on RhoGDIα expression is mediated by its upregulation of FBW7, which specifically interacted with RhoGDIα and promoted RhoGDIα ubiquitination and degradation. Mechanistic studies revealed that p65 stabilizing the E3 ligase FBW7 protein was mediated by its attenuating Pten transcription. Taken together, p65 overexpression results in Pten downregulation, and FBW7 protein degradation, and in turn leading to RhoGDIα protein degration and promotings human BC cell migration. The identification of p65/PTEN/FBW7/RhoGDIα axis provides a significant insight into understanding the nature of BC migration. Note: This abstract was not presented at the meeting. Citation Format: Yang Li, Junlan Zhu, Jingxia Li, Chuanshu Huang. NFκB p65 overexpression promotes bladder cancer migration via FBW7-mediated degradation of RhoGDIα protein [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 526. doi:10.1158/1538-7445.AM2017-526
Abstract 5717: PKR promotes EphA2 and other proteins degradation and is predictor of survival in lung cancer
Authors: Apar Pataer, Ruping Shao, Bulent Ozpolat, Bingliang Fang, Stephen G. Swisher
Journal: Cancer Research (2017)

Abstract Relative expression of PKR and EphA2 was a significant predictor of survival in non-small cell lung cancer. To study the PKR-regulated protein, we evaluated expression of 149 proteins in lung cancer cells by reverse-phase protein assay (RPPA) after induction of PKR. Expression of several proteins (EphA2, IRS1, Chk1 and c-Raf and paxillin) was inhibited by PKR. In validating the downregulated proteins by western blot analysis, we observed that PKR reduced EphA2, IRS1, Chk1 and paxillin protein expression. We next investigated the involvement of the proteasomes and lysosomes in PKR-induced protein degradation. Human lung cancer H1299 and A549 cells were transfected with Ad-PKR for 48 h in the presence or absence of the proteasome inhibitor MG132 or lysosome inhibitor (3MA: 3-methyladenine). We observed that MG132 prevented PKR-induced IRS1 and Chk1 degradation, but not PKR-induced EphA2 and paxillin degradation in these cells. However, we found that 3MA prevented PKR-induced EphA2 and paxillin degradation in these cells. These data suggest that PKR is involved in proteasome as well as lysosome function. To study the involvement of autophagy pathway in PKR mediated protein degradation, we evaluated proteins which known involved in autophagy by Western blotting after induction of PKR on these cancer cells. We observed slightly decrease of LC-3, ATG5 and Beclin1 in these cancer cells after induction of PKR. Our data suggest that PKR may directly involve in in lysosome function. Citation Format: Apar Pataer, Ruping Shao, Bulent Ozpolat, Bingliang Fang, Stephen G. Swisher. PKR promotes EphA2 and other proteins degradation and is predictor of survival in 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 5717. doi:10.1158/1538-7445.AM2017-5717
Abstract 381: Genomic alterations in mucins in cancer
Authors: Ryan J. King, Fang Yu, Pankaj K. Singh
Journal: Cancer Research (2017)

Abstract Mucins promote the growth, aggressiveness, and invasiveness of various cancer types. Changes in the expression or localization of mucins can significantly alter patient survival. Due to their predominance in multiple cancers, biomarkers and therapeutic agents have been developed to improve patient care. However, an extensive investigation across multiple cancer subtypes examining the genomic status of the cohort of mucins has not been performed and could yield significant leads into new roles of mucins in different cancers. Utilizing The Cancer Genome Atlas, the cancers of 11 mucin expressing tissues were examined for the genomic alterations in mutations, mRNA expression levels, copy numbers, methylation status, and the impact on patient survival due to these genomic features. It was discovered that different mucins across multiple tissue origins and cancer subtypes might have a different rate, pattern, and survival impact. MUC1 was not mutated in the majority of cancers; however, we did observe a frequent T112P mutation in pancreatic tumors that was also present in other cancers. MUC4 was frequently mutated at H4205 and MUC4 mutations were seen to have survival differences. Multiple significant differences were discovered in mRNA expression, which varied distinctly between cohorts. One such pattern was observed with de novo expression of MUC21 in colorectal cancers, in which mRNA expression was suddenly induced in cancer and increased in a stage dependent manner. Copy number alterations were seen for only a few cancer subtypes and mucins, including MUC4 in lung squamous cell carcinomas. Global promoter demethylation was generally observed across the cancers. MUC15 in renal cancers was seen to be one of the most demethylated mucins, in which mRNA was seen to be substantially decreased or expunged. This extensive study investigated the status of multiple mucins in multiple cancer settings and highlights a few noticeable mucins that are suggested to be further studied for roles in biomarkers, survival, and etiology for cancer progression. Citation Format: Ryan J. King, Fang Yu, Pankaj K. Singh. Genomic alterations in mucins in 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 381. doi:10.1158/1538-7445.AM2017-381
Abstract 107: Mechanism of anticancer activity of BPS-001 (lyophilized leech saliva extract)
Authors: Amr Ammar, Emma Guns, Omer Kucuk, Abdualrahman Abdualkader, Mohamed Alaama, A.B.M. Helal Uddin, Abbas Ghawi, Mohamed Hassona
Journal: Cancer Research (2017)

Abstract Recent studies, investigating the composition and therapeutic potential of leech saliva have identified many peptides and proteins with multiple therapeutic properties including anti-thrombotic, antimicrobial and anti-metastatic. In vitro anti-cancer effects were shown in breast, prostate and lung cells lines. In vivo anticancer activity of the extract was shown in multiple breast and prostate cancer xenografts studied by our lab. In our previous studies, BPS-001 was non-toxic and demonstrated various activities including pro-apoptotic properties, inhibition of cellular adhesion, angiogenesis and downregulation of AR expression. To investigate the affected pathways, mechanistic studies were carried out using in vivo and in vitro treated samples. Protein expression in samples was determined by Western blotting of in vitro and in vivo samples. AR expression was measured using an eGFP reporter assay in LNCaP cells, with PSA also measured in the media using cobas e 411 analyzer. BPS-001 inhibited Proteinase Activated Receptor 1 (PAR-1) which is responsible for hormone like cellular signals in different cancer cells including those of the breast and prostate. Moreover, in LNCaP cells AR activation and PSA expression were significantly inhibited after treatment with BPS-001. Inhibition of PI3K and PLCG2 were also observed. It has been found that BPS-001 modulates a plethora of pathways which makes it a very promising candidate for treatment of cancer with an important advantage of low toxicity and potential resistance. Citation Format: Amr Ammar, Emma Guns, Omer Kucuk, Abdualrahman Abdualkader, Mohamed Alaama, A.B.M. Helal Uddin, Abbas Ghawi, Mohamed Hassona. Mechanism of anticancer activity of BPS-001 (lyophilized leech saliva extract) [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 107. doi:10.1158/1538-7445.AM2017-107