tbuckley/cabot-search huggingface dataset:
EREG-driven oncogenesis of Head and Neck Squamous Cell Carcinoma exhibits higher sensitivity to Erlotinib therapy
Authors: Shuli Liu, Yang Wang, Yong Han, Weiya Xia, Ling Zhang, Shengming Xu, Houyu Ju, Xiangkai Zhang, Guoxin Ren, Liu Liu, Weimin Ye, Zhiyuan Zhang, Jingzhou Hu
Journal: Theranostics (2020)

Rationale: The oncogenesis of head and neck squamous cell carcinoma (HNSCC) is believed to result from oncogene activation and tumor suppressor inactivation. Here, we identified a new oncogenic role for the EREG gene in HNSCC. Methods: The TCGA database and immunohistochemistry assay were used to analyze expression of EREG in HNSCC tissues. Immunoblotting was performed to identify the EGFR-mediated pathways altered by EREG. The role of EREG in oncogenesis was investigated in vivo and in vitro. Results: Upregulated EREG expression predicted a poor prognosis and triggered HNSCC oncogenic transformation by activating the epidermal growth factor receptor (EGFR) signaling pathway. We also demonstrated the direct association of EREG with EGFR and that this binding required EGFR domains I and III and the N57 residue of EREG. Moreover, EREG overexpression was shown to promote HNSCC oncogenesis by inducing C-Myc expression, and the pharmacological inhibition of C-Myc rescued EREG-promoted HNSCC oncogenesis. Unlike other EGFR ligands, EREG could mimic EGFR mutations by sustaining the activation of the EGFR-Erk pathway, and high EREG expression was positively associated with the response to treatment with the EGFR inhibitor erlotinib. Furthermore, knockdown of EREG decreased sensitivity to erlotinib treatment in vitro and in vivo. Conclusions: These results identify the EREG-EGFR-C-Myc pathway as a crucial axis that drives HNSCC oncogenesis and show that EREG expression could be a predictive functional marker of sensitivity to erlotinib therapy in HNSCC.
Abstract 6107: Stromal and immune changes in the aged lung microenvironment create a permissive niche for the metastatic outgrowth of melanoma
Authors: Mitchell Fane, Stephen Douglass, Gretchen Alicea, Marie Webster, Julio Aguirre-Ghiso, Ashani Weeraratna
Journal: Cancer Research (2020)

Abstract Our previous data has indicated that while tumors grow more slowly in aged mouse skin, they form more lung metastases. We queried whether the lung microenvironment undergoes age-related changes that provide a permissive niche for metastatic outgrowth. Our previous data has implicated dermal fibroblasts as the drivers of age-related changes in the skin, and so we analyzed young vs aged healthy human lung fibroblasts. The secreted changes in aged lung fibroblasts suggest that the lung microenvironment evolves during aging to promote proliferation of melanoma cells. Specifically, these changes involve the secretion of factors such as sFRP1, that we find suppresses Wnt5A and AXL signaling, which typically drives a metastatic but slow-growing/dormant cancer phenotype. Interestingly, this switch promotes activation of the MER tyrosine kinase pathway, increasing proliferation. This switch is reinforced by the MER ligand PROS1, which is upregulated in the aged lung microenvironment. Consistent with this, our in vivo studies indicate that tumor cells disseminate to the lungs at the same rate in young and aged mice. However, they persist as single cell populations in the young mouse lungs, whereas they grow out rapidly in the aged mouse lung. We next queried whether the immune microenvironment also played a role in the differential outgrowth of lung metastases in young and aged mice. We find that aged lung fibroblasts secrete higher levels of immunosuppressive factors ARG-1 and CXCL1, which are both necessary for efficient metastatic outgrowth in vivo. Analysis of the aged lung microenvironment reveals that immunosuppressive MDSCs and Treg populations are significantly increased compared with the young lung, while effector CD4 and CD8 T cells are decreased. Importantly, depletion of MDSCs or Tregs in the aged lung both significantly decrease metastasis. Overall, we find that aged-induced changes in fibroblast secretory phenotypes and immune subpopulations promote efficient metastatic melanoma progression in the lung. Citation Format: Mitchell Fane, Stephen Douglass, Gretchen Alicea, Marie Webster, Julio Aguirre-Ghiso, Ashani Weeraratna. Stromal and immune changes in the aged lung microenvironment create a permissive niche for the metastatic outgrowth of melanoma [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 6107.
Abstract 5307: The impact of image analysis and multiplex hybridization on PD-L1 diagnostic case triage
Authors: Matthew P. Humphries, Victoria Bingham, Fatima Abdullahi Sidi, Stephanie G. Craig, Stephen McQuaid, Jacquline James, Manuel Salto-Tellez
Journal: Cancer Research (2020)

Abstract Introduction: Immune checkpoint blockade therapy is a new paradigm in cancer treatment with durable tumor regression and prolonged stabilization of disease in patients with advanced cancers, including non-small cell lung cancer (NSCLC). However, clinical assessment using immunohistochemistry (IHC) remains complex and ambiguous. Methods: PD-L1 IHC staining was performed as a routine clinical reflex test on 802 NSCLC cases over an 18 month period using an automated staining system with PD-L1 clone SP263. PD-L1 expression was assessed using image analysis (IA) by 2 individuals and concordance was evaluated between the recorded manual clinical score and the digitally generated score. Additionally, a subset of 330 samples, representing cases with either varying PD-L1 expression or difficulty in assessment, were stained by multiplex immunofluorescence. Sensitivity and specificity was compared between manual assessments of both chromogenic and multiplex IHC. Results: PD-L1 expression by IA showed significant concordance (R²=0.8248) to manual assessment. Sensitivity and specificity was 86.8% and 91.4%, respectively. Discordant cases were mainly due to spurious or poor staining quality, difficult classification by IA and overabundant macrophages and a low IA detection threshold. Evaluation of IA scores 10-49% and &amp;gt;70% revealed 96.8% concordance to manual assessment. Multiplex assessment enabled PD-L1+/CD68+ macrophages to be readily identified within PD-L1+/CK+ or PD-L1-/CK+ tumor nests. Manual assessment of multiplex vs. chromogenic IHC was highly concordant, with a sensitivity and specificity respectively of 97.8% and 91.8%. Conclusions: Deployment of IA in routine PD-L1 IHC assessment of NSCLC represents a beneficial time saving process and could aid case triage saving &amp;gt;50% of pathologist review time. However cases close to diagnostic thresholds still require a more comprehensive pathological evaluation. Multiplex IHC provides a higher level of confidence in PD-L1 assessment and could be offered for challenging cases by centers with access to appropriate expertise and specialist equipment. Citation Format: Matthew P. Humphries, Victoria Bingham, Fatima Abdullahi Sidi, Stephanie G. Craig, Stephen McQuaid, Jacquline James, Manuel Salto-Tellez. The impact of image analysis and multiplex hybridization on PD-L1 diagnostic case triage [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 5307.
Abstract 5767: Multiple primary cancer from a retrospective population-based cancer registry, 1991 through 2015
Authors: Pariyada Tanjak, Benjarat Thiengtrong, Kanokporn Thamapala, Tippawan Gerdsuriwong, Cholticha Songjang, Aem-on Rattanakumnerd, Onchira Acharayothin, Supatee Karakate, Nongnard Thamnongdee, Suwanit Therasakvichya, Somsri Laiteerapong, Vitoon Chinswangwatanakul
Journal: Cancer Research (2020)

Abstract Background Multiple primary cancer refers to the synchronous or metachronous appearances in the same individual. The accurate approach, which distinguishes between multiple primary cancer and metastasis, is important to make an appropriate management. This study aims to systematically classify the synchronous and metachronous multiple primary cancers, and to identify multiple primary cancer from cancer metastasis. Methods Cancer registry was compiled at the Faculty of Medicine Siriraj Hospital, Mahidol University based on guidelines from the Surveillance Epidemiology and End Results (SEER) project. Data was validated through clinical records, coded, and verified for multiple primary cancer according to International Classification of Diseases for Oncology 3rdEdition (ICD-O-3). The cancer registry for the year 1991-2015 was queried for numbers of the multiple primary cancer. Results A total of 1,913 patients presented multiple primary cancer, accounting for 1.48% of all patients (129,216). Median age at diagnosis of the first cancer was 60. The most multiple primary cancer in female is synchronous breast cancers, diagnosed two or more histologically distinct cancer within two months. In male, the most combination is prostate, urinary tract, and gastrointestinal cancer. In addition to understanding of the connections between primary and subsequent cancer, we plan to perform panel sequencing in each primary site of multiple gastrointestinal primary cancer to access for the causal driver mutation. Conclusion Cancer registry is a valuable approach to punctually identify and record multiple primary cancer. Further study in genetic profiles of each primary cancer may improve our understanding of multiple primary cancer for enhancing cancer management. Citation Format: Pariyada Tanjak, Benjarat Thiengtrong, Kanokporn Thamapala, Tippawan Gerdsuriwong, Cholticha Songjang, Aem-on Rattanakumnerd, Onchira Acharayothin, Supatee Karakate, Nongnard Thamnongdee, Suwanit Therasakvichya, Somsri Laiteerapong, Vitoon Chinswangwatanakul. Multiple primary cancer from a retrospective population-based cancer registry, 1991 through 2015 [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 5767.
Abstract 1698: Cellular cytotoxicity is a form of immunogenic cell death
Authors: Luna Minute, Alvaro Teijeira, Alfonso Rodriguez Sánchez-Paulete, Maria del Carmen Ochoa, Maite Alvarez, Itziar Otano, Iñaki Etxeberria, Elixabet Bolaños, Arantza Azpilikueta, Saray Garasa, Noelia Casares, José Luiz Pérez-Gracia, Maria Esperanza Rodríguez-Ruiz, Pedro Berraondo, Ignacio Melero
Journal: Cancer Research (2020)

Abstract Background: The immune response to cancer is often conceptualized with the Cancer Immunity Cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or NK lymphocytes, is actually immunogenic currently remains unknown. Methods: In this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated natural killer cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I MHC-multimer stainings. Mice deficient in BATF-3, IFNAR and STING were used to study mechanistic requirements. Results: We observe in co-cultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. OVA-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100 specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA+ EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient in BATF3-dependent dendritic cells (cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8+ T lymphocytes. Conclusion: These results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death. Citation Format: Luna Minute, Alvaro Teijeira, Alfonso Rodriguez Sánchez-Paulete, Maria del Carmen Ochoa, Maite Alvarez, Itziar Otano, Iñaki Etxeberria, Elixabet Bolaños, Arantza Azpilikueta, Saray Garasa, Noelia Casares, José Luiz Pérez-Gracia, Maria Esperanza Rodríguez-Ruiz, Pedro Berraondo, Ignacio Melero. Cellular cytotoxicity is a form of immunogenic cell death [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 1698.
Abstract 3460: Effects of feeding soy protein isolate diet on hepatic methylation and oxidative stress in DMBA-induced mammary tumor in obese rat model
Authors: Reza Hakkak, Stepan Melnyk, Soheila Korourian
Journal: Cancer Research (2020)

Abstract The obesity epidemic is in the United States and world for past two decades. There is a link between obesity and chronic diseases development such as diabetes, cardiovascular disease and certain types of cancers including breast cancer. Obesity has a significant impact on the metabolic profiles for a variety of cellular-tissue-organ levels in animals and humans. The objective of this study was to determine the effects of obesity and a soy protein isolate (SPI) diet on liver methylation and oxidative stress using 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor model. We hypothesize that SPI diet is capable to reduce the liver damage by reducing oxidative stress and modifying methylation status. After one week of acclimation, five weeks old female lean and obese Zucker rats were randomly fed AIN-93-G diet with either casein (CAS as control) or SPI as source of protein. All rats were orally gavaged at age 50 days with 65 mg/kg DMBA. Rats were weighed and palpated twice weekly and sacrificed 22 weeks post-DMBA treatment. Liver sample metabolites concentrations were measured using HPLC with Electrochemical Detection and LC-MS. Our results shows that: 1) Obesity increased significantly (P&amp;lt;0.001) body weight for both CAS and SPI diets; 2) 69% of the Lean casein rats developed mammary tumors compared to 50% in lean soy group (p= 0.176) and in the obese group, 76% of the soy-fed rats developed mammary tumors compared to 15% (P&amp;lt;0.001) of obese casein- fed rats; 4) Obesity in both diets significantly modify liver methylation and oxidative stress status; 5) lean SPI-fed rats significantly (P&amp;lt;0.025) increased SAM/SAH “methylation ratio” compare to lean CAS-fed rats; 6) obese SPI-fed rats significantly (P&amp;lt;0.001) decrease level of Homocysteine in liver and increase significantly (P&amp;lt;0.001) Methionine/Homocysteine ratio compared CAS obese rats; 7) obesity caused a significant increase in oxidative stress (GSH/GSSG ratio decrease) in liver for both CAS (P&amp;lt;0.004) and SPI (P&amp;lt;0.01) diets and 8) obese SPI fed rats significantly (P&amp;lt;0.02) decreased oxidative in liver (GSH/GSSG ratio increase) compared to obese CAS fed rats. In summary, we found that SPI diet capable make significant impact on methylation status by increasing a “methylation ratio”, decrease level of toxic intracellular compound homocysteine, and improving redox environment in liver triggered by obesity in mammary tumor model. Citation Format: Reza Hakkak, Stepan Melnyk, Soheila Korourian. Effects of feeding soy protein isolate diet on hepatic methylation and oxidative stress in DMBA-induced mammary tumor in obese rat model [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 3460.
No-Charge Coronary Artery Calcium Screening for Cardiovascular Risk Assessment
Authors: Sadeer G. Al-Kindi, Marco Costa, Nour Tashtish, Jared Duriuex, David Zidar, Imran Rashid, Claire Sullivan, Robert Gilkeson, Daniel Simon, Sanjay Rajagopalan
Journal: Journal of the American College of Cardiology (2020)
Abstract PR02: Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status
Authors: Farhad Ghasemi, Stephenie D. Prokopec, Danielle MacNeil, Neil Mundi, Christopher Howlett, William Stecho, Kevin Fung, John Yoo, Eric Winquist, Steven Gameiro, Axel Sahovaler, Paul Plantinga, Joe S. Mymryk, John W. Barrett, Paul C. Boutros, Anthony C. Nichols
Journal: Clinical Cancer Research (2020)

Abstract Smoking has historically been recognized as a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). This study aimed to assess the mutational differences between heavy smokers (&amp;gt;20 pack-years) and never smokers among the HNSCC patients within The Cancer Genome Atlas (TCGA). Single nucleotide variation (SNV) and copy number aberration (CNA) differences between heavy smokers and never smokers were compared within HPV-positive (n=67) and negative (n=431) TCGA HNSCC cohorts, and the impact of these mutations on survival was assessed. No genes were differentially mutated between smoking and never smoking patients with HPV-positive tumors. By contrast, in HPV-negative tumors, NSD1 and COL1A11 were found to be more frequently mutated in heavy smokers, while CASP8 was more frequently altered in never smokers. HPV-negative patients with NSD1 mutations experienced significantly improved overall survival compared with NSD1 wild-type patients. This improved prognosis was validated in an independent cohort of 77 oral cavity cancers and a meta-analysis that included two additional datasets (688 total patients, hazard ratio for death 0.44, 95% CI 0.30-0.65). NSD1 mutations are more common in HPV-negative heavy smokers and define a cohort with favorable prognosis, and may represent a clinically useful biomarker to guide treatment deintensification for HPV-negative patients. Citation Format: Farhad Ghasemi, Stephenie D. Prokopec, Danielle MacNeil, Neil Mundi, Christopher Howlett, William Stecho, Kevin Fung, John Yoo, Eric Winquist, Steven Gameiro, Axel Sahovaler, Paul Plantinga, Joe S. Mymryk, John W. Barrett, Paul C. Boutros, Anthony C. Nichols. Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr PR02.
Abstract 4029: BET inhibitor suppresses neutrophil-dependent lung metastasis of inflammatory renal cancer cells
Authors: Shogo Ehata, Jun Nishida, Kosuke Miyakuni, Daizo Koinuma, Kohei Miyazono
Journal: Cancer Research (2020)

Abstract Recent studies have shown that cancer cells alter the immune landscape by secreting inflammation-related cytokines or chemokines through a process known as cancer cell-intrinsic inflammation. Cancer cell-intrinsic inflammation facilitates both the initial progression of cancers and cancer metastasis via tumor microenvironment reconstitution, immune surveillance, and premetastatic niche formation. However, in the case of clear cell renal carcinoma (ccRCC), the role of cancer cell-intrinsic inflammation is not fully uncovered. In the present study, we explored the function and regulatory mechanisms of cancer cell-intrinsic inflammation in ccRCC. First, highly malignant derivatives were obtained through the repetitive exposure of human ccRCC cells into mouse renal microenvironment. Of note, these derivatives elicited cancer cell-intrinsic inflammation in the host mice, which facilitated lung metastasis in neutrophil-dependent manner. Thus, we defined these derivatives as inflammatory ccRCC cells and characterized in the following study. Next, the regulatory mechanisms for the transcription of genes related to neutrophil dynamics were explored. RNA-sequencing analysis revealed that mRNA-expression levels of four CXC chemokines were up-regulated in all inflammatory ccRCC derivatives. ChIP-sequencing analysis of H3K27ac or bromodomain-containing 4 (BRD4) indicated that super enhancers were recruited at each gene in inflammatory ccRCC derivatives. Finally, we evaluated the effect of the bromodomain and extra-terminal motif (BET) inhibitor on neutrophil-dependent lung metastasis of inflammatory ccRCC cells. Although the sizes of primary tumors in inflammatory ccRCC derivative-bearing mice were not altered by the treatment of BET inhibitor, those of metastatic lung tumors were significantly decreased. Overall, our findings revealed a functional role of cancer cell-intrinsic inflammation, which primes neutrophils and drives metastasis of ccRCC cells. The primary tumor microenvironment enriched inflammatory ccRCC cells via epigenetic remodeling. We also showed the utility of inflammation management in suppressing metastasis by utilizing a BET inhibitor. Citation Format: Shogo Ehata, Jun Nishida, Kosuke Miyakuni, Daizo Koinuma, Kohei Miyazono. BET inhibitor suppresses neutrophil-dependent lung metastasis of inflammatory renal cancer 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 4029.
Coronary Computed Tomography Angiography From Clinical Uses to Emerging Technologies
Authors: Khaled M. Abdelrahman, Marcus Y. Chen, Amit K. Dey, Renu Virmani, Aloke V. Finn, Ramzi Y. Khamis, Andrew D. Choi, James K. Min, Michelle C. Williams, Andrew J. Buckler, Charles A. Taylor, Campbell Rogers, Habib Samady, Charalambos Antoniades, Leslee J. Shaw, Matthew J. Budoff, Udo Hoffmann, Ron Blankstein, Jagat Narula, Nehal N. Mehta
Journal: Journal of the American College of Cardiology (2020)
Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer
Authors: Sumiya Dalangood, Zhen Zhu, Zhihui Ma, Jiaxuan Li, Qinghe Zeng, Yilin Yan, Bing Shen, Jun Yan, Ruimin Huang
Journal: Theranostics (2020)

Urinary bladder cancer (UBC) is one of the most common causes of morbidity and mortality worldwide characterized by a high risk of invasion and metastasis; however, the molecular classification biomarkers and underlying molecular mechanisms for UBC patient stratification on clinical outcome need to be investigated.