tbuckley/cabot-search huggingface dataset:
On the Clinical Pharmacology of Reactive Oxygen Species
Authors: Ana I. Casas, Cristian Nogales, Hermann A. M. Mucke, Alexandra Petraina, Antonio Cuadrado, Ana I. Rojo, Pietro Ghezzi, Vincent Jaquet, Fiona Augsburger, Francois Dufrasne, Jalal Soubhye, Soni Deshwal, Moises Di Sante, Nina Kaludercic, Fabio Di Lisa, Harald H. H. W. Schmidt
Journal: Pharmacological Reviews (2020)

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data–enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. <h3>Significance Statement</h3> Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine.
Abstract 1617: Developing new mouse models of metastatic lung cancer
Authors: Julie Wells, Richard S. Maser, Teresa McGee, Wendy Memishian, Rosalinda Doty, Carol J. Bult
Journal: Cancer Research (2020)

Abstract INTRODUCTION: The focus of this work is to develop new mouse models for metastatic lung cancer. Lung cancer is the leading cause of cancer deaths worldwide and greater than 90% of human cancer deaths are due to metastasis. Metastatic disease in most existing mouse models of lung cancer is typically sporadic and often requires aging mice for several months. These factors limit the usefulness of mouse models for basic and pre-clinical research aimed at effective treatment of metastatic disease. METHODS AND RESULTS: We have developed a new mouse model of lung cancer and are in the process of developing two additional models. In the first model, we added mutations in Dicer1, an RNAse III enzyme within the microRNA (miRNA) biosynthesis pathway to a mouse model of Kras-driven pulmonary adenocarcinoma. When we combined conditional expression of an oncogenic allele of Kras (KrasG12D), deletion of both alleles of Trp53 and one allele of Dicer1 in Club cells with expression of truncated Dicer1 in alveolar type II cells, we generated mice with metastatic pulmonary adenocarcinoma. In 30% of these mice, metastatic tumors were observed in the lymph nodes within 11 weeks of tumor induction. In a second mouse model, we switched the cell types expressing the various mutations to determine the effects of cell of origin on tumor progression and metastasis. Our preliminary results suggest that adenocarcinoma develops even faster when KrasG12D is expressed and Trp53 and one allele of Dicer1 are deleted in alveolar type II cells. Finally, based on an analysis of human lung cancer genomics data from TCGA, we generated a mouse model with mutations in Zfhx4 and are crossing these mice with our models that express oncogenic KrasG12D, delete expression of Trp53 and one allele of Dicer1 and truncate the second allele of Dicer1 to determine the effects of adding Zfhx4 mutations on progression and metastasis of pulmonary adenocarcinoma. CONCLUSIONS: Through cell type specific truncation/deletion of Dicer1 we have generated new mouse models that rapidly develop pulmonary adenocarcinomas and metastatic disease. These models have potential for both understanding the basic processes of metastasis and for pre-clinical studies aimed at preventing and/or treating metastatic lung cancer. Citation Format: Julie Wells, Richard S. Maser, Teresa McGee, Wendy Memishian, Rosalinda Doty, Carol J. Bult. Developing new mouse models of metastatic lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1617.
Abstract 4922: NEUROD1 is highly expressed in extensive small cell lung cancer by promoting migration
Authors: Yuki Ikematsu, Kentaro Tanaka, Nobuhisa Ando, Kayo Ijichi, Yasuto Yoneshima, Hiroyuki Inoue, Goji Toyokawa, Tetsuzo Tagawa, Yoichi Nakanishi, Isamu Okamoto
Journal: Cancer Research (2020)

Abstract Introduction:Small cell lung cancer (SCLC) exhibits high-grade neuroendocrine features and recent genomic analyses revealed that aberrant expression of bacic helix loop helix transcription factors such as neurogenic differentiation 1 (NEUROD1) as well as achaete-scute homolog 1(ASCL1) have also been observed in SCLC. NEUROD1 plays important role for the development, maturation in several nerve system and formation of distal lung of neuroendocrine morphology. Previous report showed that mRNA expression as well as target genes of NEUROD1 are largely distinct from those of ASCL1 in human SCLC cell lines, however, protein level and expression patterns of these transcription factors in SCLC clinical tumor samples as well as its relation to clinicopathological characteristics have not been fully elucidated. Method: We retrospectively analyzed specimens from 95 SCLC patients between June 1988 and December 2017, and immunohistochemical (IHC) staining of NEUROD1 as well as ASCL1 was performed. Furthermore, we examined the effect of gain or loss of NEUROD1 function on proliferation and migration by transfection in SCLC cell lines. Result:Dual high staining score of ASCL1 and NEUROD1 was present in SCLC samples (32/95: 34%) and IHC score of NEUROD1 was higher in extensive disease (ED) samples than those in limited disease (LD) samples (median score 160 vs 80 ; P = 0.0389).Overall survival did not significantly differ between SCLC patients with high or low score of NEUROD1 or ASCL1. Next, our vitro data showed that upregulation of NEUROD1 in SCLC cell lines promoted transwell migration whereas downregulation of NEUROD1 reduced cell migration. Conclusion: Our results from clinical and in vitro experimental data collectively indicate that NEUROD1 expression increases in extensive SCLC by promoting migration and metastasis of SCLC cells. Citation Format: Yuki Ikematsu, Kentaro Tanaka, Nobuhisa Ando, Kayo Ijichi, Yasuto Yoneshima, Hiroyuki Inoue, Goji Toyokawa, Tetsuzo Tagawa, Yoichi Nakanishi, Isamu Okamoto. NEUROD1 is highly expressed in extensive small cell lung cancer by promoting migration [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 4922.
Abstract 4747: Genomic and transcriptomic landscape of AFP-producing gastrointestinal adenocarcinoma
Authors: Jun Li, Xinlin Li, Qiancheng Ye, Yu Tian, Xiangxing Kong, Yue Liu, Xiaoming Xu, Lina Zhang, Qian Xiao, Yeting Hu, Rongzhen Xu, Jingsong Li
Journal: Cancer Research (2020)

Abstract AFP-producing gastrointestinal adenocarcinoma (APA-GI) is a rare type of cancer, typically with hepatoid differentiation, chemotherapy resistance and poor prognosis. As the mechanisms of its AFP production and hepatoid differentiation remain unclear, the present study aims to reveal the pathogenesis of APA-GI through genomic and transcriptomic profile analysis. We firstly performed 200 × whole exome sequencing of 29 APA-GI and 8 non-APA-GI cases from our hospital, but found no significant difference in single nucleotide variants (SNV) or insertion/deletion(indels). Additionally, there was no overlap gene when compared with the known genes harbored at 20q11.21-13.12 reported in gastric hepatoid adenocarcinoma. We then performed single-cell mRNA sequencing in one APA-GI, and observed several hepatoid differentiation markers in AFP positive cells including HNF4A and HNF1A. To further determine the specific alterations of APA-GI, we divided 339 gastric cancer patients from TCGA database into AFP-low group and AFP-high group by the level of AFP transcription through a dynamic grouping method named grid search. We performed a series differentially expressed genes detections within different grouping strategies and no significant SNV or indels difference was recognized. We identified hepatoid differentiation markers (i.e. HNF4A, HNF1A and ALB, et al) in AFP-high patients in mRNA level. As the difference of hepatoid differentiation markers only occurred in the mRNA level without DNA alteration, we hypothesized that it was probably caused by epigenetic regulation. We further compared these genes with an epigenetic regulators database named EpiFactors. Finally, it showed CCCTC-Binding Factor Like (CTCFL) was stably related with AFP producing within the grid search. In conclusion, comprehensive genomic analysis of APA-GI shows significant hepatoid differentiation at the transcriptomic level without disease-specific DNA alteration. The pathogenesis of APA-GI may be associated with other mechanisms like epigenetic regulation. Further study was needed to confirm the role of epigenetic regulators we detected in the present study in the development of APA-GI. Citation Format: Jun Li, Xinlin Li, Qiancheng Ye, Yu Tian, Xiangxing Kong, Yue Liu, Xiaoming Xu, Lina Zhang, Qian Xiao, Yeting Hu, Rongzhen Xu, Jingsong Li. Genomic and transcriptomic landscape of AFP-producing gastrointestinal adenocarcinoma [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 4747.
Pathophysiology of atrial fibrillation and chronic kidney disease
Authors: Wern Yew Ding, Dhiraj Gupta, Christopher F Wong, Gregory Y H Lip
Journal: Cardiovascular Research (2020)

Atrial fibrillation (AF) and chronic kidney disease (CKD) are closely related conditions with shared risk factors. The growing prevalence of both AF and CKD indicates that more patients will suffer from concurrent conditions. There are various complex interlinking mechanisms with important implications for the management of these patients. Furthermore, there is uncertainty regarding the use of oral anticoagulation (OAC) in AF and CKD that is reflected by a lack of consensus between international guidelines. Therefore, the importance of understanding the implications of co-existing AF and CKD should not be underestimated. In this review, we discuss the pathophysiology and association between AF and CKD, including the underlying mechanisms, risk of thrombo-embolic and bleeding complications, influence on stroke management, and evidence surrounding the use of OAC for stroke prevention.
Abstract A61: FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
Authors: Carlos J. Díaz Osterman, Duygu Ozmadenci, Elizabeth G. Kleinschmidt, Kristin N. Taylor, Allison M. Barrie, Shulin Jiang, Lisa M. Bean, Florian J. Sulzmaier, Jian Li, Xiao Lei Chen, Guo Fu, Marjaana Ojalill, Pekka Rappu, Jyrki Heino, Adam A. Mark, Guorong Xu, Kathleen M. Fisch, David T. Weaver, Jonathan A. Pachter, Balázs Győrffy, Michael T. McHale, Denise C. Connolly, Alfredo Molinolo, Dwayne G. Stupack, David D. Schlaepfer
Journal: Clinical Cancer Research (2020)

Abstract Gene copy number alterations, tumor cell stemness, and development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stemness phenotypes involving Wnt-beta-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous genetic gains in KRAS, MYC, and FAK (KMF) genes, in a new aggressive murine model of ovarian cancer. Noncanonical signaling via FAK sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neoadjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance, triggering tumor cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 genes elevated by a FAK activity-dependent, beta-catenin, and Myc signaling axis including pluripotency and DNA repair genes. Identified target increases in HGSOC tumors may reflect oncogenic FAK signaling. Citation Format: Carlos J. Díaz Osterman, Duygu Ozmadenci, Elizabeth G. Kleinschmidt, Kristin N. Taylor, Allison M. Barrie, Shulin Jiang, Lisa M. Bean, Florian J. Sulzmaier, Jian Li, Xiao Lei Chen, Guo Fu, Marjaana Ojalill, Pekka Rappu, Jyrki Heino, Adam A. Mark, Guorong Xu, Kathleen M. Fisch, David T. Weaver, Jonathan A. Pachter, Balázs Győrffy, Michael T. McHale, Denise C. Connolly, Alfredo Molinolo, Dwayne G. Stupack, David D. Schlaepfer. FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A61.
Abstract A57: Identification of novel targets for ovarian cancer treatment
Authors: Ricardo Noriega, Jeyshka Reyes, Blanca Quiñones, Joseline Serrano, Pablo Vivas, Josué Pérez
Journal: Clinical Cancer Research (2020)

Abstract Ovarian cancer remains one of the most lethal diseases for the female reproductive system with 22,530 new cases and more than 13,980 deaths predicted for 2019 in the United States alone, according to the American Cancer Society. Currently, there is no effective therapy for ovarian cancer patients, in particular for those who become resistant to chemotherapy (cisplatin). We need to identify novel targets for ovarian cancer therapy. We performed RNA deep-sequencing studies in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Several RNA (messengers and long noncoding) were differentially abundant in cisplatin-resistant versus cisplatin-sensitive cells. Many of these RNAs have not been previously studied in ovarian cancer. Therefore, we performed rigorous bioinformatic studies that included data filtering and survival rates (using Kaplan-Meier plot analysis) and IPA (Ingenuity Pathway Analysis) to select key candidate genes that can be used as potential targets for ovarian cancer therapy. Additional data filtering was used to select a list of candidate genes whose expression correlates with the overall survival and progression-free survival of ovarian cancer patients. Future experiments will investigate the biologic consequence of targeting each of these candidate genes in ovarian cancer cells and ovarian cancer mouse models. Citation Format: Ricardo Noriega, Jeyshka Reyes, Blanca Quiñones, Joseline Serrano, Pablo Vivas, Josué Pérez. Identification of novel targets for ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A57.
Abstract 4107: The impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptosis
Authors: Shifaa M. Abdin, Mai F. Tolba, Dana M. Zaher, Hany A. Omar
Journal: Cancer Research (2020)

Abstract Aim: The emergence of breast cancer resistance to chemotherapy represents a major obstacle in cancer therapy. Multiple cellular signalling pathways augment such resistance including the nuclear factor (NF)-κB. In the presented work, we investigated the impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptotic cell death via Annexin V/PI flow cytometry and other molecular biology-based assays. Methods: Doxorubicin (DOX)-resistant MCF-7 and MDA-MB-231 breast cancer cell lines were developed and utilized for the current study. Cytotoxicity assays were performed to evaluate the median inhibitory concentration (IC50) of different NF-κB pharmacological inhibitors. Chemotherapy-induced apoptosis in parental and resistant breast cancer cells was assessed in the presence or absence of different NF-κB pharmacologic inhibitors such as pentoxifylline (PTX) and bortezomib (BTZ). Results: Treatment of MDA-MB-231 cell line with a sub-cytotoxic concentration of PTX significantly enhanced DOX-induced apoptosis by 6-fold (p&amp;lt;0.001) in wild type cells, and by 8-fold (p&amp;lt;0.01) in the resistant subclones. Similarly, BTZ significantly boosted the percentage of apoptotic cells by 6-fold (p&amp;lt;0.001) in parental cells co-treated with DOX. However, the same treatment boosted the percentage of apoptotic cells by 11-fold (p&amp;lt;0.01) in DOX-resistant MDA-MB-231 cells. It is noteworthy that the increased sensitivity to DOX-induced apoptosis that was mediated via NF-κB inhibition was more prominent in the resistant clones. Conclusion: The data generated from this study support the potential merit of NF-κB inhibitors as adjuvants to improve breast cancer sensitivity to chemotherapy. Further mechanistic investigations are currently in progress in our laboratories to characterize the relationship between NF-κB inhibition and key signaling pathways for breast cancer chemoresistance. Funding: This work was supported by grant # 1801110326-P from the Research Funding Department, University of Sharjah, UAE, and grant #AJF2018050 from Al Jalila Foundation, UAE. Citation Format: Shifaa M. Abdin, Mai F. Tolba, Dana M. Zaher, Hany A. Omar. The impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4107.
Targeting Obesity-Induced Macrophages during Preneoplastic Growth Promotes Mammary Epithelial Stem/Progenitor Activity, DNA Damage, and Tumor Formation
Authors: Tamara Chamberlin, Megan Clack, Caylee Silvers, Genevra Kuziel, Victoria Thompson, Haley Johnson, Lisa M. Arendt
Journal: Cancer Research (2020)

Obesity enhances breast cancer risk in postmenopausal women and premenopausal women with genetic or familial risk factors. We have shown previously that within breast tissue, obesity increases macrophage-driven inflammation and promotes expansion of luminal epithelial cell populations that are hypothesized to be the cells of origin for the most common subtypes of breast cancer. However, it is not clear how these changes within the microenvironment of the breast alter cancer risk and tumor growth. Using a high-fat diet to induce obesity, we examined preneoplastic changes associated with epithelial cell-specific loss of Trp53. Obesity significantly enhanced the incidence of tumors of diverse histotypes and increased stromal cells within the tumor microenvironment. Obesity also promoted the growth of preneoplastic lesions containing elevated numbers of luminal epithelial progenitor cells, which were surrounded by macrophages. To understand how macrophage-driven inflammation due to obesity enhances tumor formation, mice were treated with IgG or anti-F4/80 antibodies to deplete macrophages during preneoplastic growth. Unexpectedly, depletion of macrophages in obese mice enhanced mammary epithelial cell stem/progenitor activity, elevated expression of estrogen receptor alpha, and increased DNA damage in cells. Together, these results suggest that in obesity, macrophages reduce epithelial cells with DNA damage, which may limit the progression of preneoplastic breast lesions, and uncovers complex macrophage function within the evolving tumor microenvironment. Understanding how obesity alters the function of macrophages during tumor formation may lead to chemoprevention options for at-risk obese women. SIGNIFICANCE: Understanding how obesity impacts early tumor growth and response to macrophage-targeted therapies may improve therapeutics for obese patients with breast cancer and identify patient populations that would benefit from macrophage-targeted therapies.
Abstract 4257: Detection of bone marrow metastases: Comparison of functional magnetic resonance imaging with bone marrow biopsy and aspiration
Authors: Hui Zhao, Zhiyu Wang, Yue Hua Li
Journal: Cancer Research (2020)

Abstract Bone marrow metastases are frequently detected by unilateral bone marrow biopsy and aspiration (BMBA), which is invasive. In this study, the value of functional magnetic resonance imaging (MRI) of pelvis was compared with BMBA and its clinical implication was evaluated. Cancer patients with bone metastasis and CT scan of pelvis showed no bone metastasis at the site of BMBA were included. BMBA was performed after MRI scan. Apparent Diffusion Coefficient (ADC), volume transfer constant (Ktrans), Pure diffusion coefficient (D), Pseudo diffusion coefficient (D*) and Perfusion fraction (f) were detected. The sensitivity, specificity and accuracy of MRI was calculate. An internal cross-validation via bootstrap was conducted for MRI performance in terms of the area under the curve (AUC). 28 oncological patients (11 breast cancer, 8 lung cancer, 5 prostatic cancer; 4 other cancers ) were enrolled. 16 patients were confirmed bone marrow metastases by BMBA. The sensitivity, specificity and accuracy of MRI was 93%, 50% and 75%. The ROC of Ktrans was 78%, which was the best. MRI can be used as a supplement to BMBA to diagnose bone marrow metastasis. Citation Format: Hui Zhao, Zhiyu Wang, Yue Hua Li. Detection of bone marrow metastases: Comparison of functional magnetic resonance imaging with bone marrow biopsy and aspiration [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 4257.