tbuckley/cabot-search huggingface dataset:
Abstract CT222: Colon cancer in elderly patients: Retrospective analysis of targeted therapy era
Authors: JIN YOUNG KIM, Sojin Shin, Mi Hwa Heo, Kang Kook Lee
Journal: Cancer Research (2020)

Abstract Purpose: This study was conducted in order to evaluate the response rate, progression free survival (PFS), safety and prognostic factors of targeted combination chemotherapy in colon cancer patients older than 65 years. Methods: This retrospective study included 69 elderly patients (≥ 65 years) with metastatic Colon cancer who have not received palliative chemotherapy before. All patients were histologically confirmed colon cancer at Keimyung university Dongsan medical center from Jan 2007 to July 2017. All recruited patients received either cetuximab or bevacizumab every 2 weeks. Results: The median age was 73.35 (65-87) and 33 were right side, 32 were left, 2 were transverse and rest of 2 patients were multiple primary sites. Bevecizumab was administerd to 42 patients (60.9%) and cetuximab was administered to 27 patients (39.1%). Complete response was 9 patients (13%), partial response was 23 (33.3%) and progression disease was 9 (13.0%). Overall response rate was 31 (46.4%) and disease control rate was 42 (62.3%). Progression free survival was 12.038 ±1.565 months (95% CI: 8.97~12.12). The most common hematologic side effects was anemia with grade 3/4 in 14 (20.3%). Systemic chemotherapy with targeted agents were moderately tolerated with grade 3/4 neutropenia 40 (57.9%). Conclusion: In elderly patients with colon cancer, clinical outcomes showed similar results compared with prior clinical trials. Preventing such complications may improve survival. Citation Format: JIN YOUNG KIM, Sojin Shin, Mi Hwa Heo, Kang Kook Lee. Colon cancer in elderly patients: Retrospective analysis of targeted therapy era [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 CT222.
Curriculum for optical diagnosis training in Europe: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement
Authors: Evelien Dekker, Britt B. S. L. Houwen, Ignasi Puig, Marco Bustamante-Balén, Emmanuel Coron, Daniela E. Dobru, Roman Kuvaev, Helmut Neumann, Gavin Johnson, Pedro Pimentel-Nunes, David S. Sanders, Mario Dinis-Ribeiro, Marianna Arvanitakis, Thierry Ponchon, James E. East, Raf Bisschops
Journal: Endoscopy (2020)

This manuscript represents an official Position Statement of the European Society of Gastrointestinal Endoscopy (ESGE) aiming to guide general gastroenterologists to develop and maintain skills in optical diagnosis during endoscopy. In general, this requires additional training beyond the core curriculum currently provided in each country. In this context, ESGE have developed a European core curriculum for optical diagnosis practice across Europe for high quality optical diagnosis training. 1: ESGE suggests that every endoscopist should have achieved general competence in upper and/or lower gastrointestinal (UGI/LGI) endoscopy before commencing training in optical diagnosis of the UGI/LGI tract, meaning personal experience of at least 300 UGI and/or 300 LGI endoscopies and meeting the ESGE quality measures for UGI/LGI endoscopy. ESGE suggests that every endoscopist should be able and competent to perform UGI/LGI endoscopy with high definition white light combined with virtual and/or dye-based chromoendoscopy before commencing training in optical diagnosis. 2: ESGE suggests competency in optical diagnosis can be learned by attending a validated optical diagnosis training course based on a validated classification, and self-learning with a minimum number of lesions. If no validated training course is available, optical diagnosis can only be learned by attending a non-validated onsite training course and self-learning with a minimum number of lesions. 3: ESGE suggests endoscopists are competent in optical diagnosis after meeting the pre-adoption and learning criteria, and meeting competence thresholds by assessing a minimum number of lesions prospectively during real-time endoscopy. ESGE suggests ongoing in vivo practice by endoscopists to maintain competence in optical diagnosis. If a competent endoscopist does not perform in vivo optical diagnosis on a regular basis, ESGE suggests repeating the learning and competence phases to maintain competence.Key areas of interest were optical diagnosis training in Barrett's esophagus, esophageal squamous cell carcinoma, early gastric cancer, diminutive colorectal lesions, early colorectal cancer, and neoplasia in inflammatory bowel disease. Condition-specific recommendations are provided in the main document.
Abstract 4617: Association between DNA oxidative damage and radiotherapy-induced skin toxicities in breast cancer patients
Authors: Moody M. Mihyu, Isildinha M. Reis, Cristiane Takita, Jean L. Wright, Eunkyung Lee, Omar L. Nelson, George R. Yang, Johnna L. Bakalar, Jennifer J. Hu
Journal: Cancer Research (2020)

Abstract Background: Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related death in the female population in the United States. Although radiotherapy (RT) has been shown to improve prognosis in breast cancer patients, RT may also lead to side effects that impact overall quality of life in some patients. The objective of this study was to investigate whether an oxidative damage biomarker, 8-hydroxy-2-deoxyguanosine (8-OHdG), is associated with RT-induced early adverse skin reactions (EASRs) in breast cancer patients. Methods: 8-OHdG data before (pre-RT) and after RT (post-RT) were obtained from 475 breast cancer patients. RT-induced EASRs were assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (v3.0) scale. Univariate logistic regression analyses were conducted to evaluate associations between above-median 8-OHdG (&amp;gt; 85 ng/ml) and RT-induced grade 2+ EASRs. A propensity score (PS) was derived from a logistic regression model for predicting RT-induced EASRs on the basis of patient, tumor, and treatment characteristics. Then, the association between 8-OHdG and RT-induced EASRs was assessed in four risk groups defined by quartiles of PS. Results: Overall, 59% of patients developed RT-induced grade 2+ EASRs and 28% developed moist desquamation. There were no significant associations between RT-induced EASRs and high 8-OHdG levels at both pre-RT and post-RT. However, there was a significant association between patients in the 2nd quartile PS that had high post-RT 8-OHdG levels and grade 2+ EASRs (OR=2.51, 95%CI=1.17, 5.40, p=0.0183). Conclusions: The results from this study suggest that 8-OHdG is a potential biomarker for RT-induced EASRs in a breast cancer population with low to medium (2nd quartile) propensity for RT-induced EASRs. Citation Format: Moody M. Mihyu, Isildinha M. Reis, Cristiane Takita, Jean L. Wright, Eunkyung Lee, Omar L. Nelson, George R. Yang, Johnna L. Bakalar, Jennifer J. Hu. Association between DNA oxidative damage and radiotherapy-induced skin toxicities in breast cancer patients [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 4617.
Kruppel-like factor 10 protects against acute viral myocarditis by negatively regulating cardiac MCP-1 expression
Authors: Jie Yang, Hongkai Zhang, Xuelian Wang, Jing Guo, Lin Wei, Yahui Song, Yuan Luo, YinXia Zhao, Malayannan Subramaniam, Thomas C. Spelsberg, Lie Wang, Wei Xu, Min Li
Journal: Cellular and Molecular Immunology (2020)
Abstract 2969: Senescent stromal cells promote cancer resistance via Sirt1 loss-potentiated biogenesis of small extracellular vesicles
Authors: Liu Han, Qilai Long, Eric Lam, Yu Sun
Journal: Cancer Research (2020)

Abstract Cellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype (SASP) and implicated in age-related pathologies including cancer. Here we report that senescent cells actively synthesize and release small extracellular vesicles (sEVs) with a distinctive size distribution. Mechanistically, SIRT1 loss supports accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Senescent stromal cell-derived sEVs carry a special set of cargoes, including small RNA species such as microRNAs (miRNAs) whose spectrum markedly differ from that of proliferating cell-secreted sEVs. Once released, senescent stromal sEVs significantly alter the expression profile of recipient cancer cells and enhance their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with an agonist SRT2104 prevents development of cancer resistance through restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients are readily detectable by routine biotechniques, presenting a novel biomarker to monitor therapeutic efficacy and predict long term outcome. Together, our study identifies a distinct mechanism supporting pathological activities of senescent cells, and provides a novel avenue to circumvent advanced human malignancies by co-targeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells. Citation Format: Liu Han, Qilai Long, Eric Lam, Yu Sun. Senescent stromal cells promote cancer resistance via Sirt1 loss-potentiated biogenesis of small extracellular vesicles [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 2969.
Abstract 5986: Inverse relationship between Giant Axonal Neuropathy gene expression and EMT in human tumors
Authors: Mysore S. Veena, Daniel Sanghoon Shin, Chan Jeong, Jenna R. Chatoff, Natarajan Venkatesan, Saroj K. Basak, David Gray, Sharon P. Wilczynski, Sharon P. Wilczynski, Steven J. Gray, Donald B. Kohn, Marilene B. Wang, Eri S. Srivatsan
Journal: Cancer Research (2020)

Abstract Gigaxonin, the protein product of the Giant axonal neuropathy (GAN) gene, is a E3 ubiquitin ligase involved in neural cell and fibroblast intermediate filament processing. We have previously shown that Gigaxonin interacts with p16 in cisplatin-mediated ubiquitination of NF-κB. We analyzed cervical and head and neck cancer cell lines and primary tumors and have found exon 8 c.1293C&amp;gt;T single nucleotide polymorphism (SNP) to occur in both HPV positive and negative tumor cells lines and primary tumors. The prevalence of this SNP in the tumor samples was double that of the normal population (47.25% vs. 22%) and there was no relationship to HPV status. Cell lines containing the SNP showed higher expression of gigaxonin, and an inverse relationship to in vitro tumor cell line growth and cisplatin sensitivity. There was a direct relationship between the expression of gigaxonin and e-cadherin and inverse relationship to the expression of twist, snail and n-cadherin. CRISPR-Cas9 mediated conversion of T to C allele in gigaxonin overexpressing cervical cancer cell line ME 180 resulted in decreased gigaxonin expression accompanied by increased expression of twist, and snail and increased in vitro cell growth. Re-expression of gigaxonin in the CRISPR-Cas9 clone with a plasmid gigaxonin cDNA construct resulted in decreased expression of twist pointing to gigaxonin mediated downregulation of the EMT marker. We therefore hypothesize that GAN, associated with the neurodegenerative disease, is also a human tumor cell growth suppressor gene. Citation Format: Mysore S. Veena, Daniel Sanghoon Shin, Chan Jeong, Jenna R. Chatoff, Natarajan Venkatesan, Saroj K. Basak, David Gray, Sharon P. Wilczynski, Sharon P. Wilczynski, Steven J. Gray, Donald B. Kohn, Marilene B. Wang, Eri S. Srivatsan. Inverse relationship between Giant Axonal Neuropathy gene expression and EMT in human tumors [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 5986.
PD1 Blockade Enhances ICAM1-Directed CAR T Therapeutic Efficacy in Advanced Thyroid Cancer
Authors: Katherine D. Gray, Jaclyn E. McCloskey, Yogindra Vedvyas, Olivia R. Kalloo, Steve El Eshaky, Yanping Yang, Enda Shevlin, Marjan Zaman, Timothy M. Ullmann, Heng Liang, Dessislava Stefanova, Paul J. Christos, Theresa Scognamiglio, Andrew B. Tassler, Rasa Zarnegar, Thomas J. Fahey, Moonsoo M. Jin, Irene M. Min
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Advanced thyroid cancers, including poorly differentiated and anaplastic thyroid cancer (ATC), are lethal malignancies with limited treatment options. The majority of patients with ATC have responded poorly to programmed death 1 (PD1) blockade in early clinical trials. There is a need to explore new treatment options. Experimental Design: We examined the expression of PD-L1 (a ligand of PD1) and intercellular adhesion molecule 1 (ICAM1) in thyroid tumors and ATC cell lines, and investigated the PD1 expression level in peripheral T cells of patients with thyroid cancer. Next, we studied the tumor-targeting efficacy and T-cell dynamics of monotherapy and combination treatments of ICAM1-targeting chimeric antigen receptor (CAR) T cells and anti-PD1 antibody in a xenograft model of ATC. Results: Advanced thyroid cancers were associated with increased expression of both ICAM1 and PD-L1 in tumors, and elevated PD1 expression in CD8+ T cells of circulating blood. The expression of ICAM1 and PD-L1 in ATC lines was regulated by the IFNγ–JAK2 signaling pathway. ICAM1-targeted CAR T cells, produced from either healthy donor or patient T cells, in combination with PD1 blockade demonstrated an improved ability to eradicate ICAM1-expressing target tumor cells compared with CAR T treatment alone. PD1 blockade facilitated clearance of PD-L1 high tumor colonies and curtailed excessive CAR T expansion, resulting in rapid tumor clearance and prolonged survival in a mouse model. Conclusions: Targeting two IFNγ-inducible, tumor-associated antigens—ICAM1 and PD-L1—in a complementary manner might be an effective treatment strategy to control advanced thyroid cancers in vivo.
Abstract 5439: Distinct genomic profile in <i>H. pylori</i> associated gastric cancer
Authors: Ao Wang, Hua Bao, Pengfei Hu, Yong Wu, Jinfeng Zhang, Xue Wu, Xiaonan Wang, Yang Shao
Journal: Cancer Research (2020)

Abstract Background: Gastric cancer is one of the most common and deadly cancer types. Currently 4 subtypes have been identified with unique molecular alterations: Epstein-Barr virus (EBV)-positive, microsatellite instability (MSI), chromosomal instability (CIN), and genomic stable (GS) tumors. However, many gastric tumors are associated with the bacterium Helicobacter pylori but the genomic landscape of this subgroup of tumors remains largely unknown. Methods: Targeted-sequencing covering 425 genes were performed retrospectively on 1759 gastric tumor tissues and matched normal blood samples. The mean sequencing depth of tumors was 1159X. Nonsynonymous mutations, copy-number variation (CNV) and MSI status were called from human DNA reads; non-human DNA reads were mapped to NCBI microbial reference genome using Kraken and significant species were identified. Results: Overall, 37 (2.67%) samples were EBV-positive, 200 (11.37%) samples were H. pylori-positive, and 10 (0.57%) samples were positive for both. Other notable species identified in tumor samples were E. coli and C. acnes. No bacteria or viral reads were found in normal blood. Among the rest, 59 (3.35%) samples were MSI, 380 (21.6%) were CIN, and 1017 (57.82%) were GS. H. pylori-positive samples tend to be GS (85.5%, p &amp;lt; 0.001) and microsatellite stable (95%, p = 0.04). The most common mutations identified in H. pylori-positive tumors were TP53 (47%), CDH1 (12%) and ARID1A (8.5%). The top CNV events were amplification in MCL1 (14.5%), TERC (9%), CCNE1 (8.5%), PTPRD (8.5%), and MYC (7.5%). Compared to other GS tumors, mutation in AKT3 (p = 0.002) and amplification of TERC (p = 0.008) as well as MCL1 (p = 0.0.029) were significantly enriched in H. pylori-positive tumors. There was no difference in patients' sex or age among subtypes (p &amp;gt;= 0.05). Conclusion: This study characterized the genomic landscape of H. pylori positive gastric tumors using targeted-sequencing, which allowed direct comparison with other subtypes of gastric cancer. Identification of DNA reads from infectious agents in the tumor samples indicates that deep sequencing platform has promising utility in uncovering the characteristics of microbial environment of tumor. Co-infection between H. pylori and EBV occurred at a low frequency. H. pylori-positive tumors were GS and microsatellite stable with unique molecular features. Future study examining difference in treatment response among these subtypes of gastric cancer are warranted. Citation Format: Ao Wang, Hua Bao, Pengfei Hu, Yong Wu, Jinfeng Zhang, Xue Wu, Xiaonan Wang, Yang Shao. Distinct genomic profile in H. pylori associated gastric 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 5439.
Abstract 5152: SJP1604, a nucleolin-targeted therapeutic agent for relapsed/refractory acute myeloid leukemia
Authors: Jihyun Um, Dohyeong Lee, Yongbin Park, Sung Hwan Moon, Soo Jin Lee, Min-Hyo Ki
Journal: Cancer Research (2020)

Abstract Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are cancers characterized by the rapid growth of abnormal white blood cells. Although the standard first-line therapy leads to high rates of remission, approximately 30% of the treated patients are refractory and more than 50% of them face a relapse because of the occurrence of drug resistance and high toxicity. Therefore, there is a strong unmet medical need for the next-generation targeted therapy to overcome drug resistance and reduce toxicity in AML/MDS. Here, we designed an aptamer-drug conjugate (SJP1604) specific for nucleolin, which is highly expressed only on the cell membrane of cancer cells including AML cells. We identified that SJP1604 (APTA-16) inhibited the growth of AML cells and drug-resistant AML cells in vitro. SJP1604 presented outstanding anti-leukemic efficacy in vivo via syngeneic mouse model and xenograft mouse model. In addition, the synergistic effects were observed upon combination treatmeant with venetoclax in vitro. We also figured out that nucleolin as a clinical biomarker was significantly highly expressed on relapsed/refractory (R/R) AML patient-derived bone marrow cells ex vivo. SJP1604 selectively targeted cancer cells by nucleolin-binding on cell membrane with its high targeting ability and plasma stability owing to its unique conformational property, therefore, it demonstrated less cytotoxicity in vitro/in vivo and a superior therapeutic index based on AUC comparison in pharmacokinetic studies. The mechanism of the anti-leukemic efficacy of SJP1604 was also studied. First of all, SJP1604 decreased the expression of nucleolin and inactivated NFκB signaling pathway via dephosphorylation of NFκB, which resulted in diminished expression of DNMT1 followed by restored p15 expression. In addition, SJP1604 increased p53 expression and decreased bcl-2 expression in the protein and mRNA level. These could be one of potential mechanism of anti-leukemogenesis of SJP1604. In conclusion, these findings suggest that SJP1604 targeting nucleolin could be developed as a first-in-class drug for relapsed/refractory AML and MDS. GLP safety/toxicology studies of SJP1604 have been completed and clinical trials will be initiated in 2020. Citation Format: Jihyun Um, Dohyeong Lee, Yongbin Park, Sung Hwan Moon, Soo Jin Lee, Min-Hyo Ki. SJP1604, a nucleolin-targeted therapeutic agent for relapsed/refractory acute myeloid leukemia [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 5152.
Abstract 5943: The role of IL-6 family cytokines in gastrointestinal cancer
Authors: Koji Taniguchi, Tetsuro Kawazoe
Journal: Cancer Research (2020)

Abstract The important effector of the Hippo pathway, YAP, is strongly activated in the majority of gastrointestinal cancer. However, the mechanism by which YAP is activated in gastrointestinal cancer remains unknown. Previously, we found that after intestinal injury, IL-6 family cytokines activate the Src family kinases (SFK)-YAP pathway, which enhances intestinal regeneration. Here, we found that in addition to β-catenin, loss of tumor suppressor adenomatous polyposis coli (APC) activates SFKs, YAP and STAT3, which are simultaneously activated in 60-70% of human colorectal cancer specimens. We also found that up-regulation of IL-6 signal transducer (IL-6ST/gp130), which is induced by YAP activation, causes the activation of SFKs, YAP and STAT3. We also found that leukemia inhibitory factor (LIF), one of the IL-6 family cytokines, plays an important role in human esophageal squamous cell carcinoma by activating the SFK-YAP pathway. The combination treatment of SFK and JAK inhibitors results in suppression of gastrointestinal tumors. These results suggest that these signaling pathways might be new attractive therapeutic targets in human gastrointestinal cancer. Citation Format: Koji Taniguchi, Tetsuro Kawazoe. The role of IL-6 family cytokines in gastrointestinal 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 5943.