bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2765: Exosomal miRNAs as circulating biomarkers for prediction of metastasis in stage II/III gastric cancer
Authors: Liu Xin , Chu Kent-Man 
Published: August 2019

Abstract
Background: Metastasis is the fatal character of cancer, leading to mortality of gastric cancer. In recent years, exosomes have been reported as extracellular vesicles secreted by cells. They contain various biological molecules including miRNAs from the original cells. Exosomal miRNAs are significant for pre-metastatic niche formation, as they can change the microenvironment and make it favorable for future metastasis. Therefore, the aim of this study was to identify dysregulated exosomal miRNAs as circulating biomarkers for prediction of metastasis of gastric cancer.
Materials and Methods: Pre-treatment serum samples of 36 metastatic patients and 55 non-metastatic patients with stage II/III gastric cancer were collected. Exosomes were extracted and validated by western blot, transmission electron microscope and nanoparticle tracking analysis. MiRCURY LNATM miRNA miRNome PCR Array (containing 752 miRNAs) was performed in three pairs of serum exosomes. Each pair samples were with the same stage, race, gender and similar age. These three pairs of samples represented stage II, IIIA or IIIB gastric cancer, respectively. A panel of commonly dysregulated exosomal miRNAs was released from the PCR Array. Expressions of exosomal miRNAs were validated in the remaining 33 metastatic and 52 non-metastatic patients by RT-qPCR, as well as in gastric cancer cell culture medium and cell lines.
Results: By comparing the expressions of exosomal miRNAs between the metastatic patients and matched non-metastatic ones, 13 upregulated and 6 downregulated miRNAs were released after normalization with miR-16-5p and miR-93-5p. Among these miRNAs, 7 of them were selected for further validation according to their fold changes, p-values and association with cancer development. MiR-379-5p and miR-410-3p were validated to be significantly upregulated in metastatic patients (P&lt;0.01). Sensitivity, specificity and AUC were 67.31%, 69.70% and 0.6894 for miR-379-5p, and 65.38%, 66.67% and 0.6719 for miR-410-3p. Higher expression of serum exosomal miR-379-5p or miR-410-3p showed shorter overall survival of the patients (P&lt;0.05). It was also found that miR-379-5p and miR-410-3p expressed significantly higher in gastric cancer cell culture medium comparing with gastric cancer cells.
Conclusions: Exosomal miRNAs are dysregulated in the serum of metastatic gastric cancer patients before they are clinically diagnosed. Upregulation of serum exosomal miR-379-5p and/or miR-410-3p are promising circulating biomarkers for prediction of metastasis in stage II/III gastric cancer.
Citation Format: Xin Liu, Kent-Man Chu. Exosomal miRNAs as circulating biomarkers for prediction of metastasis in stage II/III gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2765.
Abstract 2779: miR-142-3p as a regulator of RAC1 and a prognostic factor in melanoma
Authors: Cruz Adriana T. , Morata Júlia A. , Monteiro Ana C. , Ayub Ana Luísa P. , Soares Roseli S. , Fujita André , Andrade Fernando , Tron Victor , Jasiulionis Miriam G. 
Published: August 2019

Abstract
In order to identify miRNAs able to distinguish melanoma patients with good or poor prognosis, the expression profile of a panel of miRNAs evaluated in primary melanoma samples from 65 patients was compared to clinicopathological data from these patients (Breslow’s depth, mitotic counts, metastasis progression and survival). The miR-142-3p was identified as presenting at least 2-fold reduced expression in melanoma samples from patients with poor prognosis for 3 of 4 clinical parameters analyzed compared to melanoma samples from patients with good prognosis. The miR-142-3p expression was validated by RT-qPCR in primary human melanoma samples, confirming a significant lower expression in melanoma patients with poor prognosis compared to those with good prognosis. Searching for miR-142-3p mRNA targets in melanoma, the gene expression profile was analyzed by gene microarrays in a wild type and miR-142-3p overexpressing melanoma cell line. RAC1, ITGB8 e GNB2 were found as potential targets of this miRNA. Protein expression analyses in melanoma cell lines overexpressing the miR-142-3p reinforced the regulation of RAC1 by this miRNA. Functional assays showed that the overexpression of miR-142-3p leads to a reduced migratory ability compared to control cells, indicating its role in cell migration process. Finally, multivariate COX analyses demonstrated that high levels of RAC1 and reduced levels of miR-142-3p predict poor progression-free survival of melanoma patients, revealing these molecules as potential prognostic biomarkers for melanoma patients.
Supported by FAPESP, CNPQ and CAPES
Short title: miR-142-3p as a prognostic factor in melanoma
Note: This abstract was not presented at the meeting.
Citation Format: Adriana T. Cruz, Júlia A. Morata, Ana C. Monteiro, Ana Luísa P. Ayub, Roseli S. Soares, André Fujita, Fernando Andrade, Victor Tron, Miriam G. Jasiulionis. miR-142-3p as a regulator of RAC1 and a prognostic factor in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2779.
Abstract 2780: IL13RA2 is differentially regulated in papillary thyroid carcinoma versus follicular thyroid carcinoma
Authors: Chong Siao Ting , Kok Catherine Y. , Tan Khee Ming , Guan Shou Ping , Lai Siang Hui , Lim Cindy , Hu Jiancheng , Sturgis Charles , Eng Charis , Lam Paula Y. , Ngeow Joanne 
Published: August 2019

Abstract
The interleukin-13 receptor alpha2 (IL13RA2), which is known to overexpressed in glioblastoma multiforme, plays a role in various cellular processes such as cell migration that may contribute to tumor progression. Studies have attributed IL13RA2 to invasion and metastasis in cancers of the ovary, breast, and pancreas but the pathological role of IL13RA2 in thyroid cancer is still unclear. This study aims to evaluate the expression of IL13RA2 in thyroid carcinomas and examine the role of IL13RA2 in progression of papillary thyroid cancer (PTC). We performed IL13RA2 immunochemical staining on tissue microarrays of 137 thyroid carcinomas and observed that IL13RA2 expression was significantly correlated with advanced tumor stage (pT3 / pT4; p=0.001) and regional lymph node metastasis (pN1; p&lt;0.001). Moreover, the staining scores of IL13RA2 were significantly higher in PTC compared to follicular and anaplastic subtypes (p&lt;0.02) and correlated with advanced tumor stage amongst PTC samples (pT3 / pT4; p=0.028). This differential profile of IL13RA2 in PTC was further validated in thyroid cancer cell lines overexpressing IL13RA2 to assay the effects on cell proliferation, cell migration and epithelial-mesenchymal transition (EMT) using CCK-8, transwell migration assay, qRT-PCR and western blot analyses. Knockdown of IL13RA2 in the PTC subtype B-CPAP cell line showed significantly reduced cell viability, cell migration and EMT markers including N-cadherin, Vimentin and Snail. Exogenous overexpression of IL13RA2 in another PTC cell line, K1 increased cell migration and EMT although cell proliferation was not affected. In summary, we demonstrated that IL13RA2 is differentially regulated in PTC and is involved in cell migration by enhancing EMT. The underlying molecular mechanisms on how IL13RA2 drives progression of thyroid cancer remains to be further investigated.
Citation Format: Siao Ting Chong, Catherine Y. Kok, Khee Ming Tan, Shou Ping Guan, Siang Hui Lai, Cindy Lim, Jiancheng Hu, Charles Sturgis, Charis Eng, Paula Y. Lam, Joanne Ngeow. IL13RA2 is differentially regulated in papillary thyroid carcinoma versus follicular thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2780.
Abstract 2788: The interplay between tumor-cell derived FoxO1 and macrophage in the tumor microenvironment of esophageal squamous cell carcinoma
Authors: Wang Ying , Guan Xinyuan , Kam Woon Ngar 
Published: August 2019

Abstract
Introduction: Esophageal squamous cell cancer (ESCC) is the predominant histologic type in China with high incidence and mortality. FOXO1 is considered as a tumor suppressor in several cancers, but its role in tumor immunology still remain elusive. A better understanding of how FOXO1 mediates the secretion of downstream chemokines, such as CCL20, and thus its ability in regulating macrophage function would be of crucial for further investigation.
Materials and Methods: Quantitative PCR and immunohistochemistry were used to study the expression of FoxO1 in clinical ESCC samples. The survival analysis was performed based on the result of tissue microarray and corresponding clinicopathological information. Stable foxo1-transfected cell lines were constructed in human ESCC cell lines, and ELISA, western blotting and Quantitative PCR were conducted to evaluate the expression of foxo1 and its downstream molecule CCL20. The subsets of macrophages were identified through Flow cytometry and qPCR.
Results: The expression of FOXO1 was significantly upregulated in tumorous tissue when comparing to adjacent normal tissue and predicted a poor prognosis in ESCC patients. Besides, the analysis of TCGA database indicated that the markers of M2 macrophage were upregulated in foxo1-high expressing tumor tissues when compared with foxo1-low expressing tumor tissues. In vitro, we have successfully differentiated monocytic cell line THP-1 into macrophage M0, M1 and M2. The M1 and M2 markers (CD80, CD163 and CD68) were measured by flow cytometry, while their major cytokines (IL6, TNF-α, CCL17, CCL18, IL1β and IL10) were detected by qPCR. The ELISA, western blot and qPCR results showed that the expression of CCL20 was upregulated in foxo1-high expressing tumor cells when compared to negative control. The migration assay showed that ESCC cells transfected with foxo1 could recruit more M2 macrophages when compared with foxo1-low expression ESCC cells and the effect was diminished upon blockade with anti-CCL20 neutralizing antibody in tumor cells. Besides, we found out that M2 macrophage could promote the migration and EMT of tumor cells by using M2 conditioned medium.
Conclusions: FoxO1 displays an important role in M2 macrophage migration through the modulation of CCL20. This increased CCL20 reported in ESCC may become specific molecular/cellular processes operative in the TME of ESCC patients.
Note: This abstract was not presented at the meeting.
Citation Format: Ying Wang, Xinyuan Guan, Woon Ngar Kam. The interplay between tumor-cell derived FoxO1 and macrophage in the tumor microenvironment of esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2788.
Abstract 279: c-Jun N-terminal kinase is involved in an oxidative stress- and vacuole-associated cell death pathway in triple negative breast cancer
Authors: Soleimani Milad , Bhattacharjee Ritvik , Giri Uma , Kaoud Tamer S. , Dalby Kevin N. , Eckhardt S. Gail , Berg Carla L. Van Den 
Published: August 2019

Abstract
Breast cancer is the most prevalent type of cancer among women. Triple negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of breast cancer. It is the most challenging subtype to treat mainly due its aggressive nature and lack of targets such as HER2 (human epidermal growth factor 2), PR (progesterone receptor), and ER (estrogen receptor) found in other subtypes. We have shown that inhibiting both EGFR (epidermal growth factor receptor)/HER2 with lapatinib and JNK with JNK-IN-8 causes synergistic cell death in 11 out of 12 TNBC cell lines. EGFR is expressed in up to 90% tumors and JNK activation is linked to TNBC phenotype, metastasis, and stem cell character, among others. Synergism was achieved in the resistant, low-EGFR expressing cell line when a FGFR inhibitor (BGJ398) was used instead of lapatinib in combination with JNK-IN-8. Combination drug effects were accompanied by elevated oxidative stress. Suppression of oxidative stress restored cell viability in cells treated with the drug combination. JNK-IN-8 treatment alone or in combination with lapatinib induced massive cytoplasmic vacuolization with little apoptotic blebbing. The vacuoles were shown to be membrane-derived and acidic using Lucifer Yellow and Acridine Orange, respectively. Pre-treatment of cells with bafilomycin A1 (lysosome inhibitor), 5-(N-Ethyl-N-isopropyl) amiloride (macropinocytosis inhibitor), or N-acetylcysteine (antioxidant) reduced vacuolization. A similar effect was observed when cells were serum-starved. JNK1 knockout mouse mammary tumor cells, in comparison with JNK2 knockout, were resistant to drug synergism and displayed significantly less oxidative stress and vacuolization. Our studies demonstrated that concomitant blockade of JNK and individual tumor-appropriate targets induce synergistic cell death in TNBC cells in response to oxidative stress. Moreover, JNK blockade resulted in the formation of serum-dependent, acidic vacuoles that were reversible by lysosome or macropinocytosis inhibition. Loss-of-function studies indicated that JNK1 was the key isoform responsible for the drug response in TNBC cells. These findings suggest that JNK is involved in a novel cell death pathway and is a robust target in combination therapies against TNBC.
Citation Format: Milad Soleimani, Ritvik Bhattacharjee, Uma Giri, Tamer S. Kaoud, Kevin N. Dalby, S. Gail Eckhardt, Carla L. Van Den Berg. c-Jun N-terminal kinase is involved in an oxidative stress- and vacuole-associated cell death pathway in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 279.
Abstract 2809: The induction of CD8+ T lymphocytes and PD-L1+ immune cells by neoadjuvant chemoradiotherapy for rectal cancer
Authors: Fukuoka Eiji , Yamashita Kimihiro , Sugita Yutaka , Arimoto Akira , Nakamura Tetsu , Kakeji Yoshihiro 
Published: August 2019

Abstract
Background; The relationship between tumor immunological microenvironment and irradiation has been studied so far. Based on these findings, we examined a tumor microenvironment of rectal cancer performed by neoadjuvant chemoradiotherapy (NACRT) with immunohistochemical analysis of surgical specimens. But, for introduction to clinical settings, the analysis is not yet sufficient. So, in more detail, we investigate tumor infiltrating CD8+ T cells by irradiation in mouse CT26 colon tumor model.
Methods; Locally advanced rectal cancer were enrolled and 68 were eligible for this study. Immunohistochemical staining of programmed cell death- lignad1(PD-L1), CD8, and CD163 was performed on specimens of all cases. In a mouse model, CT26 tumor cells were inoculated in mouse, tumors are irradiated with a single dose of 10Gy after 14 days. We analyzed CD8+ T cells infiltration of both irradiated mouse and no treated mouse by flow cytometry.
Results; There were 44 cases in which NACRT was performed (NA group) and 24 cases in which surgery alone was performed (SA group). In the SA group, there was no significant change in the infiltration of PD-L1+immune cells (PD-L1+IC) nor CD8 +cells before and after treatment, but in the NA group, the infiltrations of them were significantly increased. In multivariate analysis, low infiltration of CD8 +cells were identified as poor prognostic factors in disease-free survival. Moreover, in our mouse model, elevated numbers of tumor-infiltrating CD8+ T cells between day11 and day18 after irradiation were observed in tumors of irradiated mice compared to no treated mouse. We observed that among CD8+ T cells, cells that coexpress PD-1 and Tim-3 comprise the major population in irradiated mouse. PD-1+Tim-3+ CD8+ T cells produced more INF-γ compared to that by PD-1+Tim-3-CD8+ T cells and PD-1-Tim-3- CD8+ T cells in irradiated mouse and no treated mouse. Among the three populations PD-1+Tim-3+ population contained the largest fraction of central memory (CD44hiCD62Llow) cells, but the lowest fraction of central memory (CD44hiCD62Lhi) cells.
Conclusion; The infiltration of PD-L1+IC and CD8 +cells was induced by NACRT. In the mouse model, we confirmed the kinetical and phenotypical changes of tumor-infiltrating CD8+ T cells.
Citation Format: Eiji Fukuoka, Kimihiro Yamashita, Yutaka Sugita, Akira Arimoto, Tetsu Nakamura, Yoshihiro Kakeji. The induction of CD8+ T lymphocytes and PD-L1+ immune cells by neoadjuvant chemoradiotherapy for rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2809.
Abstract 281: Sensitivity to splicing modulation of BCL2 family genes reveals cancer therapeutic strategies for splicing modulators
Authors: Aird Daniel , Teng Teng , Huang Chia-Ling , Pazolli Ermira , Banka Deepti , Cheung-Ong Kahlin , Eifert Cheryl , Furman Craig , Wu Jeremy , Seiler Michael , Buonamici Silvia , Fekkes Peter , Karr Craig , Palacino James , Park Eunice , Smith Peter , Yu Lihua , Mizui Yoshiharu , Warmuth Markus , Chicas Agustin , Corson Laura , Zhu Ping 
Published: August 2019

Abstract
Dysregulation of RNA splicing by spliceosome mutations or in cancer genes is increasingly recognized as a hallmark of cancer. Small molecule splicing modulators have been introduced into clinical trials to treat solid tumors or leukemia bearing recurrent spliceosome mutations. Nevertheless, further investigation of the molecular mechanisms that may enlighten therapeutic strategies for splicing modulators is highly desired. Here, using unbiased functional approaches, we report that the sensitivity to splicing modulation of the anti-apoptotic BCL2 family genes is a key mechanism underlying preferential cytotoxicity induced by the SF3b-targeting splicing modulator E7107. While BCL2A1, BCL2L2 and MCL1 are prone to splicing perturbation, BCL2L1 exhibits resistance to E7107-induced splicing modulation. Consequently, E7107 selectively induces apoptosis in BCL2A1-dependent melanoma cells and MCL1-dependent NSCLC cells. Furthermore, combination of BCLxL (BCL2L1-encoded) inhibitors and E7107 remarkably enhances cytotoxicity in cancer cells. These findings inform mechanism-based approaches to the future clinical development of splicing modulators in cancer treatment.
Citation Format: Daniel Aird, Teng Teng, Chia-Ling Huang, Ermira Pazolli, Deepti Banka, Kahlin Cheung-Ong, Cheryl Eifert, Craig Furman, Jeremy Wu, Michael Seiler, Silvia Buonamici, Peter Fekkes, Craig Karr, James Palacino, Eunice Park, Peter Smith, Lihua Yu, Yoshiharu Mizui, Markus Warmuth, Agustin Chicas, Laura Corson, Ping Zhu. Sensitivity to splicing modulation of BCL2 family genes reveals cancer therapeutic strategies for splicing modulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 281.
Abstract 2820: Macrophages recruited to and function to promote activation of cancer stem cells in response to chemotherapy
Authors: He Xi C. , Li Linheng 
Published: August 2019

Abstract
Failure of chemoradiotherapy for treating colorectal cancer (CRC) is often caused by the relapse of residual tumor cells that enrich cancer stem cells (CSCs). However, how CSCs are regulated by tumor microenvironment (TME), particularly myeloid derived cells (MDCs), remains unclear. Here, we used the APCMin/+ adenoma model to study the dynamic interaction between MDCs and CSCs in vivo following chemoradiotherapy. Using 3D scanning electronic microscopy, we observed that while proliferating tumor cells were dying following chemoradiotherapy, MDCs or its derivative tumor associated macrophages (TAMs) were recruited to the site where CSCs paired with necroptotic cells. TAMs functioned to promote activation of slow-cycling CSCs. Dissected with single cell RNA-seq, we observed that while proliferating tumor cells were declining following chemotherapy, an increase in MDCs was accompanied with a reduction of immune cells as well as an activation and short-term expansion of initially quiescent CSCs. Depletion of TAMs using a drugs or genetic means resulting in reduced CSCs and attenuated tumorigenesis. Mechanistically, we uncovered that TAM with secreted PGE2 activated Akt and Wnt signaling to promote activation of CSCs. Hence, targeting TAMs will benefit clinical treatment of CRC by reducing drug-resistant CSCs.
Note: This abstract was not presented at the meeting.
Citation Format: Xi C. He, Linheng Li. Macrophages recruited to and function to promote activation of cancer stem cells in response to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2820.
Abstract 2835: Breast tumor microbiota populations are modulated by chemotherapy and may be indicative of outcome
Authors: Chiba Akiko , Bawaneh Alaa , Velazquez Christine , Levine Edward , Cook Katherine L. 
Published: August 2019

Abstract
Breast tumors were identified to have their own microbiota population distinct from mammary gland tissue. Breast cancer patients that present in the clinic with larger tumors often undergo neo-adjuvant chemotherapy to reduce tumor burden before surgery. The purpose of our study was to evaluate whether chemotherapy can modulate the tumor microbiome and the potential impact of microbes in the development of distant metastases. Using snap-frozen aseptically collected breast tumor tissue from women that underwent neo-adjuvant chemotherapy or women with no prior therapy at time of surgery, we performed 16S rRNA sequencing to identify tumoral bacterial populations. We also stained breast tumor microarrays (normal breast tissue, primary breast tumor, and lymph node metastases) to confirm presence of identified microbiota. Our data indicates that chemotherapy administration significantly increased breast tumor Pseudomonas and reduced the proportional abundance of Streptococcus. Primary breast tumors from patients that developed distant metastases later on in life (regardless of therapy) displayed increased tumoral abundance of Acinetobacter, Brevundimonas, and Staphylococcus. Stratifying patients based upon BMI indicates that obesity modulates breast tumor microbiota populations and needs to be considered in analyses. Furthermore, we confirm presence of Pseudomonas in breast tumor tissue by immunohistochemical staining. Our results indicate breast tumor microbiota populations can be modified by chemotherapy and specific microbes correlate with tumor recurrence. Further studies with a larger patient cohort may provide greater insights into the role of microbiota in therapeutic outcome and for the development of novel bacterial biomarkers that could predict distant metastases.
Citation Format: Akiko Chiba, Alaa Bawaneh, Christine Velazquez, Edward Levine, Katherine L. Cook. Breast tumor microbiota populations are modulated by chemotherapy and may be indicative of outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2835.