bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 123A: The critical role of interleukin-8 chemokine axis in the development of benign prostatic hyperplasia (BPH)
Authors: Smith Diandra K. , Venugopal Natasha , Terris Martha K. , Lokeshwar Bal L. 
Published: August 2019

Abstract
Benign prostatic hyperplasia (BPH), a non-malignant proliferative disease of the prostate, has a global incidence of over 210 million men aged 50 years or older. BPH is essentially a non-cancerous (non-malignant tumor) with significant morbidity. The severity varies from mild urinary retention to severe lower urinary tract symptoms (LUTS) accounting for greater than 50% of hospital visits for difficulty with urination, retention, and pain, and close to 40% of the prostate surgeries. BPH strongly associates with prostate volume that begins to increase in men aged 40 or higher. We investigated the role of chemokine and chemokine receptors in three immortalized cell lines and primary cultures derived from fresh BPH tissue following transurethral resection of the prostate. We analyzed the levels of chemokines and chemokine receptors secreted in the culture medium and in the mRNA from cells by qPCR, western blotting and Cytokine arrays. The epithelial identity of primary cultures was established by analyzing cytokeratin expression. Two natural products isolated from Allspice were identified that inhibit the growth of BPH cultures. A cell line identified as the BPH progenitor, a BPH intermediary cell line and a cell line with frank BPH features secreted a large excess of chemokine, predominantly CXCL-VIII or Interleukin-8 (IL-8). Unusually high amount of IL-8 was secreted by BPH progenitor cells and intermediate cells as compared to a stable normal prostate cell line (RWPE1) derived from the peripheral zone of the prostate, which did not secrete any IL-8 or express its receptor. The investigation found that expression of CXC receptors CXCR1, CXCR2 and an IL-8 inducible CXCR (CXCR7) was absent in progenitor cells and in intermediate cells, but was highly expressed in the cell line derived from BPH tissue and more significantly, in primary cultures of BPH tissue. Further, primary cultures and progenitor cells expressed high levels of immune stimulatory factors indicating PMN and monocyte infiltration leading to potential chronic inflammation of the transitional zone of the prostate. The natural products from Allspice inhibited all members of the IL-8 axis and proliferation, suggesting their potential preventative potential for BPH. These results demonstrate how a novel chemokine axis is likely to enhance pathogenesis of BPH and suggest several avenues to control the abnormal growth of prostate in aging male.
Note: This abstract was not presented at the meeting.
Citation Format: Diandra K. Smith, Natasha Venugopal, Martha K. Terris, Bal L. Lokeshwar. The critical role of interleukin-8 chemokine axis in the development of benign prostatic hyperplasia (BPH) [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 123A.
Abstract 1241: Characterization of a newly developed anti-TIGIT monoclonal antibody by double staining of T cells and NK cells by IHC and FACS
Authors: Qi Weimin , Chu Joseph , Luo Lily , Scoggin Tatiana , Dickinson Kim 
Published: August 2019

Abstract
T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory domain (TIGIT) is a newly identified surface protein expressed in regulatory, memory, naturalkiller (NK), and activated T cells. Several studies indicate that mouse TIGIT is a vital immunomodulator that can control the activities of both NK and T cells and plays an important role in transplantation tolerance and tumor immune surveillance. In this study, we generated a mouse monoclonal antibody, clone: BC41, by immunizing a recombinant human TIGIT, corresponding to an extra cellular domain. The protein was injected into BALB/c mice for three times and then the splenocytes were electro fused with mouse myeloma cells. The TIGIT-specific hybridoma cells were screened and a TIGIT-specific clone, named as BC41, was selected. The BC41 antibody was characterized by Western blot and immunohistochemistry. In immunoblots, TIGIT was able to detect a 26 kda protein corresponding to human TIGIT on over-expressed cells and native protein in human spleen lysates. Moreover, the BC41 was able to bind mouse TIGIT. FACS result showed that the BC41 antibody bond specifically to CD3/CD28+ T cells. We further analyzed the antibody binding profile by Immunohistochemistry on human T cells and NK cells by double staining. BC41 was able to bond portion of CD8 T cells (EOMES+), Treg cells (FOXP3+), PD1+ T cells and NK (CD57+) cells. Our results demonstrated that the antibody is TIGIT-specific and can be applied for detecting and analyzing tumor-infiltrating cells profile in transplantation and tumor immunotherapy.
Citation Format: Weimin Qi, Joseph Chu, Lily Luo, Tatiana Scoggin, Kim Dickinson. Characterization of a newly developed anti-TIGIT monoclonal antibody by double staining of T cells and NK cells by IHC and FACS [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 1241.
Abstract 1242: Examining the role of heme and respiratory proteins in the progression of KRAS/LKB1 mutant subtype
Authors: Dey Sanchareeka , Kalainayakan Sarada Preeta , Ghosh Poorva 
Published: August 2019

Abstract
Currently there are few successful targeted therapies for non-small cell lung cancer (NSCLC). Targeting mutations in EGFR, BRAF, ALK etc. provide treatment options only for a defined subset of adenocarcinoma patients leaving majority of adenocarcinoma and squamous carcinoma patients without any options. Activating KRAS mutations are found in 15-30% of all NSCLC patients; however, existing treatment options for KRAS-mutant cancer are not effective in the subset with concomitant loss of LKB1 (kinase that phosphorylates AMPK). Several studies demonstrate the importance of mitochondrial metabolism and oxidative phosphorylation (OXPHOS) in lung tumorigenesis. Components of OXPHOS complexes and markers of mitochondrial biogenesis are highly predictive of reduced overall survival in NSCLC patients. A study using genetically engineered mouse models (GEMMs) for lung cancer (KrasLSLG12D/+Trp53-/- and KrasLSL-G12D/+Lkb1-/-) showed that along with glucose, lactate contributes to the TCA cycle. This highlights the importance of OXPHOS in these models. Also, heme is a prosthetic group for several of these OXPHOS proteins and is involved in oxygen transport and utilization. Hence, we aim to investigate unique therapeutic targets by examining the role of heme and respiratory proteins in the progression of KRAS/LKB1 mutant subtype. We used LSL-KrasG12D LKB1-/- (LSL-KRASG12D; LKBloxP/loxP; LSL-Luciferase (KLLuc)) GEMM model for our study. Briefly, the mice were infected with AdenoCre virus, and sacrificed at different intervals in the progression of the tumors. For histological and immunohistochemical analysis, lung tissues were formalin fixed, paraffin embedded and sectioned (5µm thick). H&E staining showed consistent progression in tumor size over time. We will examine the time-course expression of OXPHOS, heme pathway proteins, and hemoproteins to determine the extent to which this lung tumor subtype depends on heme and respiratory proteins for its progression.
Citation Format: Sanchareeka Dey, Sarada Preeta Kalainayakan, Poorva Ghosh. Examining the role of heme and respiratory proteins in the progression of KRAS/LKB1 mutant subtype [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 1242.
Abstract 1250: Radotinib induces cell death of multiple myeloma cells
Authors: Jo Jae-Cheol , Heo Sook-Kyoung , Noh Eui-Kyu , Kim Jeong Yi , Sung Jun Young , Yu Ho-Min , Jeong Yoo Kyung , Ju Lan Jeong , Choi Yunsuk 
Published: August 2019

Abstract
Background: Radotinib is a medicine for the treatment of some types of cancer. It is approved in South Korea for use as a second-line treatment of chronic myeloid leukemia (CML). Its mechanism of action involves inhibition of the tyrosine kinase Bcr-Abl and of platelet-derived growth factor receptor (PDGFR). It has been little known the effects of radotinib on multiple myeloma (MM) cells.
Methods: First, we examined cytotoxicity of radotinib on MM cell lines, RPMI-8226 and MM.1S. Annexin V positive cell, caspas-3 and -9 activities, cell cycle distribution and mitochondrial membrane potential (MMP, ΔΨm) were observed by analyzed with flow cytometric analysis. And diverse signaling pathways were investigated by Western blotting in MM cells.
Results: Interestingly, radotinib caused cell death of MM cells. Radotinib induced Annexin V positive cells, and caspase pathway activation including caspase-3, -7 and -9. And its treatment remarkably decreased MMP in MM cells. As well as we observed that cytochrome c accumulated dose dependently in the cytosol of radotinib-treated RPMI-8226 and MM.1S cells. Moreover, radotinib decreased the expression of Bcl-xL and Bcl-2, and increased the expression of Bax and Bak in MM cells. Moreover, radotinib significantly suppressed MM cell growth in a xenograft animal model using RPMI-8226 cells.
Conclusion: Radotinib may play an important role as a candidate or chemosensitizer for treatment agent in MM. These data indicate that radotinib has a potential for anti-cancer therapy in MM.
Figure 1. Radotinib significantly suppressed MM cell growth in a xenograft animal model using RPMI-8226 cells.
Citation Format: Jae-Cheol Jo, Sook-Kyoung Heo, Eui-Kyu Noh, Jeong Yi Kim, Jun Young Sung, Ho-Min Yu, Yoo Kyung Jeong, Lan Jeong Ju, Yunsuk Choi. Radotinib induces cell death of multiple myeloma cells [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 1250.
Abstract 1252: Intracellular iron chelation by a novel compound, C7, reactivates Epstein-Barr virus (EBV) lytic cycle via the ERK-autophagy axis in EBV-positive epithelial cancers
Authors: Chiang Alan K S , Yiu Stephanie PT , Hui Kwai F. , Choi Chung K. , Kao Richard YT , Yang Dan 
Published: August 2019

Abstract
Pharmaceutical reactivation of lytic cycle of Epstein-Barr virus (EBV) represents a potential therapeutic strategy against EBV-associated epithelial malignancies e.g. gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC). A novel lytic inducing compound, C7, which exhibits structural similarity to Dp44mT, a known chelator of intracellular iron, is found to reactivate EBV lytic cycle in GC and NPC. This study aims to investigate the role of intracellular iron chelation by C7 and other iron chelators in lytic reactivation of EBV in GC and NPC. Testing of 6 structural analogues of C7 revealed only those which had high affinity towards transition metals could induce EBV lytic cycle. Pre-complexing C7 and iron chelators to iron prior to treatment of the cells abolished EBV lytic reactivation. Though hypoxia signaling pathway was activated, it was not the only pathway associated with EBV reactivation. Specifically, C7 and iron chelators initiated autophagy by activating extracellular signal-regulated kinase (ERK1/2) to reactivate EBV lytic cycle since autophagy and EBV lytic reactivation were abolished in cells treated with ERK1/2 blockers whilst autophagy inhibition by 3-MA and ATG5 knockdown significantly abolished EBV lytic reactivation. In summary, we discover a novel mechanism of reactivation of EBV lytic cycle through intracellular iron chelation and induction of ERK-autophagy axis in EBV-positive epithelial malignancies, raising the question whether clinically available iron chelators can be combined with existing therapeutic modalities to treat these cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Alan K S Chiang, Stephanie PT Yiu, Kwai F. Hui, Chung K. Choi, Richard YT Kao, Dan Yang. Intracellular iron chelation by a novel compound, C7, reactivates Epstein-Barr virus (EBV) lytic cycle via the ERK-autophagy axis in EBV-positive epithelial cancers [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 1252.
Abstract 1253: MDM2 inhibitor APG-115 synergizes with CDK4/6 inhibitors in a patient-derived xenograft model of dedifferentiated liposarcoma
Authors: Fang Douglas D. , Zhai Guoqin , Xu Chunhua , Gu Qingyang , Wang Jingwen , Zhu Saijie , Yang Dajun , Zhai Yifan 
Published: August 2019

Abstract
Liposarcoma is a rare but highly recurrent soft tissue neoplasm. Combination of surgery and radiotherapy is the main treatment for liposarcoma patients while chemotherapy remains experimental and limited depends on disease subtypes. Well-differentiated and dedifferentiated liposarcoma (WDLPS/DDLPS) represents ~50% of all diagnosed liposarcoma and their benefit from chemotherapy has been documented to be minimal. Concomitant amplifications of MDM2 and CDK4 are frequently found in WDLPS/DDLPS patients, suggesting that the combination with two targeted agents may worth further development for the treatment. APG-115 is a potent, selective, orally bioavailable small molecule inhibitor of MDM2-p53 protein-protein interaction and thus activates tumor suppression activity of p53 in p53 wild-type tumors. Currently, APG-115 is in clinical development as a single agent or in combination with PD-1 blockade immunotherapy for solid tumors, including sarcoma. To further explore the sensitive patient population and predictive biomarkers for APG-115, in this study, we evaluated the effect of the combined MDM2/CDK4 inhibition in p53 wild-type, MDM2 and CDK4 amplified liposarcoma using a preclinical xenograft tumor model derived from a dedifferentiated liposarcoma patient (PDX). Tumor-bearing mice were treated with MDM2 inhibitor APG-115, CDK4 inhibitors palbociclib/ribociclib, or their combinations. In the first experiment, APG-115 administered at 40 mg/kg as a single agent demonstrated antitumor activity in the DDLPS PDX model. In comparison with the single agents, the combination treatment with APG-115 and palbociclib or APG-115 and ribociclib exerted synergistic antitumor effects, resulting in T/C values of 16.9% and 27.1%, respectively (T/C value, average tumor volumes in treatment group vs. the vehicle control group). Partial tumor regression (PR) was achieved in 1/5 animals in both combination treatment groups but not in single arms. Another independent experiment with a higher dose of APG-115 (80 mg/kg) combined with palbociclib showed further improved antitumor activity with T/C value of 7.0% (2/5 PR). Collectively, our results suggest that the combination therapy of APG-115 and a CDK4 inhibitor may benefit WDLPS/DDLPS patients with p53 wild-type, and MDM2 and CDK4 amplifications clinically.
Citation Format: Douglas D. Fang, Guoqin Zhai, Chunhua Xu, Qingyang Gu, Jingwen Wang, Saijie Zhu, Dajun Yang, Yifan Zhai. MDM2 inhibitor APG-115 synergizes with CDK4/6 inhibitors in a patient-derived xenograft model of dedifferentiated liposarcoma [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 1253.
Abstract 1259: HYAL4: The first study on a potential molecular driver and biomarker of invasive bladder cancer
Authors: Morera Daley S. , Lahorewala Sarrah S. , Lokeshwar Soum D. , Jordan Andre R. , Lokeshwar Vinata B. 
Published: August 2019

Abstract
INTRODUCTION AND OBJECTIVE: The majority of morbidity and mortality in bladder cancer (BCa) patients is due to muscle invasive bladder cancer (MIBC). The prognosis of patients with MIBC could be improved by identification of novel biomarkers and therapeutic agents. Chondroitin sulfate proteoglycans are known to promote tumor growth and metastasis. However, a Chondroitinase (Chase) that degrades chondroitin sulfate has not been identified. HYAL4, a member of the glycosaminoglycan (GAG) degrading enzyme-family, potentially has Chase activity; however, HYAL4 (HY4) has not be studied in any biological system, normal or disease. In this study, we evaluated the expression of all six members of the GAG-degrading enzyme family in BCa specimens and evaluated HY4 functions in preclinical models of BCa.
METHODS: Cohort 1: 79 bladder tissues (normal (NBL) = 31; tumor (TBL) = 52); cohort 2: 40 cystectomy specimens from MIBC patients who received adjuvant Gemcitabine plus cisplatin (G+C) treatment for metastatic disease with chemotherapy. Gene expression was measured by q-PCR in both cohorts. HY4 was either overexpressed (HY4) or knocked-down in immortalized normal urothelial (Urotsa) and 3 BCa cell lines. Transfectants were assayed for Chase activity, anchorage independent growth, motility, invasion, molecular signaling. Tumor growth and metastasis in intravesical examined in HT1376 bladder orthotopic model.
RESULTS: In cohort 1 HYAL1, HYAL4 mRNA levels were significantly (6-13-fold) elevated in TBL tissues when compared to NBL tissues (P&lt;0.001). HY4 levels were 7-fold elevated in MIBC. HY4 levels were an independent predictor of metastasis and death due to BCa (chi-sq: 6.9; P=0.0087; chi-sq: 7.59; P=0.006). In cohort 2, high HY4 levels significantly correlated with G+C treatment failure (chi-sq: 8.7; P=0.003) with &gt; 80% accuracy. HY4-expressing transfectants secreted HY4 and Chase activity in their conditioned media. Overexpression of HY4 in normal urothelial and BCa cells significantly increased, while its knockdown abrogated, anchorage-independent growth, invasion, chemotactic motility (&gt; 3-fold). HY4 expression induced Gemcitabine resistance (IC50: vector: 3.1 nM; HY4: 126 nM). HY4 expression upregulated a stem cell signature. Urothelial cells expressing HY4 formed tumors in NOD/SCID mice. HY4-expressing BCa cells metastasized to lung and spleen in an orthotopic BCa model.
Citation Format: Daley S. Morera, Sarrah S. Lahorewala, Soum D. Lokeshwar, Andre R. Jordan, Vinata B. Lokeshwar. HYAL4: The first study on a potential molecular driver and biomarker of invasive bladder 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 1259.
Abstract 126: Multidimensional gene expression models for characterizing response and metastasis in solid tumor samples
Authors: Carney Walter P. , Bhagat Milan , LaFranzo Natalie 
Published: August 2019

Abstract
Predicting response to standard of care therapies and new immunotherapies is enabled by tools that quantitatively analyze the complex heterogeneity of the tumor microenvironment. Current methods to do so primarily rely either on single gene or protein markers, and often report solely on one feature of the multifaceted immune cycle. Unlike other molecular approaches, the ImmunoPrismTM Immune Profiling Assay has been built using multidimensional gene expression models validated to accurately identify immune cells in a complex mixture with high correlation to flow cytometry measurements, but accessible for formalin-fixed paraffin-embedded (FFPE) tissues. We will report results showing the assay is highly sensitive, capable of detecting immune cells present to as little as 2% of the specimen, important for critical immune cell types such as M1 and M2 macrophages and Tregs. Further, the assay requires as few as two sections of FFPE solid tumor tissue or as little as 20 ng of total RNA which enables the analysis of rare clinical archives. In this study, we apply the ImmunoPrism assay to cohorts of patients with indications including non-small cell lung carcinoma (NSCLC), triple-negative breast cancer (TNBC) and pancreatic adenocarcinoma (ADC) treated with standard of care therapies. Immune profile changes for pre vs. post treatment and primary vs. metastatic tissue are reported in the context of clinical data, such as therapy response. Resulting biomarkers, including a novel machine-learning based multidimensional marker are also reported with predictive accuracy, PPV, NPV, and selection thresholds.
Citation Format: Walter P. Carney, Milan Bhagat, Natalie LaFranzo. Multidimensional gene expression models for characterizing response and metastasis in solid tumor samples [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 126.
Abstract 1261: Targeting Wee1 in laryngeal squamous cell carcinoma
Authors: Yuan Meng-Ling , Jiang Qi-Wei , Yang Yang , Huang Jia-Rong , Shi Zhi 
Published: August 2019

Abstract
WEE1 is a tyrosine kinase that regulates G2/M cell cycle checkpoint and frequently overexpressed in various tumors. However, the expression and clinical significance of WEE1 in human laryngeal squamous cell carcinoma (LSCC) are still unknown. In this study, we found that WEE1 was highly expressed in LSCC tissues compared with adjacent normal tissues. Importantly, overexpression of WEE1 was correlated with T stages, lymph node metastasis, clinical stages and poor prognosis of LSCC patients. Furthermore, inhibition of WEE1 by MK-1775 induced cell growth inhibition, G2/M cell cycle arrest and apoptosis with the increased intracellular reactive oxygen species (ROS) levels in LSCC cells. Pretreatment with ROS scavenger N-acetyl-L-cysteine could reverse MK-1775-induced ROS accumulation and cell apoptosis in LSCC cells. MK-1775 also inhibited the growth of LSCC xenografts in nude mice. Altogether, these findings suggest that WEE1 is a potential therapeutic target in LSCC, and inhibition of WEE1 is the prospective strategy for LSCC therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Meng-Ling Yuan, Qi-Wei Jiang, Yang Yang, Jia-Rong Huang, Zhi Shi. Targeting Wee1 in laryngeal 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 1261.