bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5541: Proteasome inhibitor synergizes with histone deacetylase inhibitor to trigger ROS- and ER stress-induced apoptosis of nasopharyngeal carcinoma independent of aggresome disruption
Authors: Chiang Alan K. , Hui Kwai Fung 
Published: May 2015

Abstract
Proteasome inhibitor and histone deacetylase inhibitor (HDACi) can synergistically induce apoptosis of cancer cells through aggresome disruption or induction of endoplasmic reticulum (ER) stress. We previously reported that suberoylanilide hydroxamic acid (SAHA), a pan-HDACi, and bortezomib, a proteasome inhibitor can synergistically induce apoptosis of nasopharyngeal carcinoma (NPC) cells through reactive oxygen species (ROS)-driven caspase-dependent mechanism. Here, we wish to investigate the role of aggresome disruption or ER stress in the process. We first tested the effect of bortezomib combining with a more specific HDACi, including MS-275, apicidin or romidepsin, on proliferation of NPC cells. Bortezomib could synergize with each of the specific HDACis to induce killing of the NPC cells. Strong apoptosis was demonstrated by the proteolytic cleavage of PARP and caspase-3, -8 and -9 as well as the high percentage of annexin V/propidium iodide (AV/PI)-positive NPC cells upon treatment with combination of bortezomib at 7.5 to 15 nM and romidepsin at 2.5 to 5 nM. Consistently, the apoptosis was ROS- and caspase-dependent. Interestingly, α-tubulin, a key substrate of histone deacetylase 6, was not acetylated, arguing against the involvement of aggresome disruption. In contrast, ER stress induction might be involved because ATF-4 and CHOP, which are markers of ER stress, were up-regulated by combined bortezomib/romidepsin and inhibition of caspase-4 could suppress the apoptosis. Furthermore, addition of ROS scavenger, N-acetyl-cysteine, suppressed the expression of ATF-4 and CHOP. We conclude that proteasome inhibitor can synergize with HDACi to trigger ROS- and ER stress-induced apoptosis of NPC cells, independent of aggresome disruption.
This project is funded by NPC Area of Excellence (AoE/M 06/08 Center for Nasopharyngeal Carcinoma Research), CRCG (#10401264) and Epstein-Barr virus research (# 20004525) grants of A.K.S. Chiang.
Citation Format: Alan K. Chiang, Kwai Fung Hui. Proteasome inhibitor synergizes with histone deacetylase inhibitor to trigger ROS- and ER stress-induced apoptosis of nasopharyngeal carcinoma independent of aggresome disruption. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5541. doi:10.1158/1538-7445.AM2014-5541
Abstract 5550: SNPs in UDP-glucuronosyltransferase1A4 (UGT1A4) and multidrug resistant protein (MRP) and their influence on anastrozole metabolism and disposition
Authors: Edavana Vineetha Koroth , Penney Rosalind , Borengasser Aiwei Yao- , Rogers Lora , Dhakal Ishwori , Williams Suzanne , Kadlubar Susan 
Published: May 2015

Abstract
Anastrozole is an aromatase inhibitor (AI) used as adjuvant therapy for breast cancer. Anastrozole belongs to the non-steroidal triazole-derivative group of AIsand is predominantly metabolized by Phase I oxidation followed by other Phase II reactions, including glucuronidation. Anastrozole is also subject to direct glucuronidation catalyzed by UDP-glucuronosyltransferase1A4 (UGT1A4). We have demonstrated a significant association between expression levels of the drug transporter genes MRP2 and MRP3 and anastrozole glucuronidation. We hypothesized that genetic variability in UGT1A4 and MRPs could influence anastrozole metabolism and disposition.
Using normal human liver samples obtained from the Cooperative Human Tissue Network, we analyzed the correlation of UGT1A4, MRP2 and MRP3 mRNA and protein expression levels with anastrozole glucuronidation. UGT1A4 and MRP2 mRNA and protein expression levels were significantly correlated with anastrozole gucuronidation (p&lt;0.05). Further, we examined the correlation of UGT1A4 and MRP2 SNPs with anastrozole glucuronidation. We observed a significant correlation (p&lt;0.05) of UGT1A4 promoter SNPs (-163G&gt;A, -217T&gt;G, -219C&gt;T) and MRP2 SNPs (3563T&gt;A, 4430C&gt;T and -24C&gt;T) with anastrozole glucuronidation (Table 1).
These data indicate that UGT1A4 and MRP2 SNPs could interact to influence anastrozole metabolism and disposition. Pharmacogenetic studies are needed to elucidate the role of UGT1A4 and MRP2 SNPs in the inter-individual variability in anastrozole metabolism and disposition, as well as the overall efficacy of anastrozole treatment.
Table 1
SNPUGT_mRNAMRP2 mRNAMRP3 mRNAAna-gluc-Nm/uL/ugUGT1A4 -36(G/A)0.260.130.560.26UGT1A4 -163(G/A)&lt;0.00010.030.64&lt;0.0001UGT1A4-217(T/G)0.0180.0570.810.01UGT1A4-219(C/T)&lt;0.00010.010.05&lt;0.0001MRP2 3563(T/A)0.051&lt;0.00010.030.033MRP2 4544(G/A)0.15&lt;0.0010.720.14MRP2 1249(G/A)0.25&lt;0.0110.430.34MRP2 2366(C/T)0.12&lt;0.00010.180.14MRP2 4430(C/T)0.02&lt;0.00020.0610.01MRP2 -24(C/T)0.01&lt;0.00010.0010.02MRP3 -1767 (G/A)0.780.690.0010.93MRP3 -211 (C/T)0.860.55&lt;0.00010.81
Citation Format: Vineetha Koroth Edavana, Rosalind Penney, Aiwei Yao- Borengasser, Lora Rogers, Ishwori Dhakal, Suzanne Williams, Susan Kadlubar. SNPs in UDP-glucuronosyltransferase1A4 (UGT1A4) and multidrug resistant protein (MRP) and their influence on anastrozole metabolism and disposition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5550. doi:10.1158/1538-7445.AM2014-5550
Abstract 557: Noninvasive analysis of acquired resistance to EGFR-TKI
Authors: Kimura Hideharu , Nishio Makoto , Daito Tsutomu , Nishio Kazuto 
Published: May 2015

Abstract
BACKGROUND
Epidermal growth factor receptor (EGFR) T790M mutation is associated with EGFR tyrosine kinase inhibitors (EGFR-TKIs) resistance in non-small cell lung cancer (NSCLC). However, the tissue availability limits the genotyping of EGFR T790M mutation in the clinical setting. The aims of this study are to develop a blood-based, non-invasive approach to detect the EGFRT790M mutation in advanced NSCLC patients. Additionally, plasma concentrations of HGF, MET and amphiregulin which are also resistant factors of EGFR-TKIs
EXPERIMENTAL DESIGN
Plasma sample were collected from NSCLC patients with activating EGFR mutations, who had resistant to EGFR-TKIs treatment. EGFR T790M mutations were detected using droplet-digital PCR (ddPCR) system from plasma DNA at resistance to EGFR-TKI. Plasma concentrations of HGF, soluble MET (sMET) and amphiregulin were determined using enzyme-linked immunosorbent assay. The relationships between the EGFR T790M mutation status and the plasma concentrations, progression-free survival (PFS) overall survival (OS) were analyzed.
RESULTS
Twenty-one (35%) of the patients had EGFR T790M mutation in plasma DNA using ddPCR system. The levels amphiregulin tended to be increased at the resistance in the patients with EGFR T790M mutation. The PFS and OS of the patients with EGFR T790M mutation was significantly shorter than that of the patients without EGFR T790M mutation (P =0.03 and 0.04). The PFS of the patients who had high amphiregulin at the resistance and the OS of the patients who had high amphiregulin at pre-treatment were shorter than these of t low amphiregulin (P = 0.05 and 0.05)
CONCLUSIONS
The ddPCR system is a detectable method for determining the plasma EGFR T790M mutation status. The combination of EGFR T790M mutation status by ddPCR and the amphiregulin levels may aid in monitoring drug resistance and in predicting a prognosis.
Citation Format: Hideharu Kimura, Makoto Nishio, Tsutomu Daito, Kazuto Nishio. Noninvasive analysis of acquired resistance to EGFR-TKI. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 557. doi:10.1158/1538-7445.AM2014-557
Abstract 5572: Auto-analysis of immunohistochemical findings and one-day instant quality fluorescence in situ hybridization increase quality of breast cancer therapy
Authors: Taniyama Daiki 
Published: May 2015

Abstract
Background:Currently, the therapeutic strategy for a breast cancer patient is designed according to his/her histopathological, immunohistochemical and molecular findings. These findings are obtained through the collected efforts of many individual pathologists or medical technologists and are thus limited by intra-observer error and potentially subjective decision-making. The assessment of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is demanded to be prompt, objective, and reproducible. In our institute, the authors are utilizing the whole slide imaging system (NanoZoomer 2.0-HT, Hamamatsu photonics, Japan) and a software for image analysis (Genie, Vista, CA), specifically for an auto-analysis of IHC. We succeeded in gaining objective and highly reproducible results. On the other hand, current FISH technique is time-consuming and takes two days to complete due to the overnight incubation required to obtain proper hybridization result. The authors tried to compare the results with current FISH (cFISH) and one-day Instant Quality FISH (IQFISH) for human epidermal growth factor receptor 2 (HER2).
Methods: Auto-analysis arm. Twenty-five breast cancer specimens were examined for IHC of estrogen receptor (ER), progesterone receptor (PgR) HER2, Topoisomerase (Topo) II alpha, and Ki-67, and the results were compared by ocular observation and auto-analysis. Fifty-one cancer specimens were compared in terms of IHC and cFISH of HER2.IQFISH arm. Thirty-four biopsy samples from pre-therapeutic breast cancers (29 primary invasive ductal carcinomas and five metastatic cancers) were examined and the results of cFISH and IQFISH were compared.
Results: Auto-analysis arm. For all antibodies, expect for HER2, concordant results were obtained in 100% of 24 ER positive cases. Ki-67 index (r=0.96) and TopoIIalpha index (r=0.95) also showed a significant correlation (p&lt;0.001). For cHER2, all four specimens with Hercep-score 2 by ocular observation but 1 by auto-analysis revealed no HER2 gene amplification. IQFISH arm. IQFISH (r=0.66) showed a significant correlation (p&lt;0.0001) with cFISH. Both auto-analysis and IQFISH reduced substantially the time for analysis.
Conclusion: Well-organized auto-analysis is more likely to result in an objective observation and provide a means by which to standardize the methods of IHC in breast cancer. IQFISH may contribute to an earlier decision regarding therapeutic strategy for a breast cancer.
Citation Format: Daiki Taniyama. Auto-analysis of immunohistochemical findings and one-day instant quality fluorescence in situ hybridization increase quality of breast cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5572. doi:10.1158/1538-7445.AM2014-5572
Abstract 5574: Gli2 protein and the AR operational switch to the castration resistant prostate cancer transcription program
Authors: Li Na , Buttyan Ralph , Truong Sarah , Yu Yue , Chen Mengqian 
Published: May 2015

Abstract
Gli proteins are transcription factors that mediate Hedgehog (HH) signaling in cells. Previously, we reported that Gli2 binds to the androgen receptor (AR) protein in prostate cancer (PCa) cells and further upregulates expression of genes under AR control. This “co-activator” effect allows the growth of Gli2 overexpressing LNCaP cells in androgen-depleted medium, mimicking the behavior of castrate resistant variants of PCa. We report here our success in localizing the specific binding domains between Gli2 and AR proteins. Outcomes of GST-pulldown and co-immunoprecipitation studies showed that Gli2 binds to AR via a limited domain (aa628-aa897) within the C-terminal region and this recognizes the tau5/AF5 domain (aa 392-558) within the N-terminal region of the AR protein. Because tau5/AF5 is conserved in truncated (splice variant) ARs, we also showed that Gli2 recognizes and co-activates the transcriptional activity of a truncated variant AR (AR-V7). To further define Gli2 regulatory functions on AR transcriptional activity in CRPC, we overexpressed Gli2ΔN (a constitutive-active form of Gli2) in LNCaP-AI (androgen-independent) cells and examined its effects on AR target gene expressions. Surprisingly, we found that Gli2Δ overexpression coincided with significant downregulated expression of genes considered “traditional” AR targets (i.e., KLK3 and KLK2), while increasing the expression of M-phase check-point genes, such as UBE2C, CDK1 and CDC20. In contrast, treatment of unmodified LNCaP-AI cells with the Gli-inhibitor, GANT61, significantly increased expression of KLK2 and KLK3 while downregulating UBE2C, CDC20 and CDK1. Our outcomes now imply that Gli2 differentially affects the AR transcriptional program in androgen-dependent (LNCaP) vs androgen-independent (LNCaP-AI) cells. In androgen-dependent cells, Gli2 co-activates expression of the traditional AR target genes while suppressing expression of genes involved in the CRPC transcriptional program whereas in androgen-independent cells, Gli2 co-activates expression of CRPC program genes while downregulating expression of traditional AR target genes. This dichotomy suggests that Gli2 participates in the decisions through which AR transcriptional activity is redirected in castration resistant disease. Supported by the DOD PCRP (W81XH-10-1-0493, to RB)
Citation Format: Na Li, Ralph Buttyan, Sarah Truong, Yue Yu, Mengqian Chen. Gli2 protein and the AR operational switch to the castration resistant prostate cancer transcription program. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5574. doi:10.1158/1538-7445.AM2014-5574
Abstract 560: Distinct protein expression patterns of solid pseudopapillary neoplasm of pancreas
Authors: Park Minhee , Cho Minhee , Yoon SeongJu , Kim Hoguen 
Published: May 2015

Abstract
Solid pseudopapillary neoplasm (SPN), is an uncommon pancreatic tumor with distinct clinicopathologic features. SPNs are characterized by mutation in exon 3 of CTNNB1. However, little is known about SPN tumorigenesis but CTNNB1 mutation. In order to identify the characteristic gene expression patterns of SPN, we performed proteome analysis of SPN and compared to gene expression data. We analyzed pooled SPNs and pooled non-neoplastic pancreas tissues using LTQ-Orbitrap. In total, we identified 862 (444 up-regulated and 418 down-regulated) proteins showed differential expression in SPN compared to non-neoplastic pancreas. We compared proteome profiling compared to mRNA expression of SPNs, and then selected 544 significant proteins presented the same expressional tendency.
Many of the overexpressed proteins are related to the activated signaling pathways of SPN consistently with our previous study. Specifically, DKK4 (6.1-fold), APC (1.5-fold), RUVBL1 (1.4-fold) and β-catenin (1.3-fold) involved in Wnt signaling were up-regulated in protein level of SPNs compared to non-neoplastic pancreas. Besides Wnt signaling, we detected several up-regulated proteins including FUS and NONO. The interaction of β-catenin with FUS was reported that involved in the regulation of pre-mRNA splicing. We identified that FUS and NONO interacted directly with β-catenin by immunoprecipitation in β -catenin active cell lines (SW480, HCT116). We found that molecules involved in glycolysis, metabolism and sumoylation were activated in SPNs; HK1 (3.2-fold), PKM2 (3.3-fold), ENO2 (2.1-fold), PDHA (1.5-fold) and SUMO2 (1.6-fold). We also detected that several proteins involved in epithelial-mesenchymal transition were up or down-regulated including CTSB (3.98-fold), VIM (1.98-fold) and JUP (-2.29-fold).
Our proteomic profiling study of SPNs provides 1) SPN-specific molecular mechanism for solid-pseudopapillary neoplasm tumorigenesis similar with mRNA expression pattern including Wnt signaling, 2) SPN-specific epithelial-mesenchymal transition, and 3) a metabolism is activated in SPNs. These findings can be used for an early diagnosis biomarker development or molecular therapeutic target.
Citation Format: Minhee Park, Minhee Cho, SeongJu Yoon, Hoguen Kim. Distinct protein expression patterns of solid pseudopapillary neoplasm of pancreas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 560. doi:10.1158/1538-7445.AM2014-560
Abstract 568: Few Carney's Triad patients have mutations in two subunits of the succinate dehydrogenase enzyme (SDHB, SDHC)
Authors: Boikos Sosipatros A. , Xekouki Paraskevi , Faucz Fabio R. , Pacak Karel , Raygada Margarita , Adams Karen , Szarek Evan , Ball Evan , Kim Su Young , Fumagalli Elena , Helman Lee J. , Carney J Aidan , Stratakis Constantine A. 
Published: May 2015

Abstract
Carney's triad (CTr) is a non-hereditary condition, primarily seen in young women, characterized by gastrointestinal stromal tumors (GIST), extra-adrenal paragangliomas and pulmonary chondromas. Most CTr patients present with GIST and pulmonary chondroma (incomplete CTr). A marked decrease in the enzymatic activity of succinate dehydrogenase (SDH) has been detected in these tumors, but the presence or absence of SDH mutations in CTr is controversial. A related disease, known as Carney-Stratakis Syndrome (CSS), has no female predisposition and presents with extra-adrenal paragangliomas and GIST tumors, without pulmonary chondromas. In distinction to CTr, CSS is hereditary due to germline SDH mutations in the enzyme's subunits (SDHA, SDHB, SDHC and SDHD) with corresponding decreased SDH activity in associated tumors. We have investigated 64 patients with CTr for germline mutations and/or deletions in the SDH subunit genes; four patients were found to have germline mutations in SDHB or SDHC. All four patients had multifocal gastric GIST and pulmonary chondromas at diagnosis; two subsequently developed paragangliomas, confirmed by biopsy. One of the patients with CTr and a SDHB mutation had a nephew with the same mutation and a neuroblastoma, confirming a previously reported association of neuroblastoma with gist (JMG 2009; 46:215, and AJMG 2010; 152A: 1531). We conclude that few CTr patients maybe more correctly classified as having CSS; the genetic distinction of CTr from CSS needs further study.
[S.A.B. and P.X. should be regarded as joint first authors.]
Citation Format: Sosipatros A. Boikos, Paraskevi Xekouki, Fabio R. Faucz, Karel Pacak, Margarita Raygada, Karen Adams, Evan Szarek, Evan Ball, Su Young Kim, Elena Fumagalli, Lee J. Helman, J Aidan Carney, Constantine A. Stratakis. Few Carney's Triad patients have mutations in two subunits of the succinate dehydrogenase enzyme (SDHB, SDHC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 568. doi:10.1158/1538-7445.AM2014-568
Abstract 584: NVP-BEZ235 decreases mutant p53 and downregulates miR-23a-24-27a to inhibit metastasis in breast cancer cells
Authors: Wang Dongsheng , Du Qin , He Binfeng , Deng Yibin , Guo Xiaolan 
Published: May 2015

Abstract
Nearly half of human cancers harbor TP53 mutations, which are predominantly through missense mutations that result in accumulation of mutant p53 proteins in cancer cells. More and more findings indicate that the mutant p53 proteins acquire gain-of-function abilities to promote carcinogenesis, metastasis, tumor recurrence and chemoresistance. TP53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas, especially the triple negative breast cancer (TNBC),which most easily metastasizes and confers chemoresistance. Therefore targeting TP53 mutation in breast cancer might be another promising approach of therapeutics. Our previous investigation showed that the AKT-mTOR dual inhibitor, NVP-BEZ235(called BEZ235 thereafter), could inhibit AKT-mTOR pathway activation, most interestingly mutant p53 was significantly reduced with BEZ235 treatment(unpublished data). In this study, three TNBC cell lines MDA-MB-231, MDA-MB-436, MDA-MB-468 as TP53 mutation group and MCF-7 as control were employed with BEZ235 treatment at different dosages and time points. We found that AKT-mTOR signaling pathway were highly activated in these TNBC cells but were inhibited obviously after BEZ235 treatment; most importantly, mutant p53 in these TNBC cells decreased significantly, but rare changes were detected in MCF-7 cells with BEZ235 treatment. Interestingly, we found miR-23a-24-27a cluster was about 2 fold upregulation in TNBC cells after BEZ235 treatment while exploring the decline of p53 by detecting microRNAs expression in those cell lines. To address whether BEZ235 could affect the metastasis ability of TNBC cells, cell invasion assay Transwell was used to measure the invasiveness of TNBC cells with BEZ235, and we observed that BEZ235 could inhibit the metastasis of TNBC cells, on the other hand miR-23a-24-27a cluster mimics could also induce the inhibition of metastasis in TNBC cells. Our results suggest that BEZ235 might target mutant p53 accumulation and downregulate miR-23a-24-27a cluster to inhibit the metastasis abilities of triple negative breast cancer cells, which might provide an important direction to further study the breast cancer harboring mutant p53, and also have promising therapeutic benefits for cancer patients carrying such p53 mutations.
Citation Format: Dongsheng Wang, Qin Du, Binfeng He, Yibin Deng, Xiaolan Guo. NVP-BEZ235 decreases mutant p53 and downregulates miR-23a-24-27a to inhibit metastasis in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 584. doi:10.1158/1538-7445.AM2014-584