bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4097: Significance of glypican-1 expression on tumor stromal cells in gastric carcinoma
Authors: Miki Yuichiro , Yashiro Masakazu , Kitayama Kishu , Kasashima Hiroaki , Masuda Go , Kubo Naoshi , Sakurai Katsunobu , Toyokawa Takahiro , Tanaka Hiroaki , Muguruma Kazuya , Ohira Masaichi , Hirakawa Kosei 
Published: July 2016

Abstract
Background: Glypican1 (GPC1) is a cell surface heparan sulfate proteoglycan that acts as a co-receptor for heparin-binding growth factors, and it plays a crucial role in cancer growth. Recently, it has been reported that GPC1 enriched on cancer-derived exosomes, and GPC1-positive exosomes in the circulation was frequently found in the patients with early pancreatic cancer. However role of GPC1-positive exosomes derived from tumor stromal cells remains to be unclear. The aim of this study is to clarify the significance of GPC1 expression on stromal cells in gastric carcinoma.
Methods: A total of 597 patients with gastric cancer was enrolled in this study. An anti-GPC1 antibody was used for immunohistochemical staining. GPC1 expression was scored by the intensity of staining and the percentage of positive cells. GPC1 expression on cancer cells or stromal cells was evaluated. The corelation between GPC1 expression and clinicopathological features was statistically analyzed.
Results: GPC1 expression on cancer cells was found in 473 (79%) of 597 cases. GPC1 expression on stromal cells was found in 147 (75%) of 597 cases. A Kaplan-Meier survival curve showed that overall survival of patients with GPC1-positive stromal cells was significantly better (log-rank p = 0.0028) than that with GPC1-negative stromal cells (5-year survival rate; 72.5% vs 57.9%, respectively). In contrast, overall survival was not statistically different (log rank p = 0.090) between patients with GPC1-positive tumor cells and GPC1-negative tumor cells (5-year survival rate; 71.8% vs. 64.6%, respectively). GPC1 expression on stromal cells was significantly correlated with T stage, lymph node metastasis, lymphatic vessel invasion, and clinical stage.
Conclusions: GPC1 expression on stromal cells was associated with the good prognosis of patients with gastric cancer. GPC1-positive exosomes in stromal cells might be correlated with the progression of gastric cancer.
Citation Format: Yuichiro Miki, Masakazu Yashiro, Kishu Kitayama, Hiroaki Kasashima, Go Masuda, Naoshi Kubo, Katsunobu Sakurai, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Masaichi Ohira, Kosei Hirakawa. Significance of glypican-1 expression on tumor stromal cells in gastric carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4097.
Abstract 410: Exhaustive scanning of mutation hotspot regions using a new tool: The MHS-ddPCR
Authors: Decraene Charles , Bidard Francois-Clement , Belaabi Samia , Rouleau Etienne , Saliou Adrien , Houy Alexandre , Milder Maud , Lantz Olivier , Ychou Marc , Pierga Jean-Yves , Stern Marc-Henri , Proudhon Charlotte 
Published: July 2016

Abstract
Background: Recent progress in the ‘liquid biopsy’ field in combination with the development of the droplet digital PCR (ddPCR) technology now enables non-invasive monitoring of cancer-related genomic alterations with high detection accuracy. Current ddPCR techniques represent the gold standard for the detection of point mutations that have been previously characterized on tumor tissues. However, ddPCR screen for only one mutation (or a few mutations, with multicolor ddPCR) per reaction. This is a clear limitation to use it as a discovery tool, to detect resistance-associated mutations that may appear during therapy (e.g. ESR1 activating mutations in breast cancer) or when tumor tissue is not available (e.g. EGFR activating mutations in lung cancers).
Methods:
We developed the Multiple Hotspot mutations detection by Single droplet digital PCR (MHS-ddPCR) method, a variant of the conventional ddPCR technique, which detects all genomic alterations within a hotspot region, using a unique couple of Taqman oligo-probes. We first established two specific assays covering KRAS and EGFR mutation hotspot regions, which are of clinical importance in the context of colorectal cancer. The assay for KRAS scans for the 7 most common mutations in codons 12 and 13 of the gene as well as all other mutations with lower frequency (&lt;1%). The EGFR assay screens for all in-frame deletions of exon 19, which are frequent activating events in EGFR.
Results:
Sensitivity and specificity of MHS-ddPCR were assessed on decreasing fractions of tumor DNA mutated for KRAS. The KRAS assay reaches a sensitivity of 0.02% and was validated on plasma and tumor samples harboring a panel of different KRAS mutations. Similarly, the EGFR assay can detect numerous exon 19 deletions from patient samples and with limited amounts of tumor DNA.
Conclusions:
The MHS-ddPCR is extremely sensitive, works for numerous hotspot regions with different types of alterations (SNV, deletion) and is cost-effective as it combines multiple assays in one reaction.
Citation Format: Charles Decraene, Francois-Clement Bidard, Samia Belaabi, Etienne Rouleau, Adrien Saliou, Alexandre Houy, Maud Milder, Olivier Lantz, Marc Ychou, Jean-Yves Pierga, Marc-Henri Stern, Charlotte Proudhon. Exhaustive scanning of mutation hotspot regions using a new tool: The MHS-ddPCR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 410.
Abstract 4122: Ceramide is a key factor that regulates the crosstalk between TGF-ß and sonic hedgehog signaling at the basal cilia to control cell migration and tumor metastasis
Authors: Gencer Salih , Oleinik Natalia , Dany Mohammed , Ogretmen Besim 
Published: July 2016

Abstract
Recent studies indicate that ceramide species with different fatty-acid chain lengths play diverse biological functions in various cellular processes, highlighting the importance of ceramide synthases (CerS) in these processes. Migration and cell mobility, a part of these processes, also are effected by ceramide metabolism. However, the molecular mechanism of CerS/and ceramide involved is unknown. Here, we investigated the effect of CerS/and ceramide on migration and its related signal pathways in situ and in vivo model. Interestingly, our data show that among CerS only CerS4/ceramide is involved to cell migration and tumor metastasis. Here, we also have generated CerS4-/- mice for in vivo studies. Interestingly, we observed that genetically loss of CerS4 resulted in severe irreversible alopecia, which was associated with hyper-proliferation and migration of keratinocytes. Mechanistically, we show here that genetic loss or shRNA-mediated knockdown of CerS4 enhances cell migration by which ligand-independent signaling of TGF-beta receptors I and II in various cell types, including keratinocytes, mouse embryonic fibroblasts and cancer cells. Moreover, we found that ceramide directly interact with Smad7 and this interaction was decreased by shRNA-mediated knockdown of CerS4. Thus, ceramide-Smad7 binding modulates plasma membrane association of TGF-ßR1 at primary basal cilia, and inhibits its signaling through Sonic-Hedgehog (Shh) for migration. Furthermore, Ceramide accumulation at the primary basal cilia was decreased by knockdown of CerS4. Thus, these data revealed that CerS4/ceramide signaling plays key roles in the regulation of cell migration and metastasis via controlling the TGF-ßR and Shh axis at primary basal cilia.
Citation Format: Salih Gencer, Natalia Oleinik, Mohammed Dany, Besim Ogretmen. Ceramide is a key factor that regulates the crosstalk between TGF-ß and sonic hedgehog signaling at the basal cilia to control cell migration and tumor metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4122.
Abstract 4132: Multiple drug resistance-associated protein 4 (MRP4): Role in triple negative breast cancer
Authors: Kochel Tyler , Ma Xinrong , Kundu Namita , Reader Jocelyn , Goloubeva Olga , Fulton Amy M. 
Published: July 2016

Abstract
Introduction: MRP4 is responsible for the active export of prostaglandin E2 (PGE2) from cells. PGE2, derived from cyclooxygenase-2-mediated synthesis, contributes to tumor growth and metastasis of many epithelial tumors; however, the role of MRP4 in breast cancer has not been investigated. Methods: We employed publicly available breast cancer gene expression datasets and a panel of breast cancer cell lines to examine the expression and function of MRP4 as well as other members of the PGE2 pathway. In contrast to the export function of MRP4, the prostaglandin transporter PGT/SLCO2A1 imports PGE2 into the cell where 15-prostaglandin dehydrogenase (5-PGDH/HPGD) metabolizes PGE2 to terminate ligand-mediated activation of the prostaglandin E (EP) receptors. Results: We found that ABCC4, which encodes the MRP4 protein, is widely expressed in breast cancer but breast cancer subtypes have different expression profiles of PGE2 pathway members. ABCC4/MRP4 is elevated more frequently in basal breast tumors than in apocrine or luminal tumors. This is the first report that elevated expression of MRP4 is found in breast cancer subtypes (basal, HER2-enriched) with the worst prognoses. ABCC4 expression was also higher in breast cancer-associated stroma compared to healthy mammary tissue. Basal-type tumors also expressed the highest levels of PTGS2/COX-2 while the genes responsible for PGE2 metabolism (HPGD and SLCO2A1) are negatively correlated with TNBC. The same pattern was observed in breast cancer cell lines, where basal-type and HER2-enriched cell lines highly express MRP4 but luminal breast cancers do not. HPGD was decreased in most cancer cell lines compared to MCF10A immortalized cells, consistent with the known tumor suppressor role of HPGD/15PGDH. MRP4 exports PGE2 which was reduced in the presence of MRP4 small m.w. inhibitors or by MRP4 gene silencing. Lastly, expression of shMRP4 in highly metastatic, basal-type MDA-MB-231 human breast cancer cells reduced the ability of these cells to spontaneously metastasize to the lungs of NOD/SCID mice but did not affect the tumor growth properties of tumor cells implanted proximal to the mammary gland. Conclusions: Elevated MRP4 is a characteristic of aggressive breast cancer subtypes and is partially responsible for the high levels of PGE2 in the tumor microenvironment. Silencing of MRP4 reduces spontaneous metastasis in a xenograft model of TNBC. Further investigation of MRP4 as a potential therapeutic target is warranted.
Citation Format: Tyler Kochel, Xinrong Ma, Namita Kundu, Jocelyn Reader, Olga Goloubeva, Amy M. Fulton. Multiple drug resistance-associated protein 4 (MRP4): Role in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4132.
Abstract 4151: APC control of retinoic acid suppresses immune cell mediated intestinal proliferative response
Authors: Templeton Amanda K. , Hammoud Saher , Cairns Brad , Jones David 
Published: July 2016

Abstract
Adenomatous polyposis coli (APC) tumor suppressor function is centered on its role in antagonizing Wnt/B-catenin mediated colonic proliferation. Our previous studies, however, established a second role wherein APC's control of retinoic acid (RA) results in intestinal epithelial cell differentiation. Surprisingly, the loss of APC or RA alone in zebrafish embryos was not sufficient to drive nuclear accumulation of B-catenin or intestinal cell proliferation. However, combining APC or RA deficiency with a KRAS mutation was sufficient to induce nuclear localization of B-catenin and the proliferative response. In contrast, the loss of RA alone in adult zebrafish results in both intestinal differentiation defects and proliferation. We were therefore interested in investigating these seemingly contradictory results. Using adult zebrafish, we show for the first time that following loss of retinoic acid adaptive immune cells (but not innate immune cells) are indirectly required to elicit the proliferative response independent of Kras activation. We demonstrate that IL-17 secretion from adaptive immune cells in response to loss of RA predisposes colonic epithelium to inflammation resulting in compromised barrier function, loss of cell polarity, reactivation of a progenitor intestinal program, and proliferation. Importantly, we find in both mouse and human intestinal organoid cultures an evolutionarily shared response with zebrafish of T cell dependent intestinal inflammation and proliferation following loss of RA. Our model demonstrates that loss of RA causes an increase in inflammatory mediators (Cox2 and Prostaglandins) that induces infiltration of IL-17 secreting T cells. In a feed-forward loop, the IL-17 acts on the primed epithelium to up-regulate proliferative signaling mediators (Raf and Rac1). Together, these studies provide an important new perspective on the ordering of molecular events that may underlie colon tumor progression.
Citation Format: Amanda K. Templeton, Saher Hammoud, Brad Cairns, David Jones. APC control of retinoic acid suppresses immune cell mediated intestinal proliferative response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4151.
Abstract 4195: Targeting the immune microenvironment to improve colorectal cancer anti-angiogenic therapy
Authors: Jung Keehoon , Heishi Takahiro , Yun Andy , Padera Timothy P. , Jain Rakesh K. , Fukumura Dai 
Published: July 2016

Abstract
Colorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Anti-angiogenic therapy with bevacizumab has been proven efficacious in metastatic CRC. However, the improvement in overall survival has been modest and rather disappointing. Thus, there is an urgent need to identify the underlying mechanisms responsible for the resistance to anti-angiogenic therapy and develop strategies to overcome it. Clinical and preclinical interest in tumor immunotherapy has been renewed in a significant manner recently. However, the role of the immune microenvironment in colorectal cancer resistance to anti-angiogenic therapy is not well understood.
We have developed miniaturized confocal endomicroscopy technique for spontaneous CRC models in mice. We also established a novel cecum window recently. These unique systems enable us to monitor the CRC and its immune microenvironment longitudinally with a video-rate intravital multi-photon microscope. Using these CRC models and in vivo imaging methods, we found that anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody increases infiltration of Gr1+ myeloid-derived suppressor cells (MDSCs) and they alter the tumor microenvironment toward an immune-suppressive condition to avoid attack of the host immune system. We also found that the Gr1+ MDSCs express CXCR4, which has important roles in cell-autonomous survival and chemotaxis, through its downstream signaling pathways. When we treat the VEGF signaling blocker together with a CXCR4-specific inhibitor, the level of the Gr1+ MDSC infiltration is dramatically decreased nearly to that of control group, and subsequently, tumor growth is significantly delayed compared to separate treatment of each inhibitor.
Taken together, we identified Gr1+ MDSCs as key players in tumor resistance to anti-angiogenic therapy in CRCs, and the blockade of CXCR4 signaling has a synergistic effect with anti-VEGF therapy, proven by state-of-the-art in vivo imaging modalities.
Citation Format: Keehoon Jung, Takahiro Heishi, Andy Yun, Timothy P. Padera, Rakesh K. Jain, Dai Fukumura. Targeting the immune microenvironment to improve colorectal cancer anti-angiogenic therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4195.
Abstract 4206: A dual-motif CAIX inhibitor, [64Cu]XYIMSR-06, for PET imaging of clear cell renal cell carcinoma
Authors: MINN IL , Koo Soo Min , Lee Hye Soo , Brummet Mary , Rowe Steven P. , Gorin Michael A. , Sysa-Shah Polina , Lewis William D. , Ahn Hye-Hyun , Wang Yuchuan , Ray Sangeeta , Mease Ronnie C. , Nimmagadda Sridhar , Allaf Mohamad E. , Pomper Martin G. , Yang Xing 
Published: July 2016

Abstract
Carbonic anhydrase IX (CAIX) is a cell surface enzyme that is over-expressed in approximately 95% of clear cell renal cell carcinomas (ccRCCs), the most common renal cancer. CAIX is also a surrogate marker of hypoxic tumors for various human cancers; however, a clinically viable molecular imaging agent targeting CAIX is not available. We have synthesized and performed in vitro and in vivo evaluation of a dual-motif, low-molecular-weight inhibitor of CAIX, [64Cu] XYIMSR-06, for imaging CAIX expression on ccRCC tumors using positron emission tomography (PET). [64Cu] XYIMSR-06 was synthesized in two steps from reported dual-motif precursor 1. Upon radiolabeling, [64Cu] XYIMSR-06 was evaluated in immunocompromised mice bearing CAIX-expressing SK-RC-52 tumors for in vivo PET imaging and biodistribution. [64Cu] XYIMSR-06 was generated in radiochemical yields of 51.0 ± 4.5% (n = 5) and specific radioactivity of 6.0 GBq/μmol (170Ci/mmol ± 70, n = 5). Tumor could be visualized on PET images by 1 h post-injection with high tumor-to-background levels achieved within 24 h. Biodistribution studies of [64Cu] XYIMSR-06 demonstrated a maximum tumor uptake of 19.3 ± 4.51% injected dose per gram of radioactivity at 4 h. Tumor-to- blood, muscle and kidney ratios were 129.6 ± 18.8, 84.3 ± 21.0 and 2.1 ± 0.26, respectively, at 8 h post-injection. At 24 h, a tumor-to-kidney ratio of 7.1±2.5 was achieved. These findings represent increased tumor-to-background ratios at the indicated times relative to previously reported CAIX-targeted imaging agents. [64Cu] XYIMSR-06 is a promising candidate for PET imaging of CAIX expressing tumors, especially ccRCC.
Citation Format: IL MINN, Soo Min Koo, Hye Soo Lee, Mary Brummet, Steven P. Rowe, Michael A. Gorin, Polina Sysa-Shah, William D. Lewis, Hye-Hyun Ahn, Yuchuan Wang, Sangeeta Ray, Ronnie C. Mease, Sridhar Nimmagadda, Mohamad E. Allaf, Martin G. Pomper, Xing Yang. A dual-motif CAIX inhibitor, [64Cu]XYIMSR-06, for PET imaging of clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4206.
Abstract 424: Urine cf-DNA SNPs as early biomarkers of prostate cancer
Authors: Datta Amrita , Kim Hogyoung , Feibus Allison , Badoo Melody , Johnson Adedoyin , Moustafa Ahmed , Silberstein Jonathan , Moparty Krishnarao , Thomas Raju , Abdel-Mageed Asim B. 
Published: July 2016

Abstract
Background: The current strategies of prostate cancer (PC) detection, such as serum PSA, digital rectal examination (DRE) and prostate biopsy have been hampered by many limitations, including the degree of aggressiveness, invasiveness, non-specificity to PCa, over diagnosis and over treatment. Recent studies have proposed the use of cell-free circulating DNA (cf-DNA) as non-invasive biomarkers for cancer diagnosis, prediction of tumor burden and prognosis. We hypothesize that a selective subset of PC associated Single Nucleotide Polymorphisms (SNPs) in urine cf-DNA detects PCa with high specificity and sensitivity.
Aim: To identify PC specific SNPs in urine cf-DNA from prostate cancer (PC) patients and further validate their clinical utilities as non-invasive biomarkers for early detection of PC in comparison to other genitourinary conditions, such as benign prostate hyperplasia (BPH) and prostatitis.
Method and Results: A protocol was optimized for collection, processing and storage of urine samples and isolation of urine cf-DNA. Our discovery dataset was constructed by comparative Illumina HiSeq next generation sequencing (NGS) of urine cf-DNA from three different cohorts of patients presenting with PC (Gleason score 6), benign prostatic hyperplasia (BPH) or prostatitis. The data was analyzed by SNAPE-pooled and annotated using ANNOVAR; revealing 24 PC-specific non-synonymous SNPs. The selective detection of urine cf-DNAs in PC patients was verified by conventional PCR using primers flanking their genomic sites. Our validation analysis was performed in patients (n = 50/group) diagnosed with PC (Gleason score ≤ 3+4), Gleason score ≥ than 4 + 3, or patients deemed as “no cancer seen”. This was performed by Droplet Digital PCR (ddPCR) targeting wild-type versus variant (SNP) DNA in each patient sample. The results have revealed detection of two PC specific SNPs in urine cf-DNA (&gt;60% for SNP1 and &gt;75% SNP2 in 91 patients; patent pending).
Conclusion: Our study brings forth the potential clinical utility for two novel urine cf-DNA SNPs as early biomarkers for prostate cancer.
Citation Format: Amrita Datta, Hogyoung Kim, Allison Feibus, Melody Badoo, Adedoyin Johnson, Ahmed Moustafa, Jonathan Silberstein, Krishnarao Moparty, Raju Thomas, Asim B. Abdel-Mageed. Urine cf-DNA SNPs as early biomarkers of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 424.