bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1849: High nuclear expression of the p53 target Wig-1 is associated with poor prognosis in cervical carcinoma
Authors: Xu Lidi , Muller Susanne , Lerner Mikael , Lagercrantz Svetlana , Grandér Dan , Wallin Keng-Ling , Wiman Klas G. , Andersson Sonia , Larsson Catharina 
Published: May 2015

Abstract
Cervical cancer is the third most common cancer in women worldwide, and is the most common cancer in Eastern Africa, South-Central Asia and Melanesia. Persistent HPV infection is an important feature of cervical cancer. The central role of chromosome 3q for progression from low-grade dysplastic lesions to higher grades and to invasive carcinomas has been well established. Gain of 3q can occur in morphologically normal cytology of women who developed cervical carcinomas after only a short latency. The Wig-1 gene (wt p53-induced gene 1) is located at the frequently gained chromosomal region 3q. We examined Wig-1 in eight cervical cancer cell lines (Ca Ski, ME-180, MS751, SiHa, SW 756, C-4I, C-33A, and HT-3) by FISH, Southern, Northern, qRT-PCR, and Western blotting. We did not detect any Wig-1 gene alterations in these cell lines. C33-A and HT-3 with strong Wig-1 mRNA expression were HPV negative while the HPV positive cells only exhibited low / moderate Wig-1 expression by Northern blotting. However, no association was found between Wig-1 protein expression and HPV infection. We also assessed Wig-1 expression in a series of 38 cervical tumors, including both squamous cell carcinoma (SCC) and adenocarcinoma (ADCA), by immunohistochemistry. Interestingly, patients who showed moderate nuclear Wig-1 expression levels and positive cytoplasmic Wig-1 staining in their tumors had significantly better prognosis than patients with high nuclear Wig-1 expression and no cytoplasmic staining (Log Rank P value = 0.042). Moreover, higher nuclear Wig-1 expression levels were associated with HPV negative cervical tumors (P=0.003). These results suggest that a marker like Wig-1 could have considerable impact on prediction of the prognosis in women with cervical cancer. Our previous results indicate that Wig-1 acts as a survival factor. Thus, high levels of nuclear Wig-1 may promote tumor growth and survival. The exact role of Wig-1 at the molecular level during cervical carcinoma development needs further investigation.
Citation Format: Lidi Xu, Susanne Muller, Mikael Lerner, Svetlana Lagercrantz, Dan Grandér, Keng-Ling Wallin, Klas G. Wiman, Sonia Andersson, Catharina Larsson. High nuclear expression of the p53 target Wig-1 is associated with poor prognosis in cervical carcinoma. [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 1849. doi:10.1158/1538-7445.AM2014-1849
Abstract 1855: SCT methylation is a potential cancer biomarker for lung cancer
Authors: Zhang Yu-An , Ma Xiaotu , Fujimoto Junya , Wistuba Ignacio , Lam Stephen , Stastny Victor , Gao Boning , Larsen Jill , Liu Xiaoyun , Minna John D. , Zhang Michael Q. , Gazdar Adi F. 
Published: May 2015

Abstract
Purpose: To validate SCT (secretin) methylation as a potential cancer biomarker for lung cancer. Background: There is an urgent need for specific and sensitive biomarkers for lung cancer. The human secretin (SCT) gene is located on chromosome 11p15.5 and encodes the precursor gene of secretin, an endocrine hormone. From analysis of The Cancer Genome Atlas methylation array data, we (XM and MQZ) observed that the exon 1 promoter region of SCT gene is differentially hypermethylated in lung cancer (unpublished). These observations led us to further validate whether SCT methylation can be a useful cancer biomarker for lung cancer. Methods/Results: (1). We designed a novel nested PCR assay for SCT bisulfite sequencing of the promoter and exon 1 region of SCT. Bisulfite sequencing showed that SCT was fully methylated in nearly all CpG sites examined in 10 lung cancer cell lines, whereas SCT was non-methylated in 11 normal WBC blood cells. Accordingly we designed a semi-quantitative SCT qMSP assay. (2). We applied SCT qMSP on genomic DNA from frozen tissues of 131 lung tumors and 65 non-malignant adjacent lung tissues (53 paired). The level of SCT methylation was significantly higher (&gt;24 fold) in all 111 malignant lung tumors (64 adenocarcinomas, 19 squamous cell carcinomas, 12 large cell neuroendocrine carcinomas, 16 NSCLC-other type), as compared to 65 non-malignant adjacent lung tissues. The high SCT methylation was further confirmed in malignant lung tumor formalin-fixed paraffin-embedded (FFPE) tissues samples (8 pairs tested). SCT methylation distinguishes malignant lung from non-malignant adjacent lung with area under curve (AUC) score of 0.92 (p&lt;0.0001). (3). Interestingly, SCT hypermethylation does not significantly distinguishes low grade lung carcinoids tumors (n=20) from non-malignant adjacent lung with AUC score of 0.54 (p=0.5759). (4). Nearly full SCT methylation was detected in lung cancer cell lines (n=27) as compared to absent or lower levels of SCT methylation in immortalized human respiratory cell lines (n=38). Conclusions: SCT methylation is a highly specific and sensitive tissue biomarker for malignant lung cancer and can be detected in FFPE samples. SCT methylation is infrequent in low grade lung carcinoids tumors. Its clinical uses need to be explored.
Citation Format: Yu-An Zhang, Xiaotu Ma, Junya Fujimoto, Ignacio Wistuba, Stephen Lam, Victor Stastny, Boning Gao, Jill Larsen, Xiaoyun Liu, John D. Minna, Michael Q. Zhang, Adi F. Gazdar. SCT methylation is a potential cancer biomarker for lung cancer. [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 1855. doi:10.1158/1538-7445.AM2014-1855
Abstract 1868: Clinical significance of cathepsin L and B expression in pediatric acute myeloid leukemia
Authors: Pandey Garima , Bakhshi Sameer , Singh Ratnakar , Chauhan Shyam S. 
Published: May 2015

Abstract
Introduction: Cathepsin L and B are commonly expressed cysteine proteinases that play a major role in lysosomal bulk proteolysis, protein processing, matrix degradation, and tissue remodelling. In tumors there is deregulation of these proteases that interferes with these normal biological processes. In a pilot study done in our lab expression of cathepsin L and B were found to be significantly elevated in peripheral blood mononuclear cells (PBMCs) of pediatric AML patients. However the expression of these proteases in bone marrow aspirate, which represents almost true population of blasts, has never been studied before.
Methods: Enzymatic activities of cathepsin L and B were assayed in PBMCs and bone marrow mononuclear cells (BMMCs) of AML patients and healthy controls. Further expression of these proteases and its inhibitor were confirmed by western blotting and real time assay. Cell cycle analysis in PBMCs and BMMCs of these patients was performed by flow cytometry using propidium iodide.
Results: In the PBMCs of pediatric AML patients activity of cathepsin L and B was found to be significantly elevated as compared to healthy controls. Similarly, increased activity of cathepsin L and B was also observed in the BMMCs when compared with PBMCs of these patients. Furthermore, protein and mRNA expression also confirmed the increased level of these proteases in pediatric AML. The protein and mRNA expression of their endogenous inhibitor cystatin-C was found to be decreased in PBMCs and BMMCs of AML patients. Moreover, expression of these proteases correlated positively with the percentage of blasts and percentage of cells in S-phase.
Conclusion: This study for the first time demonstrates the increased expression of cathepsin L and B in the BMMCs and PBMCs of pediatric AML patients, along with a positive correlation with percentage of blasts, thereby suggesting a potential role of these proteases in the severity of this disease.
Citation Format: Garima Pandey, Sameer Bakhshi, Ratnakar Singh, Shyam S. Chauhan. Clinical significance of cathepsin L and B expression in pediatric acute myeloid leukemia. [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 1868. doi:10.1158/1538-7445.AM2014-1868
Abstract 1870: Development of a standard operating procedure for exosome isolation and analysis using clinical samples: Application to cancer biomarker discovery
Authors: Setterquist Robert A. , Rai Alex J. , Zeringer Emily , Li Mu , Barta Tim , Schageman Jeoffrey , Magdaleno Susan , Vlassov Alexander V. 
Published: May 2015

Abstract
Exosomes are small vesicles (30-150 nm) found in abundance in human body fluids which function as carriers of different species of RNA and protein between diverse locations in the body. The spectrum of current scientific interest in exosomes is wide and ranges from studying their functions and pathways to utilizing them in diagnostics and therapeutics development. As such, there is a growing need for quick and easy methods for both isolation of exosomes and analysis of their cargo.
We present herein a workflow for exosome isolation and analysis which entails: (i) fast and efficient isolation of exosomes from serum, plasma, and urine of both healthy donors and patients with prostate cancer, using Total Exosome Isolation reagents; (ii) characterization of their size distribution and count with Nanosight LM10 instrument; (iii) extraction of exosome “cargo” with Total Exosome RNA and Protein Isolation kit; (iv) characterization of exosomal RNA content using the Ion Torrent PGM sequencing and qRT-PCR.
The protocol described herein lays the groundwork for the development of a standardized operating procedure (SOP) for isolation of exosomes and downstream analysis of their constituents, using clinical samples.
We demonstrate that cancer-specific RNA signatures residing within the exosomes can be delineated from different patient cohorts. This is the first step towards developing a method whereby performance characteristics can be measured and used to optimize a validated assay useful for routine testing of clinical samples.
Citation Format: Robert A. Setterquist, Alex J. Rai, Emily Zeringer, Mu Li, Tim Barta, Jeoffrey Schageman, Susan Magdaleno, Alexander V. Vlassov. Development of a standard operating procedure for exosome isolation and analysis using clinical samples: Application to cancer biomarker discovery. [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 1870. doi:10.1158/1538-7445.AM2014-1870
Abstract 1905: Defining a therapeutic classification of breast cancer by actionable targets
Authors: Salto-Tellez Manuel , Boyle David P. , McArt Darragh , Irwin Gareth , Wilhelm-Benartzi Charlotte Charlotte , LIoe Tong G. , Minter Martha , McQuaid Stephen , Mullan Paul , Kennedy Richard D. , Hamilton Peter , Harkin D P. 
Published: May 2015

Abstract
Breast cancer remains a frequent cause of female cancer death despite the great strides in elucidation of biological subtypes and their reported clinical and prognostic significance. We have defined a general cohort of breast cancers in terms of putative actionable targets, involving growth and proliferative factors, the cell cycle, and apoptotic pathways, both as single biomarkers across a general cohort and within intrinsic molecular subtypes.
We identified 293 patients treated with adjuvant chemotherapy. Additional hormonal therapy and trastuzumab was administered depending on hormonal and HER2 status respectively. We performed immunohistochemistry for ER, PR, HER2, MM1, CK5/6, p53, TOP2A, EGFR, IGF1R, PTEN, p-mTOR and e-cadherin. The cohort was classified into luminal (62%) and non-luminal (38%) tumors as well as luminal A (27%), luminal B HER2 negative (22%) and positive (12%), HER2 enriched (14%) and triple negative (25%). Patients with luminal tumors and co-overexpression of TOP2A or IGF1R loss displayed worse overall survival (p=0.0251 and p=0.0008 respectively). Non-luminal tumors had much greater heterogeneous expression profiles with no individual markers of prognostic significance. Non-luminal tumors were characterised by EGFR and TOP2A overexpression, IGF1R, PTEN and p-mTOR negativity and extreme p53 expression.
Our results indicate that only a minority of intrinsic subtype tumors purely express single novel actionable targets. This lack of pure biomarker expression is particular prevalent in the triple negative subgroup and may allude to the mechanism of targeted therapy inaction and myriad disappointing trial results. Utilising a combinatorial biomarker approach may enhance studies of targeted therapies providing additional information during design and patient selection while also helping decipher negative trial results.
Citation Format: Manuel Salto-Tellez, David P. Boyle, Darragh McArt, Gareth Irwin, Charlotte Charlotte Wilhelm-Benartzi, Tong G. LIoe, Martha Minter, Stephen McQuaid, Paul Mullan, Richard D. Kennedy, Peter Hamilton, D P. Harkin. Defining a therapeutic classification of breast cancer by actionable targets. [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 1905. doi:10.1158/1538-7445.AM2014-1905
Abstract 1908: The Wnt-target Prox1 promotes colorectal cancer stem cell survival to fuel tumor growth
Authors: Wiener Zoltan , Hyvönen Ville , Högström Jenny , Holopainen Tanja , Band Arja , Kallio Pauliina , Dufva Olli , Haglund Caj , Kruuna Olli , Oliver Guillermo , Ben-Neriah Yinon , Alitalo Kari 
Published: May 2015

Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer mortality in the Western countries. In most of the CRC patients, an initial mutation occurs in the APC or CTNNB1 genes, leading to the ligand-independent activation of the canonical Wnt pathway. Besides having a central role in the development of CRC, the Wnt pathway plays a critical role also in the maintenance of the normal intestine. Attempts at therapeutic inhibition of this pathway could thus lead to serious side effects in CRC patients. We have previously shown that the Prox1 transcription factor is induced in the intestinal epithelium by mutations activating the Wnt pathway and it critically contributes to CRC progression via an unknown mechanism. Here we provide evidence that Prox1 expression is induced in the Lgr5+ adenoma stem cells early after Apc deletion. Our in vivo models and ex vivo organoid experiments suggest that Prox1 silencing or deletion restricts the expansion of the Lgr5+ adenoma stem cell population both in humans and in mice. Interestingly, silencing the phospholipid binding protein Annexin A1 (Anxa1), a gene suppressed by Prox1, is responsible for several of the effects of Prox1 on adenoma cells, such as the re-organization of the actin cytoskeleton, enhanced stem cell activity and tumor growth. Furthermore, Prox1 deletion abnormally increases the mTORC1 pathway activity, which results in decreased survival of the adenoma stem cells. Since Prox1 is expressed at low level only in rare neuroendocrine cells and in some Paneth cells in the wild type intestinal epithelium, furthermore, its genetic deletion in the adult gut does not lead to obvious phenotypes, Prox1 may serve as an attractive therapeutic target for restricting the progression of early intestinal adenomas.
Citation Format: Zoltan Wiener, Ville Hyvönen, Jenny Högström, Tanja Holopainen, Arja Band, Pauliina Kallio, Olli Dufva, Caj Haglund, Olli Kruuna, Guillermo Oliver, Yinon Ben-Neriah, Kari Alitalo. The Wnt-target Prox1 promotes colorectal cancer stem cell survival to fuel tumor growth. [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 1908. doi:10.1158/1538-7445.AM2014-1908
Abstract 191: Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer
Authors: Whatcott Clifford J. , Watanabe Aprill , LoBello Janine , Hoff Daniel Von , Han Haiyong 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related death in the United States. PDAC is characterized by high levels of fibrosis, a feature termed desmoplasia. Desmoplasia is thought to hamper the efficacy of therapeutics treating PDAC. Agents targeting components of the tumor stroma have shown some enhancement of first-line therapeutics targeting tumor cells. As metastatic burden is one of the primary causes for mortality in PDAC, the question remains of whether stromal targeting therapeutics will benefit patients with late stage, metastatic disease. We sought to address this question by assessing the extent of desmoplasia in both primary PDAC tumors and metastatic lesions of pancreatic origin. Patient tissue staining using a pentachrome or standard immunohistochemical technique demonstrates that extracellular matrix components, such as collagen, are found in high levels in both primary tumors and metastatic lesions. The difference in the level of desmoplasia in primary tumors and metastatic lesions was statistically insignificant. We also observed a significant correlation between patient survival and extracellular matrix deposition. Kaplan-meier curves for collagen I showed median survival of 527 days in low collagen patients, and 176.5 in high level patients. Low level hyaluronan patients displayed median survival times of 2107 days as compared to 385 days in high level patients. Our results indicate that both primary tumors and metastases of PDAC have highly fibrotic stroma. Thus, stromal targeting agents may benefit PDAC patients, even those with metastatic disease.
Citation Format: Clifford J. Whatcott, Aprill Watanabe, Janine LoBello, Daniel Von Hoff, Haiyong Han. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. [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 191. doi:10.1158/1538-7445.AM2014-191
Abstract 1911: NF-κB mediated CD47 upregulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma
Authors: Lo Jessica , Lau Eunice Yuen Ting , Ng Irene Oi Lin , Lee Terence Kin Wah 
Published: May 2015

Abstract
Sorafenib, a multikinase inhibitor, is currently used as the normative treatment for advanced hepatocellular carcinoma (HCC). It can prolong survival for a few months however sorafenib insensitivity and resistance often develops in tumors hence a better understanding of resistance mechanisms is urgently needed. Tumor-initiating cells (T-ICs) have recently been implicated in the cause of treatment resistance. Recently, our group found that CD47 is preferentially expressed in liver T-ICs, which suggests a possibility of targeting CD47 in order to evade sorafenib resistance via elimination of liver T-ICs. To test this hypothesis, we have successfully developed sorafenib-resistant clones in HCC cell lines (BEL7402 and Huh-7 cells) and in vivo using patient-derived xenograft (PDTX #1) by continuous exposure to sorafenib. We found that sorafenib-resistant clones showed enhanced T-IC properties such as self-renewal, tumorigenicity and invasiveness, which is also accompanied by an increase in CD47 expression. We found increased NF-κB activation in sorafenib resistant clones indicated by upregulated levels of phosphorylated p65 and IkBα which is consistent to the bioinformatics analysis showing two putative NF-κB binding sites on the CD47 promoter. In addition, CD47 expression was found to be decreased upon treatment of NF-κB inhibitor IMD-0354 and increased upon treatment of TNF-α. These results suggested that NF-κB mediated CD47 upregulation promotes sorafenib resistance in HCC. To further confirm the role of CD47 in sorafenib resistance, we knocked down CD47 expression in CD47-high expressing HCC cells. Through annexin V staining, we found that knockdown of CD47 sensitized Huh-7 and MHCC-97L to sorafenib treatment at 10µM and 20µM respectively. Using patient derived xenograft model (PDTX #8) to investigate the effect of different treatment regimens, we found that mice treated with daily administration of sorafenib (100mg/Kg) showed tumor volume reduction by 3-fold upon 30 days of treatment and a similar effect was found in mice treated daily with and anti-CD47 antibody (500mg/Kg). Interestingly, sorafenib combined with anti-CD47 antibody exhibited maximal effect on tumor suppression. All in all, regulation of CD47 by NF-κB may enable the promotion of sorafenib resistance and anti-CD47 antibody in co-treatment with sorafenib may serve as a novel therapeutic regimen for the treatment of advanced stage HCC.
Citation Format: Jessica Lo, Eunice Yuen Ting Lau, Irene Oi Lin Ng, Terence Kin Wah Lee. NF-κB mediated CD47 upregulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma. [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 1911. doi:10.1158/1538-7445.AM2014-1911