bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2472: Acute colitis and colitis-associated cancer are exacerbated in mice deficient N-deacetylase/N-sulfotransferase-4
Authors: Jao Tzu-Ming , Tsai Ming-Hong , Huang Chi-Yen , Tzeng Sheng-Tai , Lee Jing-Xing , Lo Wei-Chen , Chang Che-Wei , Yang Ya-Chien 
Published: May 2015

Abstract
NDST4 is one member of N-deacetylase/N-sulfotransferase (heparan glucosaminyl) (NDST) family, which are responsible for heparan sulfate (HS) biosynthesis on a core protein to form heparan sulfate proteoglycans (HSPGs). The HS chains of HSPGs bind to and regulate their functions of various growth factors, cytokines and chemokines. HSPGs ubiquitously reside on cell surface, inside the cell, and in the extracellular matrix. Importantly, the content and distribution of HSPGs are altered during tumorigenesis. In the study, 30 (57.7%) of 52 primary colorectal carcinomas showed a dramatic reduction in NDST4 RNA transcripts, and genetic loss of NDST4 was significantly associated with poor survival of patients with colorectal cancer. We further generated an Ndst4-knockout mouse strain, which could develop and reproduce normally. Notably, using the dextran sodium sulfate mouse model of acute colitis, Ndst4 deficiency resulted in a significantly higher disease activity index and obviously hyperemic appearance in the cecum. In the development of colitis-associated cancer, the size of colonic tumors induced by azoxymethane/dextran sodium sulfate was significantly increased in Ndst4-deficient mice compared with wild-type mice. Taken together, loss-of-function of NDST4 might impair the modification of HS chains of specific HSPGs leading to tumor-promoting inflammation in the colon. The full spectrum of signaling pathways contributed by NDST4 to colitis and tumor progression remains to be elucidated.
Citation Format: Tzu-Ming Jao, Ming-Hong Tsai, Chi-Yen Huang, Sheng-Tai Tzeng, Jing-Xing Lee, Wei-Chen Lo, Che-Wei Chang, Ya-Chien Yang. Acute colitis and colitis-associated cancer are exacerbated in mice deficient N-deacetylase/N-sulfotransferase-4. [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 2472. doi:10.1158/1538-7445.AM2014-2472
Abstract 248: Vitamin D deficiency promotes hepatocellular carcinoma tumor growth in TGF-β impaired mice by Smad3 heterozygous deletion
Authors: Muñoz Nina M. , Katz Lior H. , Machida Keigo , Tsukamoto Hidekazu , Shetty Kirty , He Aiwu R. , Johnson Lynt B. , Rashid Asif , Kim Sang Bae , Lee Ju-Seog , Mishra Lopa 
Published: May 2015

Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Vitamin D (VD) has been implicated in the prevention of multiple cancers, some of which are characterized by inactivation of TGF-β signaling. Recently, inactivation of TGF-β signaling has been associated with development of HCC. We examined the potential role of VD in HCC chemoprevention in the context of TGF-β inactivation in a mouse model. Methods: Wild type, Sptbn1+/- and Smad3+/- male mice were treated with 50 mg/kg of the chemical carcinogen diethylnitrosamine (DEN) via i.p. injection at 14 days of age. At 8 months, the animals were changed from regular chow (2,200 IU/kg VD) to one of two diets: lower than normal VD (200 IU/kg) or high VD (10,000 IU/kg). At one year of age, the livers were harvested for tissue analysis. Several metrics were assessed including expression levels of 164 proteins from liver tumors by Reverse Phase Protein Array (RPPA). Results: Twenty three mice were treated with lower than normal dose VD while 26 received high dose VD. We did not find significant differences in blood calcium levels in animals on either diet. As expected, high VD intervention after 8 months of DEN injection did not affect the total number of tumors the mice developed; however, the lower than normal VD regimen promoted tumor growth in the context of Smad3 disruption (liver-to-body weight ratio 18.37% in Smad3+/- mice treated with low dose VD vs. 6.25% in Smad3+/- animals treated with high dose, p=0.028). Furthermore, RPPA data revealed that the lower than normal VD intake in DEN-treated Smad3 heterozygous null mice results in repression of tumor suppressing genes such as PDCD4 and concomitant up-regulation of tumor promoting genes like Stat5A, Bcl2-XL, PDGFRB and PEA15. Conclusions: Remarkably, lower than normal VD in the context of Smad3 disruption promotes tumor growth possibly through repression of tumor suppressing genes such as PDCD4 and up-regulation of oncogenes like Stat5A, Bcl2-XL, PDGFRB and PEA15. These results suggest that VD treatment strategies could potentially be significant for chemoprevention and treatment of HCC in the context of inactivation of TGF-β signaling in patient populations with underlying deficiency of VD.
Citation Format: Nina M. Muñoz, Lior H. Katz, Keigo Machida, Hidekazu Tsukamoto, Kirty Shetty, Aiwu R. He, Lynt B. Johnson, Asif Rashid, Sang Bae Kim, Ju-Seog Lee, Lopa Mishra. Vitamin D deficiency promotes hepatocellular carcinoma tumor growth in TGF-β impaired mice by Smad3 heterozygous deletion. [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 248. doi:10.1158/1538-7445.AM2014-248
Abstract 2528: Optimization of small molecules targeting BMI1 protein expression. Part 2. Improved potency, oral bioavailability, and in vivo efficacy of amino-pyrazines and amino-pyridines
Authors: Baiazitov Ramil , Sydorenko Nadiya , Ren Hongyu , Du Wu , Paget Steve , Wilde Richard , Liu Ronggang , Lee Chang-Sun , Cao Liangxian , Davis Thomas W. , Almstead Neil G. , Moon Young-Choon 
Published: May 2015

Abstract
Earlier, in our efforts to identify molecules that selectively deplete tumor stem cells, we discovered and elaborated on a series of amino-thiazoles. These first-in-class small molecule inhibitors reduce the activity and levels of BMI1 protein in vitro and in vivo (see the preceding poster).
Through our medicinal chemistry efforts, we developed a second generation of molecules that reduce levels of BMI1. In this new scaffold, the central thiazole ring has been replaced with a pyrazine or pyridine ring. There is a clear relationship between the structure of the central heterocycle and the ability of the compound to decrease the level of BMI1 protein.
The most beneficial modification on the right wing of the molecule is the introduction of benzimidazole moiety. As a result, analogs with markedly improved oral bioavailability have been identified.
The structure activity relationship on the left ring parallels the SAR observed with the amino-thiazole scaffold.
The most successful analogs in this series can be dosed orally and demonstrate dose-dependent efficacy in mouse xenograft models including the HT1080 and L1210 cell lines.
Citation Format: Ramil Baiazitov, Nadiya Sydorenko, Hongyu Ren, Wu Du, Steve Paget, Richard Wilde, Ronggang Liu, Chang-Sun Lee, Liangxian Cao, Thomas W. Davis, Neil G. Almstead, Young-Choon Moon. Optimization of small molecules targeting BMI1 protein expression. Part 2. Improved potency, oral bioavailability, and in vivo efficacy of amino-pyrazines and amino-pyridines. [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 2528. doi:10.1158/1538-7445.AM2014-2528
Abstract 255: Addition of biologic therapy to traditional disease-modifying anti-inflammatory drugs and the risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study
Authors: Chen Yi-Ju , Wu Chun-Ying , Chen Der-Yuan , Shen Jui-Lung , Ho Hsiu J. , Liu Han-Nan , Chang Yun-Ting , Kuo Ken-Nan 
Published: May 2015

Abstract
Background: Rheumatoid arthritis (RA) is associated with certain types of cancer. The add-on effect of biologics on cancer occurrence in long-term RA remains unknown. We aimed to investigate the relative risk of cancer development among RA patients combining biologics with traditional disease-modifying anti-rheumatic drugs (DMARDs).
Methods: We conducted a nationwide cohort study between March 2003 and December 2010 using the Taiwan National Health Insurance Research Database (NHIRD). A total of 42,263 patients with RA who received long term DMARDs were identified. The risk of newly diagnosed cancer was compared between patients taking biologics in addition to DMARDs (biologics cohort, N=4,119) and four-fold propensity score-matched control patients taking nonbiologic DMARDs only (biologics-naive cohort, N=16,476). Cumulative incidences and hazard ratios (HR) were calculated after adjusting for competing mortality. Multivariate analyses were performed using Cox proportional hazards model.
Results: The incidence rates of cancer among biologics and biologics-naive cohorts were 2.09 (95% confidence interval [CI] 1.31-2.86) and 3.25 (95% CI 2.76-3.74) per 1000 person-years, respectively (p=0.03). On modified Cox proportional hazards analysis, the risk of cancer was significantly reduced in subjects in biologics cohort (adjusted HR 0.61, 95% CI 0.40-0.94, p=0.025) in comparison with subjects in biologics-naive cohort, after adjusting for age, gender, disease duration, major co-morbidities, and prior use of DMARDs and corticosteroids. The effect of biologics was consistent across all multivariate stratified analyses; and the association between biologics use and cancer risk was independent of dosage of concomitant use of non-biological DMARDs.
Conclusion: RA patients taking biologics plus long term traditional DMARDs therapy are associated with a lower risk of cancer when compared with RA patients taking traditional DMARDs alone.
Citation Format: Yi-Ju Chen, Chun-Ying Wu, Der-Yuan Chen, Jui-Lung Shen, Hsiu J. Ho, Han-Nan Liu, Yun-Ting Chang, Ken-Nan Kuo. Addition of biologic therapy to traditional disease-modifying anti-inflammatory drugs and the risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study. [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 255. doi:10.1158/1538-7445.AM2014-255
Abstract 2550: Translational study on circulating markers in advanced melanoma patients undergoing Dacarbazine and Bevacizumab treatment
Authors: Ferrucci Pier Francesco , Martinoli Chiara , Cocorocchio Emilia , Anichini Andrea , Gandini Sara 
Published: May 2015

Abstract
Purpose:
Chemotherapy (CT) with Dacarbazine (DTIC) in association with an anti-VEGF treatment could be an intriguing exploiting path, since metastatic melanoma (MM) in vitro models showed VEGF as a possible target, due to its transcription up-regulation by DTIC. The purpose of this study was to indentify modulated circulating factors which may be used as specific biomarkers in patients (pts) affected by MM undergoing DTIC plus Bevacizumab (B = Avastin) combination and to test its tolerability and efficacy.
Patients and Methods:
Between July 2006-September 2009, 40 untreated MM pts underwent CT with DTIC (800mg/mq q4w) + B (10mg/kg q2w). Clinical benefit, response duration, safety and feasibility were analyzed. Moreover, 13 pts participating to the clinical study agreed to provide blood for translational research. The blood samples for this study were drawn at the same time points as for regular follow-up tests and were evaluated for the following several soluble factors: vascular endothelial growth factor (VEGF)-A, VEGF-C, VEGF-R1, VEGF-R2, angiopoietin (Ang)-2, E-cadherin, E-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, matrix metalloproteinase (MMP)-2 and -9, tissue inhibitor of metalloproteinase (TIMP)-1 and -2. Correlations with pts clinical outcome were performed as well.
Results:
36/40 pts were evaluated at the analysis-time. Median age was 57yr (male 60yr; female 47yr) and 23 were male. Three pts (8.3%) experienced a complete remission (CR), 3 pts (8.3%) developed partial response (PR), 13 (36.1%) stable disease (SD); 17 (47.2%) progressive disease (PD). Clinical benefit (CR+PR+SD) was 52.7% and treatment was well tolerated. Time to progression (months) was 10.9, respectively 22.6 for PR pts, 8.2 for SD pts and 2 for PD pts. Median-survival in the whole group was 16.5 months (PR pts 22.6; SD pts 17; PD pts 4.23). DTIC/B treatment modulates not only VEGF-A, but also VEGF-C, Ang-2 VEGF-R1 and VEGF-R2. Among soluble adhesion molecules, we observed an increase of VCAM-1 in non responder pts.
Conclusions:
Long-lasting responses obtained in both SD and CR/PR pts and mild side effects make DTIC/B a promising combination in advanced melanoma. The companion translational study partially clarified these clinical results by molecularly characterizing and profiling responders vs non-responders pts.
Citation Format: Pier Francesco Ferrucci, Chiara Martinoli, Emilia Cocorocchio, Andrea Anichini, Sara Gandini. Translational study on circulating markers in advanced melanoma patients undergoing Dacarbazine and Bevacizumab treatment. [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 2550. doi:10.1158/1538-7445.AM2014-2550
Abstract 2928: AZD6244 inhibits cisplatin induced ERK1/2 activation and potentiates its cytotoxic effects in NSCLC preclinical models
Authors: Kim Eun Young , Kim Arum , Byun Min Kwang , Kim Se Kyu , Kim Hyung Jung , Chang Joon , Ahn Chul Min , Chang Yoon Soo 
Published: May 2015

Abstract
Introduction; Lung cancer is still the leading cause of cancer death worldwide, indicating that there are urgent needs for elucidating the mechanisms of resistance and developments of strategies to overcome it. Cisplatin is still one of the most commonly used drugs for the treatment of advanced lung cancer and, however, the underlying mechanism of activation of MAPK/ERK1/2 after cisplatin administration is still complex and elusive. It is considered one of the main mechanisms mediating resistance to cisplatin based doublet chemotherapy. In this study we aimed to evaluate the effectiveness of combination of MAPK inhibitor, AZD6244, with cisplatin in NSCLC models. Materials and Methods; NSCLC cells harbouring oncogenic RAS mutation, NCI-H1299, -H2009, -H460, and A549 cells, and LSL K-Ras G12D mouse model was used. Protein expression was evaluated by immunoblotting and cytotoxicity was measured by FACS followed by annexin-V and PI staining. LSL Kras G12D mouse were inhaled 5X 107 PFU AdCre virus at 8 weeks after birth and, in 24 weeks after inhalation, were taken microCT, randomized into 4 groups, and then treated with AZD6244 (25mg/kg bid by oral gavage) and/or cisplatin (5 mg/kg weekly) for two weeks. Results; There was a dose dependent increase of pERK1/2, which is most prominent at 24 hr after cisplatin treatment. Expression of proapoptotic protein, BIM, was decreased whereas that of antiapoptotic proteins, BCL-2 and MCL-1, was increased with cisplatin treatment. Treatment of AZD6244 prevented phosphorylation mediated degradation of BIM after cisplatin treatment. AZD6244 itself did not show cytotoxic effects up to 10 uM whereas combination of 1 uM of AZD6244 potentiates cytotoxic effects of cisplatin. Combined treatment of AZD6244 with cisplatin showed significant tumor reduction in 2 weeks in LSL K-ras G12D mouse model when compared those treated with single agents or vehicle. Conclusion; Combination of AZD6244 with cisplatin potentiates cytotoxic effects and anti-tumor activities in NSCLC preclinical models. These findings suggest that clinical trials using combination with AZD6244 and cisplatin may be beneficial in advanced NSCLC patients.
Citation Format: Eun Young Kim, Arum Kim, Min Kwang Byun, Se Kyu Kim, Hyung Jung Kim, Joon Chang, Chul Min Ahn, Yoon Soo Chang. AZD6244 inhibits cisplatin induced ERK1/2 activation and potentiates its cytotoxic effects in NSCLC preclinical models. [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 2928. doi:10.1158/1538-7445.AM2014-2928
Abstract 2931: Cancer cells deficient in DNA mismatch repair (MMR) are selectively sensitive to inhibition of the DNA dependent protein kinase (DNA-PK)
Authors: Hewish Madeleine , Fontebasso Yari , Martin Sarah A. , Elliott Richard , Perks Kerry L. , Konde Asha , Bajrami Ilirjana , Weverwijk Antoinette Van , Cunningham David , Lord Christopher J. , Ashworth Alan 
Published: May 2015

Abstract
Many solid tumors, including a significant proportion of colorectal, endometrial, gastric and urothelial tract cancers, are functionally deficient in MMR. This results in an altered clinicopathological phenotype. With the objective of identifying potential MMR-deficient (dMMR) synthetic lethal vulnerabilities, we performed a large scale screen of drugs which included a library of kinase inhibitors.
Using a pair of isogenic colorectal cancer (CRC) cell lines, deficient and proficient for MLH1, we identified that exposure to an inhibitor of the catalytic subunit of DNA-PK (Ku-57788) was associated with a reduction in cell viability in MLH1-deficient cells at nanomolar concentrations. Validation studies demonstrated a ten-fold difference in sensitivity in clonogenic assays and a significant correlation between MMR status and Ku-57788 across a panel of cancer cell lines. Inhibition of expression of DNA-PK using RNA interference reproduced the dMMR selectivity. The dMMR phenotype was associated with a reduction in cellular proliferation, leading to apoptosis. Given the role of MMR in the repair of oxidative damage, we assayed levels of 8-oxo-dG, a marker of oxidatively damaged DNA, and observed increased levels in dMMR cells. Upregulation of the anti-oxidant response was observed on exposure to Ku-57788, whilst addition of antioxidants to culture media resulted in complete abrogation of dMMR selectivity. We assessed the effect of combining Ku-57788 with standard chemotherapeutics used in CRC and observed a supra-additive effect with irinotecan. In vivo, treatment of CD1 nude mice with a DNA-PK inhibitor was associated with a reduction in growth of MLH1-deficient cancer cell line xenografts with no effect observed in MLH1-proficiency.
We report for the first time that inhibition of DNA-PKcs using small molecule inhibitors, either as a single agent or in combination with chemotherapeutics, may be a potential therapeutic strategy for the treatment of cancers deficient in DNA MMR.
Citation Format: Madeleine Hewish, Yari Fontebasso, Sarah A. Martin, Richard Elliott, Kerry L. Perks, Asha Konde, Ilirjana Bajrami, Antoinette Van Weverwijk, David Cunningham, Christopher J. Lord, Alan Ashworth. Cancer cells deficient in DNA mismatch repair (MMR) are selectively sensitive to inhibition of the DNA dependent protein kinase (DNA-PK). [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 2931. doi:10.1158/1538-7445.AM2014-2931
Abstract 2949: YK-4-279 is a small molecule inhibitor of ETV1 and inhibits metastasis in a mouse model
Authors: Rahim Said , Justvig Sarah , Hong Sung-Hyeok , Tosso Perrer , Celik Haydar , Sayedigar-Kont Yasemin , Brown Milton , Morrissey Colm , Toretsky Jeffrey , Üren Aykut 
Published: May 2015

Abstract
The erythroblastosis virus E26 transforming sequences (ETS) family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. Chromosomal translocations fusing ETS factors to promoters of androgen responsive genes have been found in a majority of prostate cancers, including the most clinically aggressive forms. ERG and ETV1 are the most commonly translocated ETS proteins. Over-expression of these proteins in prostate cancer cells results in a more invasive phenotype. The high prevalence of these rearrangements, and their biological significance represents a novel therapeutic target for the treatment of prostate cancer.
We recently demonstrated that the small molecule YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present our findings in an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP and fusion-negative PC-3 tumors. Animals were treated with YK-4-279 and its effect on tumor size, lung metastasis and survival were observed. YK-4-279 treatment resulted in decreased tumor size in the LNCaP cohort only. A reduction in tumor metastasis to the lungs was observed in compound treated LNCaP animals with comparable tumor sizes. YK-4-279 also increased survival in LNCaP mice. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 was reduced as well. ETS fusion-negative PC-3 xenografts were unresponsive to the compound. YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. As part of this study, we also established that (S) -YK-4-279 is the active enantiomer in prostate cancer cells. (S) -YK-4-279 binds to ETV1 with comparable kinetics as the racemic mixture and inhibits ETV1 activity. (R) -YK-4-279 does not demonstrate ETV1 binding or inhibition.
Our results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and should be further evaluated for its clinical applications in prostate cancer.
Citation Format: Said Rahim, Sarah Justvig, Sung-Hyeok Hong, Perrer Tosso, Haydar Celik, Yasemin Sayedigar-Kont, Milton Brown, Colm Morrissey, Jeffrey Toretsky, Aykut Üren. YK-4-279 is a small molecule inhibitor of ETV1 and inhibits metastasis in a mouse model. [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 2949. doi:10.1158/1538-7445.AM2014-2949