tbuckley/cabot-search huggingface dataset:
Abstract 5811: Evaluation of antitumor efficacy of CA102N, H-Nim and hyaluronic acid (HA) conjugate, alone or in combination with 5-fluorouracil (5-FU) in <i>in vivo</i> human colorectal cancer models
Authors: Eskouhie Tchaparian, Louis Lin
Journal: Cancer Research (2018)

Abstract CA102N is a conjugate of HA and H-Nim (N-(4-Amino-2-phenoxyphenyl, methanesulfonamide), a derivative of cyclooxygenase-2 inhibitor Nimesulide, and a CD44 receptor targeted system currently in preclinical development for metastatic colorectal cancer. The in vivo antitumor activities of CA102N was evaluated singly or combined with 5-FU in CR5038 (Patient Derived Xenograft (PDX) and HT29 Xenograft models. Inhibitory activity was assessed according to tumor-volume changes. CA102N (i.v. 200mg/kg, BIW) monotherapy did not show significant tumor growth inhibition at either the end of the treatment (21 days) or prolonged observational (45 days) period, in CR5038 PDX-SCID metastatic model in comparison to vehicle control or 5-FU (i.v. 50mg/kg, QW). Notably, the combination therapy displayed a marked reduction in tumor growth (&amp;gt;70%) compared to 5-FU alone (p=0.0003) or vehicle control (p&amp;lt;0.0001) in addition to prolonged median survival (p&amp;lt;0.05). Alternatively, HT29 xenografts nude mice were found to have significantly reduced tumor burden treated with either single agents CA102N (400 mg/kg, QW) or 5-FU (50 mg/kg, QW), (p&amp;lt;0.012) compared to control vehicle. The drug combination further displayed a synergistic antitumoral effect and greater median survival (p &amp;lt;0.05) in HT29 model. CA102N was well tolerated alone or in the combination therapy. Based on the results of this study, combined treatment of CA102N and 5-FU resulted in a complete response at the regimen given. The combination of CA102N and 5-FU represents a promising potential therapeutic strategy and a new approach to reverse drug resistant in the treatment of colorectal cancer. Studies presently are ongoing to further evaluate its efficacy in CT26 murine colorectal models. Citation Format: Eskouhie Tchaparian, Louis Lin. Evaluation of antitumor efficacy of CA102N, H-Nim and hyaluronic acid (HA) conjugate, alone or in combination with 5-fluorouracil (5-FU) in in vivo human colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5811.
Abstract 1225: Rare variants in DNA damage repair genes are associated with male breast cancer predisposition
Authors: Sarah L. Maguire, Katarzyna Tomczyk, Eleni Perrakis, Edward Saunders, Daniel Leongamornlert, ZSofia Kote-Jarai, Rosalind Eeles, Montserrat Garcia-Closas, Paul Pharoah, Douglas Easton, Christopher J. Lord, Alan Ashworth, Anthony Swerdlow, Nick Orr
Journal: Cancer Research (2018)

Abstract Male breast cancer accounts for approximately 1% of all breast cancers diagnosed each year in the UK. Germline mutations in DNA damage response genes are known to be associated with many forms of cancer, including breast cancer. In order to identify low frequency male breast cancer predisposition genes, we performed targeted resequencing of more than 300 genes that were selected on the basis of involvement in DNA maintenance and repair pathways. Using a cost-effective protocol based on an automated library preparation method and a multiplexed hybridization enrichment step, we sequenced 1,029 male breast cancer cases from the UK Breast Cancer Now male breast cancer study (MBCS) and 1,254 controls from the MBCS and the ICR1000 UK exome series. Rare variants localising to 19 genes were significantly associated with risk of male breast cancer. Genes with an excess of rare coding mutations included the known breast cancer susceptibility genes BRCA2, CHEK2 and ATM as well as multiple members of the Fanconi anaemia (FA) pathway. Loss of heterozygosity (LOH) affecting the wildtype allele of putative predisposition genes was observed more than 10% of cases with matched tumor samples. In addition to LOH in BRCA2 mutation carries, somatic losses were observed that affected CCNE1, ATM, PALB2, BARD1, CHEK2, POLL and RAD9A. These data represent the largest analysis of rare variants in male breast cancer to date and have enabled the identification of known and putative novel susceptibility genes. Citation Format: Sarah L. Maguire, Katarzyna Tomczyk, Eleni Perrakis, Edward Saunders, Daniel Leongamornlert, ZSofia Kote-Jarai, Rosalind Eeles, Montserrat Garcia-Closas, Paul Pharoah, Douglas Easton, Christopher J. Lord, Alan Ashworth, Anthony Swerdlow, Nick Orr. Rare variants in DNA damage repair genes are associated with male breast cancer predisposition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1225.
Abstract 18815: High Dose Aspirin is Associated With Decrease of Hemoglobin and Do Not Affect the Disease Outcome in Acute Stage of Kawasaki Disease
Authors: Ho-Chang Kuo, Kai-Sheng Hsieh
Journal: Circulation (2015)

Introduction: Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Although intravenous immunoglobulin (IVIG) has been shown to reduce the incidence of coronary artery lesions (CAL) effectively, the role and appropriate dose of aspirin during acute phase is still unclear. Thus, this study was conducted to evaluate the effect of treatment and the change of serum hepcidin with or without high dose aspirin in the acute stage of KD. Hypothesis: High dose aspirin is not benefit for acute stage of KD. Methods: Retrospective analysis of KD patients from two medical centers during 1999-2009 in Taiwan. All patients were initially treated with a single dose of IVIG (2 g/kg) during a 12-h period. High dose aspirin was given (&gt; 50 mg/kg/day) until the fever subsided then low-dose aspirin (3-5 mg/kg/day) was prescribed until all signs of inflammation resolved at group 1. Low-dose aspirin was prescribed without high-dose aspirin at group 2. A total of 851 KD patients (group 1, N= 305, group 2, N= 546) were enrolled in this study. patients. Results: There were no significant difference between group 1 and group 2 including gender distribution (p=0.51), IVIG resistant rate (31/305 vs. 38/546, p=0.07), CAL formation rate (52/305 vs. 84/546, p=0.67), and total hospital days (6.3 ± 0.2 vs. 6.7 ± 0.2, p=0.13). There were also no significant difference between total white blood counts, hemoglobin levels, platelet counts, CRP and serum hepcidin levels before IVIG treatment between group 1 and group 2 (all p&gt;0.1). After IVIG treatment, there were significant lower hemoglobin and higher CRP as well as lower decrease of CRP levels in group 1 than in group 2 (p=0.006, &lt;0.001 and =0.012, respectively). Furthermore, there were also high serum hepcidin and lower decrease of hepcidin levels in group 1 than in group 2 (p=0.04, and =0.02, respectively). Conclusions: These results provide evidence supporting high dose aspirin in acute phase of KD may affect the improvement of inflammatory markers. It also caused lower hemoglobin level that was associated with higher hepcidin level after IVIG treatment. It seems unneeded of high dose aspirin in acute phase of KD.
Abstract 4692: High density of cytotoxic and regulatory T-lymphocytes in gastric cancers with microsatellite instability
Authors: Hyoung-Il Kim, Su-Jin Shin, Sang Yong Kim, Yoon Young Choi, Taeil Son, Jae-Ho Cheong, Woo Jin Hyung, Sung Hoon Noh
Journal: Cancer Research (2018)

Abstract Introduction: MSI-high (MSI-H) colorectal cancer is known to be associated with increased tumor-infiltrating lymphocytes (TILs) and good prognosis. In gastric cancer, however, MSI status has rarely been evaluated in accordance with TILs. The objectives of our study were to clarify the relationships between MSI status and antitumor host immune response and to identify the impact of these factors on the prognosis of gastric cancer. Methods: We evaluated 345 patients with gastric cancer who underwent gastrectomy with MSI typing. The numbers of TILs in tumor center was counted after immunohistochemical staining with anti-CD3, CD4, CD8, Foxp3, and granzyme B to quantify the subset of TILs. To evaluate systemic immune response, differential white blood cell count and prognostic nutritional index (PNI) were obtained. Results: Of the 345 patients, 57 were MSI-H and 288 were non-MSI-H groups. MSI-H tumors carried significantly higher numbers of CD8+ T-cells, Foxp3+ T-cells, GZB+ T cells and higher ratio of Foxp3/CD4 and GZB/CD8. The prognostic effect of TILs was different in MSI-H and non-MSI-H groups. All subsets of TILs were not significant prognostic factor for recurrent-free survival (RFS) and overall survival (OS) in MSI-H group. However, in non-MSI-H group, multivariate analysis showed that stage, PNI and CD4+ T cells was independent prognostic factor for RFS; on the other hand, stage, PNI and ratio of Foxp3/CD4 was independent prognostic factor for OS. Conclusions: The number of subset of TILs and the prognostic influence of systemic and local immune response were different between MSI-H and non-MSI-H tumors. The immunogenicity caused by microsatellite instability and subsequent host immune response is associated with cancer progression and patient prognosis of gastric cancer. Citation Format: Hyoung-Il Kim, Su-Jin Shin, Sang Yong Kim, Yoon Young Choi, Taeil Son, Jae-Ho Cheong, Woo Jin Hyung, Sung Hoon Noh. High density of cytotoxic and regulatory T-lymphocytes in gastric cancers with microsatellite instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4692.
Abstract 19633: Comparison of Angiotensin II Receptor Blocker versus Beta-blocker Therapy in Genetically Classified Children With Marfan Syndrome
Authors: Erica E Gonzalez, Lisa C D’Alessandro, Nitya K Viswanathan, Shaine A Morris, Dianna M Milewicz
Journal: Circulation (2015)

Background: Children with Marfan syndrome (MFS) treated with angiotensin II receptor blocker (ARB) or beta-blocker (BB) therapy show a reduction in the rate of aortic root (AR) growth, yet substantial variability in effect remains. Adult data suggests that patients with haploinsufficient (HI) mutations may be more responsive to ARBs compared with dominant negative (DN) mutations. This study sought to assess the effect of genotype on the rate of AR growth in children treated with either ARB or BB. Methods: A retrospective review of all individuals with MFS assessed at our institution since 1980 was undertaken; those with ≥2 echocardiograms a minimum of 1 year apart and a documented disease-causing fibrillin-1 (FBN1) mutation were included. One patient with infantile MFS was excluded given extremely AR growth. Genotypes were classified by predicted protein effect as either HI or DN. Multivariable longitudinal linear regression analysis was used to compare average rate of AR growth by genotype and medical therapy using serial echocardiographic data. Results: Overall 41 children were included, including 18 with HI and 23 with DN mutations. Males comprised 58%. There was no difference in median age at first echo (HI 5.4 years, IQR 3.9-9.3 vs. DN 5.2 years, IQR 3.4-10.6 years, p=0.97), follow-up time (HI 5.8 years, IQR 4.6-8.2 vs. DN 4.9 years, IQR 3.3-8.7, p=0.35), AR dimension (HI 26 mm, IQR 23-29 vs DN 26 mm, IQR 22-37, p=0.81), or AR z-score (HI 3.0, IQR 2.3-4.0 vs DN 3.4, IQR 2.4-4.2, p=0.58). AR growth rate was greater in children with DN mutations (z-score annual change HI -0.04 vs DN +0.07, p&lt;0.0001). When evaluating AR growth only in patients on ARB or BB monotherapy, patients on ARB with DN mutations grew significantly faster than those on BB therapy with DN mutations (p=0.02). Conclusions: In our cohort, patients with MFS and DN mutations had slower growth on BB therapy compared to those on ARB therapy. Genetic testing may play an important role in targeted medical therapy in MFS.
Abstract 3069: DSP-0692, a novel and selective stearoyl-CoA desaturase (SCD) inhibitor targeting cancer stem cells
Authors: Eiji Sugaru, Yudai Furuta, Yuichi Fukunaga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Futoshi Hasegawa, Shingo Tojo, Miki Hashizume, Hitoshi Ban
Journal: Cancer Research (2018)

Abstract In recent years evidence has accumulated in support of the cancer stem cells (CSCs) model in cancer chemotherapy resistance, highlighting the urgency and necessity of identifying CSC-specific targets for new cancer therapeutics. SCD, a key enzyme for lipid metabolism, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. In particular, recent studies have implicated SCD involved also in the maintenance of CSCs. Here, the identification and the functional characterization of DSP-0692, a novel and selective SCD inhibitor, is reported, using various pharmacological approaches to address the mechanism of SCD inhibition in cancer cells and its efficacy in preclinical tumor models. In these preclinical models, DSP-0692 inhibited human SCD activity with low nanomolar IC50 values. SCD expression was induced in tumor cells cultured in sphere conditions, which were resistant to conventional agents within therapeutic concentration. DSP-0692 showed strong growth inhibition when tumor cells were cultured in sphere conditions, but had little impact on cells cultured under normal two-dimensional conditions. In addition, DSP-0692 inhibited the CSC-related signaling pathway and decreased CSC markers expression in tumor cells as well as in tumor tissues. Treatment of DSP-0692 as single agent suppressed tumor growth in multiple models. Furthermore, this efficacy was enhanced in combination with conventional chemotherapies in those tumor models. Of note, SCD protein expression in tumor tissues was useful as a predictive marker for the susceptibility to DSP-0692 treatment. Taken together, these data suggest that inhibition of fatty acid desaturation by DSP-0692 could be a new therapeutic strategy in SCD-positive cancer, with potential to overcome resistance to standard chemotherapies. Citation Format: Eiji Sugaru, Yudai Furuta, Yuichi Fukunaga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Futoshi Hasegawa, Shingo Tojo, Miki Hashizume, Hitoshi Ban. DSP-0692, a novel and selective stearoyl-CoA desaturase (SCD) inhibitor targeting cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3069.
Abstract 3889: <i>RPL28</i> promoter polymorphism rs4806668 is associated with reduced survival in FOLFIRI-treated metastatic colorectal cancer patients
Authors: Adrien Labriet, Éric Lévesque, Elena De Mattia, Erika Cecchin, Derek Jonker, Félix Couture, David Simonyan, Angela Buonadonna, Mario D'Andrea, Lyne Villeneuve, Giuseppe Toffoli, Chantal Guillemette
Journal: Cancer Research (2018)

Abstract Fluorouracil (5-FU), folinic acid, and irinotecan (FOLFIRI) is a standard treatment of metastatic colorectal cancer (mCRC). Our study aimed to investigate genetic variability in candidate genes in relation to patients' outcomes using two independent cohorts of 417 FOLFIRI-treated mCRC cases recruited in Canada and Italy. We used a haplotype-tagging polymorphism (htSNP) approach to maximize the coverage of genetic variability of the selected genes and genotyping was performed using time-of-flight mass spectrometry iPLEX Sequenom Technology. Associations between polymorphisms and clinical outcomes were tested using Cox proportional hazards model adjusted for covariates. Of the genes tested, RPL28 encodes a ribosomal protein and its silencing was shown to enhance sensitivity to 5-FU and irinotecan in vitro.1 RPL28 rs4806668G&amp;gt;T was associated with a shorter progression-free survival (PFS) in the Canadian (hazard ratio (HR) 3.23, P = 0.013), Italian (HR 3.28, P = 0.021) and combined (HR 3.36, P &amp;lt; 0.001) cohorts. This marker was also associated with a reduced overall survival (OS) in the Canadian (HR 3.09, P = 0.032), Italian (HR 3.05, P = 0.030) and combined (HR 3.07, P = 0.002) cohorts. These carriers of the rs4806668 TT genotype associated with reduced survival represent less than 5% of the population of European ancestry and its frequency varies greatly among ethnic groups. This htSNP, located in the promoter region of RPL28, is in strong linkage disequilibrium with six other polymorphisms and may affect RPL28 gene expression. In support, the rs4806668T allele was associated with increased RPL28 expression in colon tissues of healthy individuals of the GTEx cohort, compared to rs4806668G carriers. Functional investigations are required to elucidate the underlying molecular mechanism. These results suggest a role for the ribosomal RPL28 protein in cancer cell response to FOLFIRI treatment. This work is supported by the Canadian Institutes of Health Research. 1Allen et al. Mol Cancer Ther. 2012 Jan;11(1):119-31 Citation Format: Adrien Labriet, Éric Lévesque, Elena De Mattia, Erika Cecchin, Derek Jonker, Félix Couture, David Simonyan, Angela Buonadonna, Mario D'Andrea, Lyne Villeneuve, Giuseppe Toffoli, Chantal Guillemette. RPL28 promoter polymorphism rs4806668 is associated with reduced survival in FOLFIRI-treated metastatic colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3889.
Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression
Authors: MotoyukiIgata, HiroyukiMotoshima, KakuTsuruzoe, KanouKojima, TakeshiMatsumura, TatsuyaKondo, TetsuyaTaguchi, KazuhikoNakamaru, MiyukiYano, DaisukeKukidome, KazuyaMatsumoto, TetsushiToyonaga, TomoichiroAsano, TakeshiNishikawa, EiichiAraki
Journal: Circulation Research (2005)

Vascular smooth muscle cell (VSMC) proliferation is a critical event in the development and progression of vascular diseases, including atherosclerosis. We investigated whether the activation of adenosine monophosphate-activated protein kinase (AMPK) could suppress VSMC proliferation and inhibit cell cycle progression. Treatment of human aortic smooth muscle cells (HASMCs) or isolated rabbit aortas with the AMPK activator 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) induced phosphorylation of AMPK and acetyl Co-A carboxylase. AICAR significantly inhibited HASMC proliferation induced by both platelet-derived growth factor-BB (PDGF-BB) and fetal calf serum (FCS). Treatment with AICAR inhibited the phosphorylation of retinoblastoma gene product (Rb) induced by PDGF-BB or FCS, and increased the expression of cyclin-dependent kinase inhibitor p21CIP but not that of p27KIP. Pharmacological inhibition of AMPK or overexpression of dominant negative-AMPK inhibited both the suppressive effect of AICAR on c...
Abstract 205: Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies
Authors: Mariangela Russo, Simona Lamba, Annalisa Lorenzato, Alberto Sogari, Giorgio Corti, Giuseppe Rospo, Monica Montone, Luca Lazzari, Sabrina Arena, Daniele Oddo, Michael Linnebacher, Andrea Sartore-Bianchi, Filippo Pietrantonio, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli
Journal: Cancer Research (2018)

Abstract Clinical effectiveness of targeted therapies is often transitory and virtually all patients develop secondary resistance. The heterogeneous mechanisms of resistance and the sub-clonal evolution pattern of cell populations that emerge upon pharmacological selection limit disease control with subsequent lines of therapy. We used colorectal cancer (CRC) to test the hypothesis that ancestral oncogenic event (such as WNT pathway alterations) shared by every cell sub-clone might be better suited as therapeutic targets than heterogeneous events in the branches, as the former remain present in each drug-resistant cell independently from its genetic drift.To test our assumption, we first generated a panel of CRC cells resistant to commonly used targeted agents, including EGFR and BRAF inhibitors. Treatment with targeted therapies, although initially effective, fuels clonal evolution and further amplifies molecular diversity. Exome sequencing and phylogenetic tracking unveiled a complex sub-clonal architecture in CRC resistance cell populations, indicating parallel evolution of multiple independent cellular lineages, associated with distinct genomic landscapes.Functional and pharmacological modulation of WNT signaling induces cell death in CRC preclinical models from patients that relapsed during treatment, regardless of drug type or resistance mechanisms. Pharmacological blockade of WNT ligands secretion resulted in translocation of β-catenin from the cytoplasm and nucleus to the plasma membrane, decreased of β-catenin dependent Tcf/LEF transcriptional activity, and cell growth impairment despite massive molecular drift of resistant derivatives. Concomitant blockade of WNT and MAPK signalling restrained evolution of drug-resistant clones.In summary, reliance of CRC on the WNT pathway is preserved in later phases of colorectal carcinogenesis when tumors face genomic bottlenecks and sub-clonal evolution driven by administration of target therapies; thus offering the possibility of a common therapeutic strategy to overcome secondary resistance to treatments. Citation Format: Mariangela Russo, Simona Lamba, Annalisa Lorenzato, Alberto Sogari, Giorgio Corti, Giuseppe Rospo, Monica Montone, Luca Lazzari, Sabrina Arena, Daniele Oddo, Michael Linnebacher, Andrea Sartore-Bianchi, Filippo Pietrantonio, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli. Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 205.