tbuckley/cabot-search huggingface dataset:
Abstract 3011: Dietary fat, fatty acids, and ovarian cancer risk: Preliminary findings from the Shanghai Women’s Health Study
Authors: Eftitan Y. Akam, Harvey J. Murff, Yong-Bing Xiang, Nikhil K. Khankari, Hui Cai, Xiao O. Shu, Wei Zheng, Alicia Beeghly-Fadiel
Journal: Cancer Research (2017)

Abstract Introduction: Dietary fat is an essential nutrient for human growth and development, but epidemiological studies have linked excess fat to the development of multiple malignancies. The few existing studies on ovarian cancer risk are inconsistent, possibly due to differences in sources and subtypes of fat. For example, omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are thought to be antineoplastic, while omega-6 (n-6) PUFAs may promote carcinogenesis. Approach: We evaluated dietary fat in relation to ovarian cancer risk in the prospective Shanghai Women’s Health Study (SWHS). Intake levels were determined from food frequency questionnaires (FFQ) administered at baseline and during follow-up; specific nutrient components were based on the sum of specific foods multiplied by nutrient content from the Chinese Food Composition Table. Cox proportional hazards regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) for dietary fat and fatty acid components categorized into quintiles. Minimal models included age and residual adjustment for total energy intake; fully adjusted models also included education, years of menstruation, years of oral contraceptive use, parity, years of breastfeeding, family history of ovarian cancer, smoking, drinking, NSAID use, BMI, and physical activity. Results: Among 73,144 SWHS participants, we identified a total of 219 ovarian cancer cases in 1,114,828 person-years of follow-up. We found significant dose-response relationships between increasing total PUFA (P-trend=0.032) and n-6 PUFA (P-trend=0.022) intakes and decreased ovarian cancer risk. In both minimally and fully adjusted models, women with the highest quintile of total dietary PUFAs were approximately 35% less likely to develop ovarian cancer (RR=0.65, 95% CI: 0.43-1.00), and women with the highest n-6 PUFA intake had a nearly 40% lower risk (RR=0.61, 95% CI: 0.40-0.93). Total fat, monounsaturated fat, and n-3 PUFA intake were not significantly related to ovarian cancer risk. Conclusions: Findings from our preliminary analysis of a large prospective cohort of Chinese women suggest that total PUFA intake may be protective of ovarian cancer, and that this association may be driven by n-6 rather than n-3 PUFAs. Further evaluation, including stratification, sensitivity analysis, and evaluation of source of dietary fatty acids, is currently underway. Citation Format: Eftitan Y. Akam, Harvey J. Murff, Yong-Bing Xiang, Nikhil K. Khankari, Hui Cai, Xiao O. Shu, Wei Zheng, Alicia Beeghly-Fadiel. Dietary fat, fatty acids, and ovarian cancer risk: Preliminary findings from the Shanghai Women’s Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3011. doi:10.1158/1538-7445.AM2017-3011
Abstract 2903: 1-Methoxyphaseollidin: Novel gamma secretase inhibitor targeting notch-1 signaling in breast cancer stem cells
Authors: Venkatesh Kolluru, Deeksha Pal, Becca Baby, Houda Alatassi, Arun Kumar Sharma, Murali Ankem, Chendil Damodaran
Journal: Cancer Research (2017)

Abstract We recently showed that two different ALDH+ and CD44+/CD24-/low breast cancer stem cells (BSCSs) exhibited stem cell characteristics that include self-renewal, extensive proliferation, the ability to form non-adherent spherical clusters, chemotherapy resistance and high Notch1 expression. We have identified a compound compound: 6-(3-methylbut-2-enyl) coumestrol (Pso) and treatment with Pso resulted in growth inhibition and an EMT phenotype in both BCSCs and BC cells. Oral Pso administration at physiologically achievable doses (25 mg/kg/BW) suppressed the growth of BCSCs and BC xenografts without toxicity. In the current studies, we identified several novel Pso-derived analogs that may be more potent than the parent compound. One such compound, 1-methoxyphaseollidin (1MP), obtained via three main functional group changes: (i) translocation of the isoprenyl moiety from the phenyl ring fused to the pyran ring (as in Pso) to the phenyl ring adjacent to the furan ring, (ii) removal of the carbonyl group from the pyran ring, and (iii) introduction of a methoxy group at the 1-position, inhibited Notch1 activity and growth of both BSCS and BC cells at nM concentration (IC50: 300nM), which is 100 times more potently than Pso in cell culture models. Molecular studies suggest that 1MP inhibits Notch signaling pathways (Hes1, Hey1 and Presenilin) in both BCSC and BC cells. Further, downregulation of AKT signaling (pAKT (S473), p65 and BCl-2 were seen in 1MP treated cells. Docking studies suggest that 1MP binds outside of the catalytic unit of γ-secretase and induces a conformational change, resulting in Notch1 inhibition in both BCSCs and BC cells. More importantly, administration of 1MP significantly inhibited the growth of BCSC and BC tumors without causing gastrointestinal toxicity in tumor-bearing mice. H&amp;E staining suggests that 1MP treated tumors show infiltrate to margins are less as compared to vehicle treated mice’s. We believe targeting notch1 signaling and optimizing 1MP could be an effective therapeutic strategy for treating breast cancer. Note: This abstract was not presented at the meeting. Citation Format: Venkatesh Kolluru, Deeksha Pal, Becca Baby, Houda Alatassi, Arun Kumar Sharma, Murali Ankem, Chendil Damodaran. 1-Methoxyphaseollidin: Novel gamma secretase inhibitor targeting notch-1 signaling in breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2903. doi:10.1158/1538-7445.AM2017-2903
MicroRNA29a Treatment Improves Early Tendon Injury
Authors: Ashlee E. Watts, Neal L. Millar, Josh Platt, Susan M. Kitson, Moeed Akbar, Raquel Rech, Jay Griffin, Roy Pool, Tom Hughes, Iain B. McInnes, Derek S. Gilchrist
Journal: Molecular Therapy (2017)

Tendon injuries (tendinopathies) are common in human and equine athletes and characterized by dysregulated collagen matrix, resulting in tendon damage. We have previously demonstrated a functional role for microRNA29a (miR29a) as a post-transcriptional regulator of collagen 3 expression in murine and human tendon injury. Given the translational potential, we designed a randomized, blinded trial to evaluate the potential of a miR29a replacement therapy as a therapeutic option to treat tendinopathy in an equine model that closely mimics human disease. Tendon injury was induced in the superficial digital flexor tendon (SDFT) of 17 horses. Tendon lesions were treated 1 week later with an intralesional injection of miR29a or placebo. miR29a treatment reduced collagen 3 transcript levels at week 2, with no significant changes in collagen 1. The relative lesion cross-sectional area was significantly lower in miR29a tendons compared to control tendons. Histology scores were significantly better for miR29a-treated tendons compared to control tendons. These data support the mechanism of microRNA-mediated modulation of early pathophysiologic events that facilitate tissue remodeling in the tendon after injury and provides a strong proof of principle that a locally delivered miR29a therapy improves early tendon healing. Tendon injuries (tendinopathies) are common in human and equine athletes and characterized by dysregulated collagen matrix, resulting in tendon damage. We have previously demonstrated a functional role for microRNA29a (miR29a) as a post-transcriptional regulator of collagen 3 expression in murine and human tendon injury. Given the translational potential, we designed a randomized, blinded trial to evaluate the potential of a miR29a replacement therapy as a therapeutic option to treat tendinopathy in an equine model that closely mimics human disease. Tendon injury was induced in the superficial digital flexor tendon (SDFT) of 17 horses. Tendon lesions were treated 1 week later with an intralesional injection of miR29a or placebo. miR29a treatment reduced collagen 3 transcript levels at week 2, with no significant changes in collagen 1. The relative lesion cross-sectional area was significantly lower in miR29a tendons compared to control tendons. Histology scores were significantly better for miR29a-treated tendons compared to control tendons. These data support the mechanism of microRNA-mediated modulation of early pathophysiologic events that facilitate tissue remodeling in the tendon after injury and provides a strong proof of principle that a locally delivered miR29a therapy improves early tendon healing.
Abstract 2288: Effects of tobacco smoking and alcohol consumption on risks of CYP1B1 polymorphisms for prostate cancer
Authors: Taku Kato, Yutaka Hashimoto, Shigekatsu Maekawa, Marisa Shiina, Mitsuho Imai-Sumida, Pritha Dasgupta, Priyanka Kulkarni, Soichiro Yamamura, Shahana Majid, Sharanjot Saini, Varahram Sharryari, Guoren Deng, Rajvir Dahiya, Yuichiro Tanaka
Journal: Cancer Research (2017)

Abstract Cytochrome P450 1B1 (CYP1B1) converts xenobiotics to carcinogens and polymorphic variants have been shown to increase activity levels. Lifestyle choices such as tobacco smoking and alcohol consumption are known to enhance the carcinogenesis process and in this study, how these factors may interact with CYP1B1 polymorphisms and affect prostate cancer risk was assessed. Blood genomic DNA from a Caucasian population consisting of 405 healthy men and 400 prostate cancer patients were obtained. Of these, 507 were current or former smokers and 407 were alcohol drinkers. Eight polymorphic sites of the promoter region of CYP1B1 (rs2551188 G to A, rs2567206 G to A, rs2567207 A to G, rs162556 A to G, rs10175368 C to T, rs163090 T to A, rs162330 T to G, and rs162331 A to G) were analyzed in samples using Taqman genotyping assays and real-time PCR. Lifestyle factors and its influence on CYP1B1 polymorphisms toward cancer risks were also evaluated. Overall, both alcohol (P=0.006) and smoker (P=0.069) status were associated with prostate cancer. CYP1B1 variants were also risks for cancer at rs2551188 (P=0.043), rs2567206 (P=0.008), and rs10175368 (P=0.001). Evaluation of linkage disequilibrium show rs2551188, rs2567206, rs2567207, and rs10175368 to be linked and interestingly, the G-G-A-C haplotype (wildtype at respective sites) was significantly reduced in cancer (P=0.0282). When classified by lifestyle factors, no associations for CYP1B1 variants were found for cancer among non-smokers with rs10175368 (P=0.051) being a risk among non-drinkers. On the other hand, variants at both rs2567206 and rs10175368 showed increased cancer risk among smokers (P=0.032 and 0.002, respectively) as well as drinkers (P=0.044 and 0.019, respectively). No genotyping differences were observed when analyzing cancers by pathological grades. These results demonstrate smoker and alcoholic drinker status to modify the risks of CYP1B1 polymorphisms for prostate cancer and this is of importance in understanding their role in the pathogenesis of this disease. Citation Format: Taku Kato, Yutaka Hashimoto, Shigekatsu Maekawa, Marisa Shiina, Mitsuho Imai-Sumida, Pritha Dasgupta, Priyanka Kulkarni, Soichiro Yamamura, Shahana Majid, Sharanjot Saini, Varahram Sharryari, Guoren Deng, Rajvir Dahiya, Yuichiro Tanaka. Effects of tobacco smoking and alcohol consumption on risks of CYP1B1 polymorphisms for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2288. doi:10.1158/1538-7445.AM2017-2288
Abstract 3397: Post-mortem examination of an aggressive case of medullary thyroid cancer characterised by catastrophic genomic abnormalities
Authors: Darran P. O'Connor, Sudipto Das, Deirdre Kelly, Bruce Moran, Kathleen Han, Niall Mulligan, Ciara Barrett, Patrick Buckley, Peter McMahon, J McCaffrey, Henrik van Essen, Kate Connor, Bauke Ylstra, Diether Lambrechts, William M. Gallagher, Catherine M. Kelly
Journal: Cancer Research (2017)

Abstract Catastrophic genomic alterations may drive aggressive cancer phenotypes. We describe a diagnostically challenging and rapidly fatal case of medullary thyroid carcinoma (MTC) occurring in a young, morbidly obese man presenting with diffuse bone marrow involvement and disseminated intravascular coagulation. Whole-exome (WES) and shallow whole-genome sequencing (sWGS) were carried out for the primary tumour, adjacent normal, bone marrow tissues, multiple metastases and blood samples derived from the patient. We identified three germline single nucleotide polymorphisms (SNPs) within the RET proto-oncogene that remained undetected using routine hospital genetic testing procedures. One variant (L769L) has been previously reported to be associated with aggressive MTC presentation yet remains untested for in the routine diagnosis of MTC. Supported by findings from both WES and sWGS, we report for the first time in thyroid cancer on the occurrence of a “chromothripsis-like pattern”, which involved shattering of chromosome 4 leading to complete abrogation of normal chromosomal function, along with dramatic widespread copy number aberrations across both primary tumour and bone marrow samples. Based on the somatic variants identified, we describe the evolutionary pathway of the case, showing that bone marrow metastasis occurred separately to other metastatic sites. The presence of disease-associated SNPs within the RET proto-oncogene supports their inclusion as part of routine genetic testing for MTC cases. The copy number aberrations and chromothripsis-like pattern affected a much broader range of genes than single mutations and may have led to the widespread chromosomal instability evident, possibly contributing to the rapid fatal course of the case. These results provide a rationale for the application of comprehensive genomic analysis of cancers presenting with unusual and aggressive phenotypes to facilitate more appropriate therapeutic options and diagnoses. Citation Format: Darran P. O'Connor, Sudipto Das, Deirdre Kelly, Bruce Moran, Kathleen Han, Niall Mulligan, Ciara Barrett, Patrick Buckley, Peter McMahon, J McCaffrey, Henrik van Essen, Kate Connor, Bauke Ylstra, Diether Lambrechts, William M. Gallagher, Catherine M. Kelly. Post-mortem examination of an aggressive case of medullary thyroid cancer characterised by catastrophic genomic abnormalities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3397. doi:10.1158/1538-7445.AM2017-3397
Abstract 5517: Antitumor effect of LRIG1, negative regulator of ErbB, in lung cancer harboring mutant-EGFR
Authors: Hidejiro Torigoe, Shinichi Toyooka, Masakiyo Sakaguchi, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi
Journal: Cancer Research (2017)

Abstract Introduction: EGFR is a member of the ErbB family of tyrosine kinase receptors (RTKs) and plays important roles in the pathogenesis of certain human cancers. In non-small cell lung cancer (NSCLC), mutations in EGFR gene are commonly known as oncogenic driver mutation and targeted for treatment. Leucine rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell surface protein and known as a negative regulator of ErbB family. In brain tumor, LRIG1 was reported to downregulate not only wild-type EGFR, but also EGFRvIII, mutant-type EGFR. But there has been no report about the relationship between LRIG1 and EGFR mutation in the kinase domain frequently found in lung cancer. In this study, we investigate the role of LRIG in EGFR mutant lung cancer from the view point of its effect on signal transduction and cell proliferation and invasion. Method: We examined the LRIG1 expression levels in lung cancer cell lines and the surgically resected primary lung cancer tissues by quantitative PCR assay. We made stable clone of EGFR-mutant cell line (HCC827; exon19del E746-A750) overexpressing GFP tagged LRIG1, and compared with stable clone overexpressing GFP alone. Results: The LRIG1 expression levels in lung cancer cell lines and the surgically resected primary lung cancer tissues were much lower than that in normal bronchial epithelial cells and their normal tissues, respectively. The introduction of LRIG1 decreased EGFR expression and their phosphorylation in EGFR-mutant cell line. LRIG1 strongly suppressed cell proliferation, invasion and migration of EGFR-mutant cell line. In addition, a phospho-RTK array revealed that LRIG1 also downregulated the other RTKs, such as HER2, HER3, MET, and IGF-1R. Conclusion: Our findings demonstrates that LRIG1 decreases the expression and phosphorylation of mutant-EGFR protein and has strong anti-tumor effect in lung cancer harboring EGFR mutation. These findings suggest the importance of LRIG1 related studies to develop a novel strategy for EGFR mutant cancers. Citation Format: Hidejiro Torigoe, Shinichi Toyooka, Masakiyo Sakaguchi, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi. Antitumor effect of LRIG1, negative regulator of ErbB, in lung cancer harboring mutant-EGFR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5517. doi:10.1158/1538-7445.AM2017-5517
Abstract 87: Treatment schedules influence acquisition of Doxorubicin resistance through epigenetic mechanism in breast cancer cells
Authors: Logeswari Ponnusamy, Prathap Kumar S. Mahalingaiah, Kamaleshwar P. Singh
Journal: Cancer Research (2017)

Abstract Breast cancer is the leading cause of cancer related mortality in women. Chemotherapy resistance is a major limitation in clinical treatment of breast cancer. Mounting evidence implicates the epigenetic aberrations in acquired chemoresistance. However, the influence of treatment schedules and associated epigenetic changes on acquisition of doxorubicin resistance in breast cancer is not clear. Therefore, objective of this study was to evaluate the impact of treatment schedules on acquisition of doxorubicin resistance and the molecular mechanistic basis of this process in breast cancer cells. To address this question, two different treatment strategies viz, continuous exposure and intermittent exposure were used to generate doxorubicin resistant cells lines from ER-positive MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. The level of resistance against doxorubicin and the temporal sequence of molecular changes associated with the resistance phenotype were evaluated at 4 months and 18 months’ following exposure to doxorubicin. Results revealed that intermittent exposure to doxorubicin resulted in significantly higher level of resistance as compared to continuous exposure. ER-positive MCF-7 cells developed relatively earlier and high level of resistance when compared to MDA-MB-231 cells. Additionally, the resistance to doxorubicin-induced cytotoxicity was associated with transient acquisition of EMT and CSC-like phenotype in breast cancer cells around 4 months following doxorubicin. Gene and protein expression analysis further revealed temporal changes in the expression of epigenetic regulatory genes and histone modifications respectively. The temporal changes in expression of genes were positively correlated with doxorubicin exposure time during resistance development. In summary, the result of this study for the first time suggests that the treatment schedules influence the acquisition of doxorubicin resistance potentially through epigenetic mechanisms. The findings of this study will be helpful in chemotherapy of breast cancer to achieve the best clinical result Note: This abstract was not presented at the meeting. Citation Format: Logeswari Ponnusamy, Prathap Kumar S. Mahalingaiah, Kamaleshwar P. Singh. Treatment schedules influence acquisition of Doxorubicin resistance through epigenetic mechanism in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 87. doi:10.1158/1538-7445.AM2017-87
Extraction of an ingested denture embedded in the jejunum by mucosal cutting
Authors: Takahito Takezawa, Satoshi Shinozaki, Tomonori Yano, Keijiro Sunada, Yoshikazu Hayashi, Alan Lefor, Hironori Yamamoto
Journal: Endoscopy (2017)

A 55-year-old woman accidentally ingested a denture, and it did not pass per anus after 4 days. Her local doctor followed her for 15 days, but the denture did not pass, and she was referred to our institution. She did not complain of any abdominal symptoms, and laboratory data did not show any abnormal findings. Abdominal radiograph ([Fig. 1]) and computed tomography scan showed a denture lodged in the jejunum. Antegrade double-balloon enteroscopy showed sharp, elongated teeth embedded in the jejunal mucosa ([Fig. 2]).
Abstract 4293: Siramesine and lapatinib induce ferroptosis in glioblastoma and lung adenocarcinoma cells
Authors: Anna R. Blankstein, Shumei Ma, Spencer B. Gibson
Journal: Cancer Research (2017)

Abstract Ferroptosis, a morphologically and biochemically distinct cell death pathway, is characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor, has been shown to synergistically induce cell death in breast cancer cells. This cell death was blocked by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The objective of the present study was to determine whether lysosome disruptors and tyrosine kinase inhibitors, in combination, induced synergic cell death via the ferroptotic pathway in additional types of cancer. U87 (glioblastoma) and A549 (lung adenocarcinoma) cells were treated with various lysosome disruptors (siramesine or desipramine) in combination with tyrosine kinase inhibitors (lapatinib or sorafenib), and the amount of cell death was measured by trypan blue exclusion. We found that these combinations synergistically induced cell death in U87 and A549 cells. To determine whether ferroptosis was the mechanism of cell death, cells were pretreated with either Fer-1 or DFO (inhibitors of ferroptosis), or with exogenous iron chloride (an inducer of ferroptosis) before treatment with the combination of siramesine and lapatinib. Pretreatment with Fer-1 or DFO decreased cell death by approximately 35%. Pretreatment with iron chloride increased the effect of the drug combination by approximately 45%. Prussian Blue staining demonstrated that there was an increase in intracellular iron accumulation following treatment with the combination of siramesine and lapatinib. Collectively, these data show that in U87 and A549 cells, the combination of lysosome disruptors and tyrosine kinase inhibitors, specifically siramesine and lapatinib, induces ferroptotic cell death. Therefore, inducing ferroptosis in tumor cells is a potential strategy for therapy in these cancers with limited treatment options. Citation Format: Anna R. Blankstein, Shumei Ma, Spencer B. Gibson. Siramesine and lapatinib induce ferroptosis in glioblastoma and lung adenocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4293. doi:10.1158/1538-7445.AM2017-4293