tbuckley/cabot-search huggingface dataset:
Abstract 4912: Effect of the combined treatment with mifepristone and chemotherapy on breast cancer brain metastases
Authors: Ayelen Rubin, Veronica de la Fuente, Edgardo Salvatierra, Silvia Vanzulli, Osvaldo Podhajcer, Claudia Lanari, Paola Rojas
Journal: Cancer Research (2017)

Abstract The treatment of brain metastasis is limited due to the drug’s inability to cross the blood brain barrier, because of the presence of endothelial cells’ multidrug resistance efflux transporters, such as the P-glycoprotein (P-gp). The antiprogestin Mifepristone (MFP) is known to inhibit the P-gp activity. We hypothesize that a combination of MFP and Pegylated doxorubicin liposomes (doxo) improves the drug efficacy on breast tumors that do not express progesterone receptors. Using the metastatic triple negative MDA-231-BrM2 breast cancer cell line, transfected with GFP and luciferase, we explored different protocols to generate tumors growing in the brain of NSG mice. Spontaneous metastases were obtained by subcutaneous injection (sc) of 2 x 106 cells, and experimental metastases by intracardiac injection (ic) of 1 x 106 cells or by intracranial injection of 2 x 105 cells. In the ic and sc models small and scattered brain metastases as well as liver, lung and kidney metastases were observed. The intracranial model enabled us to obtain measurable brain tumors in a short time. Thus we selected this method to evaluate the effect of MFP (6 mg pellets, sc) and /or doxo (4,5 mg/kg, iv) on tumors growing in the brain. Treatment was initiated 10 days after cell inoculation. The amount of tumor cells after brain excision was measured by flow cytometry (GFP) and by luminometry (luciferase activity). A decreased luminescence signal was observed in brains from mice treated with both agents as compared with the control mice (p&amp;lt;0.05), whereas no effects were observed between the single treatment groups and the controls. Moreover, the flow cytometry analysis showed that the combined treatment, MFP+doxo, reduced the number of tumor cells further than the single chemotherapeutic agent (p&amp;lt;0.05). Our data suggest that MFP may be a promising agent to treat brain metastasis of breast cancers, which do not necessarily express progesterone receptors, to increase the effectiveness of chemotherapeutic agents. The participation of the P-gp mediating this effect needs to be confirmed. Citation Format: Ayelen Rubin, Veronica de la Fuente, Edgardo Salvatierra, Silvia Vanzulli, Osvaldo Podhajcer, Claudia Lanari, Paola Rojas. Effect of the combined treatment with mifepristone and chemotherapy on breast cancer brain metastases [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 4912. doi:10.1158/1538-7445.AM2017-4912
Abstract 2125: Flavokawain A, a kava chalcone, inhibits growth and invasion of human osteosarcoma cells by targeting Skp2
Authors: Yidan Zhang, Wendong Zhang, Nikolas Zaphiros, Xiuquan Du, Pratistha Koirala, Michael Roth, Jonathan Gill, Sajida Piperdi, David Geller, Rui Yang, Jinghang Zhang, Richard Gorlick, Xiaolin Zi, Tao Ji, Bang H. Hoang
Journal: Cancer Research (2017)

Abstract Purpose: Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Flavokawain A (FKA), a major chalcone from kava extract, has been reported to have antitumor effects on multiple cancer cell lines. The consumption of kava-containing beverage has been associated with a low cancer incidence. In a previous report, mice treated with high-dose FKA did not demonstrate any significant major organ toxicity. However, the efficacy and anticancer mechanisms of FKA in OS is still to be elucidated. Experimental Design: OS cell lines were treated with increasing dosage of FKA and tested for cell motility, proliferation, and invasion by MTT assay and Matrigel invasion assay. Cell cycle analysis was performed using flow cytometry. We examined Skp2 expression in several OS cell lines using western blot and in patient tissue array by immunostaining. Kaplan-meier analysis and log rank test were used to compare overall survival. Both Skp2-dependent cell cycle progression and Skp2-related RhoA expression were also examined after FKA treatment. The effects of FKA on lung metastasis were evaluated after orthotopic injection of OS cells into the tibia. Results: We show that FKA inhibits the growth and motility of multiple OS cell lines in vitro. Flow cytometry analysis confirms cellular apoptosis and arrest in G2/M phase after FKA treatment, whereas cellular invasion is also inhibited in a dose-dependent manner. Skp2 is expressed in several OS cell lines and is associated with a poor prognosis in OS patients. Skp2 levels in OS cell lines decreased after FKA treatment. The expression of cell cycle regulators including p21 and p27, which are downstream of Skp2, was upregulated. Moreover, Skp2-related RhoA expression is inhibited by FKA and confirmed at protein level. Conclusions: Taken together, the evidence suggests FKA exerts anti-invasive effects in association with Skp2-dependent cell cycle progression and Skp2-related RhoA expression. Since Skp2 is a negative prognostic factor for OS patients, FKA should be investigated further as an anti-Skp2 therapeutic strategy for OS. Citation Format: Yidan Zhang, Wendong Zhang, Nikolas Zaphiros, Xiuquan Du, Pratistha Koirala, Michael Roth, Jonathan Gill, Sajida Piperdi, David Geller, Rui Yang, Jinghang Zhang, Richard Gorlick, Xiaolin Zi, Tao Ji, Bang H. Hoang. Flavokawain A, a kava chalcone, inhibits growth and invasion of human osteosarcoma cells by targeting Skp2 [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 2125. doi:10.1158/1538-7445.AM2017-2125
Abstract 4894: Identification of small molecules for the prevention and treatment of colon cancer
Authors: Deeksha Pal, Becca Von Baby, Balaji Chandrasekaran, Arun Sharma, Chendil Damodaran
Journal: Cancer Research (2017)

Abstract Metastatic colon cancer or colorectal cancer (CRC) is associated with poor survival rate which is less than 5% due to chemo resistance. We previously showed that overexpression of AKT and Notch1 are key players for progression of metastasis of colon cancer cells. Withaferin-A (WA) is a potent herbal molecule that inhibited CRC growth by down regulating AKT and Notch1 signaling in both in vitro and in vivo colon cancer models. We found that WA binds to AKT with a predicted binding affinity of -10.6 kcal/mol and inhibited its activation. So, we designed and developed several analogs of WA, that exhibits a stronger AKT binding (binding energy higher than -10 kcal/mole) and more potent than the parental WA. UL16 is one such compound which inhibited the growth of colon cancer cells (HCT-116 and SW-620: IC50-300nM) at nanomolar concentration. Western blot analysis revealed that UL16 inhibits AKT/NF-κβ/ Bcl2- signaling axis in colon cancer cells. In addition, UL16 concurrently inhibited Notch1 signaling pathway in colon cancer cells. Then we systematically investigated the anti-migratory and anti-invasive effect of UL16by cell migration and invasion assays. Inhibition of both migration and invasion of colon cancer cells corresponds with downregulation of mesenchymal markers of Snail, Slug and β-catenin expression. We also examined the in vivo efficacy of UL16 in ApcMin/+ mouse model. Treatment of ApcMin/+ with UL16 (0.5 mg/kg/IP/twice a week) over 12 weeks significantly reduced the number of intestinal polyps (distal 84%; Middle 63% and Proximal 2%) as compared vehicle treated mice. In addition, we also observed 50% reduction in number of colon tumors in UL16 treated mice. Our ongoing immunohistochemistry studies may confirm the in vitro mechanistic results. In conclusion, our studies suggest that UL16 inhibits both AKT and Notch1 signaling and suppresses intestinal polyp formation in ApcMin/+ mice. Hence UL16could be a viable therapeutic agent for treating patients with metastatic colon cancer. Citation Format: Deeksha Pal, Becca Von Baby, Balaji Chandrasekaran, Arun Sharma, Chendil Damodaran. Identification of small molecules for the prevention and treatment of colon 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 4894. doi:10.1158/1538-7445.AM2017-4894
Abstract 5511: Lineage-specific and shared cytokine-sensing genes respond distinctly to the master regulator STAT5
Authors: xianke zeng, Michaela Willi, Ha Youn Shin, Chaochen Wang, Lothar Hennighausen
Journal: Cancer Research (2017)

Abstract JAK/STAT signaling pathways are critical for cell response to cytokines across multiple tissues, genetic variation in this pathway could associate with neoplastic diseases. STAT5, the most common used STAT family member, differently activates two distinct classes of genes. It activates cell-specific genes up to two orders of magnitude higher than shared genes expressed across different cell types. Socs2 (Suppressors of cytokine signaling 2), a widely expressed STAT5 target gene and a negative regulator of cytokine feedback loops, contains STAT5 response element within its promoter region. In our study, we demonstrated that STAT5 preferentially binds to promoter sequence of shared STAT5 targeted genes and to distal putative enhancers of lineage-specific genes. DNase-seq demonstrated that chromatin accessibility of STAT5-based enhancers was greatly dependent on cytokine exposure, while common STAT5 promoter targets were constitutively accessible. CRIPSR /Cas9 gene editing was used to delete the generic STAT5 binding sites in Socs2 locus in mice. Prolactin induction of Socs2 was abrogated both in liver and mammary gland, and resulted in elevated STAT5 activation and precocious mammary development in mutant mice. Taken together, we demonstrated that promoter-bound STAT5 modulates cytokine responses of universal STAT5 target genes, while enhancer-bound STAT5 is necessary for linage-specific target gene activation. This study provides new insight into the mechanism of used by a generic cytokine response element controlling lineage-specific transcription. Citation Format: xianke zeng, Michaela Willi, Ha Youn Shin, Chaochen Wang, Lothar Hennighausen. Lineage-specific and shared cytokine-sensing genes respond distinctly to the master regulator STAT5 [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 5511. doi:10.1158/1538-7445.AM2017-5511
Abstract 5463: Disulfiram suppresses metastasis via induction of anoikis and calpain activation in triple-negative breast cancer
Authors: Eunhye Oh, Daeil Sung, Youngkwan Cho, Ji Young Kim, Nahyun Lee, Yoon-Jae Kim, Tae-Min Cho, Jae Hong Seo
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancers (TNBC) exhibit aggressive phenotypes and are associated with poor clinical outcomes due to a lack of effective therapeutic strategies. Disulfiram (DSF) is a clinical therapeutic drug for the treatment of alcoholism, and has also been shown to exhibit antitumor activity in TNBC cells in a copper (Cu)-dependent manner, although how this occurs has not been clearly elucidated. We sought to investigate the mechanisms responsible for DSF/Cu-dependent induction of apoptosis and suppression of lung colonization by TNBC cells. DSF/Cu treatment significantly induced apoptosis, accompanied by an increase in the sub-G1 population, as well as caspase-3 activation. DSF/Cu strongly suppressed cell migration and invasion, while inducing suppression of focal adhesion kinase (FAK) phosphorylation and focal adhesions, concomitant with an observed reorganization of cytoskeletal F-actin and collapse of the plasma membrane. These effects were associated with calpain activation, coinciding with the breakdown of vimentin, FAK and talin, presumably allowing for cell detachment. In a xenograft tumor model, DSF suppressed tumor growth and lung colonization, which was also associated with calpain activation. Taken together, these findings warrant further investigation of disulfiram as a potential treatment for metastatic TNBC. Citation Format: Eunhye Oh, Daeil Sung, Youngkwan Cho, Ji Young Kim, Nahyun Lee, Yoon-Jae Kim, Tae-Min Cho, Jae Hong Seo. Disulfiram suppresses metastasis via induction of anoikis and calpain activation in triple-negative breast 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 5463. doi:10.1158/1538-7445.AM2017-5463
Innateness of magnitude perception? Skill can be acquired and mastered at all ages
Authors: Orly Rubinsten, Avi Karni
Journal: Behavioral and Brain Sciences (2017)

Abstract We agree with Leibovich et al.'s argument that the number sense theory should be re-evaluated. However, we argue that highly efficient skills (i.e., fluent and highly accurate, “automatic,” performance) can be acquired and mastered at all ages. Hence, evidence for primacy or fluency in perceiving continuous magnitudes is insufficient for supporting strong conclusions about the innateness of this aptitude.
Abstract 5270: Disease subtype independent biomarkers of breast cancer prevention by withaferin a
Authors: Eun-Ryeong Hahm, Suman K. Samanta, Anuradha Sehrawat, Su-Hyeong Kim, Subrata K. Pore, Krishna B. Singh, Susan M. Christner, Yongli Shuai, Jan H. Beumer, Ruchi Roy, Nancy E. Davidson, Shivendra V. Singh
Journal: Cancer Research (2017)

Abstract Breast cancer is a rather complex and heterogeneous disease broadly grouped into four major subtypes, including luminal-type, basal-like, HER2 amplified, and normal-like, and each with a distinct molecular signature. A non-toxic chemopreventive intervention efficacious against different subtypes of breast cancer is still a clinically unmet need. The present study not only demonstrates chemoprevention of breast cancer in rats by the Ayurvedic medicine phytochemical withaferin A (WA) but also identifies its mechanistic biomarkers common to different subtypes of this disease. Chemopreventive efficacy of WA (4 and 8 mg per kg body weight) was determined using a rat model of breast cancer induced by N-methyl-N-nitrosourea (MNU). The mechanisms underlying breast cancer chemoprevention by WA were elucidated by western blotting, biochemical assays, immunohistochemistry, and cytokine profiling using plasma and tumors from the MNU-rat and/or mouse mammary tumor virus-neu (MMTV-neu) models. Inhibitory effect of WA on exit from mitosis and leptin-induced oncogenic signaling was determined using MCF-7 and MDA-MB-231 cells. Incidence, multiplicity, and burden of MNU-induced breast cancer in rats were decreased by WA administration. For example, the tumor weight in the 8 mg per kg group was lower by 67% compared with controls (P = 0.004). Mitotic arrest and apoptosis induction were common determinants of breast cancer chemoprevention by WA in the MNU-rat and MMTV-neu models. Cytokine profiling showed suppression of plasma leptin levels by WA in rats. WA inhibited leptin-induced oncogenic signaling in cultured MCF-7 and MDA-MB-231 cell lines. WA is a promising phytochemical with the ability to inhibit at least two different subtypes of breast cancer, including neu-driven estrogen receptor negative (ER-) breast cancer in MMTV-neu model and MNU-induced ER+ breast cancer in rats. This study was supported by the grant RO1 CA142604-07 awarded by the National Cancer Institute. Citation Format: Eun-Ryeong Hahm, Suman K. Samanta, Anuradha Sehrawat, Su-Hyeong Kim, Subrata K. Pore, Krishna B. Singh, Susan M. Christner, Yongli Shuai, Jan H. Beumer, Ruchi Roy, Nancy E. Davidson, Shivendra V. Singh. Disease subtype independent biomarkers of breast cancer prevention by withaferin a [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 5270. doi:10.1158/1538-7445.AM2017-5270
Hepatomas in Mice Induced with Carbon Tetrachloride
Authors: Jesse E. Edwards
Journal: JNCI Journal of the National Cancer Institute (1941)

Hepatomas in Mice Induced with Carbon Tetrachloride Get access Jesse E. Edwards Jesse E. Edwards research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 2, October 1941, Pages 197–199, https://doi.org/10.1093/jnci/2.2.197 Published: 01 October 1941
Abstract 2492: DNA polymerase beta participates in DNA end-joining
Authors: Sreerupa Ray, Michelle DeVeaux, Gregory Breuer, Ranjit Bindra, Daniel Zelterman, Joann Sweasy
Journal: Cancer Research (2017)

Abstract DNA double strand breaks (DSBs) are one of the most deleterious lesions. If left unrepaired, DSBs lead to genomic instability and carcinogenesis. The cells combat DSBs by two classical pathways that include homologous recombination (HR) which requires the sister chromatid for sequence homology, and non-homologous end-joining (NHEJ), wherein the two DNA ends are re-joined. Recently a back-up NHEJ pathway has been reported and is referred non-canonical NHEJ which has been given many names, such as alternative NHEJ or microhomology-mediated end joining (MMEJ). The enzymatic mechanisms of non-canonical NHEJ are not well defined. NHEJ requires processing enzymes including nucleases and polymerases, although the roles of these enzymes in the pathway are poorly understood. Recent studies have implicated a role for DNA polymerase theta (Pol θ), an A-family polymerase is essential for non-canonical NHEJ pathway. Emerging evidence indicates X-family polymerases, mammalian DNA polymerases lambda (λ) and mu (μ) and yeast Pol 4 promote DNA end-joining. Our laboratory has recently provided evidence for a role for DNA polymerase beta (Pol β), another X-family polymerase, in V(D)J recombination, a process that requires end-joining. Here, using a recently developed fluorescence based assay that monitors non-canonical NHEJ and HR, we provide evidence that Pol β plays a role in the non-canonical NHEJ process. DNA sequencing at the break point junctions revealed Pol β-depleted cells have fewer small deletions than control cells, but significantly greater numbers of insertions and large deletions. We further demonstrate that Pol β-depleted cells have increased sensitivity to DNA damaging agents that induce double-strand breaks and that there is persistent accumulation of DSBs in these cells. In combination, our results suggest that Pol β is critical for double-strand break repair. Citation Format: Sreerupa Ray, Michelle DeVeaux, Gregory Breuer, Ranjit Bindra, Daniel Zelterman, Joann Sweasy. DNA polymerase beta participates in DNA end-joining [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 2492. doi:10.1158/1538-7445.AM2017-2492
Abstract 4283: BRCA1 and BRCA 2 mutation predictions using BRACAPRO and MYRIAD models in patients with Korean ethnicity
Authors: Kyung Jin Eoh, Hyung Seok Park, Ji Soo Park, Seung-Tae Lee, Jeongwoo Han, Jung-Yun Lee, Sunghoon Kim, Sang Wun Kim, Young Tae Kim, Eun Ji Nam
Journal: Cancer Research (2017)

Abstract Introduction: This study is aimed to compare the predictive efficacy of BRCAPRO and MYRIAD BRCA risk calculator in patients tested in Korean ethnicity. Methods: Individuals, who received gene test on BRCA mutation from November 2010 to August 2016, were recruited from database of department of obstetrics and gynecology at a single institute in Korea. Observed BRCA1 and BRCA2 mutation status was compared with predicted carrier probabilities under the BRCAPRO, and MYRIAD BRCA risk calculator. Risk assessment for all patients was calculated using the CancerGene assessment software. Results: Total of 279 patients was recruited, and 99.3% (277 out of 279) had Korean ethnicity. The mean age at presentation was 52 years. Out of the 279 individuals, 206 had ovarian cancer, 36 had breast cancer, 26 had double primary ovarian/breast cancer, and 11 had no cancer. Fifty five individuals had family history of ovarian/breast cancer in first degree relatives. Sixty three patients (22.6%) tested positive for a BRCA mutation (45 BRCA1, 18 BRCA2). The mean BRCAPRO and MYRIAD score for all patients was 6.4% and 7.7%, respectively. The BRCAPRO and MYRIAD scores were significantly higher for patients who tested positive for a BRCA mutation (30.4% vs. 6.3%, P &amp;lt; 0.001, 12.1% vs. 7.7%, P &amp;lt; 0.001, respectively). The area under the receiver operating characteristics curves were 0.762, and 0.751 for all patients for the BRCAPRO and MYRIAD score to predict the risk of carrying a BRCA mutation. Conclusion: BRCAPRO and MYRIAD appear to be valid risk assessment tools for determining the risk of carrying a BRCA mutation in Korean ethnicity. Citation Format: Kyung Jin Eoh, Hyung Seok Park, Ji Soo Park, Seung-Tae Lee, Jeongwoo Han, Jung-Yun Lee, Sunghoon Kim, Sang Wun Kim, Young Tae Kim, Eun Ji Nam. BRCA1 and BRCA 2 mutation predictions using BRACAPRO and MYRIAD models in patients with Korean ethnicity [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 4283. doi:10.1158/1538-7445.AM2017-4283