tbuckley/cabot-search huggingface dataset:
Abstract 5253: Arctigenin inhibits prostate tumor growth in vitro and in vivo in obese state
Authors: Piwen Wang, Tanya Diaz, Susanne Henning, Jaydutt Vadgama
Journal: Cancer Research (2017)

Abstract Arctigenin is a novel anti-inflammatory lignan derived mainly from the seeds of Arctium lappa which is an herb widely used in traditional Chinese medicine to treat inflammation related diseases. We previously demonstrated that arctigenin strongly inhibited prostate tumor cell growth in cell culture and mouse models in non-obese state. The present study investigated the tumor inhibitory effect of arctigenin in obese state. An in vitro obese setting was created by co-culture of mouse adipocytes 3T3-L1 with androgen-sensitive LAPC-4 and LNCaP prostate cancer cells. An ELISA analysis of 3T3-L1 conditioned medium revealed that three cytokines/growth factors were prominently secreted by 3T3-L1 cells, including IGF-1, VEGF, and MCP-1, and the sensitivity of prostate cancer cells to arctigenin was decreased in the obese state. However, arctigenin at a moderate concentration (10 µM) significantly inhibited the proliferation of both LAPC-4 and LNCaP cell by 40-50% at 96h in the co-culture system. Male severe combined immunodeficiency (SCID) mice was implanted subcutaneously with LAPC-4 xenograft tumors to confirm the tumor-inhibitory effect of arctigenin in vivo. Mice were fed high-fat diet containing 45% energy from fat, and treated with arctigenin at 50mg/kg b.w. orally or vehicle control for 6 weeks (n=10 per group). The tumor growth in arctigenin group was significantly inhibited by 40% compared to control, along with decreased blood concentrations of several cytokines including IGF-1, VEGF, and MCP-1. Immunohistochemistry analysis is ongoing to determine the molecular changes involved in tumor cell proliferation and apoptosis in response to arctigenin treatment. This study provides a promising natural compound to enhance chemoprevention of prostate cancer especially in obese patients. These results warrant future clinical trial studies to confirm the anti-carcinogenic effect of arctigenin in humans. Citation Format: Piwen Wang, Tanya Diaz, Susanne Henning, Jaydutt Vadgama. Arctigenin inhibits prostate tumor growth in vitro and in vivo in obese state [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 5253. doi:10.1158/1538-7445.AM2017-5253
Abstract 3535: Methylation regulates HEY1 expression in glioblastoma
Authors: Maheedhara Reddy Guda, Andrew J. Tsung, Swapna Asuthkar, Collin M. Labak, Yining Lu, Sarah E. Martin, Prasad V. Durbaka, Kiran K. Velpula
Journal: Cancer Research (2017)

Abstract Glioblastoma multiforme (GBM) remains one of the most lethal and difficult-to-treat cancers of the central nervous system despite the existence of multi-modal therapeutic approaches. The poor prognosis in GBM patients is due in part to its resistance to available treatments, which calls for identifying novel molecular therapeutic targets. In this study, we identified an interesting biomarker, Hairy/Enhancer-Of-Split related with YRPW Motif (HEY1), a mediator of Notch signaling, which contributes to the pathogenesis of GBM. Datamining studies and our immunohistochemistry and immunoblot analysis showed that HEY1 is highly expressed in GBM patient specimens. Recent studies indicate that methylation status may control the expression of cancer phenotype. Our studies using bisulphite sequencing on the patient samples showed that HEY1 promoter was hypermethylated in the normal brain when compared to GBM specimens. Treatment on the 4910 and 5310 xenograft cell lines with sodium butyrate (NaB) greatly decreased HEY1 expression owing to its promoter hypermethylation with a concomitant increase in DNMT1 expression confirming that promoter methylation regulate the HEY1 expression in GBM. NaB treatment also induced cell apoptosis as evaluated by flow cytometric analysis. Silencing HEY1 reduced invasion, migration and proliferation in 4910 and 5310 cells. Further, immunoblot and q-PCR analysis demonstrated the existence of a potential positive regulatory loop between HEY1 and p53. Additionally, DNA microarrays with HEY1 recombinant protein demonstrated good correlation with p53 and provided various bonafide targets of HEY1. Collectively, these studies suggest HEY1 as an important predictive marker for GBM, thus indicating a potential target for future GBM therapy. Citation Format: Maheedhara Reddy Guda, Andrew J. Tsung, Swapna Asuthkar, Collin M. Labak, Yining Lu, Sarah E. Martin, Prasad V. Durbaka, Kiran K. Velpula. Methylation regulates HEY1 expression in glioblastoma [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 3535. doi:10.1158/1538-7445.AM2017-3535
Abstract 486: Production of an unbiased, highly reproducible small RNA library for NGS using a novel circularization technology
Authors: Marta Gonzalez-Plasky, Amanda McNulty, Konstantinos Charizanis, Jing Ning, Edward Jan, Matthew Carroll, Emmanuel Kamberov, Karl Hecker
Journal: Cancer Research (2017)

Abstract MicroRNA sequencing (miRNA-Seq) is a useful tool for aiding researchers in the examination of miRNA expression patterns, the characterization of novel miRNAs, and for uncovering miRNA-disease associations. Since miRNAs are also unusually well-preserved in a range of samples (e.g. urine, FFPE tissue, plasma), profiling their expression is becoming a powerful diagnostic tool. However, current methods for sequencing miRNA require large amounts of total RNA, are not very reproducible and, more importantly, have considerable systematic bias resulting in loss of many prospective biomarkers. This bias severely affects the trustworthiness of results as libraries are not a true representation of the biological state of the sample. We have recently developed a technology that efficiently captures miRNA species with extremely low bias. Through a circularization approach, Illumina P5 and P7 adapters are ligated to miRNA, resulting in sequenceable libraries in under 5 hours in a single tube. These libraries are then purified and size-selected prior to sequencing. Analysis of read distributions of libraries prepared from an equimolar mixture of 963 miRNAs demonstrated the technology is able to efficiently capture all species with high reproducibility between replicates and input amounts (correlation coefficient of ≥0.97). Furthermore, 80-86% of these captured miRNA read numbers fall within a +/- 2-fold variation of the expected read number demonstrating unbiased representation. In contrast, frequency distribution analyses for other technologies reveal that 47-56% of miRNAs are greatly under-represented (i.e. less than 2X fewer reads than expected), 29-38% of miRNAs are represented within a +/- 2-fold variation of the expected read number, and around 15% are over-represented by more than 2X. These findings highlight the fact that the current technical state of library preparation for miRNA sequencing fails to accurately represent miRNA expression patterns. This in turn leads researchers to perform more costly validation experiments than necessary. Our product is designed and developed for more accurately reflecting the true biological state of a sample. This will provide researchers with a tool that can aid in advancing miRNA sequencing in translational research. Note: This abstract was not presented at the meeting. Citation Format: Marta Gonzalez-Plasky, Amanda McNulty, Konstantinos Charizanis, Jing Ning, Edward Jan, Matthew Carroll, Emmanuel Kamberov, Karl Hecker. Production of an unbiased, highly reproducible small RNA library for NGS using a novel circularization technology [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 486. doi:10.1158/1538-7445.AM2017-486
Abstract 4308: Cordycepin induces apoptosis by caveolin-1-mediated JNK regulation of Foxo3a in human lung adenocarcinoma cells
Authors: Eunbi Jo, Hyun Jin Jang, Ik-Soon Jang
Journal: Cancer Research (2017)

Abstract Forkhead transcription factor (Foxo3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the caveolin-1 (CAV1)-mediated JNK/Foxo3a pathway is involved in cancer cell apoptosis. We found that cordycepin upregulates CAV1 expression, which was accompanied by JNK phosphorylation (p-JNK), and, subsequently Foxo3a translocation into the nucleus, resulting in the upregulation of Bax protein expression. Furthermore, we found that CAV1 overexpression upregulated p-JNK whereas CAV1 siRNA downregulated p-JNK. Additionally, SP600125, a specific JNK inhibitor, significantly increased Foxo3a phosphorylation, which attenuated Foxo3a translocation into the nucleus, indicating that CAV1 mediates JNK regulation of Foxo3a. Foxo3a siRNA downregulated Bax protein and attenuated A549 apoptosis, indicating that the CAV1-mediated JNK/Foxo3a pathway induces the apoptosis of A549 lung cancer cells. Cordycepin significantly decreased tumor volume in nude mice. Taken together, these results indicate that cordycepin promotes CAV1 upregulation to enhance JNK/Foxo3a signaling pathway activation inducing apoptosis in lung cancer cells and support its potential as a therapeutic agent for lung cancer. Citation Format: Eunbi Jo, Hyun Jin Jang, Ik-Soon Jang. Cordycepin induces apoptosis by caveolin-1-mediated JNK regulation of Foxo3a in human 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 4308. doi:10.1158/1538-7445.AM2017-4308
Clinical presentation of terbinafine‐induced severe liver injury and the value of laboratory monitoring: a Critically Appraised Topic
Authors: O.N. Kramer, J. Albrecht
Journal: British Journal of Dermatology (2017)

Many physicians monitor liver function tests during terbinafine therapy. To evaluate the symptoms of published cases of terbinafine‐associated severe drug‐induced liver injury (DILI) to assess the utility of laboratory monitoring. We based our search on the LiverTox database of the National Institutes of Health, but we also searched both PubMed and Embase. In addition, we hand searched the references of the papers we found. All reports of patients with DILI on terbinafine and with reported clinical symptoms, or absence thereof, were evaluated. Two independent reviewers (J.A. and O.N.K.) assessed articles for eligibility of inclusion, and collected and evaluated the data. Thirty‐eight papers fulfilled the inclusion criteria, with reports of 69 symptomatic patients. The mean duration of terbinafine treatment until onset of symptoms was 30·2 days (range 5–84). Symptoms in order of frequency were jaundice, flu‐like symptoms, dark urine and pruritus. Patients experienced symptoms for a mean and median of 14·8 and 16 days, respectively (range 0–42) until seeking medical attention. Patients who had DILI were symptomatic, usually with jaundice, abdominal pain and general malaise, but also with severe pruritus. No asymptomatic patient was identified through laboratory screening. The timeline of DILI onset varies significantly, but most cases occur between 4 and 6 weeks. There was no time point at which monitoring was meaningful, and we do not recommend monitoring of liver function tests on terbinafine; however, patients should be advised to discontinue treatment and look for medical care when symptoms of DILI occur.
Abstract 1896: Soluble lung-derived selectins promote breast cancer cell migration
Authors: Sami U. Khan, Jenny E. Chu, Ying Xia, Alison L. Allan
Journal: Cancer Research (2017)

Abstract Ninety percent of all breast cancer-related deaths are attributed to metastasis, as current therapies are largely non-curative in the metastatic setting. One of the most common sites of breast cancer metastasis is the lung. Previous work from our lab has demonstrated that there are over 70 soluble factors produced by murine lung tissue, many of which have been associated with cancer cell growth, migration, invasion and metastasis. However, the relative contribution of each individual factor in enhancing the metastatic behavior of breast cancer cells has not been examined in detail. Three of the identified soluble lung-derived proteins are E-, L- and P-selectin, and these were the focus of the current study. The selectins are a family of glycoproteins with known physiological roles in vascular/immune cell migration, and soluble selectins have been clinically observed to be elevated in the sera of cancer patients. We hypothesized that soluble lung-derived selectins enhance the metastatic behavior of breast cancer cells. We used a 2D ex vivo model of the soluble lung microenvironment, generated by isolating conditioned media from dissociated healthy murine lung. E-, L- and P-selectin were then individually immunodepleted from the lung-conditioned media (lung-CM) and the subsequent functional effect on breast cancer cell migration and proliferation was assessed using transwell migration and BrdU incorporation assays, respectively. MDA-MB-231 and SUM149PT human breast cancer cells demonstrated significantly enhanced cell migration toward lung-CM relative to basal media, and this migration was significantly reduced when E-, L- or P-selectin were depleted (p&amp;lt;0.05). In contrast, although MDA-MB-231 and SUM149PT human breast cancer cells demonstrated significantly enhanced cell proliferation in response to lung-CM relative to basal media (p&amp;lt;0.05), depletion of soluble E-, L- or P-selectin from lung-CM had no influence on reducing proliferation (p&amp;gt;0.05). Ongoing studies are aimed at elucidating the pathways through which soluble lung-derived selectins exert their pro-migratory function. If these results implicate a common receptor and downstream signalling pathways for all three selectins, these ligand-receptor interactions may have value as potential therapeutic targets for the prevention of pulmonary metastasis in breast cancer patients. Citation Format: Sami U. Khan, Jenny E. Chu, Ying Xia, Alison L. Allan. Soluble lung-derived selectins promote breast cancer cell migration [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 1896. doi:10.1158/1538-7445.AM2017-1896
Abstract 1273: Pathway analysis of insulin-like growth factor candidate genes and risk of pediatric rhabdomyosarcoma
Authors: Libby Morimoto, XIaorong Shao, Anand Chokkalingam, Joseph Wiemels, Xiaomei Ma, Catherine Metayer
Journal: Cancer Research (2017)

Abstract Pediatric rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children under 15 years of age. Due largely to its rarity, the etiology of pediatric RMS is poorly understood. Patterns of fetal growth were previously shown to be independent risk factors for RMS among non-Hispanic white (NHW) children; however, the underlying biologic mechanisms remain unclear. Alterations in the insulin-like growth factor (IGF) system, the primary regulator of growth during the fetal and early life period, may provide clues. Using an innovative linkage between the California birth records and cancer registry information, we conducted a population-based case-control study (1982-2009) of candidate genes involved in IGF signaling and risk of pediatric RMS. Fifteen genes involved in the IGF pathway were selected: IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, INS, INSR, IRS1, GH1, and GHRH. DNA extracted from the archived newborn blood spots of all available RMS cases (n=644) was genotyped on the Illumina OmniExpress Exome array (n=964,043 SNPs); after stringent quality control (QC), a total of 633 RMS cases (360 embryonal RMS [eRMS] and 197 alveolar RMS [aRMS]) were available for analysis. A total of 815 controls genotyped on the Illumina OmniExpress Exome array and 3,922 controls genotyped on the Affymetrix Axion LAT array (n=801,830 SNPs) from the same base population of California children, with no evidence of RMS, were included in this analysis. After imputation to increase coverage of the genome and post-imputation QC to identify and remove platform effects, a total of 5,556,335 SNPs were available for analysis. Among NHW children, SNPs in IGF1 (rs10860869, p=0.0031) and IGF1R (rs62023616, p=0.00074; rs62023648, p=0.00076) were significantly associated with RMS risk after adjustment for multiple comparisons. Analyses stratified by histologic subtype showed that these associations were limited to eRMS, and of stronger magnitude. Among Hispanic children, 12 SNPs in IGF1R (p-value range: 0.0007-0.0027) and 3 SNPs in IGFBP1 (p-values: 0.0016-0.0023) were significantly associated with eRMS risk. The SNPs found to be associated with RMS were located in intergenic and intronic areas of the genes, areas that may influence gene regulation. Our results support the hypothesis that genetic variation in IGF1 signaling pathway modulate the risk of RMS, especially eRMS, among NHW and Hispanic children. Citation Format: Libby Morimoto, XIaorong Shao, Anand Chokkalingam, Joseph Wiemels, Xiaomei Ma, Catherine Metayer. Pathway analysis of insulin-like growth factor candidate genes and risk of pediatric rhabdomyosarcoma [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 1273. doi:10.1158/1538-7445.AM2017-1273
Abstract 2621: Microsatellite instability is a potential biomarker for immune checkpoint inhibitor in endometrial cancer
Authors: Hitomi Yamashita, Kentaro Nakayama, Noriyoshi Ishikawa, Toshiko Minamoto, Tomoka Ishibashi, Kohei Nakamura, Kaori Sanuki, Ruriko Ono, Masako Ishikawa, Takeshi Isobe, Satoru Kyo
Journal: Cancer Research (2017)

Abstract [Introduction] In recent years, tumor cells have immune escape mechanism and immune checkpoint inhibitor therapy (anti PD-1/ PD-L1 antibody) has shown benefit in various cancers. Somatic mutations have the potential to encode ‘’non-self’’immunogenic antigens and lymphocytes infiltrate tumor cells in Microsatellite-instable (MSI) endometrial cancers. Therefore, immune checkpoint inhibitor therapy might be effective in MSI endometrial cancers. [Method] Mismatch repair protein (MLH1, PMS2, MSH2, and MSH6), tumor-infiltrating lymphocytes (CD8), and PD-1/PD-L1 expression were assessed by immunohistochemistry in 60 patients with endometrial cancer. We examined whether MSI status have enhanced immune microenvironment and become the therapeutic effect predictor of PD-1/PD-L1 immunotherapy in endometrial cancer. [Results] Loss of mismatch repair protein (MSI group) was identified in 8 (13.3 %) of 60 patients with endometrial cancer. Expression of tumor-infiltrating lymphocytes (CD8) and PD-L1/PD-1 were significantly higher in MSI group compared to MSS group (p=0.001, p=0.044 and p=0.013). [Conclusion]These results suggested that immune checkpoint inhibitor (anti PD-1/PD-L1 antibody) is effective in endometrial cancers with MSI. MSI testing is likely to be a biomarker for PD-1/PD-L1 immunotherapy in endometrial cancer. Citation Format: Hitomi Yamashita, Kentaro Nakayama, Noriyoshi Ishikawa, Toshiko Minamoto, Tomoka Ishibashi, Kohei Nakamura, Kaori Sanuki, Ruriko Ono, Masako Ishikawa, Takeshi Isobe, Satoru Kyo. Microsatellite instability is a potential biomarker for immune checkpoint inhibitor in endometrial 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 2621. doi:10.1158/1538-7445.AM2017-2621
Abstract 2332: Integral modulation of nuclear factor-kappa B activation by C/EBPβ and the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in estrogen-deprived breast cancer cells
Authors: Ping Fan, Amit K. Tyagi, Fadeke A. Agboke, Niranjana Pokharel, V. Craig Jordan
Journal: Cancer Research (2017)

Abstract Stress responses are critical for estrogen (E2) to induce apoptosis in E2-deprived breast cancer cells. Nuclear factor-kappa B (NF-κB) is well known as a therapeutic target to prevent stress responses in chronic inflammatory diseases including cancer. However, whether E2 activates NF-κB to participate in stress-associated apoptosis in E2-deprived breast cancer cells is unclear. We demonstrated that E2 differentially modulates NF-κB activity in E2-deprived breast cancer cells according to the treatment time. Because E2 initially has significant potential to down modulate the NF-κB activation, it completely suppresses the tumor necrosis factor alpha (TNFα)-induced NF-κB activation. We found that E2 preferentially and constantly enhances the expression of transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) which is responsible for suppression of NF-κB activation by E2 in MCF-7:5C cells. The mTOR signaling pathway promotes repression of NF-κB by C/EBPβ which is confirmed by the evidence that inhibition of mTOR is synergistic with E2 to upregulate NF-κB-dependent genes, such as TNFα. Interestingly, NF-κB p65 activity is upregulated when E2-treatment is administered for 48 hours, leading to induction of TNFα. Blocking the nuclear translocation of NF-κB completely prevents E2 from induction of TNFα and apoptosis. Importantly, protein kinase RNA-like endoplasmic reticulum kinase (PERK), a stress sensor of unfolded protein response, is activated by E2 and plays an essential role in increasing NF-κB p65 DNA binding through the activation of STAT3, independently of canonical IκBα signal pathway. Thus, inhibition of PERK kinase activity completely blocks nuclear activation of NF-κB and NF-κB-dependent induction of TNFα, thereby preventing E2-induced apoptosis. All of these findings illustrate a crucial role for the novel PERK/NF-κB/TNFα axis in E2-induced apoptosis which is integrally modulated by the stress responsive transcription factor C/EBPβ and endoplasmic reticulum stress. This study provides an important rationale for exercising caution in clinical trials when considering targeting PERK or NF-κB following the development of acquired resistance to aromatase inhibitors whereas mTOR may be a target to enhance the therapeutic effects of E2 in antihormone resistant breast cancer. Citation Format: Ping Fan, Amit K. Tyagi, Fadeke A. Agboke, Niranjana Pokharel, V. Craig Jordan. Integral modulation of nuclear factor-kappa B activation by C/EBPβ and the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in estrogen-deprived 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 2332. doi:10.1158/1538-7445.AM2017-2332