tbuckley/cabot-search huggingface dataset:
Abstract 2810: Using CRISPR/Cas9 to generate primary soft tissue sarcoma in genetically engineered and wild-type mice
Authors: Jianguo Huang, Mark Chen, Melodi J. Whitley, Hsuan-Cheng Kuo, Andrea Walens, Yvonne M. Mowery, David V. Mater, William Eward, Diana M. Cardona, Lixia Luo, Yan Ma, Christopher E. Nelson, Jacqueline N. Robinson-Hamm, Charles A. Gersbach, Rebecca D. Dodd, David G. Kirsch
Journal: Cancer Research (2017)

Abstract Genetically engineered mouse models (GEMMs) that employ site-specific recombinase (SSR) technology are important tools for pre-clinical studies, but this approach is costly and time-consuming. Here, we show that the CRISPR/Cas9 system can be used to efficiently complement existing GEMMs of sarcoma and generate primary sarcomas in wild type mice. Mice with the genotype KrasLSL-G12D/+; Rosa26LSL-Cas9-EGFP/+ received intramuscular delivery of an adenovirus expressing Cre recombinase and a single guide RNA (sgRNA) targeting Trp53. Cre-mediated expression of oncogenic Kras and Cas9, in combination with CRISPR/Cas9-mediated knockout of Trp53, was sufficient to generate primary soft tissue sarcomas. These tumors arose with kinetics similar to those generated using the Cre-loxP system to activate oncogenic Kras and delete Trp53 alleles. Additionally, we injected an adenovirus containing Cas9 and sgRNAs targeting Nf1 and Trp53 into the sciatic nerve of wild type mice. These mice formed malignant peripheral nerve sheath tumors (MPNSTs) in the same timeframe as MPNSTs generated using the Cre-loxP system to delete Nf1 and Ink4a/Arf alleles in GEMMs. These data demonstrate that CRISPR/Cas9 can be used to generate soft tissue sarcomas in wild type mice. Moreover, these results suggest that this technology can complement existing GEMMs for rapid assessment of tumor-modifying genes. These tools should decrease the time and expense associated with employing autochthonous mouse models of sarcoma for preclinical research. Citation Format: Jianguo Huang, Mark Chen, Melodi J. Whitley, Hsuan-Cheng Kuo, Andrea Walens, Yvonne M. Mowery, David V. Mater, William Eward, Diana M. Cardona, Lixia Luo, Yan Ma, Christopher E. Nelson, Jacqueline N. Robinson-Hamm, Charles A. Gersbach, Rebecca D. Dodd, David G. Kirsch. Using CRISPR/Cas9 to generate primary soft tissue sarcoma in genetically engineered and wild-type mice [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 2810. doi:10.1158/1538-7445.AM2017-2810
Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial
Authors: Nicola Logallo, Vojtech Novotny, Jörg Assmus, Christopher E Kvistad, Lars Alteheld, Ole Morten Rønning, Bente Thommessen, Karl-Friedrich Amthor, Hege Ihle-Hansen, Martin Kurz, Håkon Tobro, Kamaljit Kaur, Magdalena Stankiewicz, Maria Carlsson, Åse Morsund, Titto Idicula, Anne Hege Aamodt, Christian Lund, Halvor Næss, Ulrike Waje-Andreassen, Lars Thomassen
Journal: The Lancet Neurology (2017)
Abstract 4735: Expression of Notch1 and Numb in small cell lung cancer
Authors: Hajime Kikuchi, Jun Sakakibara-Konishi, Megumi Furuta, Hiroshi Yokouchi, Hiroshi Nishihara, Shigeo Yamazaki, Uramoto Hidetaka, Fumihiro Tanala, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Toshiyuki Harada, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Satoshi Oizumi, Hiroyuki Suzuki, Takashi Ishida, Hiotoshi Dosaka-Akita, Hiroshi Isobe, Mitsuru Munakata, Masaharu Nishimura
Journal: Cancer Research (2017)

Abstract Background: Notch signaling plays an important role in tumorigenesis. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC. Methods: We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated. Results: Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC (hazard ratio = 0.503, P = 0.023). Conclusions: We demonstrate that Notch1 expression, but not Numb, is associated with prognosis in SCLC and may provide a novel prognostic marker of SCLC. Citation Format: Hajime Kikuchi, Jun Sakakibara-Konishi, Megumi Furuta, Hiroshi Yokouchi, Hiroshi Nishihara, Shigeo Yamazaki, Uramoto Hidetaka, Fumihiro Tanala, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Toshiyuki Harada, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Satoshi Oizumi, Hiroyuki Suzuki, Takashi Ishida, Hiotoshi Dosaka-Akita, Hiroshi Isobe, Mitsuru Munakata, Masaharu Nishimura. Expression of Notch1 and Numb in small cell lung 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 4735. doi:10.1158/1538-7445.AM2017-4735
Abstract 2047: The muscarinic receptor antagonist, benztropine, blocks the expansion of a temozolomide resistant subpopulation of glioma cells
Authors: Damian A. Almiron Bonnin, Joseph M. Howard, Alison L. Young, Mark A. Israel, Matthew C. Havrda
Journal: Cancer Research (2017)

Abstract Virtually all malignant gliomas become drug-resistant and recur after initial treatment, recurrent tumors are fatal within two-years, and no therapies exist that cure gliomas. The recognition that subpopulations of primitive cells with an oligodendrocyte precursor-like (OPC-like) phenotype capable of resisting standard therapy and contributing to recurrence, frames the question of whether adjuvant therapies designed to modify or eliminate OPC-like cells could slow the progression of glioma. Agents that force the differentiation of treatment-resistant OPC-like glioma cells, a phenomenon that requires cessation of proliferation, are compelling candidates for targeting OPC-like GSCs. Recently, it was observed that OPC proliferation was driven by activation of the M1, M3 and M4 muscarinic receptors. In another report, a large-scale drug screen designed to seek drugs to induce OPC differentiation in the context of multiple sclerosis identified a muscarinic receptor antagonist, benztropine (a.k.a. Cogentin), as a promoter of OPC differentiation and cell cycle exit. We have conducted studies in glioma cell lines supporting a role for benztropine in suppressing the development of drug-resistance to the standard glioma chemo-therapeutic temozolomide (TMZ). Upon treatment with TMZ, we identified the emergence of an OPC-like subpopulation of glioma cells identifiable by the co-expression of CD44, CD15 and PDGFRa. Treatment with pre-inhibitory doses of benztropine significantly reduced the TMZ IC50 in all glioma lines examined in association with blocking emergence of the CD44/CD15/PDGFR-positive subpopulation. Ongoing studies are designed to determine the tumor initiating potential of the CD44/CD15/PDGFR-positive subpopulation and whether benztropine will suppress the development of TMZ resistance in animal models of glioma. Citation Format: Damian A. Almiron Bonnin, Joseph M. Howard, Alison L. Young, Mark A. Israel, Matthew C. Havrda. The muscarinic receptor antagonist, benztropine, blocks the expansion of a temozolomide resistant subpopulation of glioma 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 2047. doi:10.1158/1538-7445.AM2017-2047
Abstract 2759: Technical limitations of capture-based, targeted deep sequencing for the detection of somatic variations in cell-free DNA
Authors: Gahee Park
Journal: Cancer Research (2017)

Abstract Despite widespread applications of capture-based targeted deep sequencing, its limitations on detecting circulating tumor DNA (ctDNA) have not been systematically elucidated. Here, we analyze and characterize parameters critically determining its detection limits; depth of coverage and background errors. The depth increase by using more cell-free DNA (cfDNA) was saturated at around ~3000x with ~50 ng of cfDNA primarily due to a deduplication artifact, which limited the detection sensitivity of the method. Next, characterizing background errors, we uncovered that a majority of errors were not derived from biological origins but technical artifacts, especially during sample preparation and library construction rather than sequencing. Thus, it is important to use an appropriate protocol for those steps minimizing background errors. Considering the depth of coverage and the background error rate, we estimated the detection limit of the method approximately to be 0.4% variant allele frequency at 95% confidence level. Applying the method to pancreatic cancer patients, we found that the levels of ctDNAs measured by cfDNA sequencing well correlated with clinical responses to therapy and/or disease progression, but biopsy-free profiling of somatic variants was limited by the moderate sensitivity of 72% and PPV of 74% at the variant level. Our results clarify technical limitations of targeted deep sequencing and provide a guideline for applying the technique to analyze cfDNA. Citation Format: Gahee Park. Technical limitations of capture-based, targeted deep sequencing for the detection of somatic variations in cell-free DNA [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 2759. doi:10.1158/1538-7445.AM2017-2759
Abstract 2246: Anti-proliferative activities of lipid fraction of extract from the skin of the catfish <i>Arius Bilineatus, Valenciennes</i>
Authors: Peiying Yang, Jibin Ding, Yong Pan, Yan Jiang, Mohammad Afzal, Bincy M. Paul, Sosamma O. George, Jassim M. Al-Hassan
Journal: Cancer Research (2017)

Abstract The catfish (Arius bilineatus, Val.) secretes a gelatinous substance composed of biochemically active lipids and proteins from its skin upon stress or injury. Preparations from the skin have previously been shown to affect blood clotting and accelerates healing of non-healing diabetic foot ulcers in man. We have reported previously fish skin preparation (CSP) derived from the skin of the Catfish and it’s lipid fraction exerted anti-inflammatory activity in the in vitro cells and in vivo animal models. Here anti-proliferative effect of a lipid fraction of fish skin preparation (CSP-L) derived from the skin of the catfish and its plausible mechanism were investigated in human hepatocellular carcinoma (HCC) Hep3B and human pancreatic cancer Panc-1 cells. Cells were treated with CSP-L (0 to 100 μg/ml) for 72 hrs and cell proliferation was measured by the MTT assay. The results showed much stronger inhibition by CSP-L in Panc-1 cells than that of Hep3B cells with IC50 of 5.5 ± 1.4 μg/ml and 19.5 ± 7.7 μg/ml, respectively. Cell cycle analysis with PI staining suggested that CSP-L (25 - 100 μg/ml) led to G1 phase arrest in Hep3B cells whereas S phase arrest was observed in Panc-1 cells, suggesting the differential molecular mechanisms responsible for CSP-L induced cell growth suppression in Hep3B and Panc-1 cells. The alteration of cell cycle was concentration dependent. Additionally, CSP-L concentration dependently suppressed the invasion of Hep3B and Panc-1 cells. The molecular mechanism associated with CSP-L’s anti-proliferative effect was examined by Western blotting in both Hep3B and Panc-1 cells. Intriguingly, CSP-L (50 and 100 μg/ml) notably decreased protein levels of cyclin D, Stat3, pRB and pERk in Hep3 B cells in a concentration dependent manner. In contrast, only pRB and pERK protein expression were reduced in CSP-L treated Panc-1 cells. These again suggest that CSP-L inhibited the proliferation of Hep3B and Panc-1 cells by different molecular mechanisms. Collectively, our preliminary data suggest that CSP-L has a great potential to be developed as an anticancer or preventive agent for both HCC or pancreatic cancer and warrants further investigation. This study was support by a grant from Kuwait Foundation for the Advancement of Science No. KFAS 2013-120701A-D, and Kuwait University Research Grant No. SL03/14. Citation Format: Peiying Yang, Jibin Ding, Yong Pan, Yan Jiang, Mohammad Afzal, Bincy M. Paul, Sosamma O. George, Jassim M. Al-Hassan. Anti-proliferative activities of lipid fraction of extract from the skin of the catfish Arius Bilineatus, Valenciennes [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 2246. doi:10.1158/1538-7445.AM2017-2246
Abstract 5753: Inhibition of CCAR1, a coactivator of β-catenin, suppresses the proliferation and migration of gastric cancer cells
Authors: Te-Sheng Chang, Chung-Kuang Lu, Kuo-Liang Wei, Yi-Hsing Chen, Ying-Tung Cheng, Shui-Yi Tung, Cheng-Shyong Wu, Ming-Ko Chiang
Journal: Cancer Research (2017)

Abstract Given a current hypothesis that cancer arises from cancer stem cells (CSCs), targeting key signaling pathways that support CSC self-renewal appears to be a useful approach to cancer therapy. Derranged expression of Wnt signaling is among the major pathways implicated in regulating the stenmess properties of a variety of human cancers, including gastric cancer. Cell cycle and apoptosis regulator 1 (CCAR1) is a transcriptional coactivator which has been shown to be a component of Wnt/β-catenin signaling, and plays an important role in transcriptional regulation by β-catenin. However, the function and clinical significance of CCAR1 in gastric cancer have not been elucidated. Here we show the elevated CCAR1 nuclear expression correlates with the occurrence of gastric cancer. In addition, RNAi-mediated CCAR1 reduction not only suppressed the cell growth and increased apoptosis in gastric cell lines AGS and MKN28, but also reduced the migration and invasion ability of these cells. Furthermore, In vivo xenograft assay revealed that the expression level of CCAR1 was critical for tumorigenesis. Our data demonstrates that CCAR1 contributes to carcinogenesis in gastric cancer and is required for the survival of gastric cancer cells. Moreover, CCAR1 may serve as a diagnostic marker and a potential therapeutic target. Citation Format: Te-Sheng Chang, Chung-Kuang Lu, Kuo-Liang Wei, Yi-Hsing Chen, Ying-Tung Cheng, Shui-Yi Tung, Cheng-Shyong Wu, Ming-Ko Chiang. Inhibition of CCAR1, a coactivator of β-catenin, suppresses the proliferation and migration of gastric 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 5753. doi:10.1158/1538-7445.AM2017-5753
Abstract 3253: Targeting G-quadruplex nucleic acids: a series of <i>β</i>-carboline alkaloids with new skeletons from the seeds of <i>Peganum harmala</i>
Authors: Kaibo wang, Huiming Hua, Danzhou Yang
Journal: Cancer Research (2017)

Abstract G-quadruplexes are DNA secondary structures implicated in essential physiological and pathological processes, such as tumorgenesis. Small molecules which can stabilize or induce G-quadruplex formation have potential as antitumor agents through the alteration of oncogene expression levels or the disruption of telomere maintenance. Targeting G-quadruplex nucleic acids, we screened 17 medicinal plants for binding activity to a model G-quadruplex d(TTGGGTT)4 system by 1H NMR experiment. We found that the crude extract of Peganum harmala L. seeds showed the most potential binding activity and specific cytotoxicity against the PC-3 cancer cell line with an IC50 value of 13.65 μg/mL. Subsequently, 1H NMR and bioassay co-guided isolation of the extract of P. harmala L. was performed and obtained 21 new alkaloids, including 10 novel β-carboline alkaloids with unprecedented carbon skeletons, and 12 known analogues. Their structures including the absolute configurations were determined by extensive analysis of spectroscopic data, X-ray crystallography, ECD calculations, and ECD exciton chirality approaches. The antiproliferative activities and G-quadruplex binding activities were evaluated for these newly discovered and previously reported alkaloids. Some of the isolates showed pronounced cytotoxic effects with IC50 values below 10 µM and significant G-quadruplex binding activities. More interestingly, pegaharmine D (4), which showed the strongest G-quadruplex interaction, exhibited significant cytotoxic activity against HL-60, PC-3 and SGC-7901 cell lines, with IC50 values of 3.81 ± 0.32, 11.52 ± 0.62, and 15.16 ± 0.42 µM, respectively. The G-quadruplex interactions positively correlated with antiproliferative activities suggesting these β-carboline alkaloids may exert their anti-cancer effects through G-quadruplex interactions. This work contributed a practical strategy at first time for the discovery of novel G-quadruplex ligands from natural products and provided potential insights for using β-carboline alkaloids as anticancer lead compounds specifically targeting G-quadruplexes. Citation Format: Kaibo wang, Huiming Hua, Danzhou Yang. Targeting G-quadruplex nucleic acids: a series of β-carboline alkaloids with new skeletons from the seeds of Peganum harmala [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 3253. doi:10.1158/1538-7445.AM2017-3253
Abstract 265: Global transition in cardia and non-cardia gastric cancer incidence, 1998-2007
Authors: Aesun Shin, Dalis Seungeun Kim, Hyungtaek Woo
Journal: Cancer Research (2017)

Abstract Gastric cardia and non-cardia cancer differs in their descriptive patterns and risk factors. The objective of this study was to determine the global trends in incidence of cardiac and non-cardiac gastric cancer. Ninety two high quality registries with the proportion of Not Otherwise Specified (NOS) gastric cancer (ICD-10 code C16.8-9) below 50% and the total number of gastric cancer cases above 300 were selected from 225 registries in Cancer Incidence of Five Continent (CI5) volume 9 and 262 registries from CI5 volume 10. The NOS cases were re-distributed to cardia and non-cardia according to the registry-specific proportion. Age-standardized incidence rates (ASRs) per 100,000 population and incidence rate ratios (IRR) from 1998-2002 to 2003-2007 were calculated. Non-cardia cancer incidence was significantly decreased in 5 out of 10 Asian registries, 17 out of 18 European registries, 27 out of 56 North American registries, and all 5 Oceanian registries in men. Only two registries in Asia showed a significant increase in non-cardia cancer incidence. In contrast, cardia cancer significantly increased in one Asian registry, two European registries, and two North American registries. Significant decrease in cardia cancer was observed in 3 Asian registries, 6 European registries, 11 North American registries, and 3 Oceanian registries in men. In women, six registries (1 Asian, 2 European, and 3 North American) showed significant increase in non-cardia cancer, whereas registries 25 (3 Asian, 13 European, 8 North American, and 1 Oceanian) showed significant decrease in non-cardia cancer incidence. Cardia cancer in women increased in 16 registries (2 Asian and 14 North American) and decreased in 9 registries (1 Asian, 5 European, and 3 North American). In conclusion, non-cardia cancer incidence decreased in most registries, whereas decrease in cardia cancer is more prominent in men but not in women. Citation Format: Aesun Shin, Dalis Seungeun Kim, Hyungtaek Woo. Global transition in cardia and non-cardia gastric cancer incidence, 1998-2007 [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 265. doi:10.1158/1538-7445.AM2017-265
Abstract 4306: Combined effects of chemotherapy to reduce metastasis caused by insufficient hyperthermia
Authors: Tae Hee Lee, Jiyoon Bu, Byoung Hyuck Kim, Young Jun Kim, Yoon-Tae Kang, Jung Eun Moon, Young-Ho Cho
Journal: Cancer Research (2017)

Abstract Hyperthermia therapy is one of the most widely studied non-surgical methods for breast tumors, which eliminates tumor by inducing acute stress on tumor cells. However, it has been extensively known that the viability of the tumor cells is highly influenced by the applied temperature. Insufficient thermal stress during hyperthermia treatments may alter tumor microenvironment by promoting epithelial to mesenchymal-like transition (EMT) and as a result, enhancing the outgrowth of residual tumor cells. Therefore, cells that have survived from sublethal thermal stress and experienced EMT may cause substantial clinical problems. In this case, hyperthermia requires additional therapy in order to promote cell death of more invasive tumor cells that have resisted to the thermal stimulus. In this study, we confirmed that the co-treatment of chemotherapy with hyperthermia may overcome the phenotypical transition caused by insufficient heat treatment. After exposing breast cancer cells (MCF-7) into two different temperature conditions (42°C and 47°C) for an hour, we have verified that 10.51 ± 1.71% and 18.27 ± 10.66% of cells experienced apoptosis or necrosis when the cells were exposed to 42°C and 47°C, respectively. At the same time, cancer cells showed higher invasiveness, spear-like morphology, and enhanced migratory behaviors as the exposed temperature increases, which is mainly shown among the cells that have experienced EMT. Further western blot assay and quantitative real-time polymerase chain reaction (qRT-PCR) using mesenchymal marker (vimentin) and epithelial marker (E-cadherin) also support that the mesenchymal-like phenotype has been highly increased on the cells that have resisted to the thermal stress. However, when chemotherapy was conducted after the heat treatment, cell viability was highly reduced. Paclitaxel (11.7 nM), cisplatin (3.3 μM), and combination of two anticancer drugs were treated for 24 hours on the cells that have been exposed to different temperatures, respectively. As a result, death rate of tumor cells has increased from 11.31 to 66.69%. Especially, when paclitaxel and cisplatin were co-treated, the death rate was up to 73.75 ± 4.37% after cells were exposed to 47°C. In conclusion, cancer cells that have survived from insufficient hyperthermia showed high potential to promote metastasis or recurrence but additional chemotherapy can successfully reduce the side effects induced by insufficient hyperthermia treatment. Citation Format: Tae Hee Lee, Jiyoon Bu, Byoung Hyuck Kim, Young Jun Kim, Yoon-Tae Kang, Jung Eun Moon, Young-Ho Cho. Combined effects of chemotherapy to reduce metastasis caused by insufficient hyperthermia [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 4306. doi:10.1158/1538-7445.AM2017-4306