tbuckley/cabot-search huggingface dataset:
Abstract 653: Identification of metastasis promoting genes using the PiggyBac insertional mutagenesis system
Authors: Qiu N. Tinghu, Laura Vera Ramirez, Roland Rad, Jeffrey E. Green
Journal: Cancer Research (2016)

Abstract The Myc oncogene is overexpressed in approximately 30% of human breast cancers. Mice carrying the mammary tumor virus LTR/c-myc (MMTV-c-Myc) develop mammary tumors, but display a relatively low rate of metastases to the lung. However, not all cells that express the transgene develop neoplasms indicating that Myc-induced tumorigenesis requires additional cooperating events for full transformation. To identify genes that cooperate with Myc-induced tumorigenesis leading to the acceleration of tumor progression or an increase in metastases in MMTV-Myc transgenic mice, we have employed the PiggyBac (PB) transposon system. The PiggyBac system used in our studies was (developed by Rad et al, Science, 2010) is composed of two elements, the ATP-1 PiggyBac transposon and transposase. ATP-1 transposons are mobile DNA elements that can randomly integrate throughout the genome in the presence of transposase resulting in the activation or loss of gene function. The insertion sites can be identified through sequencing. It has been used successfully for genomic modification of cells in vivo leading to cancer gene discovery. In order to better adapt the PB system for studing mammary gland biology, we have designed a system to express a hyperactive transposase and luciferase specifically in the mammary gland using the MMTV LTR (MMTV-hyTPase-luc). The efficiency of MMTV-hyTPase-luc expression was first examined in vitro by transfection with an ATP-1 containing plasmid using the HC11 mouse mammary epithelial cell line. Selection for integration of ATP1 in the cells using puromycin selection and crystal violet staining, RT-QPCR and luciferase assays confirmed that MMTV-hyTPase-luc led to efficient integration of ATP-1 into the HC11 cells. HC11 cell proliferation further increased in the presence of dexamethasone, a hormone that stimulates MMTV promotor function. The MMTV-HyPB-Luc construct was subsequently used to generate transgenic mice and multiple founder lines are being analyzed for mammary specific transposase expression. The best expressing line will be crossed with MMTV-cMyc mice and mice carrying multiple copies of the ATP1 transposon. Transposon integration sites will be determined from tumors or metastases in mice with accelerated tumor development and/or increased metastases compared to controls. Further molecular characterization and validation of candidate genes will identify novel genes that cooperate with Myc to augment tumorigenesis and metastases. Citation Format: Qiu N. Tinghu, Laura Vera Ramirez, Roland Rad, Jeffrey E. Green. Identification of metastasis promoting genes using the PiggyBac insertional mutagenesis system. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 653.
Prognostic Role Of Monoclonal and Polyclonal Gammopathy Measured By Serum Free Light Chain and Immunofixation In Diffuse Large B-Cell Lymphoma
Authors: Yu Ri Kim, Soo Jeong Kim, Yundeok Kim, Doh Yu Hwang, Ji Eun Jang, Shin Young Hyun, June-Won Cheong, Yoo Hong Min, Jin Seok Kim
Journal: Blood (2013)
Abstract B37: The real deal: Using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells.
Authors: Matthew Trendowski
Journal: Clinical Cancer Research (2015)

Abstract Background/Aim: Sonodynamic therapy (SDT) is a form of ultrasound therapy in which chemotherapeutic agents known as sonosensitizers are administered to increase the efficacy of ultrasound's preferential damage to neoplastic cells. Perhaps one of the most intriguing capabilities of ultrasound is its ability to preferentially lyse cells based on size. Cytochalasin B is a cytokinesis inhibitor that preferentially enlarges and multinucleates malignant cells, making them much more sensitive to ultrasonic irradiation. Materials and Methods: The present study investigated the extent of preferential damage inflicted by cytochalasin B on U937 leukemia/human blood cell populations. Cell mixtures were treated with cytochalasin B and then sonicated under a relatively low intensity (3W/cm2). Results: Cytochalasin B preferentially damages U937 cells both before and after sonication. This agent also reduces rapid proliferation as the clonogenicity of U937 cells was considerably reduced following treatment. Conclusion: Cytochalasin B may have profound therapeutic applications when combined with SDT. Citation Format: Matthew Trendowski. The real deal: Using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B37.
Abstract 4763: Targeted therapy by MET inhibitors against small-cell lung cancer with aberrant activation of HGF/MET pathway
Authors: Hirokazu Taniguchi, Shinji Takeuchi, Koji Fukuda, Tadaaki Yamada, Shuichi Sakamoto, Manabu Kawada, Seiji Yano
Journal: Cancer Research (2016)

Abstract Small-cell lung cancer (SCLC) is one of the most aggressive malignancy, characterized by rapid growth and metastatic spread to multiple organs. Approximately 70% of SCLC patients have distant metastases at the diagnosis. Recent studies reported some genomic aberrations in SCLC and several molecular target drugs have been evaluated in clinical trials. However, no molecular target agents have been approved yet for SCLC. Hepatocyte growth factor (HGF), also known as scatter factor, is only one ligand for MET receptor. HGF/MET pathway plays the crucial role in the growth of various types of cancers. The purpose of this study is to examine the role of HGF/MET pathway activation in SCLC and to evaluate therapeutic potential of MET inhibitors, including crizotinib and golvatinib, against metastasized SCLC. We used eight human SCLC cell lines. Expression of HGF and MET was evaluated by ELISA and western blot, respectively. Cell viability was examined by MTT assay. Four cell lines produced discernible levels of HGF and four cell lines expressed phosphorylated MET, respectively. MET inhibitors, crizotinib and golvatinib, remarkably inhibited the viability of three cell lines, SBC-5, DMS273 and DMS273B1. Knockdown of either MET or HGF by specific siRNA suppressed the growth of these cell lines, indicating that HGF/MET pathway activation is essential for survival of these SCLC cell lines. These observations suggest that MET-TKIs may be useful for a subset of SCLC with aberrant HGF/MET pathway activation. We recently established in vivo imaging model of multiple organ metastasis (including liver and bone metastases) with SBC-5 cells. We are now evaluating the anti-metastatic effect of MET-TKIs, crizotinib and golvatinib, in the in vivo imaging model. At the annual meeting, we will present the results of MET-TKI treatment and discuss their potential against multiple-organ metastasis produced by SCLC with aberrant HGF/MET pathway activation. Citation Format: Hirokazu Taniguchi, Shinji Takeuchi, Koji Fukuda, Tadaaki Yamada, Shuichi Sakamoto, Manabu Kawada, Seiji Yano. Targeted therapy by MET inhibitors against small-cell lung cancer with aberrant activation of HGF/MET pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4763.
Abstract 2470: Isolation and characterization of cancer stem cells from the human medulloblastoma cell line DAOY: adherent vs. suspension in vitro cell cultures
Authors: Javier de la Rosa, Ander Sáenz Antoñanzas, Xing Fan, Bárbara Meléndez, Juan A. Rey, Javier S. Castresana
Journal: Cancer Research (2016)

Abstract Brain tumor stem cells (BTSC) in vitro cultures have been made possible by the formation of neurospheres in suspension conditions with the use of serum free medium supplemented with specific growth factors, as B27, EGF, or b-FGF. In this work, we tested a more recent alternative method for the culture of BTSC, using laminin pre-coated flasks and the same medium used for the neurosphere growth, which leads to BTSC expansion attached to a layer. BTSC cultures in adherence conditions by the use of laminin can afford a more homogeneous exposition to growth factors than sphere cultures do, which promotes a higher enrichment in stem-like cells. Also, it is known that the laminin interactions with integrines or other components of the cell matrix can lead to inhibition signals of cell differentiation. Moreover, the monolayer conditions can support a higher number of cells in the flask. The medulloblastoma cell line DAOY was cultured in different conditions of normoxia and hypoxia, and several cell populations were obtained for in vitro and molecular experiments. An increase in the stem features was shown when cells were successively cultured in hypoxia conditions. By contrast, a reduction in these properties was appreciated when cells were exposed to differentiation. In addition, the CD133+ and CD133- subpopulations were isolated from cells grown in laminin pre-coated flasks, and in vitro experiments showed that the CD133+ fraction represented the stem population and it could have BTSC with a higher probability than the CD133- fraction. The colony formation assay presented similar results for the two cultured methods, but clonogenicity in soft agar was higher in the laminin culture cells. In the cell migration assay, medullospheres migrated similarly to the laminin cultured cells, since both cell populations lost their adherence capacity after being cultured with serum free medium. Gene expression of CD133, CD15 and EZH2 was compared as well, and significant differences were not detected between the two cell populations. We can conclude that the laminin culture method in adherent conditions and the medullosphere traditional culturing method in suspension are similarly good for obtaining BTSC in DAOY medulloblastoma cell line. Citation Format: Javier de la Rosa, Ander Sáenz Antoñanzas, Xing Fan, Bárbara Meléndez, Juan A. Rey, Javier S. Castresana. Isolation and characterization of cancer stem cells from the human medulloblastoma cell line DAOY: adherent vs. suspension in vitro cell cultures. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2470.
Low-dose interleukin-2 treatment selectively modulates CD4+ T cell subsets in patients with systemic lupus erythematosus
Authors: Jing He, Xia Zhang, Yunbo Wei, Xiaolin Sun, Yaping Chen, Jun Deng, Yuebo Jin, Yuzhou Gan, Xin Hu, Rulin Jia, Chuanhui Xu, Zhaohua Hou, Yew Ann Leong, Lei Zhu, Jinhong Feng, Yuan An, Yuan Jia, Chun Li, Xu Liu, Hua Ye, Limin Ren, Ru Li, Haihong Yao, Yuhui Li, Shi Chen, Xuewu Zhang, Yin Su, Jianping Guo, Nan Shen, Eric F Morand, Di Yu, Zhanguo Li
Journal: Nature Medicine (2016)
Abstract 2147: Overcoming mTOR resistance mutations with a new generation mTOR inhibitor
Authors: Vanessa S. Rodrik-Outmezguine, Masanori Okaniwa, Zhan Yao, Chris Novotny, Claire McWhirter, Arpitha Banaji, Helen Won, Wai Wong, Mike Berger, Elisa de Stanchina, Derek G. Barratt, Sabina Cosulich, Teresa Klinowska, Neal Rosen, Kevan M. Shokat
Journal: Cancer Research (2016)

Abstract First generation mTOR inhibitors (rapalogs) have modest activity in some tumors. We sought to delineate the likely resistance mechanisms to existing mTOR inhibitors as a guide for next generation therapies. We identified FRB domain and kinase domain mutations as causing acquired-resistance to rapamycin and mTOR kinase inhibitor respectively. Resistance to rapamycin was due to loss of binding of the FKBP12-rapamycin complex to the FRB domain of mTOR mutant protein. Resistance to the mTOR kinase inhibitor was not due to a gatekeeper mutation but rather to an increase in the intrinsic kinase activity of the mTOR kinase domain mutant. These and similar mutations have also been identified in tumors from untreated patients. These findings suggest that these mutations are gain of function mutants but also that tumors with these activating mutations will be intrinsically resistant to second generation mTOR kinase inhibitors. We have designed a new class of mTOR inhibitor, RapaLink-1, that takes advantage of the juxtaposition of two drug binding pockets to create a bivalent interaction. This compound potently inhibits mTOR activation in cells with mTOR wild-type and overcomes resistance to existing first and second generation inhibitors. Moreover, intermittent dosing of RapaLink-1 effectively suppresses mTOR-dependent tumor growth in vivo. Thus, such third generation mTOR inhibitors could be useful for treating tumors with activating mutations of mTOR and for tumors with acquired-resistance to current mTOR inhibitors.[N.R. and K.S. contributed equally to this work.] Citation Format: Vanessa S. Rodrik-Outmezguine, Masanori Okaniwa, Zhan Yao, Chris Novotny, Claire McWhirter, Arpitha Banaji, Helen Won, Wai Wong, Mike Berger, Elisa de Stanchina, Derek G. Barratt, Sabina Cosulich, Teresa Klinowska, Neal Rosen, Kevan M. Shokat. Overcoming mTOR resistance mutations with a new generation mTOR inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2147.
Abstract 4832: Overcoming breast cancer chemoresistance and blocking metastasis by targeting RNA-binding protein HuR
Authors: Xiaoqing Wu, Rebecca T. Marquez, Shuang Han, Ke Li, Lan Lan, Yuxiao Guo, Dan A. Dixon, Jeffrey Aubé, Danny R. Welch, Liang Xu
Journal: Cancer Research (2016)

Abstract Patients with metastatic breast cancer have a dismal 5-year survival rate of only 24%. Chemoresistance is another contributor to the high mortality of advanced breast cancer. The RNA-binding protein, Hu antigen R (HuR), is overexpressed at all stages of breast cancer development. Cytoplasmic HuR accumulation correlates with high-grade malignancy, poor distant disease-free survival and serves as a prognostic factor for poor clinical outcome in breast cancer. HuR promotes tumorigenesis by promoting mRNA stability and translation of proteins implicated in proliferation, survival, angiogenesis, invasion, and metastasis. HuR also modulates sensitivity of breast cancer cells to chemotherapy. Taken together, HuR is an emerging target for breast cancer therapy, especially metastatic breast cancer. Using shRNA and CRISPR technologies to modulate HuR expression in breast cancer cells, we found that cells with HuR KD/KO were less invasive and more sensitive to chemotherapy. In an effort to discover small molecules that disrupt the HuR-mRNA interaction and block HuR functions in breast cancer progression, metastasis and chemoresistance, high throughput screening (HTS) was carried out using several chemical libraries (∼23,000 compounds) using fluorescence polarization (FP) assay and identified several initial hits with sub-micromolar inhibitory constants (Ki). Those potential disruptors were then validated by ALPHA assay (Amplified Luminescent Proximity Homogeneous Assay), confirmed by Surface Plasmon Resonance (SPR). In cell-based assays, top hit KH-3 and its optimized analogs, specifically shortened HuR target mRNA half-lifes and decreased the level of the encoded proteins. Moreover, those compounds inhibited invasion and restored chemosensitivity. qPCR arrays focusing on specific pathways revealed that HuR inhibitors potently upregulated metastatic suppressors and downregulated genes frequently overexpressed in lung metastases. In animal studies, KH-3 not only powerfully exhibited antitumor efficacy in orthotopic xenografts, but also efficiently blocked experimental metastasis. In conclusion, we identified potent and specific small molecule disrupters of HuR-mRNA interaction for potential anti-metastatic therapy for breast cancer with HuR overexpression. Citation Format: Xiaoqing Wu, Rebecca T. Marquez, Shuang Han, Ke Li, Lan Lan, Yuxiao Guo, Dan A. Dixon, Jeffrey Aubé, Danny R. Welch, Liang Xu. Overcoming breast cancer chemoresistance and blocking metastasis by targeting RNA-binding protein HuR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4832.
RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation
Authors: Guillermo Yoldi, Pasquale Pellegrini, Eva M. Trinidad, Alex Cordero, Jorge Gomez-Miragaya, Jordi Serra-Musach, William C. Dougall, Purificación Muñoz, Miguel-Angel Pujana, Lourdes Planelles, Eva González-Suárez
Journal: Cancer Research (2016)

RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remains unknown. RANKL and its receptor RANK are downstream effectors of the progesterone signaling pathway. However, RANK expression is enriched in hormone receptor negative adenocarcinomas, suggesting additional roles for RANK signaling beyond its hormone-dependent function. Here, to explore the role of RANK signaling once tumors have developed, we use the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT), which mimics RANK and RANKL expression patterns seen in human breast adenocarcinomas. Complementary genetic and pharmacologic approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation, and enhances sensitivity to chemotherapy. Mechanistically, genome-wide expression analyses show that anti-RANKL therapy promotes lactogenic differentiation of tumor cells. Moreover, RANK signaling in tumor cells negatively regulates the expression of Ap2 transcription factors, and enhances the Wnt agonist Rspo1 and the Sca1-population, enriched in tumor-initiating cells. In addition, we found that expression of TFAP2B and the RANK inhibitor, OPG, in human breast cancer correlate and are associated with relapse-free tumors. These results support the use of RANKL inhibitors to reduce recurrence and metastasis in breast cancer patients based on its ability to induce tumor cell differentiation. Cancer Res; 76(19); 5857-69. ©2016 AACR.
P0523 : Modification of expression of MIR-20A, MIR-92A and MIR-122 during fibrosis in patients with chronic hepatitis C
Authors: K. Appourchaux, E. Estrabaud, P. Broet, M. Lapalus, M. Martinot-Peignoux, N. Boyer, M. Vidaud, P. Bedossa, P. Marcellin, T. Asselah
Journal: Journal of Hepatology (2015)
Serrated colorectal neoplasia: detection, characterization … what next?
Authors: Charles Kahi
Journal: Endoscopy (2016)

It has been 20 years since Emina Torlakovic and Dale Snover published their seminal description of “serrated adenomatous polyposis” [1]. Few could have foreseen at that time that the serrated pathway would emerge from relative obscurity to becoming one of the main actors in the field of colorectal neoplasia. The serrated class of colorectal lesions is distinct from conventional adenomas and includes hyperplastic polyps, sessile serrated polyps (SSPs), and traditional serrated adenomas (TSAs) [2]. The serrated pathway contributes significantly to the burden of colorectal cancer (CRC), particularly of right-sided interval cancers whose molecular signature (hypermethylation, microsatellite instability) often overlaps with that of serrated neoplasms [3] [4] [5]. SSPs and TSAs are considered premalignant (unlike hyperplastic polyps), although SSPs are arguably more relevant given the rarity of TSAs. SSPs are considered equivalent to conventional adenomas in screening and surveillance guidelines [6].
Review: Some NSAIDs, notably diclofenac, improved knee or hip pain and function in osteoarthritis vs other NSAIDs
Authors: Ami Schattner
Journal: Annals of Internal Medicine (2016)

Source Citation da Costa BR, Reichenbach S, Keller N, et al. Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. Lancet. 2016 Mar 17. [Epub ahead of print]. 26997557 (Corrected and republished in Lancet. 2017;390:e21-e33.)
Abstract 2449: Hedgehog pathway inhibition sensitizes embryonal rhabdomyosarcoma to standard chemotherapy
Authors: Gabriele Manzella, Tina Kottarathil, Beat W. Schaefer
Journal: Cancer Research (2016)

Abstract Hedgehog (Hh) is one of the key pathways orchestrating embryonic development as well as regulating homeostasis of postnatal organs. Perturbation of Hh signaling activity is associated with the onset of different childhood cancer entities such as embryonal rhabdomyosarcoma (eRMS). According to this, previous findings from our laboratory revealed that the tumor initiating populations (TIPs) of eRMS retain high activity of the pathway, which boosts their tumorigenic potential and self-renewal ability. Moreover, TIPs are well known to be responsible for seeding recurrent tumors following standard chemotherapy. This phenomenon might explain the failure of cytotoxic drugs in high-risk eRMS patients for whom conventional therapeutic approaches remain inadequate. Therefore, in this study we investigated the role of Hh pathway in the context of chemoresistance. We established several patient-derived xenograft (PDX) models and primary cells derived from diagnostic and relapsed tumor specimens. Histological and immunofluorescence analysis confirmed that both cellular and patient heterogeneity were preserved in our cohort. Interestingly, we found that Hh target genes were significantly upregulated in chemoresistant PDX tumors and demonstrated that the use of Hh antagonists could significantly sensitize eRMS cells toward debulking drugs such as doxorubicin, actinomycin and vincristine. Ongoing experiments aim at confirming these results in cells with selective knock- out of components of Hh pathway as well as at elucidating if chemotherapy might induce a selection of resistant clones or a transition of sensitive cancer cells toward a resistant phenotype with high Hh pathway activity. In conclusion, our data indicate that inhibition of Hh signaling might represent a promising strategy to enhance the therapeutic window of standard cytotoxic agents. Citation Format: Gabriele Manzella, Tina Kottarathil, Beat W. Schaefer. Hedgehog pathway inhibition sensitizes embryonal rhabdomyosarcoma to standard chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2449.
A pH-sensitive stearoyl-PEG-poly(methacryloyl sulfadimethoxine)-decorated liposome system for protein delivery: An application for bladder cancer treatment
Authors: Marian Vila-Caballer, Gaia Codolo, Fabio Munari, Alessio Malfanti, Matteo Fassan, Massimo Rugge, Anna Balasso, Marina de Bernard, Stefano Salmaso
Journal: Journal of Controlled Release (2016)