tbuckley/cabot-search huggingface dataset:
Abstract 915: Thrombomodulin expression regulates the tumor stroma differentiation of mesenchymal stem cells for controlling tumor growth
Authors: Tsung-Hsien Shih, Jhy-Ming Li, Guey-Yueh Shi, Hua-Lin Wu
Journal: Cancer Research (2017)

Abstract Introduction: Thrombomodulin (TM), a thrombin receptor on endothelial cell surface, acts as an anti-coagulant factor in thrombin-catalyzed protein C activation and inhibits the pro-coagulant functions of thrombin. Owing to TM’s widely expression patterns on various cell types, our studies have demonstrated that beside anti-coagulation, TM also participates in controlling cell-cell adhesion, tumor growth, inflammation, angiogenesis, and atherosclerosis. However, the significance of TM expression in mesenchymal stem cells (MSCs) has never been investigated. The non-hematopoietic MSCs could specifically home into the developing tumors and becomes the active components of tumor stroma, which affects tumor’s growth, immunity, progression, and therapeutic resistance. Recently, we investigated the role of TM on the tumor microenvironment differentiation of MSCs for establishing the active stroma that assists tumor growth. Materials &amp; methods: Normal and TM gene-targeting transgenic mice-isolated bone marrow-derived MSCs were used as the research models to investigate the expressing significance of TM on MSC’s biological activities and differentiations during mouse melanoma B16F10 cell’s conditioning in vitro and in vivo. Results: Our data showed that MSC's TM expression was low in the quiescent state but was up-regulated while treating with B16F10 cell’s conditioned medium in the mechanism of plate-derived growth factor signaling dependence. Accordingly, using conditional gene knockout strategy, under the condition of tumor cell other than normal culture resulted in that TM gene knockout significantly affected MSC’s proliferation, migration, interleukin-6 secretion, angiogenic activity, and tumor-associated fibroblast differentiation in vitro. Furthermore, TM knockout notably reduced the capacity of MSCs on regulating the growth, vasculogenesis, and active stroma establishment of B16F10 melanoma xenograft in vivo. Conclusion: These results indicate that the secretion of tumor-associated plate-derived growth factor is a critical event for MSC’s TM expression that controls MSC’s stroma differentiation for developing active tumor microenvironment, which promotes tumor progression. This study further suggests that the modulation of TM expression on MSCs has the therapeutic potential via diminishing the establishment of functional tumor stroma that sensitizes tumor for the therapies. Citation Format: Tsung-Hsien Shih, Jhy-Ming Li, Guey-Yueh Shi, Hua-Lin Wu. Thrombomodulin expression regulates the tumor stroma differentiation of mesenchymal stem cells for controlling tumor growth [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 915. doi:10.1158/1538-7445.AM2017-915
Hevylite® to Monitor Hypogammaglobulinemia, a Predictor of Response to Therapy in Multiple Myeloma
Authors: Guillemette Fouquet, Susanna Schraen, Jean-Luc Faucompré, Lionel Karlin, Margaret Macro, Cyrille Hulin, Brigitte Onraed, Laurent Garderet, Murielle Roussel, Bertrand Arnulf, Brigitte Pegourie, Brigitte Kolb, Anne-Marie Stoppa, Sabine Brechiniac, Gerald Marit, Claire Mathiot, Anne Banos, Mourad Tiab, Mamoun Dib, Jean-Gabriel Fuzibet, Marie Odile Petillon, Philippe Rodon, Marc Wetterwald, Bruno Royer, Laurence Legros, Lotfi Benboubker, Olivier Decaux, Denis Caillot, Martine Escoffre-Barbe, Jean Paul Fermand, Philippe Moreau, Michel Attal, Hervé Avet-Loiseau, Thierry Facon, Xavier Leleu, Stephen Harding
Journal: Blood (2014)
INDIFFERENCE TO PAIN
Journal: JAMA (1964)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Gemcitabine-Induced TIMP1 Attenuates Therapy Response and Promotes Tumor Growth and Liver Metastasis in Pancreatic Cancer
Authors: Zenobia D'Costa, Keaton Jones, Abul Azad, Ruud van Stiphout, Su Y. Lim, Ana L. Gomes, Paul Kinchesh, Sean C. Smart, W. Gillies McKenna, Francesca M. Buffa, Owen J. Sansom, Ruth J. Muschel, Eric O'Neill, Emmanouil Fokas
Journal: Cancer Research (2017)

Abstract Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in preclinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC. We verified the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1) in primary pancreatic tumors and metastases using both in vitro techniques and animal models. We identified potential pathways affected downstream of TIMP1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increased inflammatory cytokines including TIMP1 in the KPC mouse model. TIMP1 was upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. In addition, TIMP1 played a role in tumor clonogenic survival and vascular density, while TIMP1 inhibition resensitized tumors to gemcitabine and radiotherapy. We observed a linear relationship between TIMP-1 expression, liver metastatic burden, and infiltration by CD11b+Gr1+ myeloid cells and CD4+CD25+FOXP3+ Tregs, whereas the presence of tumor cells was required for immune cell infiltration. Overall, our results identify TIMP1 upregulation as a resistance mechanism to gemcitabine and provide a rationale for combining chemo/radiotherapy with TIMP1 inhibitors in PDAC. Cancer Res; 77(21); 5952–62. ©2017 AACR.
Abstract 2968: Examining the role of breast cancer Neuregulin1 and macrophage ErbB3 in intravasation
Authors: Ramon Cabrera, Serena Chiang, Jeffrey Segall
Journal: Cancer Research (2017)

Abstract The purpose of our studies is to investigate the role of Neuregulin1 (NRG1) and ErbB3 signaling between breast cancer cells and macrophages in facilitating tumor cell intravasation. The interaction of breast cancer cells with other cell types within the tumor microenvironment plays an important role in metastasis. These interactions are thought to influence tumor cell invasion and intravasation, two important steps in the process of metastasis. Our studies are specifically interested in examining the signaling occurring between tumor cells and macrophages. Previous studies have established the presence of paracrine signaling between breast cancer cells and macrophages, where colony stimulating factor 1 (CSF-1) produced by the tumor cells stimulates the production of epidermal growth factor (EGF) by macrophages, leading to chemotactic invasion of the tumor cells. In addition to this paracrine loop signaling between tumor cells and macrophages, it has been seen that macrophage expression of ErbB3, a member of the EGFR family of receptor tyrosine kinases, may play a role in facilitating tumor cell invasion. In order to examine the effects of signaling between tumor cells and macrophages in intravasation, we utilize an in vitro transendothelial migration (iTEM) assay. This assay uses transwells coated with matrigel and endothelial cells in order to mimic the entry of tumor cells into blood vessels. We show that using an ErbB3 blocking antibody results in a significant reduction of macrophage-induced transendothelial migration of breast cancer cells. Additionally, reduction of expression of the ErbB3 receptor ligand Neuregulin1 in tumor cells yields a similar result. Stimulation of macrophages with NRG1 leads to increased expression of Jagged1 (JAG1), a ligand of the Notch receptor. Activation of the Notch receptor pathway has been shown to be involved in tumor cell invasion. Overall our studies look to further examine the interaction between tumor cells and macrophages, and these observations indicate that ErbB3, NRG1, and JAG1 could all serve as novel targets in metastasis and the tumor microenvironment. Citation Format: Ramon Cabrera, Serena Chiang, Jeffrey Segall. Examining the role of breast cancer Neuregulin1 and macrophage ErbB3 in intravasation [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 2968. doi:10.1158/1538-7445.AM2017-2968
Abstract 5097: An industrial method of manufacturing a novel RNAi anticancer drug, DFP-10825, for the treatment of peritoneal disseminated gastric cancer
Authors: Tatsuhiro Ishida, Hidenori Ando, Masakazu Fukushima, Cheng-Long Huang, Hiromi Wada
Journal: Cancer Research (2017)

Abstract We have developed an RNAi based anticancer drug, DFP-10825 [a cationic liposome and short-hairpin RNAi molecule for thymidylate synthase (TS shRNA)] and here established an industrial method of manufacturing the formulation. The therapeutic efficacy of the DFP-10825 was examined in a MKN45 human gastric carcinoma xenograft mouse model (peritoneal disseminated gastric cancer model). The mice were received intraperitoneal injection with 5 doses of DFP-10825 or control formulation (short-hairpin RNA for luciferase) (1 mg shRNA/kg/day) once every 3 days. The treatment with DFP-10825 obviously prolonged survival time of the mice compared to control formulation and significantly suppressed the target mRNA level in the peritoneal disseminated tumors. We recently reported that DFP-10825 showed a significant therapeutic efficiency in the human malignant pleural mesothelioma orthotopic xenograft model. Accordingly, DFP-10825 may lead a clinical benefit to patients with pulmonary malignant mesothelioma or disseminated peritoneal tumor. In addition, we established an industrial method of manufacturing DFP-10825, which provides a large scale preparation. Water solution of TS shRNA was gently mixed at an optimal ratio with ethanol solution of cationic lipids, composed of DC-6-14 (a cationic lipid), DOPE and DOPC. Then, the mixture was lyophilized under optimal condition. The freeze-dried cake provided a ready for injection formulation by a one-step hydration with saline. Physicochemical properties of the obtained DFP-10825 such as particle size, zeta-potential, and size distribution were almost comparable with those of conventionally prepared DFP-10825, which prepared with conventional preparation method, mixing TS shRNA solution and cationic liposomes. Our findings in this study demonstrate that intraperitoneal chemotherapy with a simple freeze-dried RNAi medicine, DFP-10825, showing an equivalent pharmaceutical and therapeutic potency with conventionally prepared DFP-10825, meets a criteria to use for clinical settings and will have a clinical benefit to treat patients with disseminated peritoneal and pulmonary cancers. Citation Format: Tatsuhiro Ishida, Hidenori Ando, Masakazu Fukushima, Cheng-Long Huang, Hiromi Wada. An industrial method of manufacturing a novel RNAi anticancer drug, DFP-10825, for the treatment of peritoneal disseminated gastric 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 5097. doi:10.1158/1538-7445.AM2017-5097
Abstract 5568: Towards decoding the interplay between glycolysis and oxidative phosphorylation in cancer
Authors: Dongya Jia, Linglin Yu, Mingyang Lu, Eshel Ben-Jacob, Jianpeng Ma, Herbert Levine, Benny A. Kaipparettu, Jose Onuchic
Journal: Cancer Research (2017)

Abstract Abnormal metabolism is a hallmark of cancer, yet its regulatory mechanism is poorly understood. Cancer cells were considered to mostly utilize glycolysis, referred to as the Warburg effect. However recent evidence suggests that oxidative phosphorylation also plays a crucial role during cancer progression. Here we utilized a systems biology approach to decipher the regulatory principle of glycolysis and oxidative phosphorylation. Integrating information from literature, we constructed a regulatory network of genes and metabolites, from which we extracted a core circuit containing HIF-1, AMPK and ROS. Our circuit analysis showed that while normal cells have an oxidative state and a glycolytic state, cancer cells can access an additional hybrid state with both metabolic modes coexisting, due to higher ROS production and/or oncogenic activation, such as RAS, MYC and c-SRC. The anti-correlation between AMPK and HIF-1 and the association of metabolic states with oncogenes were further confirmed using TCGA patient transcriptomics data of multiple cancer types and single-cell RNA-seq data of lung adenocarcinoma. We propose that the hybrid phenotype contributes to metabolic plasticity, allowing cancer cells to adapt to various microenvironments. Using model simulations, we predicted the efficacies of several metabolic cancer therapies based on their effectiveness in reducing metabolic plasticity. Our theoretical framework of metabolism can serve as a platform to decode cancer metabolic plasticity and design cancer therapies targeting metabolism. Citation Format: Dongya Jia, Linglin Yu, Mingyang Lu, Eshel Ben-Jacob, Jianpeng Ma, Herbert Levine, Benny A. Kaipparettu, Jose Onuchic. Towards decoding the interplay between glycolysis and oxidative phosphorylation in 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 5568. doi:10.1158/1538-7445.AM2017-5568
Expression of PD-L1 and NY-ESO-1 in early and advanced triple-negative breast cancer.
Authors: Anna Tessari, Biagio Paolini, Luigi Mariani, Lorenzo Pilla, Maria Luisa Carcangiu, Angela Moliterni, Filippo G. De Braud, Sara Cresta
Journal: Journal of Clinical Oncology (2014)

1110 Background: Advanced triple negative breast cancer (TNBC) is a poor prognosis disease to which no targeted therapies are available. PD-L1 is a key player in tumor immune escape, and significant responses have been obtained inhibiting this pathway in various malignancies. NY-ESO-1 is a tumor-specific antigen and represents a possible target for vaccine therapy. Here we evaluate PD-L1 and NY-ESO-1 expression in early and advanced TNBC patients. Methods: 26 metastatic TNBC patients who underwent both primary surgery and distant lesion biopsy were selected. From representative paraffin-embedded block, we obtained 3 tissue-cores of 1.5 mm diameter for the construction of a tissue microarray, which was evaluated by immunohistochemistry. Results: In primary and metastatic lesions NY-ESO-1 was expressed in 12% and 24% of the samples respectively (30.8% overall positivity). PD-L1 was expressed in 100% of early TNBC and in 92% of corresponding metastatic lesions. Two patients lost PD-L1 expression in the distant lesion: one patient received anthracyclines, taxanes and CMF as adjuvant treatment and one received also paclitaxel and carboplatin as first line therapy before the distant lesion biopsy. All but one patient maintaining the PD-L1 expression in the advanced disease received anthracycline for early breast cancer, 52% and 91% adjuvant taxanes and CMF respectively, 26% various first line treatments before the biopsy. This observation is apparently in conflict with the hypothesis that doxorubicin inhibits PD-L1 expression. No correlation between NY-ESO-1 expression and age, time to relapse, presence of metastasis and cytotoxic treatments were observed. Conclusions: This study first investigates PD-L1 expression in TNBC patients and reports 100% positivity in the early stage, mostly maintained in the advanced disease. No clear correlation with PD-L1 loss and chemotherapy could be identified. This study reports that NY-ESO-1 is expressed in a subpopulation of TNBC, also in the metastatic setting, that could benefit from an anti-NY-ESO-1 vaccine, and indicates that TNBC is an ideal subgroup for anti-PD-L1 therapies. Patients positive on the early breast cancer specimen could then avoid a further biopsy of the metastatic site.
Abstract 2443: Massively parallel single-cell RNA-Seq identifies diverse subpopulations displaying EMT and stem-like features
Authors: Billy Lau, Jiamin Chen, Hanlee P. Ji
Journal: Cancer Research (2017)

Abstract Single-cell transcriptome analysis enables a new paradigm for studying complex systems in cancer. As opposed to bulk sequencing, which averages genomic signals across thousands or millions of cells and obscures the presence of rare subtypes, single cell sequencing enables the interrogation of individual cells. In cancer, intratumoral heterogeneity is observed at both genomic and epigenomic levels, and its analysis enables the discovery of new actionable targets and treatment modalities tailored to individual subpopulations. As an example, many cancer cell lines and those derived from patients contain subpopulations marked by distinct patterns of surface markers such as CD44, and are linked to drug resistant and tumor initiating phenotypes. A complete characterization of such cellular populations ideally requires marker-free sampling, followed by clustering into distinct subgroups. In this study, we demonstrate the significant advantages of such an approach; we utilize a high-throughput single-cell RNA-Seq method to characterize the transcriptomic profiles of cellular populations. We performed single-cell RNA-Seq on thousands of cells in the matched SW480 (primary) and SW620 (metastatic) colorectal cell lines using a microfluidic droplet barcoding technology that enables the tracking of single cells during library preparation. By focusing on genes with high inter-cell variability, we discovered a small subpopulation of cells that displayed a distinct gene expression signature from the major subpopulation. Differential gene expression analysis of this subpopulation yielded genes virtually all enriched in the epithelial-to-mesenchymal transition (EMT) pathway. These cells showed significant increases in canonical mesenchymal marker genes such as VIM, CD44, and SOX9. Gene expression profiles of these subpopulations also correlated with established EMT signatures. Remarkably, this subpopulation did not display mutual exclusivity in gene expression with the epithelial marker EPCAM, which possibly indicates an intermediate mesenchymal phenotype. We also observed in the major population cluster a small subset of cells totaling less than 1% of the population that were significantly enriched for LGR5 expression, a common stem-like marker in colorectal cancer. Overall, we demonstrate the use of single-cell RNA-Seq to discover and characterize a diversity of cellular states that would otherwise be impossible from bulk analysis. Citation Format: Billy Lau, Jiamin Chen, Hanlee P. Ji. Massively parallel single-cell RNA-Seq identifies diverse subpopulations displaying EMT and stem-like features [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 2443. doi:10.1158/1538-7445.AM2017-2443
Abstract 115: Flubendazole targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer with trastuzumab resistance
Authors: Daeil Sung, Youngkwan Cho, Eunhye Oh, Tae-Min Cho, Yoon-Jae Kim, Ji Young Kim, Jae hong Seo
Journal: Cancer Research (2017)

Abstract Background and Propose: HER2-positive breast cancers are associated with an aggressive phenotype and trastuzumab resistance leading to poor clinical outcomes. Flubendazole (FLU) is a potent anthelmintic agent that inhibits microtubule polymerization, and also exhibits anticancer activity in several cancer types. The objective of the present study was to investigate the effect of FLU on apoptosis, HER2/Akt signaling pathway, cancer stem cell (CSC)-like properties and trastuzumab-resistance in HER2-positive breast cancer cells. Methods: FLU-induced antitumor effects were characterized by MTS assay, Sub-G1 and G2/M-phase arrest population, Annexin-V analysis, ALDH1 activity assay, Western blotting and immunofluorescence. For in vivo study, trastuzumab-resistant JIMT1 cells were injected into the mammary fat pads of BALB/c nude mice. We then determined the tumor growth and CSC-like properties. Results and conclusion: FLU significantly reduced cell viability and induced apoptosis with accompanied by activation of caspase-3, -7, and -8, as well as PARP cleavage in HER2-positive cell lines (MDA-MB-453, SKBR3 and BT474). FLU-induced apoptosis is associated with significant decreases in expression levels of HER2, p-HER2 (Tyr1221/1222), HER3, and p-HER3 (Tyr1289). FLU treatment also resulted in G2/M-phase arrest of the cell cycle, as evidenced by a marked downregulation of phospho-Histone H3 expression. These results were closely related to the decline of CSC-like properties, coinciding with the suppression of ALDH1 activity. These effects were also observed in trastuzumab-resistant JIMT-1 cells, and significant reductions in tumor growth and ALDH1A1 downregulation were observed in xenograft models together with downregulation of HER2 expression in vivo. Our findings suggest that FLU may be potentially effective for the treatment of HER2-positive breast cancer with trastuzumab resistance. Note: This abstract was not presented at the meeting. Citation Format: Daeil Sung, Youngkwan Cho, Eunhye Oh, Tae-Min Cho, Yoon-Jae Kim, Ji Young Kim, Jae hong Seo. Flubendazole targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer with trastuzumab resistance [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 115. doi:10.1158/1538-7445.AM2017-115