tbuckley/cabot-search huggingface dataset:
Compliance and safety of neoadjuvant intensity modulated radiotherapy (IMRT) with concurrent capecitabine for locally advanced rectal cancer: Updated results from a phase II trial (ChiCTR-TNC-10001094).
Authors: Yongheng Li, Lin Wang, Ziyu Li, Zhongwu Li, Yingshi Sun, Jin Gu, Jiafu Ji, Yong Cai, Xiaofan Li
Journal: Journal of Clinical Oncology (2014)

3598 Background: We have prospectively studied the neoadjuvant IMRT with concurrent capecitabine followed by TME for locally advanced rectal cancer to assess efficacy, compliance and toxicity in a phase II trial. Here, we report updated results. Methods: A total of 260 patients with clinical stage II-III mid-low rectal cancer received IMRT and surgery from December 2008 to May 2013. Patients received IMRT with gross targeting volume (GTV)/ clinical targeting volume (CTV) of 50.6/41.8 Gy in 22 fractions plus concurrent capecitabine (825 mg/m2twice daily) in 30 days. The interval from IMRT to surgery is 6 to12 weeks. The short-term results were analyzed. Results: The compliance rate is 99.6%, one patient discontinued treatment following 17 fractions of radiation for diarrhea. There was no Grade 4 toxicity recorded. The incidence of Grade 3 toxicities is 5.8%, including: diarrhea (4.2%), neutropenia (1.5%) and radiation dermatitis (0.4%). The toxicity was listed in the Table. Pathological complete response occurred in 18.5% (48/260) of patients. Anastomotic leakage rate was 2.6% (4/152) in patients with sphincter preservation. Perineal wound infection (20.8%, 20/96) or skin dehiscence (8.3%, 8/96) were main complications in patients who received abdominoperineal excision. Surgical re-interventions were needed in three patients and no mortality was recorded. Conclusions: Neoadjuvant IMRT plus concurrent capecitabine for rectal cancer achieved high rate of pCR, excellent compliance and minor acute toxicity. This high intensity regimen might be considered as a component for intensified treatment with induction or consolidation chemotherapy to maximize the effect to achieve clinical complete response in future trials. Clinical trial information: 10001094.Toxicities during the neoadjuvant treatment. Toxicity Total (%) G1 G2 G3 G4 Neutropenia 116 (44.6%) 90 (34.6%) 22 (8.5%) 4 (1.5%) Thrombocytopenia 12 (4.6%) 8 (3.1%) 4 (1.5%) Diarrhea 231(88.8%) 170 (65.4%) 50 (19.2%) 11 (4.2%) Radiation dermatitis 235 (90.4%) 210 (80.8%) 24 (9.2%) 1 (0.4%) Fatigue 71 (27.3%) 67 (25.8%) 4 (1.5%) Vomiting 40 (15.4%) 37 (14.2%) 3 (1.2%)
Abstract 1955: Targeting ribonucleotide reductase (RNR) in Ewing sarcoma
Authors: Kelli Goss, Stacia Koppenhafer, Kathryn Harmoney, David Gordon
Journal: Cancer Research (2017)

Abstract Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. The EWS-FLI1 oncoprotein functions, in part, as an aberrant transcription factor and is required for tumor growth and survival. In order to identify downstream targets of EWS-FLI1, we used human embryonic stem cells that express inducible EWS-FLI1 to model the initiation and development of Ewing sarcoma in a genetically defined system. We then used this model system and a gene expression based approach to identify that Ewing sarcoma cells are uniquely vulnerable to inhibitors of ribonucleotide reductase (RNR), which impair DNA replication by blocking the synthesis of deoxyribonucleotides. Here we report that the treatment of Ewing sarcoma cells with gemcitabine, an irreversible inhibitor of the RRM1 subunit of RNR, results in impaired DNA replication, cell cycle arrest, and apoptosis in Ewing sarcoma cells. Additionally, we have found that the effect of gemcitabine on the viability of Ewing sarcoma cells is sustained even after removal of the drug from the cell culture medium. Moreover, ataxia telangiectasia and rad3-related protein (ATR) and checkpoint kinase 1 (CHK1) inhibitors increase the toxicity of gemcitabine in Ewing sarcoma cells by blocking the adaptive response to impaired DNA replication. Currently, ongoing work is focused on the in vivo testing of gemcitabine, alone and in combination with CHK1 and ATR inhibitors, as a novel therapeutic approach for the treatment of Ewing sarcoma. Citation Format: Kelli Goss, Stacia Koppenhafer, Kathryn Harmoney, David Gordon. Targeting ribonucleotide reductase (RNR) in Ewing sarcoma [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 1955. doi:10.1158/1538-7445.AM2017-1955
Abstract 4944: Modeling tumor dormancy by using EMT lineage tracing under chemotherapy
Authors: Jay Lopez, Robert Bednarczyk, Nasser Altorki, Vivek Mittal, Dingcheng Gao
Journal: Cancer Research (2017)

Abstract Tumor dormancy and recurrence after initial effective treatment arose as one of most challenging questions in cancer research. Up to now, there is still no established animal model of tumor dormancy, which significantly hurdles our exploration in this field. In an effort to trace the phenotypic changes of metastatic tumor cells in vivo, we found that the dormant tumor cells were derived through a mechanism of epithelial to mesenchymal transition (EMT). We established an EMT lineage tracing model in triple transgenic mice (Tri-MMTV) carrying Fsp1-cre, Rosa26-RFP-GFP and MMTV-PyMT alleles. Tumor cells from these mice are able to switch their fluorescent marker from RFP to GFP due to the specific activation of CRE recombinase during the EMT process. Using this EMT lineage tracing model, we confirmed that within a predominantly epithelial primary tumor, a small portion of tumor cells undergo EMT. Strikingly, lung metastases were mainly derived from non-EMT tumor cells maintaining their epithelial phenotype. However, under chemotherapy condition, EMT cells significantly contributed to recurrent lung metastasis. The EMT tumor cells survived the chemotherapy due to reduced proliferation and apoptotic tolerance, which are common characters of dormant tumor cells. More interestingly, the GFP+ EMT tumor cells reversed back to epithelial phenotype through mesenchymal to epithelial transition (MET) and formed recurrent metastatic lesions in the lung. These results suggest that our EMT lineage tracing model may provide a unique tool to study tumor dormancy and recurrence. The EMT process may represent a major mechanism for tumor dormancy under chemotherapy condition, while MET is a driving mechanism for tumor recurrence. Citation Format: Jay Lopez, Robert Bednarczyk, Nasser Altorki, Vivek Mittal, Dingcheng Gao. Modeling tumor dormancy by using EMT lineage tracing under chemotherapy [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 4944. doi:10.1158/1538-7445.AM2017-4944
Polypectomie à l’anse froide pour les adénomes duodénaux: une étude clinique prospective
Journal: Endoscopy (2017)

L’intérêt de la résection des petits polypes de moins de 10 mm à l’anse froide et des plus petits polypes (“diminutive” polypes) de moins de 5 mm à la pince à biopsie a été démontré par de nombreuses études dans la littérature. En revanche très peu de données concernant l’utilisation de ces techniques existent concernant la résection des petits polypes du duodénum.
Abstract 121: Identification and characterization of calcium channel blockers as inhibitors of YAP/TAZ and glioblastoma cells
Authors: Wei Li, Zhijun Liu, Jennifer Xavier, Hong-Gang Wang
Journal: Cancer Research (2017)

Abstract Glioblastomas (GBM) are the most aggressive primary brain tumors. Despite major advances in neuroimaging and neurosurgical techniques over the past decades, the neurosurgical management of GBM patients remains challenging. Median survival of the patients is about 14.6 months. In order to radically alter the clinical course of these tumors, it is important to develop targeted therapies based on identified oncogenic mutations and signaling pathways that drive their development and sustain their maintenance. In a screen for small molecules, which can inhibit the growth of human glioblastoma cells, we identified a set of calcium channel blockers (CCB). We found that these CCB induce cell death through an apoptosis-independent process. To understand the mechanisms of the non-apoptotic cell death induced by these CCB, we dissected cellular signaling which is responsible for the cell death induction. We found that these CCB are able to inhibit YAP and TAZ, two oncogenic effectors of the Hippo tumor suppressor pathway. Importantly, GBM cells expressing the YAP active mutant or overexpressing YAP are less sensitive to these CCB. These results suggested that inhibition of YAP/TAZ is a mechanism by which CCB suppress tumor cell growth. The Hippo pathway is an essential signaling network in regulating tissue homeostasis. In this pathway, the transcription co-activators YAP and TAZ promote a gene expression program favoring cell proliferation, survival and self-renewal. In normal brain, the nuclear accumulation of YAP is largely limited to regions harboring neural progenitor cells. However, increased nuclear accumulation of YAP is found in various brain tumors, especially those more aggressive subsets of gliomas. In addition, high expression of YAP is associated with reduced mean survival in astrocytoma patients. Our results identified a novel approach to target the Hippo pathway for GBM treatment. We will present our work in further characterizing these regulations and therapeutic potentials of these calcium channel blockers in the conference. Citation Format: Wei Li, Zhijun Liu, Jennifer Xavier, Hong-Gang Wang. Identification and characterization of calcium channel blockers as inhibitors of YAP/TAZ and glioblastoma 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 121. doi:10.1158/1538-7445.AM2017-121
Abstract 357: NKX2-1 regulates SMAD and non-SMAD pathways in thyroid stem cells
Authors: Manabu Iwadate, Yoshinori Takizawa, Shioko Kimura
Journal: Cancer Research (2017)

Abstract NKX2-1 plays a critical role in thyroid differentiation. Recently, we established Side Population cells-derived Thyroid cell line (SPTL) from mouse thyroid Side Population cells. In SPTL cells, NKX2-1, PAX8 and E-cadherin were not expressed when examined by western blotting. Immunocytochemistry revealed that only 1% of SPTL cells were NKX2-1 positive. When GFP-SPTL cells were directly injected into mouse thyroid, a few GFP-SPTL cells with weak expression of NKX2-1 were found in part of thyroid follicle, suggesting that SPTL cells have potential of thyroid stem cells. Comprehensive gene expression analysis indicated that TGF-beta signaling pathway is critical for SPTL cells. TGF-beta signaling and NKX2-1 appear to play an important role in thyroid stem cells and thyroid differentiation. Here we show that NKX2-1 regulates both SMAD and non-SMAD pathways in SPTL cells. To examine the role of NKX2-1 in SPTL cells, we produced SPTL cells having doxycycline-inducible Nkx2-1 expression (named SPTL(Nkx2-1on)). In SPTL(Nkx2-1on) cells, doxycycline induced NKX2-1 as expected, while PAX8 and E-cadherin expression was not. Upon overexpression of NKX2-1 in SPTL(Nkx2-1on) cells, TGF-beta-induced phospho-SMAD3 expression was inhibited. Additionally, NKX2-1 enhanced the expression of phospho-AKT. In GFP-myrAKT(constitutively active AKT)-overexpressing SPTL cells, AKT was found localized in their cytoplasm. TGF-beta did not induce phospho-SMAD3 in these cells. The data indicate that NKX2-1 inhibits SMAD pathway through AKT activation. Ourwork demonstrates that TGF-beta signaling is controlled by NKX2-1 in thyroid stem cells. Citation Format: Manabu Iwadate, Yoshinori Takizawa, Shioko Kimura. NKX2-1 regulates SMAD and non-SMAD pathways in thyroid stem 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 357. doi:10.1158/1538-7445.AM2017-357
Abstract 22: MM-161, a first-in-class pan-FGFR antibody
Authors: Tamara Dake, Greg Finn, Melissa Geddie, Neeraj Kohli, Maja Razlog, Lihui Xu, Violette Paragas, Haluk Yuzugullu, Sara Ghassemifar, Yasmin Hashambhoy-Ramsay, Charlotte McDonagh, Marco Muda, Birgit Schoeberl
Journal: Cancer Research (2017)

Abstract Aberrant signaling of the FGFR pathway has long been known to promote tumorigenesis and angiogenesis across multiple cancer indications. However, the development of an effective and well-tolerated FGFR targeted inhibitor has been hindered by the need to block the activation of multiple mitogenic receptors while avoiding significant toxicities associated with blocking endocrine FGF ligands. Here we disclose for the first time a novel FGFR targeted antibody, MM-161, designed to block ligand-dependent signaling driven by all four FGF receptors, specifically the IIIc-isoforms. MM-161 is well tolerated in mice and cynomolgus monkeys with no significant weight loss observed in either species. Efficacy studies demonstrated that MM-161 monotherapy leads to significant tumor growth inhibition or tumor regression of xenografts of human lung, renal and endometrial cancer amongst others. Importantly, MM-161 has a dual mechanism of action by inhibiting both proliferation and angiogenesis. We will present data illustrating that inhibition of multiple FGFRs is desirable to achieve tumor regression. Furthermore, we will show combination studies with relevant standard of care therapies in models of lung and renal cancer. Taken together, our preclinical data strongly supports the clinical evaluation of MM-161 in cancer patients. Citation Format: Tamara Dake, Greg Finn, Melissa Geddie, Neeraj Kohli, Maja Razlog, Lihui Xu, Violette Paragas, Haluk Yuzugullu, Sara Ghassemifar, Yasmin Hashambhoy-Ramsay, Charlotte McDonagh, Marco Muda, Birgit Schoeberl. MM-161, a first-in-class pan-FGFR antibody [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 22. doi:10.1158/1538-7445.AM2017-22
08.27 Impact of toll-like receptor 9 in inflammatory arthritis and osteoclastogenesis
Authors: Anita Fischer, Christina Böhm, Marije Koenders, Wim van den Berg, Tobias Rothe, Gerhard Krönke, Diana Dudziak, Günter Steiner
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Release and insufficient removal of endogenous nucleic acids may be involved in triggering harmful autoimmune reactions important in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). Nucleic acid sensing molecules, such as the endosomal Toll-like receptors (TLRs) 7 and 9, have been linked to pathogenic autoimmune processes, but their role in RA is less clear. To gain more insight into the role of TLR9 in autoimmune arthritis, rats with pristane-induced arthritis (PIA) were treated with a TLR9 antagonist. To further investigate TLR9 involvement, serum transfer arthritis was induced in TLR9 knock-out mice. <h3>Materials and methods</h3> Arthritis was induced in mice with arthritogenic K/BxN serum and in rats with the mineral oil pristane. Rats were treated with a TLR9 antagonist every other day, starting one day before disease induction. Arthritis was scored using established scoring systems, inflammation and bone erosion were quantified by histological analysis. Furthermore, the role of TLR9 in osteoclast differentiation and activation was investigated <i>in vitro</i>. <h3>Results</h3> In the serum transfer model, which is independent of the adaptive immune system, arthritis severity was not changed in mice lacking a functional tlr9 gene. In PIA, which is T cell-dependent, the TLR9 antagonist reduced arthritis severity by ~50%. TLR9 inhibition led to reduced inflammation, bone erosion and cartilage degradation. However, when treatment was started after the onset of arthritis TLR9 inhibition did not influence disease severity. Treatment with the TLR9 antagonist influenced downstream signalling, mainly via NFκBp65, in lymph nodes. Remarkably, mRNA levels of TLR7 and TLR9 strongly differed in the course of <i>in vitro</i> osteoclastogenesis. Whereas TLR7 expression did not change throughout osteoclastogenesis, expression of TLR9 was higher in precursor cells than in mature osteoclasts and stimulation with a TLR9 agonist (CpG) completely inhibited osteoclastogenesis. <h3>Conclusions</h3> Taken together, the results suggest a role for TLR9 in the T cell-dependent initiation phase of PIA and thus an important involvement of the DNA (CpG) recognising TLR9 in the initiation of autoimmune arthritis and during osteoclastogenesis. The precise role(s) of TLR9 in the different stages of arthritis needs to be further elucidated in future experiments.
Abstract 2902: Epithelial-type CD133+ stem-like lung cancer cells emerge higher drug resistance through MDFIC-mediated Wnt/β-catenin signaling pathway
Authors: Chao-Ju Chen, Chih-Jen Yang, Ming-Shyang Huang, Yu-Peng Liu
Journal: Cancer Research (2017)

Abstract Background: The epithelial-to-mesenchymal transition (EMT) has been described to promote drug resistance and cancer stem cell (CSC) properties. Many studies demonstrated that a major proportion of circulating tumor cell (CTC) exhibits EMT and CSC characteristics. A recent finding revealed the presence of epithelial type (EpCAM+) CTC was associated with poor outcome, whereas the mesenchymal type (EpCAM-) CTC were not. We therefore hypothesize that the epithelial-type CSC may exhibit higher drug resistant ability. Methods: We isolated epithelial type (E+) and mesenchymal type (E-) CD133+ cells and CD133- cells from PC14 lung cancer cell line by fluorescence assisted cell sorting. We used western blot, QPCR, immunofluorescence, sphere formation assay and tumor xenograft assay to characterize the 4 subpopulations. The drug resistant ability was determined by cell viability assay and in vivo drug response assays. The drug resistant signature was identified by comparing the gene expression profile from four subpopulations and Gene Expression Omnibus (GEO) database. Knockdown and overexpression of MDFIC in PC14 subpopulations were established by using lentivirus vectors. Immunoprecipitation and subcellular fractionation were performed for drug resistant mechanism investigation. Results: The epithelial type PC14 CD133+ cells (E+/CD133+ subpopulation) exhibited higher sphere formation ability and was more resistant to the treatment of chemotherapy agents compared to the mesenchymal type CD133+ cells (E-CD133+ subpopulation) in vitro and in vivo. Gene expression profiling showed 86 genes were bioinformatically predicted as drug resistant signature and were correlated with the disease free survival of the patients with lung cancer. Among these genes, the mRNA level of 20 genes were significantly related to the patient’s prognosis in the GSE31210 dataset. Human I-mfa domain-containing protein (MDFIC) was highly expressed in E+/CD133+ subpopulation. Knockdown and overexpression of MDFIC modulates drug resistance ability in cancer cells. MDFIC increased the level of free β-catenin through binding and stabilizing the axin-GSK3-β-β-catenin destruction complex and increased the transcriptional activity of Wnt/β-catenin signaling. Conclusion: The epithelial-type CD133+ stem-like lung cancer cells are more resistant to the chemotherapy through MDFIC-mediated Wnt/β-catenin signaling activation. Citation Format: Chao-Ju Chen, Chih-Jen Yang, Ming-Shyang Huang, Yu-Peng Liu. Epithelial-type CD133+ stem-like lung cancer cells emerge higher drug resistance through MDFIC-mediated Wnt/β-catenin signaling pathway [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 2902. doi:10.1158/1538-7445.AM2017-2902
Abstract 4323: Metabolic reprogramming in acute myeloid leukemia cells by mesenchymal stromal cell-derived exosomes induces chemoresistance
Authors: Hongyun Zhao, Abhinav Achreja, Ziwen Zhu, Ahmed N. Rawi, Marina Konopleva, Michael Andreeff, Deepak Nagrath
Journal: Cancer Research (2017)

Abstract Mesenchymal stromal cells play an important role in acute myeloid leukemia (AML) development. Altered cellular metabolism supports AML cells' survival in multiple aspects, such as drug resistance. Here, we demonstrate the role of MSC-derived exosomes in metabolic regulation of AML cells, and put forward a combinatorial strategy to sensitize AML cells to chemodrugs. Exosomes secreted by MSCs can reprogram the metabolic machinery following their internalization by AML cells. Through 13C tracing experiments and flux analysis, we elucidate that MSC-derived exosomes enhance oxidative phosphorylation and glutamine's entry into TCA cycle, which replenish the pool of carbon sources in mitochondria. Further, our work shows that inhibiting the interactions between MSCs and AML cells by targeting the metabolic regulation exerted by MSC-derived exosomes sensitizes AML cells to chemodrugs. Taken together, our work reveals a novel role of the TME in regulating the metabolic adaptation in AML cells and uncovers the improved strategy for AML therapy. Citation Format: Hongyun Zhao, Abhinav Achreja, Ziwen Zhu, Ahmed N. Rawi, Marina Konopleva, Michael Andreeff, Deepak Nagrath. Metabolic reprogramming in acute myeloid leukemia cells by mesenchymal stromal cell-derived exosomes induces chemoresistance [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 4323. doi:10.1158/1538-7445.AM2017-4323