tbuckley/cabot-search huggingface dataset:
Abstract 3634: A gain-of-function mutation in tyrosine phosphatase SHP-2 enhances breast carcinoma malignant phenotypes
Authors: Zhongqian Hu, Haoshu Fang, Siying Wang
Journal: Cancer Research (2015)

Abstract Breast cancer is the most common malignant tumor in women worldwide, and it is the second leading cause of cancer-related mortality in the US women. Evidences suggested that overexpression of Src homologous protein phosphotyrosyl phosphatase 2 (SHP2) has been observed in most of the breast cancer cell lines and in breast cancer tissues, and accompanied with lymph nodes metastasis. Inhibition of SHP2 in the breast cancer cell lines abolishes the growth and decrease survival of tumor cells, which leads to the differentiation of malignant cells into normal breast epithelial phenotype. These observations suggest that SHP2 promotes the tumor development though increase tumor formation and metastasis. However, the pathophysiologic role of SHP2 (overexpression or gain-of-function mutation) and its relevance to tumorigenesis are still largely unknow. In this study, we focused on the in vivo and in vitro effects of the gain-of-function mutant SHP-2 on phenotypes of breast cancer. Mutant PTPN11 cDNA (D61G) was transduced into MDA-MB231 and MCF-7 cells. The effects of D61G mutant on breast cancer tumorigenesis and malignant behaviours, such as cell adhesion, proliferation, migration and invasion were tested. The potential underlying molecular mechanisms, i.e., the activation of the Gab1-Ras-Erk axis were also examined. In vitro studies found that, in SHP2 D61G mutant groups, the tumour adhesion, proliferation, migration and invasion were increased significantly. Consistently, in vivo studies also found that the incidence of tumour and the tumour weights of the SHP-2 D61G-MB231 group were increased significantly (P&amp;lt;0.001), which is also associated with tumour metastasis. Mechanistically, the PTPN11 D61G mutation resulted in the activation of Ras-ErK pathway. And interestingly, the interaction between Gab1 and mutant SHP2 was also significantly increased. The mutant SHP-2 significantly promoted tumour migration and invasion at least partially through the activation of Gab1-Ras-Erk axis. In conclusion, our findings clearly establish a role for the SHP-2 GOF mutant in breast tumour growth and provide novel insight into the mechanisms of SHP-2 GOF mutant-mediated tumor promotion. This finding could have direct implications for breast cancer therapy. This study was supported by a grant from the National Natural Science Foundation of China (codes: 30873046, 30973424, and 81072663) and by the Fundamental Research Funds for the Central Universities (code:3290004402). Note: This abstract was not presented at the meeting. Citation Format: Zhongqian Hu, Haoshu Fang, Siying Wang. A gain-of-function mutation in tyrosine phosphatase SHP-2 enhances breast carcinoma malignant phenotypes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3634. doi:10.1158/1538-7445.AM2015-3634
Abstract 3058: Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents
Authors: Sandeep Kumar, Neelu Yadav, Tim Marlowe, Ajay Chaudhary, Jianmin Wang, Jordan O'Malley, Patrick Boland, Srinivas Jayanthi, Thallapuranam Krishnaswamy Suresh Kumar, Nagendra Yadava, Dhyan Chandra
Journal: Cancer Research (2015)

Abstract Although cancer cells develop resistance to multiple types of anticancer agents, whether they adopt similar or differential mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. We show differential sensitivity, caspase activation, and cytokines/chemokines release in response to multiple anticancer agents. We demonstrated that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induced apoptosis in OXPHOS-independent manner. DNA-damaging agents induced mitochondrial biogenesis accompanied by increased production of cellular and mitochondrial ROS. Mitochondrial biogenesis upregulated both mitochondrial protein-folding machinery and unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA damage-induced caspase activation, whereas inhibition of complex II or gross complexes did not modulate the caspase activity. Interestingly, DNA damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted upon OXPHOS complex I-deficiency but not by OXPHOS complex II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross-complexes whereas a reverse trend was observed with apicidin. Together, our findings define the specific targets of apoptosis induction in response to a broad range of anticancer therapeutics, which provide a new strategy for differential mitochondrial targeting for cancer therapy. Citation Format: Sandeep Kumar, Neelu Yadav, Tim Marlowe, Ajay Chaudhary, Jianmin Wang, Jordan O'Malley, Patrick Boland, Srinivas Jayanthi, Thallapuranam Krishnaswamy Suresh Kumar, Nagendra Yadava, Dhyan Chandra. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3058. doi:10.1158/1538-7445.AM2015-3058
A Study of Growth and Development: Observations in Successive Years on the Same Children
Journal: JAMA (1934)

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Long Term Clinical Benefit of Lenalidomide (Revlimid) Treatment in Patients with Myelodysplastic Syndrome without Del 5q Cytogenetic Abnormalities.
Authors: Azra Raza, James E. Reeves, Eric J. Feldman, H. Joachim Deeg, Luke Dreisbach, Charles A. Schiffer, Jamile M. Shammo, Virginia M. Klimek, Peter L. Greenberg, John M. Bennett, Gordon W. DeWald, Jerome B. Zeldis, Kenton Wride, Michele Schmidt, Robert D. Knight, Alan F. List
Journal: Blood (2006)
Human cytochrome P450 and UDP-glucuronosyltransferase reaction phenotyping of MPC-3100, an oral HSP90 inhibitor.
Authors: D. I. Papac, K. Bulka, C. Bradford, J. S. Patton, A. Bajji, G. G. Mather
Journal: Journal of Clinical Oncology (2011)

e13019 Background: MPC-3100 is an oral synthetic inhibitor of HSP90, in a phase I safety study in cancer patients. Major cytochrome P450 (CYP450) and UDP-glucuronosyltransferase (UGT) isozymes were identified to define the inclusion and exclusion criteria necessary to ensure patient safety. Methods: CYP450 isozymes responsible for the metabolism of MPC-3100 were assessed by two methods. The first entailed the use of recombinant human Supersomes (1A2, 2C8, 2C9, 2C19, 2D6 and 3A4) suspended in phosphate buffer (pH 7.4) with 40 pmoles of CYP450. An NADPH regenerating system was used with a 5 minute pre-incubation prior to adding 10 µM MPC-3100. The second used human donor liver microsomes suspended in phosphate buffer (pH 7.4) with 0.5 mg/mL of protein. The microsomes were pre-incubated with CYP450 isozyme selective chemical inhibitors prior to addition of 10 µM MPC-3100 and NADPH. UGT isozymes responsible for glucuronidation of MPC-3100 and a major oxidative metabolite were identified using recombinant UGT Supersomes suspended in Tris-HCl buffer (pH 7.5) at a final protein concentration of 1 mg/mL. The UGT Supersomes were pre-incubated with alamethicin and the reaction was initiated with UDPGA. The disappearance of MPC-3100 and formation of metabolites was monitored by HPLC-ESI-MS/MS. Results: MPC-3100 was metabolized by CYP450 1A2, 2C19, 2D6 and 3A4, but not by 2C8 or 2C9. With the use of selective chemical inhibitors in pooled human liver microsomes, the percent of MPC-3100 metabolized at 40 minutes was inhibited greatest by azamulin (31.4%), ketoconazole (20.9%) and quinidine (5.5%). MPC-3100 was glucuronidated by UGT 1A3, 1A8 and 1A4, but not by 1A1, 1A6, 1A7, 1A9, 1A10, 2B4, 2B5, 2B15, and 2B17. The major oxidative metabolite of MPC-3100 was a substrate for UGT 1A3, 1A7, 1A9, 1A10, 2B4, 2B17 with 1A1, 1A8, and 2B7 predominating. Conclusions: CYP450 3A4 is the primary isozyme involved in the metabolism of MPC-3100. UGT 1A4 is the major isozyme responsible for direct glucuronidation of MPC-3100; whereas multiple UGTs (1A1, 1A8, and 2B7) are capable of glucuronidating the major oxidative metabolite. Therefore current clinical studies preclude co-administration of potent CYP3A4 inhibitors with MPC-3100.
Circulating baseline plasma cytokines and angiogenic factors (CAF) as markers of tumor burden and therapeutic response in a phase III study of pazopanib for metastatic renal cell carcinoma (mRCC).
Authors: Y. Liu, H. T. Tran, Y. Lin, A. Martin, A. J. Zurita, C. N. Sternberg, R. G. Amado, L. N. Pandite, J. Heymach
Journal: Journal of Clinical Oncology (2011)

4553 Background: Pazopanib is a multi-kinase inhibitor approved for the treatment of mRCC. Plasma CAF analyses from phase II and III studies previously identified candidates (HGF, IL-6, IL-8, TIMP-1, VEGF, E-Selectin and OPN) that significantly correlated with PFS for patients receiving pazopanib (ASCO 2010, #4522). IL-8, and OPN were also found to be prognostic in patients enrolled in the placebo arm, while IL-6 was both prognostic and predictive (GU,ASCO 2011 #334). Methods: In this study, plasma samples (n=344) from a phase III randomized, placebo-controlled trial were analyzed for CAFs by SearchLight multiplex assays in a CLIA-certified laboratory. Correlations of baseline CAF levels with baseline sum of longest tumor diameter (SLD), maximum tumor shrinkage, and other clinical parameters were completed using the Spearman method. A seven factor angiogenic signature (IL6, IL8, HGF, OPN, TIMP1, VEGF, and E-Selectin) was generated by hierarchical clustering (UPGMA, Euclidean distance). Patients were stratified into signature high and low groups and correlation to PFS was assessed. Results: IL6, IL8, HGF, OPN, TIMP1 (p<.0001) and VEGF (p=.0012) showed significant association with baseline SLD while E-Selectin (p=.7211) did not. Higher IL6 (p=.020), HGF (p=.015), and OPN (p=.049) were associated with less tumor shrinkage. Applying the 7 factor angiogenic signature, patients with a higher signature profile were associated with significantly shorter PFS in both the placebo (p=.001, high 11 wks vs.low 24 wks) and pazopanib (p=.001, high 25 wks vs. low 48 wks) arms. Conclusions: Circulating baseline IL6, IL8, HGF, OPN, TIMP1 and VEGF correlated with baseline SLD, while higher levels of IL6, HGF, and OPN were associated with reduced tumor shrinkage after treatment with pazopanib. The seven angiogenic signature was associated with PFS in both arms. Plasma CAF profiling may be used to aid in the prognostic evaluation of patients and determine potential therapeutic response to VEGF inhibitors in mRCC patients.
572. Antibiotic-Free Nonviral pFAR4 Vector Displays Efficient Transgene Delivery in Mouse and Human Cells
Authors: Marie Pastor, Sandra Johnen, Mickael Quiviger, Zsuzsanna Izsvak, Daniel Scherman, Gabriele Thumann, Corinne Marie
Journal: Molecular Therapy (2015)

New generations of plasmid vectors used for non-viral gene therapy have a reduced size, thus allowing an increase in transfection efficiency and expression levels. We designed a novel vector, called pFAR4, which is Free of Antibiotic Resistance markers. In bacteria, the production of pFAR4 derivatives relies on a plasmid-borne function that suppresses a nonsense mutation introduced into an essential Escherichia coli gene. Thanks to its reduced size, pFAR4 appears to be an efficient gene vector as it displays a superior transgene expression level either after transfection of cultured B16 melanoma cells or electrotransfer into skin or tumors. Furthermore, hydrodynamic delivery into liver revealed that pFAR4 allowed a prolonged expression level, in comparison with kanamycin resistant plasmids that promote transgene silencing. We took advantage of the pFAR4 superiority in liver to assess a novel therapeutic approach for the Mucopolysaccharidosis type IIIA (MPS-IIIA) or Sanfilippo A syndrome. MPS-IIIA is a lysosomal storage genetic disease which results from the deficiency of the N-sulfoglucosamine sulfohydrolase (SGSH) protein, a sulfamidase required for the degradation of heparan sulfate glycosaminoglycans (GAGs). The accumulation of these macromolecules leads to somatic organ pathologies, severe neurodegeneration and patients' death. In MPS-IIIA mice, hydrodynamic delivery of a pFAR4 derivative expressing the deficient enzyme from a liver-specific promoter allowed high and prolonged serum levels of sulfamidase protein that was efficiently taken-up by neighboring organs after its endocytosis by mannose 6-phosphate receptors-expressing cells. This led to the correction of GAG accumulation in all peripheral organs as well as in the brain, albeit at early stages of the disease. Improvement of our approach is provided by fusing the SGSH protein with peptides mediating transcytocis across the blood-brain barrier. Having established that pFAR4 is a potent expression vector in a non-integrative approach, our next step consisted in combining the pFAR4 technology and the Sleeping Beauty (SB) transposon system, which is composed of a transposase that excises the transgene-containing transposon from a donor plasmid and mediates its integration into the host cells' genome. The reduced size of pFAR4 allowed an efficient delivery of SB components into human cells. Our current goal is to take the pFAR4 and Sleeping Beauty technologies to the clinic, in the context of an ex vivo gene therapy approach involving the transfection of autologous primary pigment epithelial cells for the treatment of neovascular age-related macular degeneration disease, in two phase I/II clinical trials.
A Phase II Study with Cyclophosphamide, Vincristine, Liposomal Doxorubicin (Myocet™), and Prednisone Plus Rituximab, Administered in a Two Weeks Regimen (R-COMP-14) as Primary Treatment for NHL: Efficacy and Safety Interim Analysis.
Authors: J. Herrero, J. Gómez-Codina, M. Provencio, A. Rueda, M. Llanos, P. Sabín, F. Lobo, D. Vicente, F. García-Arroyo, C. Iglesias
Journal: Blood (2007)
Abstract 354: Resistance to TGF-beta-induced apoptosis is not associated with the de-differentiation in hepatocellular carcinoma
Authors: Tomomi Kogiso, Etsuko Hashimoto, Kazuhisa Kodama, Yuichi Ikarashi, Nobuyuki Torii, Makiko Taniai, Katsutoshi Tokushige, Keiko Shiratori
Journal: Cancer Research (2015)

Abstract Aim: Transforming growth factor (TGF)-beta is a cytokine which induces apoptosis of hepatocellular carcinoma (HCC) cells. However, some HCC cells show resistance to the induction of apoptosis by TGF-beta. The analyses of the molecular mechanism underlying these phenomena may be related with the mechanisms of acquirement of drug-resistance. Thus, we examined molecularly the apoptosis-resistant HCC cells which we previously established, especially emphasizing on the analyses of the stem-cell marker expression in this study. Methods: Previously established HuH7R cells, which acquired a resistance to TGF-beta-induced apoptosis after a long-term culture under small amount of TGF-beta, and control parental HuH7 cells, were used. Apoptosis rate and cell cycle state of these cells after TGF-beta treatment were determined by a flow-cytometry. The expression levels of stem-cell surface markers, such as epithelial cell adhesion molecule (EpCAM) and CD133, and those of transcriptional factors: Oct4, HNF3alfa, HNF4beta, and C/EBPbeta, were analyzed by fluorescent labeling using specific antibodies, at 24hrs and 48hrs after TGF-beta treatment. Results: 1) HuH7 cells showed apoptosis after 48hrs of TGF-beta treatment, whereas HuH7R did not show apoptosis but entered cell-cycle arrest. 2) The expression levels of CD133 were not affected at both 24hrs and 48hrs after TGF-beta treatment, while EpCAM expression levels increased from 24hrs, in both HuH7 and HuH7R cells. 3) The expression levels of Oct4, HNF3alfa, HNF4beta, and C/EBPbeta were also increased in HCC cells. However, those expression profiles were almost comparable in between HuH7 and HuH7R cells. Conclusions: The acquisition of the resistance to TGF-beta-induced apoptosis in HCCs were not related with the expression changes of stem-cell markers. The acquisition of drug-resistance in HCC cells was considered through mechanisms other than the changes of the cellular differentiation status of HCC cells. Citation Format: Tomomi Kogiso, Etsuko Hashimoto, Kazuhisa Kodama, Yuichi Ikarashi, Nobuyuki Torii, Makiko Taniai, Katsutoshi Tokushige, Keiko Shiratori. Resistance to TGF-beta-induced apoptosis is not associated with the de-differentiation in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 354. doi:10.1158/1538-7445.AM2015-354
PTH-075 Is there a need for combined gastrointestinal and diabetes clinics? A prospective study of the prevalence of diarrhoea in patients with type 1 diabetes mellitus and findings on investigation
Authors: J S Leeds, A D Hopper, S Tesfaye, M Hadjivassiliou, D S Sanders
Journal: Gut (2010)

Although there are several empirical approaches that enable the comparison of relative agonist efficacy, the molecular basis that underlies differences in the ability of G protein-coupled receptor agonists to elicit a response is still largely unexplained. Several models have been described that incorporate the kinetics of receptor-mediated initiation of the G protein cycle, but these have not directly addressed the influence of agonist-binding kinetics. To test this, we investigated the relationship between the efficacy of seven M<sub>3</sub> muscarinic receptor agonists and their rate of dissociation (<i>k</i><sub>off</sub>) from the M<sub>3</sub> receptor. The association and dissociation rate constants of the agonists were determined using a <i>l</i>-[<i>N</i>-methyl]-[<sup>3</sup>H]scopolamine methyl chloride competition binding assay in the presence of GTP. The agonists displayed a range of association and dissociation rates. Relative agonist efficacy was measured at two points after M<sub>3</sub> receptor activation: the stimulation of guanosine 5′-<i>O</i>-(3-[<sup>35</sup>S]thio)triphosphate binding to Gα subunits, and the subsequent increase in intracellular calcium levels. These experiments revealed a range of intrinsic efficacy, from the low-efficacy pilocarpine and oxotremorine to high-efficacy acetylcholine. There was no relationship between agonist efficacy and the equilibrium binding affinity of each agonist (<i>K</i><sub>d</sub>). When efficacy was compared with the dissociation rate constant, however, the two were highly correlated, suggesting a relationship between the duration of agonist binding at the receptor and the intrinsic efficacy. These data suggest that kinetic models incorporating the mean lifetime of specific complexes will be required to fully explain the nature of agonist efficacy.
Forced HoxB4 Sustains CD45-c-kit+ Pre-Hematopoieitc Stem Cells (HSCs) Derived from Murine Induced-Pluripotent Stem Cells, Which Develop Long-Term and Short-Term Repopulating HSCs According to GATA2 Expression Level
Authors: Kiyoko Izawa, Tomoya Kakegawa, Masayuki Yamamoto, Arinobu Tojo
Journal: Blood (2014)
Abstract 5092: Midkine as a potential target for combating drug resistance and invasion in melanoma
Authors: Amanpreet Kaur, Michael O'Connell, Marie Webster, Reeti Behera, Vanessa Dang, Abibatou Ndoye, Ashani Weeraratna
Journal: Cancer Research (2015)

Abstract Melanoma is an aggressive disease. Although about 13% of melanoma cases are diagnosed at metastatic stage, the 5-year survival rate for these patients is 16%. We have previously shown that metastatic melanoma cells express high levels of Wnt5a. Wnt5a is a member of the Wnt family of proteins, which play an important role during development and tumorigenesis. In melanoma, Wnt5a signaling is mediated by an autocrine loop that also modulates the activity of midkine. Midkine is a 16kDa protein that is elevated in many different cancers. Overexpression of midkine promotes the growth, migration, survival and angiogenic capability of the tumors. However, the molecular mechanisms that regulate the activity of midkine are unknown, especially in metastatic melanoma. We asked whether Wnt5a can positively regulate the functions of midkine to promote the progression of metastatic melanoma. To address this, we analyzed melanoma cells for midkine expression and observed that Wnt5a high melanoma cells also express high levels of midkine. Further, an increase in Wnt5a signaling by treatment with recombinant Wnt5a led to an increased midkine signaling. By performing 3D spheroid assays, we observed that higher expression of midkine is correlated with an increased metastatic ability of the cells. The expression of midkine also correlated with an increased resistance to BRAF inhibitors in BRAF V600E mutated melanoma. This indicates that midkine may signal through MAPK pathway to affect invasion and drug resistance in metastatic melanoma. Developing adjuvant therapies targeting midkine can prolong the overall survival of patients with metastatic melanoma. Citation Format: Amanpreet Kaur, Michael O'Connell, Marie Webster, Reeti Behera, Vanessa Dang, Abibatou Ndoye, Ashani Weeraratna. Midkine as a potential target for combating drug resistance and invasion in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5092. doi:10.1158/1538-7445.AM2015-5092
Retrospective evaluation of chemotherapy options in non-squamous non-small cell lung cancer (non-Sq NSCLC) patients (pts) unfit for standard platinum-based chemotherapy in clinical practice
Authors: A. Cortellini, G. Bruera, I. Sarno, P. Lanfiuti Baldi, K. Cannita, A. Dal Mas, A. Marchetti, C. Ficorella, E. Ricevuto
Journal: Annals of Oncology (2015)