1,721,008 research outputs found
Novel Molecular Findings in Protein Tyrosine Phosphatase Receptor Gamma (PTPRG) Among Chronic Myelocytic Leukemia (CML) Patients Studied By Next Generation Sequencing (NGS): A Pilot Study in Patients from the State of Qatar and Italy
Full text linkBackground: Chronic Myelocytic Leukemia (CML) is a clonal myeloproliferative disorder characterized by constitutive phosphorylation of Protein Tyrosine kinases (PTKS) that continuously activates multiple proliferative and antiapoptotic signaling pathways. Protein Tyrosine Phosphatases (PTPs) on the other hand is potential natural inhibitory mechanism for regulating the tyrosine kinase activities in which phosphorylation is reciprocally controlled and maintained in equilibrium state by PTKs and PTPs. As a member of PTPs family, Protein Tyrosine Phosphatase Receptor Gamma (PTPRG) was found to act as a tumor suppressor gene. This negative regulatory mechanism of PTPRG was observed to be down-regulated and disabled in CML and one of the possible mechanisms that alter the  negative regulatory effect of PTPs is mutations. Several mutations have been identified in PTPs in many different leukemias such as Acute Myeloid Leukemia (AML), Juvenile MyeloMonocytic Leukemia (JMML), Myelodysplasic Syndrome (MDS), B- cell Acute Lymphoblastic Leukemia (B-ALL) and these mutations are associated with hyper- cellular proliferation, disease progression and poor outcome. However, relatively little is known about PTPRG mutations and no studies on CML are available in the literature while mutations inBCR-ABL1tyrosine kinase have been extensively characterized. Thus, understanding the role of PTPRG in antagonizing the PTK phosphorylation of BCR-ABL1 will be important to determine its role in CML development and progression. Aim: 1) To identify potential genetic alterations causing inactivation of PTPRG and 2) correlate the PTPRG findings with patients' response to the Tyrosine kinase Inhibitors. Methods: 16 CML patients, 9 from Qatar and 7 from Italy respectively, were studied for PTPRG mutations by exome sequencing. Custom primers were designed for Human PTPRG gene (5 Kb of exonic region of interest) using Ion AmpliSeq Designer. Target regions were enriched and amplified for the 16 DNA samples using Ion AmpliSeq Library kit 2.0. The amplicons were partially digested with FuPa reagent and phosphorylated prior to ligation of Ion Xpress Barcode Adapters followed by cleanup using HighPrep reagent. The adapter ligated molecules were enriched with adapter specific primers using a limited cycle PCR followed by a cleanup using HighPrep reagent. The final libraries were quantified on Qubit Flurometer using Qubit dsDNA HS Assay Kit and Agilent Bioanalyzer using Agilent High Sensitivity DNA Kit. All samples were pooled according to the concentrations on the Bioanalyzer and loaded on Ion 318TM Chip kit V2 to be sequenced on Ion Personal Genome Machine (PGM) system. European Leukemia Net (ELN) 2013 criteria were employed to assess the response/resistance of patients to treatment. Responses are defined at the hematological, cytogenetic and molecular levels. Patients response was classified into optimal and failure Results: Four mutations/variants were identified in PTPRG genes, three were missense Y92H, G574S, S561Y and 1 was frameshift Y285fs in the 16 CML patients. PTPRG Y92H was identified in 5 (1 Homozygous and 4 heterozygous alleles) patients and the 5 patient failed the Imatinib Mesylate (IM) treatment. On the other hand, The PTPRG G574S was identified in 6 (2 homozygous and 4 heterozygous alleles) patients. Out of the 6 patients, 4 were classified as failure to the treatment and 2 responded optimally. In addition, the PTPRG S561Y and Y285fs were identified on 1 and 3 patients respectively and these patients responded optimally to IM treatment. Discussion and Conclusions: This is the first prospective pilot study to investigate PTPRG gene mutations as underlying mechanism to explain treatment failure. Our preliminary data showed that the identified variant PTPRG Y92H might be associated with IM failure although it has been reported as Single Nucleotide Polymorphisms (SNPs) (rs62620047) and this could be attributed that some polymorphisms might behave like a mutation. On the other hand, PTPRG G574S variant (rs2292245) showed various clinical outcomes regardless to its allele zygosity as 67% (4/6) of patients failed the TKIs treatment. From the results of our pilot study we recommend carrying out PTPRG sequencing in a significantly larger cohort of patients to further explore and pinpoint the crucial mutations that can be correlated with CML resistance/response to treatment
Abstract 5731: The prognostic significance of EGFR, HER-2, HER-4, EGFRvIII, c-MET, Ki67 and CD44 in patients with FIGO stages III and IV ovarian cancer
No full textAbstract
Overexpression and activation of HER (human epidermal growth factor receptor) family members have been reported in a wide range of epithelial tumours. Although several monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs) specific for the HER members have been approved for the treatment of patients with a wide range of tumours, none has yet been approved for the treatment of patients with ovarian cancer. In some studies, the co-expression of other growth factor receptors (e.g. c-MET), the presence of cancer stem cells (CSCs) have been associated with resistance to therapy with the HER inhibitors. The aim of the present study was to determine the expression level and prognostic significance of the EGFR, HER-2, HER-4 and EGFRvIII, as well as c-MET, CD44 and cell proliferation marker Ki67 in 60 patients with FIGO stage III and IV ovarian cancer. The expression levels of these markers were determined, at different cut off values, using immunohistochemistry (IHC), and their associations with the overall survival and disease free survival were evaluated using Chi-squared and Kaplan-Meier survival curves and log-rank test as well as the univariate Cox-regression analysis. At cut off values of >5% of tumour cells with positive immunostaining, 62%, 93%, 45%, 3%, 21%, 48%, and 95%, of the cases were positive for EGFR, HER-2, HER-4, EGFRvIII, c-MET, CD44, Ki67 respectively and 28% were positive for the co-expression of EGFR/HER-2/HER-4. The cellular location of immunostaining was membranous for EGFR, HER-2, c-MET and CD44 and was present in 33%, 10%, 3% and 50% of the cases examined respectively. In univariate analysis, the expression of EGFR at cut-off values of >50% (HR, 3.57; 95% CI, 1.07 to 11.85; P= <0.0001) and CD44 with 3+ intensity at cut-off values >5 % (HR, 8.20; 95% CI, 2.02 to 33.2; P= <0.0001) were associated with poorer overall survival. In contrast, the positive immunostaining of Ki67 at cut-off value >5% of tumour cells, was associated with better overall survival (HR, 0.13; 95% CI, 0.02 to 0.73; P= 0.021 respectively). In addition, at cut-off value of >5% of tumour cells with positive immunostaining, EGFR expression (HR, 2.83; 95% CI 1.18 to 6.77; P = 0.019) and >10% (HR, 2.40; 95% CI 1.07 to 5.37; P= 0.032 ), as well as the co-expression of EGFR/HER-2 (HR, 2.83; 95% CI 1.18 to 6.77; P= 0.019), EGFR/c-MET (HR, 3.05; 95% CI 1.2 to 7.75; P= 0.019) and EGFR/Ki67 (HR, 2.83; 95% CI 1.18 to 6.77; P= 0.019) were all associated with poorer disease free survival in these patients. Our results suggest that co-expression of EGFR\HER-2\HER4 is common in patients with Stages III and IV ovarian cancers and support the need for investigations on the therapeutic potential of various forms of pan-HER inhibitors in such patients.
Citation Format: Soozana Puvanenthiran, Sharadah Essapen, Ben Haagsma, Izhar Bagwan, Alan Seddon, Helmout Modjtahedi. The prognostic significance of EGFR, HER-2, HER-4, EGFRvIII, c-MET, Ki67 and CD44 in patients with FIGO stages III and IV ovarian 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 5731. doi:10.1158/1538-7445.AM2017-5731</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Production and Characterization of a Monoclonal Antibody against an Antigen on the Surface of Non-Small Cell Carcinoma of the Lung Production and Characterization of a Monoclonal Antibody against an Antigen on the Surface of Non-Small Cell Carcinoma of th
No full textABSTRACT Background: Lung carcinoma is a multiple type cancer comprising of small cell and non-small cell carcinomas (NSCLC). For therapeutic and diagnostic purposes, serum monoclonal antibodies have been produced against lung cancer. Objective: To characterize a murine monoclonal antibody (ME3D11) reactive with human NSCLC. Methods: A murine monoclonal antibody (ME3D11) reactive with human NSCLC was selected after immunization of BALB/c mice with a human large cell carcinoma with neuroendocrine differentiation, and was tested by immunofloursence staining and Western blot analysis. Results: Our study showed that the antigen recognized by ME3D11 antibody was a cell surface antigen of 170kDa. This antigen is expressed on the cell surface of all NSCLC and a few carcinoma cell lines. In contrast, this antigen is neither expressed on the cell surface of human sarcoma, nor on the hematopoietic and normal cell lines. This antibody had no effect on spontaneous proliferation of Mehr-80 cell line in vitro. Conclusion: High degree of binding of this monoclonal antibody to NSCLC and some other carcinoma cells warrants further studies on its potential use in diagnosis and therapy of cancer by conjugation to drugs, toxins or radionuclides
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