Search results for "Pyrimidinones"
showing 10 items of 20 documents
Disruption of TCF/β-Catenin Binding Impairs Wnt Signaling and Induces Apoptosis in Soft Tissue Sarcoma Cells
2017
Abstract Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumors with more than 50 different subtypes. The Wnt signaling pathway is involved in the development and in the regulation, self-renewal, and differentiation of mesenchymal stem cells, and plays a role in sarcomagenesis. In this study, we have tested pharmacologic inhibition of Wnt signaling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects. We have shown that disruption of TCF/β-catenin binding with PKF118-310 produces in vi…
PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
2017
AbstractCombined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoprote…
Current practice of chronic hepatitis B treatment in Southern Italy
2012
Abstract Background Treatment choice for chronic HBV infection is a continuously evolving issue, with a wide range of options. We aimed to evaluate the current practice of HBV therapies in the real world in Southern Italy. Methods A prospective study enrolling over a six month period (February–July 2010) all consecutive HBsAg positive subjects, never previously treated, referred to 16 liver units in two Southern Italy regions (Calabria and Sicily). Results Out of 247 subjects evaluated, 116 (46.9%) had HBV-DNA undetectable or lower than 2000 UI/ml. There were 108 (43.7%) inactive carriers, 103 (41.7%) chronic hepatitis, and 36 (14.6%) liver cirrhosis. Antiviral treatment was planned in 94 (…
β-Catenin Signaling Drives Differentiation and Proinflammatory Function of IRF8-Dependent Dendritic Cells
2014
Abstract β-Catenin signaling has recently been tied to the emergence of tolerogenic dendritic cells (DCs). In this article, we demonstrate a novel role for β-catenin in directing DC subset development through IFN regulatory factor 8 (IRF8) activation. We found that splenic DC precursors express β-catenin, and DCs from mice with CD11c-specific constitutive β-catenin activation upregulated IRF8 through targeting of the Irf8 promoter, leading to in vivo expansion of IRF8-dependent CD8α+, plasmacytoid, and CD103+CD11b− DCs. β-Catenin–stabilized CD8α+ DCs secreted elevated IL-12 upon in vitro microbial stimulation, and pharmacological β-catenin inhibition blocked this response in wild-type cells…
Low Rate of Virological Failure and Maintenance of Susceptibility to HIV-1 Protease Inhibitors with First-Line Lopinavir/Ritonavir-Based Antiretrovir…
2010
Protease inhibitor (PI)-resistant HIV-1 has hardly ever been detected at failed boosted PI-based first-line antiretroviral regimens in clinical trials. However, this phenomenon has not been investigated in clinical practice. To address this gap, data from patients starting a first-line lopinavir/ritonavir (LPV/rtv)-based therapy with available baseline HIV-1 RNA load, a viral genotype and follow-up viral load after 3 and 6 months of treatment were extracted from the Italian Antiretroviral Resistance Cohort Analysis (ARCA) observational database. Based on survival analysis, 39 (7.1%) and 43 (7.8%) of the 548 examined patient cases had an HIV-1 RNA >500 and >50 copies/ml, respectively, after …
Role of Kras Status in Patients with Metastatic Colorectal Cancer Receiving First-Line Chemotherapy plus Bevacizumab: A TTD Group Cooperative Study
2012
Background: In the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates. Methodology/Principal Findings: KRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses. These data were then cross-referenced with efficacy da…
Density Functional Theory Study of the Trans-Trans-Cis (TTC)→Trans-Trans-Trans (TTT) Isomerization of a Photochromic Spiropyran Merocyanine
2008
Density Functional Theory (DFT) calculations have been performed on the TTC→TTT isomerization reaction of the open forms of the 1',3'-dihydro-8-bromo-6-nitro- 1',3',3'-trimethylspiro[2H-1-benzopyran-2,2'-(2H)indole (8-Br-6-nitro-BIPS) system. The calculations were carried out in vacuo and in methylene chloride solution at different temperatures. Results are compared with the available experimental values of free energy difference and activation energy in solution.
Design and Synthesis of 4-Substituted Indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine Derivatives with Antitumor Activity
2008
New derivatives of the indolo[3,2- e][1,2,3]triazolo[1,5- a]pyrimidine system, substituted in the 4 position, were designed as novel antitumor agents because of their theoretical capability to form stable complexes with DNA fragments. The calculated free energies of binding were found in the range -12.76 --> -39.68 Kcal/mol. The docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs, whereas the side chain lies along the minor groove. Compounds, selected on the basis of the docking studies and suitably synthesized, showed antiproliferative activity against each type of tumor cell line investigated, generally in the low micromolar range. The mo…
Synthesis of pyrido[2,3-d]pyrimidinones by the reaction of aminopyrimidin-4-ones with benzylidene meldrum's acid derivatives
1997
A series of pyrido[2,3-d]pyrimidine-4,7-diones 5a-h were prepared from 6-amino-4-pyrimidones 1 and benzylidene Meldrum's acid derivatives 2 by cyclization reactions in boiling nitrobenzene. The structure of 5, determined by nmr measurements, reveals a selective orientation of 1 and 2 in the addition step.
ChemInform Abstract: Synthesis of Pyrido(2,3-d)pyrimidinones by the Reaction of Aminopyrimidin-4-ones with Benzylidene Meldrum′s Acid Derivatives.
2010
A series of pyrido[2,3-d]pyrimidine-4,7-diones 5a-h were prepared from 6-amino-4-pyrimidones 1 and benzylidene Meldrum's acid derivatives 2 by cyclization reactions in boiling nitrobenzene. The structure of 5, determined by nmr measurements, reveals a selective orientation of 1 and 2 in the addition step.