Search results for "Pten"
showing 10 items of 211 documents
AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.
2009
SummaryDysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PI…
Abstract B154: A first-in-human trial of GDC-0068: A novel, oral, ATP-competitive Akt inhibitor, demonstrates robust suppression of the Akt pathway i…
2011
Abstract GDC-0068 is a highly selective ATP-competitive small molecule that inhibits all three isoforms of Akt with IC50 values of 5 to 30 nM. GDC-0068 selectively inhibits cancer cells with activated Akt signaling (e.g. via PTEN loss or PIK3CA mutations). Patients with advanced solid tumors were treated with GDC-0068 using a 3+3 escalation design. GDC-0068 was dosed PO QD on a 21-day on, 7-day off schedule; endpoints included safety, pharmacokinetics (PK) and determination of pathway knockdown. Pharmacodynamics (PD) endpoints in surrogate tissue [platelet rich plasma (PRP)] were evaluated in all patients. In addition, at least two patients per cohort had pre- and on-treatment (day 15) tumo…
Clinical and Molecular-Based Approach in the Evaluation of Hepatocellular Carcinoma Recurrence after Radical Liver Resection
2021
Background: Hepatic resection remains the treatment of choice for patients with early-stage HCC with preserved liver function. Unfortunately, however, the majority of patients develop tumor recurrence. While several clinical factors were found to be associated with tumor recurrence, HCC pathogenesis is a complex process of accumulation of somatic genomic alterations, which leads to a huge molecular heterogeneity that has not been completely understood. The aim of this study is to complement potentially predictive clinical and pathological factors with next-generation sequencing genomic profiling and loss of heterozygosity analysis. Methods: 124 HCC patients, who underwent a primary hepatic …
Antibody generation and immunoassay development in diverse formats for pyrimethanil specific and sensitive analysis
2012
Immunochemical techniques are complementary tools to modern analytical requirements. These methods rely on the production of immunoreagents with adequate binding properties. In the present study, a rationally designed and functionalized derivative of pyrimethanil-a modern anilinopyrimidine fungicide-was synthesized in order to generate for the first time high-affinity and selective antibodies to this xenobiotic. A single coupling procedure-based on hapten activation using N,N′-disuccinimidyl carbonate and purification of the active ester-was followed to prepare both immunizing and assay conjugates. Polyclonal antibodies were produced and characterized by enzyme-linked immunosorbent assay (E…
Circulating specific antibodies enhance systemic cross-priming by delivery of complexed antigen to dendritic cells in vivo
2012
Increasing evidence suggests that antibodies can have stimulatory effects on T-cell immunity. However, the contribution of circulating antigen-specific antibodies on MHC class I cross-priming in vivo has not been conclusively established. Here, we defined the role of circulating antibodies in cross-presentation of antigen to CD8(+) T cells. Mice with hapten-specific circulating antibodies, but naϊve for the T-cell antigen, were infused with haptenated antigen and CD8(+) T-cell induction was measured. Mice with circulating hapten-specific antibodies showed significantly enhanced cross-presentation of the injected antigen compared with mice that lacked these antibodies. The enhanced cross-pre…
Quantitative analysis of mixtures of metal-carbonyl complexes by Fourier-transform infrared spectroscopy: application to the simultaneous double immu…
1996
Abstract The feasibility of a double immunoassay of haptens by the nonisotopic carbonyl metalloimmunoassay (CMIA) method is demonstrated. Three different pairings of antiepileptic medications from the groups carbamazepine, diphenylhydantoin, and phenobarbital (for each of which a mono-CMIA is already available) were assayed by double CMIA. The assay method employs as tracers metal–carbonyl complexes that give very strong signals in the range of 1850–2200 cm −1 in the infrared spectrum, permitting quantitative analysis by Fourier-transform infrared spectroscopy. The fact that the signals are individually assignable and of comparable intensity permits quantitative analysis of mixtures of two …
Immunoanalytical approaches for the control of xenobiotics and biotoxins in food
2020
[ES] El control efectivo de la calidad y seguridad de los alimentos requiere de métodos analíticos que garanticen la determinación fiable de cualquier sustancia potencialmente perjudicial para el consumidor que pueda estar presente en el alimento antes de su distribución y comercialización. Una de las aproximaciones analíticas que contribuye a garantizar este objetivo engloba una serie de técnicas que tienen en común la utilización de anticuerpos como elementos esenciales para la detección del analito diana, y que en conjunto reciben el nombre de métodos inmunoquímicos. Este artículo pretender aportar una visión básica de los principios bioquímicos subyacentes a estas tecnologías y cuáles…
Activation and translocation of p38 mitogen-activated protein kinase after stimulation of monocytes with contact sensitizers.
2002
Recently we described the induction of tyrosine phosphorylation by contact sensitizers as an early molecular event during the activation of antigen- presenting cells. In this study, the role of the p38 mitogen-activated protein kinase for the activation of human monocytes after exposure to four structurally unrelated contact sensitizers was analyzed in comparison with the irritant benzalkonium chloride and an inductor of oxidative stress (H 2 O 2 ) using immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay techniques. Bio chemical analysis revealed a translocation of p38 from the cytoplasm to the detergent-resistant cell fraction only upon stimulation with contact sen…
Nuclear Localization of PTEN by a Ran-dependent Mechanism Enhances Apoptosis: Involvement of an N-Terminal Nuclear Localization Domain and Multiple N…
2006
The targeting of the tumor suppressor PTEN protein to distinct subcellular compartments is a major regulatory mechanism of PTEN function, by controlling its access to substrates and effector proteins. Here, we investigated the molecular basis and functional consequences of PTEN nuclear/cytoplasmic distribution. PTEN accumulated in the nucleus of cells treated with apoptotic stimuli. Nuclear accumulation of PTEN was enhanced by mutations targeting motifs in distinct PTEN domains, and it was dependent on an N-terminal nuclear localization domain. Coexpression of a dominant negative Ran GTPase protein blocked PTEN accumulation in the nucleus, which was also affected by coexpression of importin…
Site-heterologous haptens and competitive monoclonal antibody-based immunoassays for pyrimethanil residue analysis in foodstuffs
2015
Pyrimethanil is a widely used post-harvest fungicide whose residues are commonly found in fruits and vegetables. We herein report the synthesis of two new functionalized derivatives of pyrimethanil carrying an equivalent spacer arm at different positions of the molecule. The influence of the linker tethering site on the affinity of monoclonal antibodies was shown. Moreover, the development of competitive immunoassays in different formats and with high sensitivity to the target analyte - IC50 values below 0.3μg/L - is described. Optimized assays were characterized by the determination of the limit of quantification, trueness, and precision using water-diluted QuEChERS extracts of fruits and …