23 research outputs found
Customizing the therapeutic response of signaling networks to promote antitumor responses by drug combinations
No full textThis work was supported by grants from Breakthrough Breast Cancer and Scottish Funding Council (SRDG), and personal support to Alexey Goltsov from Scottish Informatics and Computer Science Alliance (SICSA) and to James Bown from The Northwood Trust.Drug resistance, de novo and acquired, pervades cellular signaling networks (SNs) from one signaling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anti-cancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where SN sensitivity increases due to combination components or as a result of de novo or acquired mutations. Additionally, successive drug combinations have shown low resistance potential. To promote a rational, systematic development of combination therapies, it is necessary to establish the underlying mechanisms that drive the advantages of combination therapies, and design methods to determine drug targets for combination regimens. Based on a joint systems analysis of cellular SN response and its sensitivity to drug action and oncogenic mutations, we describe an in silico method to analyze the targets of drug combinations. Our method explores mechanisms of sensitizing the SN through a combination of two drugs targeting vertical signaling pathways. We propose a paradigm of SN response customization by one drug to both maximize the effect of another drug in combination and promote a robust therapeutic response against oncogenic mutations. The method was applied to customize the response of the ErbB/PI3K/PTEN/AKT pathway by combination of drugs targeting HER2 receptors and proteins in the down-stream pathway. The results of a computational experiment showed that the modification of the SN response from hyperbolic to smooth sigmoid response by manipulation of two drugs in combination leads to greater robustness in therapeutic response against oncogenic mutations determining cancer heterogeneity. The application of this method in drug combination co-development suggests a combined evaluation of inhibition effects together with the capability of drug combinations to suppress resistance mechanisms before they become clinically manifest.Peer reviewe
The Society of Orthodox Parishes of Petrograd and its Province (1920–1922): the Experience of Sobornost under Persecution
No full textThis article is devoted to the history of the Society of Orthodox Parishes of Petrograd and its Province — a public organization registered by the Soviet government in 1920, which during its 18 months of existence united around 70 parishes of the Petrograd diocese. In 1922, it was administratively dissolved, and its board members found themselves at the centre of accusations of resisting the seizure of church valuables. In addition to the general issues that have been considered to a greater or lesser extent in historiography (the circumstances of the Society’s emergence, its purpose, structure, and main activities), in this article the author explores the founders’ ecclesiological views, finding that their key category for conceiving of church life was sobornost. The author also focuses on the peculiarities of the Society’s legal status and its actual position within the contexts of life within the church and under Soviet legislation in the early 1920s. Here, for the first time, the question of the organization’s relationship with the Petrograd Diocesan Council is posed, and analysis leads us to conclude that there was a conflict between the agencies of diocesan administration and the social movement within the church, which was clearly manifest in the late 1910s and early 1920s. The Society’s potential was realized after the liquidation of the Diocesan Council, when as a group free from the reins of the diocesan administration system, it turned out to be the largest and most representative church association in Petrograd, striving to influence a whole range of issues related to parish life. The article also attempts to outline the connection between the Society and preceding and subsequent phenomena within post-revolutionary church life, including the Local Council of 1917–1918 and the Renovationist movement, whose participants were directly related to the Society
A simple, rapid, and highly informative PCR‐based procedure for prenatal diagnosis and carrier screening of phenylketonuria
No full textIdentification and characterization of RTVP1/GLIPR1-like genes, a novel p53 target gene cluster
No full textAbstractOur previous finding of RTVP1 (GLIPR1) as a p53 target gene with tumor suppressor functions prompted us to initiate a genome-wide sequence homology search for RTVP1/GLIPR1-like (GLIPR1L) genes. In this study we report the identification and characterization of a novel p53 target gene cluster that includes human RTVP1 (hRTVP-1) together with two GLIPR1L genes (GLIPR1L1 and GLIPR1L2) on human chromosome 12q21 and mouse Rtvp1 (mRTVP-1 or Glipr1) together with three Glipr1-like (Glipr1l) genes on mouse chromosome 10D1. GLIPR1L1 has two and GLIPR1L2 has five differentially spliced isoforms. Protein homology search revealed that hRTVP-1 gene cluster members share a high degree of identity and homology. GLIPR1L1 is testis-specific, whereas GLIPR1L2 is expressed in different types of tissues, including prostate and bladder. Like hRTVP-1, GLIPR1L1 and GLIPR1L2 are p53 target genes. The similarities of these novel p53 target gene cluster members in protein structure and their association with p53 suggest that these genes may have similar biological functions
Complete Spectrum of PAH Mutations in Tataria: Presence of Slavic, Turkic and Scandinavian Mutations
No full textAbstract A38: Caveolin-1 as a biomarker of drug response and therapeutic target in association with tyrosine kinase inhibitor treatment in prostate cancer models
No full textAbstract
We have shown that caveolin-1 (Cav-1) is overexpressed in metastatic prostate cancer (PCa) and that virulent PCa cells secrete biologically active Cav-1. Secreted Cav-1 can be taken up by adjacent PCa and tumor-associated endothelial cells and promote tumor angiogenesis. We investigated the effect of dasatinib and sunitinib on proliferation, tyrosine kinase (TK) phosphorylation, and downstream signaling pathways, including Cav-1 expression and secretion in hormone-refractory PCa cell lines (PC-3 and DU145) in vitro. Dasatinib inhibited proliferation of PC-3 and DU145 at doses from 0.05 to 5.0 μM; sunitinib inhibited their proliferation at doses from 0.2 to 20 μM. Dasatinib and sunitinib treatment yielded a dose-dependent reduction in phosphorylation of PDGFR (Y857), VEGFR2 (Y951), Akt (S473), and Cav-1 (Y14) in PC-3 and DU145 cells relative to that in controls. Further, dasatinib treatment of PC-3 and DU145 cells resulted in reduced phosphorylation of FAK (Y861) and Src (Y416). Sunitinib did not cause a similar effect on FAK in PC-3 and DU145 cells but did cause a reduction in Src phosphorylation of DU145, though not of PC-3 cells. It was interesting that dasatinib and sunitinib treatment of PC-3 and DU145 cells each inhibited the secretion of Cav-1 and caused moderate reduction in cellular Cav-1.
To analyze the role of secreted Cav-1 as a biomarker of drug response and therapeutic target in the context of dasatinib and sunitinib treatment in vivo, we used PC-3 and DU145 subcutaneous xenograft models. PC-3 xenografts were treated with dasatinib (15 mg/kg q.d., p.o.), Cav-1 antibody (Ab; 10 μg, q.o.d., i.p.), or combined dasatinib and Cav-1 Ab, or vehicle alone. DU145 xenografts were treated with sunitinib (10 mg/kg q.d., p.o.), Cav-1 Ab (10 μg, q.o.d., i.p.), combined sunitinib and Cav-1 Ab, or vehicle alone. Treatment with either dasatinib or Cav-1 Ab produced significant tumor regression (P = 0.0072 and 0.0307, respectively) compared with that of vehicle or IgG. Combined dasatinib and Cav-1 Ab produced greater tumor regression than either treatment alone, but the differences did not achieve statistical significance. Similarly, treatment with either sunitinib or Cav-1 Ab induced significant DU145 tumor regression (P= 0.0004 and 0.0016, respectively) compared with that of vehicle or IgG. Combined sunitinib and Cav-1 Ab induced greater but not significantly different tumor regression than either treatment alone. We found it interesting that serum Cav-1 levels were significantly lower in dasatinib-treated mice than they were in vehicle-treated mice (P = 0.0271). Sunitinib treatment also led to lower serum Cav-1 levels than the vehicle did, but these differences were not statistically significant (P = 0.0871). An important note is that serum Cav-1 levels correlated positively with tumor growth (wet weight) in combined vehicle- and dasatinib-treated groups (r = 0.48, P = 0.031) and combined vehicle- and sunitinib-treated groups (r = 0.554, P = 0.0065).
Overall, our results show that dasatinib and sunitinib can each inhibit PCa cell growth both in vitro and in vivo and that growth inhibition is associated with inhibition of TK phosphorylation and downstream signaling and suppression of Cav-1 secretion. We also found that reduced serum Cav-1 was associated with dasatinib and sunitinib treatment and that serum Cav-1 levels correlate positively with tumor growth. Moreover, we showed that systemic administration of Cav-1 Ab led to suppressed tumor growth in PCa xenografts. These results suggest roles for secreted/serum Cav-1 as a biomarker of drug response and as a therapeutic target in association with dasatinib or sunitinib treatment in PCa.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A38</jats:p
Author Correction: Plasmonic nano-aperture label-free imaging of single small extracellular vesicles for cancer detection
No full textPhenylketonuria in Costa Rica: preliminary spectrum of PAH mutations and their associations with highly polymorphic haplotypes
No full textArtículo científico -- Universidad de Costa Rica, Instituto de Investigaciones en Salud. 1996. Este artículo es privado debido a limitaciones de derechos de autor.A preliminary evaluation of the molecular basis of phenylketonuria (PKU) in Costa Rica was made by performing mutational analyses in the six PKU families identified to date. These studies revealed the presence of the previously reported European mutations IVS ntS, L48S, E221G and IVS12M1 as well as the novel mutation IVS7nt3. The combined use of the STR, VNTR and Xmol polymorphic systems for the PAH gene resulted in a discriminant distribution of haplotypes among normal and mutant chromosomes and suggests its potential usefulness for future diagnostic applications in Costa Rican PKU kindreds. This is the first report of a genetic analysis in a Central American PKU population.Baylor College of Medicine, HoustonInstitute of Human and Molecular GeneticsUniversidad de Costa Rica, Instituto de Investigaciones en SaludUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA
