Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Radiocontrast media (RCM)-induced nephrotoxicity (CIN) is a major clinical problem accounting for 12% of all hospital-acquired cases of acute kidney injury (AKI). The pathophysiology of AKI due to RCM is not well understood, but direct toxic effects on renal cells have been postulated as contributing to CIN. It is believed that iso-osmolar RCM (IOCM) are less nephrotoxic than low-osmolar RCM (LOCM) but clinical data have been controversial. We have investigated the intracellular signaling pathways that may be affected by the LOCM iomeprol (IOM) and the IOCM iodixanol (IOD). Both IOM and IOD caused a dramatic decrease in phosphorylation of the kinase Akt at Ser473 and Thr308 in human renal tubular (HK-2) cells, with IOM having a greater effect; IOM also caused a greater decrease in cell viability. IOM also had a greater effect on phosphorylation of p38 MAP kinases, JNKs, and NF-kB (Ser276), and caused a marked decrease in the phosphorylation of forkhead box O3a (FOXO3a) and signal transducer and activator of transcription 3 (STAT3). However, IOD caused a greater decrease in the phosphorylation of mTOR (Ser2448) and phospho-ERK 1/2 while both RCM caused a similar decrease in the phosphorylation of phospho-p70S6 kinase (Ser371). In vivo studies showed that both IOM and IOD caused a significant decrease in both pAkt (Ser473) and pERK 1/2 in rat kidneys. Our study gives an insight into the possible mechanism of toxicity of RCM via their action on intracellular signaling pathways and may help in developing pharmacological interventions for their side-effects.
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PMID:Differential activation of signaling pathways by low-osmolar and iso-osmolar radiocontrast agents in human renal tubular cells. 2402 12

Recently, the Cancer Genome Atlas (TCGA) Research Network and Asian Cancer Research Group provided a new classification of gastric cancer (GC) to aid the development of biomarkers for targeted therapy and predict prognosis. We studied associations between genetically aberrant profiles of cancer-related genes, environmental factors, and histopathological features in 107 paired gastric tumor-non-tumor tissue GC samples. 6.5% of our GC cases were classified as the EBV subtype, 17.8% as the MSI subtype, 43.0% as the CIN subtype, and 32.7% as the GS subtype. The distribution of four GC subgroups based on the TCGA and our dataset were similar. The MSI subtype showed a hyper-mutated status and the best prognosis among molecular subtype. However, molecular classification based on the four GC subtypes showed no significant survival differences in terms of overall survival (p= 0.548) or relapse-free survival (RFS, p=0.518). The P619fs*43 in ZBTB20 was limited to MSI group (n= 5/19, 26.3%), showing similar trends observed in TCGA dataset. Genetic alterations of the RTK/RAS/MAPK and PI3K/AKT/mTOR pathways were detected in 34.6% of GC cases (37 individual cases). We also found two cases with likely pathogenic variants (NM_004360.4: c. 2494 G>A, p.V832M) in the CDH1 gene. Here, we classified molecular subtypes of GC according to the TCGA system and provide a critical starting point for the design of more appropriate clinical trials based on a comprehensive analysis of genetic alterations in Korean GC patients.
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PMID:Profiling cancer-associated genetic alterations and molecular classification of cancer in Korean gastric cancer patients. 2905 Feb 49

While extremely rare in humans, hemangiosarcoma (HSA) accounts for nearly 2% of canine neoplasia, and is characterized by both aggressive local growth/invasion and a high rate of metastasis. Both canine and human HSA exhibit sustained aberrant PI3K/Akt/mTOR pathway signaling. The purpose of this study was to examine the in vitro effects of a novel dual PI3K/mTOR inhibitor, VDC-597, in three canine HSA cell lines (DEN-, CIN-, and SB-HSA). VDC-597 suppressed activation of both Akt and 4eBP1 in canine HSA cells in a dose-dependent fashion, with an IC50 of approximately 0.3 uM, a concentration predicted to be clinically achievable based on preliminary early-phase canine and human studies. VDC-597 dose-dependently reduced proliferation, migration, and vascular endothelial growth factor production in HSA cells, while promoting tumor cell apoptosis. VDC-597 demonstrated additive antiproliferative effects when combined with doxorubicin. These results suggest that inhibitors of the PI3K/mTOR pathway may act against multiple components of the neoplastic process, including proliferation/apoptosis, chemosensitivity, migration, and angiogenesis, and justify the evaluation of PI3K/mTOR inhibitors in canine, and potentially human, HSA.
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PMID:In vitro effects of PI3K/mTOR inhibition in canine hemangiosarcoma. 3001 43