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Background Activating mutations in the KRAS gene occur frequently in human tumors, including colorectal carcinomas; most mutations occur in codons 12 and 13. Mutations in KRAS have been associated with poor response to anti-epidermal growth factor receptor antibodies. Therefore, an accurate and readily available analysis of KRAS mutational status is needed. The aim of this study was to evaluate concordance between KRAS assays performed by 6 different laboratories. Methods Forty formalin-fixed paraffin-embedded colorectal cancer tumor samples were obtained. Sample sections were submitted for KRAS mutation analysis to 5 independent commercial laboratories (Agencourt, Gentris, Genzyme, HistoGeneX, and Invitek) and to the Amgen DNA Sequencing Laboratory for direct polymerase chain reaction sequencing. The assay used by Invitek is no longer commercially available and has been replaced by an alternative technique. Results from the commercial services were compared with those from Amgen direct sequencing by κ statistics. Results KRAS mutations were observed in codon 12 and/or 13 in 20 of 40 (50%) samples in Amgen direct sequencing assays. Results from HistoGeneX (κ = 0.95), Genzyme (κ = 0.94), and Agencourt (κ = 0.94) were in almost perfect agreement with these results, and the results from Gentris were in substantial agreement with the results from Amgen (κ = 0.75). The Invitek allele-specific assay demonstrated slight agreement (κ = 0.13). Conclusions This study provides data on the comparability of KRAS mutational analyses. The results suggest that most (but not all) commercial services provide analysis that is accurate and comparable with direct sequencing.

The protein MSTO1 has been localized to mitochondria and linked to mitochondrial morphology, but its specific role has remained unclear. Lactate stress test and myopathological results suggest mitochondrial dysfunction. In patient fibroblasts, MSTO1 mRNA and protein abundance are decreased, mitochondria display fragmentation, aggregation, and decreased network continuity and fusion activity. Short‐term silencing of MSTO1 in HeLa cells reproduced the impairment of mitochondrial morphology and dynamics observed in the fibroblasts without damaging bioenergetics. At variance with a previous report, we find MSTO1 to be localized in the cytoplasmic area with limited colocalization with mitochondria. MSTO1 interacts with the fusion machinery as a soluble factor at the cytoplasm‐mitochondrial outer membrane interface. After plasma membrane permeabilization, MSTO1 is released from the cells. MSTO1 likely has a physiologically relevant role in mitochondrial morphogenesis by supporting mitochondrial fusion. § Synopsis MSTO1 has been localized to mitochondria and linked to their morphology but its role remained unclear. Here, an MSTO1 loss‐of‐function mutation is shown to be associated with a human disorder showing mitochondrial involvement. Mutation of MSTO1 is documented in a family of patients with multisystem disease. MSTO1‐deficient patient cells and HeLa cells show impaired mitochondrial morphology and fusion that can be rescued by MSTO1 overexpression. MSTO1 is a soluble cytoplasmic protein that likely interacts with the mitochondrial fusion proteins. Graphical Abstract MSTO1 has been localized to mitochondria and linked to their morphology but its role remained unclear. Here, an MSTO1 loss‐of‐function mutation is shown to be associated with a human disorder showing mitochondrial involvement.

The protein MSTO1 has been localized to mitochondria and linked to mitochondrial morphology, but its specific role has remained unclear. We identified a c.22G > A (p.Val8Met) mutation of MSTO1 in patients with minor physical abnormalities, myopathy, ataxia, and neurodevelopmental impairments. Lactate stress test and myopathological results suggest mitochondrial dysfunction. In patient fibroblasts, MSTO1 mRNA and protein abundance are decreased, mitochondria display fragmentation, aggregation, and decreased network continuity and fusion activity. These characteristics can be reversed by genetic rescue. Short‐term silencing of MSTO1 in HeLa cells reproduced the impairment of mitochondrial morphology and dynamics observed in the fibroblasts without damaging bioenergetics. At variance with a previous report, we find MSTO1 to be localized in the cytoplasmic area with limited colocalization with mitochondria. MSTO1 interacts with the fusion machinery as a soluble factor at the cytoplasm‐mitochondrial outer membrane interface. After plasma membrane permeabilization, MSTO1 is released from the cells. Thus, an MSTO1 loss‐of‐function mutation is associated with a human disorder showing mitochondrial involvement. MSTO1 likely has a physiologically relevant role in mitochondrial morphogenesis by supporting mitochondrial fusion. Synopsis MSTO1 has been localized to mitochondria and linked to their morphology but its role remained unclear. Here, an MSTO1 loss‐of‐function mutation is shown to be associated with a human disorder showing mitochondrial involvement. Mutation of MSTO1 is documented in a family of patients with multisystem disease. MSTO1‐deficient patient cells and HeLa cells show impaired mitochondrial morphology and fusion that can be rescued by MSTO1 overexpression. MSTO1 is a soluble cytoplasmic protein that likely interacts with the mitochondrial fusion proteins. MSTO1 has been localized to mitochondria and linked to their morphology but its role remained unclear. Here, an MSTO1 loss‐of‐function mutation is shown to be associated with a human disorder showing mitochondrial involvement.

The protein MSTO 1 has been localized to mitochondria and linked to mitochondrial morphology, but its specific role has remained unclear. Lactate stress test and myopathological results suggest mitochondrial dysfunction. In patient fibroblasts, MSTO 1 mRNA and protein abundance are decreased, mitochondria display fragmentation, aggregation, and decreased network continuity and fusion activity. Short‐term silencing of MSTO 1 in HeLa cells reproduced the impairment of mitochondrial morphology and dynamics observed in the fibroblasts without damaging bioenergetics. At variance with a previous report, we find MSTO 1 to be localized in the cytoplasmic area with limited colocalization with mitochondria. MSTO 1 interacts with the fusion machinery as a soluble factor at the cytoplasm‐mitochondrial outer membrane interface. After plasma membrane permeabilization, MSTO 1 is released from the cells. MSTO 1 likely has a physiologically relevant role in mitochondrial morphogenesis by supporting mitochondrial fusion. § image MSTO 1 has been localized to mitochondria and linked to their morphology but its role remained unclear. Here, an MSTO 1 loss‐of‐function mutation is shown to be associated with a human disorder showing mitochondrial involvement. Mutation of MSTO1 is documented in a family of patients with multisystem disease. MSTO 1‐deficient patient cells and HeLa cells show impaired mitochondrial morphology and fusion that can be rescued by MSTO 1 overexpression. MSTO 1 is a soluble cytoplasmic protein that likely interacts with the mitochondrial fusion proteins.

Background Previously, we identified three loci affecting HDL-cholesterol levels in a screen for ENU-induced mutations in mice and discovered two mutated genes. We sought to identify the third mutated gene and further characterize the mouse phenotype. Methods We engaged, DNA sequencing, gene expression profiling, western blotting, lipoprotein characterization, metabolomics assessment, histology and electron microscopy in mouse tissues. Results We identify the third gene as Ampd2 , a liver isoform of AMP Deaminase ( Ampd ), a central component of energy and purine metabolism pathways. The causative mutation was a guanine-to-thymine transversion resulting in an A341S conversion in Ampd2. Ampd2 homozygous mutant mice exhibit a labile hypercholesterolemia phenotype, peaking around 9 weeks of age (251 mg/dL vs. wildtype control at 138 mg/dL), and was evidenced by marked increases in HDL, VLDL and LDL. In an attempt to determine the molecular connection between Ampd2 dysfunction and hypercholesterolemia, we analyzed hepatic gene expression and found the downregulation of Ldlr , Hmgcs and Insig1 and upregulation of Cyp7A1 genes. Metabolomic analysis confirmed an increase in hepatic AMP levels and a decrease in allantoin levels consistent with Ampd2 deficiency, and increases in campesterol and β-sitosterol. Additionally, nephrotic syndrome was observed in the mutant mice, through proteinuria, kidney histology and effacement and blebbing of podocyte foot processes by electron microscopy. Conclusion In summary we describe the discovery of a novel genetic mouse model of combined transient nephrotic syndrome and hypercholesterolemia, resembling the human disorder.

Kísérleteinket metilkolantrénnel A törzsű egérben indukált, ascites formában fenntartott, erős tumorhoz asszociált transzplantációs antigénnel rendelkező fibrosarcomával végeztük szingén egerekben.A tumor imrnunogenitására vonatkozó vizsgálatainkban megállapítottuk, hogy a mitomycin C-vel való blokkolás, illetve ultrahanggal történt feltárás során a tumorsejtek rezisztenciakeltő képességüket nem veszítik el. A rezisztenciakeltés eredményessége szempontjából nincs különbség aszerint, hogy a \"tumorantigént\" élő, integrált (de osztódásukban gátolt) tumorsejtek, illetve ultrahanggal feltárt tumorsejtek (szubcelluláris partikulumok) formájában használjuk immunizálásra. A tumorsejt lizátummal keltett rezisztencia erős és tartós, de elsősorban lokális jellegű. Bizonyos kísérleti körülmények között a feltárt tumorsejtekkel kezelt egerekben rezisztenciakeltő hatás helyett a tumornövekedés fokozódása mutatható ki. Tumoros állatokon a feltárt tumorsejtek bevitele immunterápiás hatású: az esetek jelentős részében az egyébként halálos kimenetelű tumornövekedés visszafordítható.A tumorral szemben rezisztens regresszor állatokon a tumorsejtlizátummal lokális DTH reakciót lehet kiváltani, A reakció a tumorral történt első találkozás után 1 évvel is kimutatható, tehát ugyanolyan tartósan fennáll, mint a tumorral szembeni rezisztencia. Feltárt tumorsejtekkel történt emlékeztető oltással regresszor egereken fokozni lehet a DTH reaktivitást, hasonlóan ahhoz, ahogy azt az élő tumorsejtek ip emlékeztető oltása utón tapasztaltuk.Tumoros állatokban a tumoroltás után már korán kimutatható a lokális DTH reaktivitás, amely a tumornövekedés során maximumgörbét ir le. A reakció intenzitása a tumornövekedés különböző stádiumaival kapcsolatba hozható. Meghatározása alkalmasnak látszik a daganatos betegség kimenetelének előrejelzésére is.Élő tumorsejtekkel _íjd szenzibilizált, erős tumorellenes rezisztenciát mutató regresszor egerekben az állatok egy részének elhullását eredményező szisztémás túlérzékenységi reakciót, illetve igen intenzív lokális DTM reakciót lehet kiváltani. A szisztémás túlérzékenységi reakciót időbeli lefolyása és ATS-sel való gátolhatósóga alapján ugyancsak DTH reakciónak tartjuk.Kísérleteinkben szoros összefüggést találtunk a tumorral szembeni rezisztencia és a tumorantigénekkel kiváltható késői típusú túlérzékenységi reakció között. Ez arra is utalhat, hogy a DTH reaktivitás szerepet játszik a tumorral szembeni rezisztenciában .A dolgozatban leírt eredmények alapján kísérleti rendszerünket a tumornövekedést gátló, illetve fokozó immunológiai mechanizmusok vizsgálatára, továbbá immundiagnosztikai és immunterápiás eljárások kidolgozására egyaránt alkalmasnak véljük.

C-150 a Mannich-type curcumin derivative, exhibited pronounced cytotoxic effects against eight glioma cell lines at micromolar concentrations. Inhibition of cell proliferation by C-150 was mediated by affecting multiple targets as confirmed at transcription and protein level. C-150 effectively reduced the transcription activation of NFkB, inhibited PKC-alpha which are constitutively over-expressed in glioblastoma. The effects of C-150 on the Akt/ Notch signaling were also demonstrated in a Drosophila tumorigenesis model. C-150 reduced the number of tumors in Drosophila with similar efficacy to mitoxantrone. In an in vivo orthotopic glioma model, C-150 significantly increased the median survival of treated nude rats compared to control animals. The multi-target action of C-150, and its preliminary in vivo efficacy would render this curcumin analogue as a potent clinical candidate against glioblastoma.