Spectrum of mutations in gastrointestinal stromal tumor patients – a population‐based study from Slovakia

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract and are characterized by presence of mutations in tyrosine kinases cKIT (KIT) and PDGFRα (PDGFRA). Mutations identified are highly heterogeneous, but some mutations are associated with specific clinical features of the tumor. Samples from 278 GIST patients collected during the period 2004–2011 were screened for mutations in exons 9, 11, 13, and 17 of KIT and 12, 14 and 18 of PDGFRA. Results of mutation screening were summarized and tested for possible association with clinical parameters of tumors. Mutations were identified in 83.81% of patients. Most frequent mutations were found in KIT exon 11 reaching frequency of 62.95%. Other exons contributed to the mutation pool with frequencies 8.27%, 7.55%, 2.52%, 1.44%, 1.08%, and 0.00%, in decreasing order KIT exon 9, PDGRFA exons 18 and 12, KIT exon 13, PDGFRA exon 14, and KIT exon 17. General linear model analysis showed no effect of any individual analyzed mutation on the phenotypic variables, but we confirmed association between mutations KIT exon 9 p. 503‐504_dup2, and PDGFRA exon 18 p. D842V and intestinal and gastric localization of tumors.     

Dopaminergic mediation in the brain aging and neurodegenerative diseases:a role of senescent cells

正Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease(PD)and Alzheimer’s disease(AD).In aging and in the diseases,similar changes in various hallmarks of neurodegeneration(lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondria     

Age and activation determines the anticonvulsant effect of ifenprodil in rats

Ifenprodil, an antagonist of NMDA receptors containing the NR2B subunit, was expected to exhibit anticonvulsant action in rat pups up to the third postnatal week because of predominance of NR2B subunit at early development. Cortical epileptic afterdischarges (ADs) were used to study possible effects on threshold current intensities and duration of ADs in 12-, 15-, 18-, and 25-day-old rats. A series of 18 stimulation series with stepwise increasing current intensities (from 0.2 to 15 mA) was applied with 10-min intervals. The first experiment studied rats pretreated with ifenprodil (20 or 40 mg/kg), the second experiment studied an effect of ifenprodil on already present ADs—the dose of 20 mg/kg was administered after stimulation with the 3.5-mA current intensity. Pretreatment with ifenprodil resulted in an anticonvulsant effect in 15-day-old rats only, on the contrary, proconvulsant action was found in 18- and 25-day-old animals (decrease of thresholds especially for transition into the second, limbic type of ADs and increase in duration of ADs). Anticonvulsant effect was found in 12-, 15-, and 18-day-old rats in the second experiment—ADs were shortened. In contrast, no effect was observed in 25-day-old animals. An anticonvulsant action of ifenprodil is not only age-dependent but also activation-dependent.     

Mitochondrial membrane protein-associated neurodegeneration: a case report and literature review

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an autosomal recessive disorder caused by mutation in the C19orf12 gene. We report a compound heterozygous c.[32C>T];[205G>A;424A>G] (p.[Thr11Met];[Gly69Arg;Lys142Glu]) Czech patient who manifested with right foot dystonia, impaired handwriting, attention deficit, and signs of iron accumulation on brain MRI. Gradually, he developed dysarthria, spastic-dystonic gait, pedes cavi, and atrophy of leg muscles. Additionally, we report demographic parameters, clinical signs, and allelic frequencies of C19orf12 mutations of all published MPAN cases. We compared the most frequent mutations, p.Thr11Met and p.Gly69ArgfsX10; the latter was associated with younger age at onset and more frequent optic atrophy in homozygotes.     

Cuprizone [Bis(Cyclohexylidenehydrazide)] is Selectively Toxic for Mature Oligodendrocytes

Cuprizone [bis(cyclohexylidenehydrazide)]-induced toxic demyelination is an experimental animal model commonly used to study de- and remyelination in the central nervous system. In this model, mice are fed with the copper chelator cuprizone which leads to oligodendrocyte death with subsequent demyelination. The underlying mechanisms of cuprizone-induced oligodendrocyte death are still unknown, and appropriate in vitro investigations to study these mechanisms are not available. Thus, we studied cuprizone effects on rat primary glial cell cultures and on the neuroblastoma cell line SH-SY5Y. Treatment of cells with different concentrations of cuprizone failed to show effects on the proliferation and survival of SH-SY5Y cells, microglia, astrocytes, and oligodendrocyte precursor cells (OPC). In contrast, differentiated mature oligodendrocytes (OL) were found to be significantly affected by cuprizone treatment. This was accompanied by a reduced mitochondrial potential in cuprizone-treated OL. These results demonstrate that the main toxic target for cuprizone is mature OL, whilst other glial cells including OPC are not or only marginally affected. This explains the selective demyelination induced by cuprizone in vivo.