Linkage and physical mapping of X-linked lissencephaly/SBH (XLIS): a gene causing neuronal migration defects in human brain

While disorders of neuronal migration are associated with as much as 25% of recurrent childhood seizures, few of the genes required to establish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migration disorders producing epilepsy and variable cognitive impairment, can be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five families and physical mapping of a balanced X;2 translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the breakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysis. Markers used for somatic cell hybrid and fluorescence in situ hybridization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutation of a single gene, XLIS, that the milder SBH phenotype in females results from random X-inactivation (Lyonization), and that cloning of genes from the breakpoint region on X will yield XLIS.      

Coexistence of MACC1 and NM23‐H1 dysregulation and tumor budding promise early prognostic evidence for recurrence risk of early‐stage colon cancer

The tumor‐node‐metastasis (TNM) classification, the presence of a mucinous component, and signet ring cells are well‐known criteria for identifying patients at a high risk for recurrence and determining the therapeutic approach for early‐stage colon cancer (eCC). Nevertheless, recurrence can unexpectedly occur in some eCC cases after surgical resection. The aims of the present study were to evaluate the relation of dysregulated MACC1, c‐MET, and NM23‐H1 expression with the histopathological features of tumors in recurrence formation in eCC cases. A total of 100 sporadic eCC patients without poor prognosis factors were evaluated in this study. The relationship between the altered expression of MACC1, c‐MET, and NM23‐H1 and pathological microenvironmental features, including the presence of tumor budding and desmoplasia, were assessed. The primary outcomes, including 5‐year overall survival (OS) and disease‐free survival (DFS), were also measured. Compared with nonrecurrent patients, the expression level of MACC1 was 8.27‐fold higher, and NM23‐H1 was 11.36‐fold lower in patients with recurrence during the 5‐year follow‐up (p = 0.0345 and p = 0.0301, respectively). In addition, the coexistence of high MACC1 and low NM23‐H1 expression and tumor budding was associated with short OS (p < 0.001). We suggest that the combination of reduced NM23‐H1, induced MACC1, and the presence of tumor budding are promising biomarkers for the prediction of recurrence and may aid the stratification of patients with stage II colon cancer for adjuvant chemotherapy.     

The contribution of neurocognitive situation,physical capacity and daily life activities to quality of life in childhood acute lymphoblastic leukemia survivors

Background/aim There are no extensive studies on the QL in children who completed acute lymphoblastic leukemia (ALL) treatment and currently living without any disease in Turkey. Our study aimed to analyze both the QL and the effects of physical, neurocognitive capacities on QL in childhood ALL survivors aged 7–12 years at the time of recruitment.Materials and methodsPedsQL cancer module 3.0 child and proxy report, for ages 5–7 and 8–12 years, WeeFIM scale, BOTMP Short Form, RPM, reading, writing, and mathematics assessment tools, sociodemographic information form were carried out to the children and their family.Results There was no effect of the months since the completion of therapy on pain, anxiety, cognitive problems, perceived physical appearance, and the total QL scores of children and proxy reports (p > 0.05).Children’s physical capacities were significantly worse than healthy controls and have not reached the level of healthy children even after a long time since completion of ALL therapy. There was a significant association between physical capacity and daily independent living status (p < 0.001). Reading, writing, and mathematical skills were significantly associated with the mean time off-treatment (p < 0.001), and the total score of RPM and PedsQL of those with mathematical difficulties were significantly lower than those without any difficulty (p < 0.05).ConclusionThe months after the treatment (off-treatment time) have not affected total and subunit QL scores. As motor skills difficulties will lead to low academic achievement, early recognition direct the parents for immediate intervention. lead to low academic achievement, early recognition could direct the parents for immediate intervention. Planning psychosocial support programs for physical activity and age-appropriate development of patients from the initiation of treatment will increase the QL in childhood ALL with a survival rate of 80% or more.     

The inhibition of Src kinase suppresses the production of matrix metalloproteinases in from synovial fibroblasts and inhibits MAPK and STATs pathways

Background/aimThe purpose of this study was to investigate the antiarthritic potentials of the inhibition of Src kinase in vivo and in vitro settings. Materials and methodsArthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund’s adjuvant (collagen induced arthritis [CIA] model) in Wistar albino rats. One day after the onset of arthritis, dasatinib, a potent Src kinase inhibitor, (5 mg/kg/day) was given via oral gavage. Tissue Src, Fyn, MAPK and STAT mRNA expressions were determined by real-time polymerase chain reaction. On the other hand, fibroblast like synoviocytes (FLSs) were harvested patients with rheumatoid arthritis (RA) undergoing surgical knee joint replacement. FLSs were stimulated with cytokines and dasatinib was added in different concentrations. MMP –1, –3, and –13 levels in FLSs culture were determined by ELISA.ResultsThe tissue mRNA expressions of Src, Fyn, MAPK and STATs were increased in the arthritis CIA group compared to the control group. Their mRNA expressions in the CIA + dasatinib group were decreased and similar in the control group. In in vitro setting, MMP –1, –3, and –13 expressions from FLSs induced by IL-1β and TNF-α were increased, while dasatinib suppressed their productions from FLSs.ConclusionThe present study shows that the inhibition of Src kinase has antiarthritic potentials in both in vivo and in vitro settings. Src kinase inhibition may be candidate to further research in human RA.