The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome.
Patients not ...proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = 'Walk unaided', 2 = 'With walking aid' and 3 = 'Bed-bound'. The margin used to establish non-inferiority was a detrimental change of -0.4 in the mean difference between arms.
One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30-87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was -0.12 to 0.6. Since -0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2-3 AE compared with six (11%) patients in the SF arm (p = 0.093).
For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression.
Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.
Schizophrenia and bipolar disorder (BD) are complex and multidimensional disorders with high heritability rates. The contribution of genetic factors to the etiology of these disorders is increasingly ...being recognized as the action of multiple risk variants with small effect sizes, which might explain only a minor part of susceptibility. On the other site, numerous environmental factors have been found to play an important role in their causality. Therefore, in recent years, several studies focused on gene × environment interactions that are believed to bridge the gap between genetic underpinnings and environmental insults. In this article, we performed a systematic review of studies investigating gene × environment interactions in BD and schizophrenia spectrum phenotypes. In the majority of studies from this field, interacting effects of variation in genes encoding catechol-
O
-methyltransferase (
COMT
), brain-derived neurotrophic factor (
BDNF
), and FK506-binding protein 5 (
FKBP5
) have been explored. Almost consistently, these studies revealed that polymorphisms in
COMT
,
BDNF
, and
FKBP5
genes might interact with early life stress and cannabis abuse or dependence, influencing various outcomes of schizophrenia spectrum disorders and BD. Other interactions still require further replication in larger clinical and non-clinical samples. In addition, future studies should address the direction of causality and potential mechanisms of the relationship between gene × environment interactions and various categories of outcomes in schizophrenia and BD.
ABSTRACT
Esophageal atresia (EA) is one of the most frequent congenital malformations of the gastrointestinal tract. Many genetic alterations in patients with EA have been described in the ...literature. It is thought that the etiology of EA is heterogeneous. This review of the literature provides detailed information about chromosomal aberrations, gene mutations, and clinical features of neonates with EA, and serves as an excellent source to compare newly diagnosed patients with those described in the literature.
To provide characteristics of major genomic correlates in CpG island methylator phenotype-high (CIMP-H) subgroups in relation to corresponding non-CIMP-H subgroups by use of phenotypic, DNA ...methylation and RNAseq data.
Twenty-three datasets generated by The Cancer Genome Atlas project encompassing over 7200 unique samples were analyzed. We identified 23 CIMP-H clusters by use of unsupervised clustering.
More than 90% of CIMP-H clusters were significantly associated with accelerated epigenetic mitotic clock, demethylation of enhancer sites, backbone and repetitive sequences. Pronounced epigenetic drift observed in majority of CIMP-H subgroups may be related to increased cell division rate, which leads to expansion of DNA methylation errors. This may explain pan-cancer mechanism of establishing CIMP-H in majority of tissue types.
Transposable elements (TEs) are highly repetitive DNA sequences in the human genome that are the relics of previous retrotransposition events. Although the majority of TEs are transcriptionally ...inactive due to acquired mutations or epigenetic processes, around 8% of TEs exert transcriptional activity. It has been found that TEs contribute to somatic mosaicism that accounts for functional specification of various brain cells. Indeed, autonomous retrotransposition of long interspersed element-1 (LINE-1) sequences has been reported in the neural rat progenitor cells from the hippocampus, the human fetal brain and the human embryonic stem cells. Moreover, expression of TEs has been found to regulate immune-inflammatory responses, conditioning immunity against exogenous infections. Therefore, aberrant epigenetic regulation and expression of TEs emerged as a potential mechanism underlying the development of various mental disorders, including autism spectrum disorders (ASD), schizophrenia, bipolar disorder, major depression, and Alzheimer's disease (AD). Consequently, some studies revealed that expression of some sequences of human endogenous retroviruses (HERVs) appears only in a certain group of patients with mental disorders (especially those with schizophrenia, bipolar disorder, and ASD) but not in healthy controls. In addition, it has been found that expression of HERVs might be related to subclinical inflammation observed in mental disorders. In this article, we provide an overview of detrimental effects of transposition on the brain development and immune mechanisms with relevance to mental disorders. We show that transposition is not the only mechanism, explaining the way TEs might shape the phenotype of mental disorders. Other mechanisms include the regulation of gene expression and the impact on genomic stability. Next, we review current evidence from studies investigating expression and epigenetic regulation of specific TEs in various mental disorders. Most consistently, these studies indicate altered expression of HERVs and methylation of LINE-1 sequences in patients with ASD, schizophrenia, and mood disorders. However, the contribution of TEs to the etiology of AD is poorly documented. Future studies should further investigate the mechanisms linking epigenetic processes, specific TEs and the phenotype of mental disorders to disentangle causal associations.
Abstract
The Neurofascins (NFASCs) are a family of proteins encoded by alternative transcripts of NFASC that cooperate in the assembly of the node of Ranvier in myelinated nerves. Differential ...expression of NFASC in neurons and glia presents a remarkable example of cell-type specific expression of protein isoforms with a common overall function. In mice there are three NFASC isoforms: Nfasc186 and Nfasc140, located in the axonal membrane at the node of Ranvier, and Nfasc155, a glial component of the paranodal axoglial junction. Nfasc186 and Nfasc155 are the major isoforms at mature nodes and paranodes, respectively. Conditional deletion of the glial isoform Nfasc155 in mice causes severe motor coordination defects and death at 16-17 days after birth. We describe a proband with severe congenital hypotonia, contractures of fingers and toes, and no reaction to touch or pain. Whole exome sequencing revealed a homozygous NFASC variant chr1:204953187-C>T (rs755160624). The variant creates a premature stop codon in 3 out of four NFASC human transcripts and is predicted to specifically eliminate Nfasc155 leaving neuronal Neurofascin intact. The selective absence of Nfasc155 and disruption of the paranodal junction was confirmed by an immunofluorescent study of skin biopsies from the patient versus control. We propose that the disease in our proband is the first reported example of genetic deficiency of glial Neurofascin isoforms in humans and that the severity of the condition reflects the importance of the Nfasc155 in forming paranodal axoglial junctions and in determining the structure and function of the node of Ranvier.
Twenty-two neuropsychiatric (NPSLE) and 13 systemic lupus erythematosus (SLE) patients with a normal appearing brain on plain magnetic resonance (MR) as well as 20 age-matched healthy controls ...underwent MR spectroscopy (MRS), perfusion-weighted (PWI) and diffusion-tensor imaging (DTI). In MRS NAA/Cr, Cho/Cr and mI/Cr ratios were calculated from the posterior cingulate cortex and left parietal white matter. In PWI, values of cerebral blood volume (CBV) were assessed from 14 regions, including gray and white matter. In DTI fractional anisotropy (FA) values were obtained from 14 white matter tracts including projection, commissural and association fibers. All MR measurements were correlated with clinical data. SLE and NPSLE patients showed significantly (p < 0.05) lower NAA/Cr ratios within both evaluated regions and FA values within the cingulum, as well as a tendency to cortical hypoperfusion. Compared to SLE, NPSLE subjects revealed lower FA values within a wide range of association fibers and corpus callosum. Advanced MR techniques are capable of in vivo detection of complex microstructural brain damage in SLE and NPSLE subjects regarding neuronal loss, mild hypoperfusion and white matter disintegrity. MRS and DTI seem to show the highest usefulness in depicting early changes in normal appearing gray and white matter in SLE patients.
Protein tyrosine phosphatase receptor type J (PTPRJ, DEP1) is a tumour suppressor gene that negatively regulates such processes as angiogenesis, cell proliferation and migration and is one of the ...genes important for tumour development. Similar to other phosphatase genes, PTPRJ is also described as an oncogene. Among various genetic changes characteristic for this gene, single nucleotide polymorphisms (SNPs) constituting benign genetic variants that can modulate its function have been described. We focused on Gln276Pro and Arg326Gln missense polymorphisms and performed a meta-analysis using data from 2930 and 852 patients for Gln276Pro and Arg326Gln respectively in different cancers. A meta-analysis was performed based on five articles accessed via the PubMed and Research Gate databases. Our meta-analysis revealed that for Arg326Gln, the presence of the Arg (C) allele was associated with lower risk of some cancers, the strongest association was observed for colorectal cancer patients, and there was no association between Gln276Pro (G>T) polymorphism and cancer risk. The polymorphisms Arg326Gln and Gln276Pro of the PTPRJ gene are not associated with an increased risk of cancer except for the Arg326Gln polymorphism in colorectal cancer. Large-scale studies should be performed to verify the impact of this SNP on individual susceptibility to colorectal cancer for given individuals.
Autophagy is a catabolic process, which is involved in the maintenance of intracellular homeostasis by degrading redundant molecules and organelles. Autophagy begins with the formation of a ...double-membrane phagophore, followed by its enclosure, thus leading to the appearance of an autophagosome which fuses with lysosome. This process is highly conserved, precisely orchestrated and regulated by autophagy-related genes. Recently, autophagy has been widely studied in different types of cancers, including colorectal cancer. As it has been revealed, autophagy plays two opposite roles in tumorigenesis, as a tumor suppressor and a tumor enhancer/activator, and therefore is called a double-edge sword. Recently, interaction between autophagy and apoptosis has been found. Therefore, we aimed to study the mRNA levels of genes engaged in autophagy and apoptosis in colorectal cancer tissues. Colorectal cancer and adjacent healthy tissues were obtained from 73 patients diagnosed with primary colorectal cancer. Real-time PCR analysis employing Universal Probe Library was used to assess the expression of the seven following selected genes:
BECN1
,
UVRAG
,
ULK1
,
ATG13
,
Bif
-
1
,
BCL2
and
BAX
. For all but one of the tested genes, a decrease in expression was observed. An increase in expression was observed for
BAX. BAX
expression decreases consistently from early to more advanced stages. High expression of
BAX
was strongly associated with negative
UVRAG
expression. The high expression of the
BAX
gene seems to be a negative regulator of autophagy in colorectal cancer cells. The relative downregulation of autophagy-related genes was observed in colorectal cancer samples.
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