OBJECTIVES
Both preoperative (disease-related) and operative (management-related) variables make the assessment of the outcomes of acute type A aortic dissection (ATAAD) surgery a difficult task. Our ...aim was to evaluate the impact of operative factors, including arterial cannulation site, route of cerebral perfusion and surgeon's specific experience with ATAAD (‘aortic surgeon’), on the early results of surgical management, with particular attention to neurological injury.
METHODS
Penn classification was used to identify clinically homogeneous risk groups of ATAAD patients undergoing surgery. Between January 2007 and June 2014, 111 of 183 ATAAD patients treated with open surgery in a single centre were in Penn Class Aa (no ischaemic complications at presentation). They were divided in two groups depending on the arterial cannulation site: femoral artery (FemA; 56 patients) or right axillary artery (RAxA; 55 patients). Study outcomes included: 30-day mortality, major adverse cardiac and cerebrovascular events at 30 days, neurological complications and in particular, patterns of stroke as defined by Bamford classification.
RESULTS
No significant differences in preoperative variables were observed between cannulation-site groups, except for myocardial ischaemic time (60.9 ± 30.4 min in the RAxA group vs 81.7 ± 52.3 in the FemA group, P = 0.014) and cerebral perfusion time (42.1 ± 25.5 min in the RAxA group vs 52.9 ± 32.6 in the FemA group, P = 0.048). Outcomes in terms of mortality and neurological injury did not differ except for a higher incidence of lacunar cerebral infarction (LACI) in the RAxA group (14.5 vs 3.6%, P = 0.043), mainly but not exclusively explained by a higher incidence of LACI in unilateral (17.2%) than in bilateral cerebral perfusion (6.9%) within the RAxA group. The ‘non-aortic surgeon’ was associated instead with 30-day mortality and composite outcome in multivariable analysis (respectively, OR 6.40, P = 0.002 and OR 4.68, P = 0.001).
CONCLUSIONS
The RAxA cannulation and FemA cannulation are associated with comparable 30-day mortality following surgery for aortic dissection. However, the possible higher risk of LACI-type strokes in the RAxA group, especially when associated with unilateral brain perfusion, should be considered when RAxA cannulation is performed in ATAAD. The hypothesis that more experienced surgeons may produce better earlier outcomes warrants further investigation.
Purpose: To describe the clinical features of a large kindred with familial infantile myoclonic epilepsy (FIME) with autosomal recessive inheritance, and to discuss the nosology of the early ...infantile myoclonic epilepsies (IMEs).
Methods: The family descends from the intermarriage of two couples of siblings. In a previous study, we mapped the genetic locus to chromosome 16p13.We analyzed results of family records and personal history, psychomotor development, neurologic examination, epilepsy features, and EEG recordings for each subject.
Results: FIME has a strong penetrance (eight affected of 14 subjects) and a homogeneous clinical picture. Like the benign form of infantile myoclonic epilepsy (BIME), FIME is a true idiopathic IME with unremarkable history, no neurologic or mental impairment, good response to treatment, and normal interictal EEG pattern. Conversely, onset with generalized epileptic seizures without fever (four patients) or with fever (one patient), frequency and duration of the myoclonic seizures, occurrence of generalized tonic–clonic seizures (GTCSs) in all patients and persistence of seizures into adulthood are characteristics of the severe infantile myoclonic epilepsy (SIME).
Conclusions: Clinical overlap probably exists among the myoclonic epilepsies of infancy. FIME differs from other forms of IME in its phenotypic features. The peculiar mode of inheritance is explained by the genetic background of the family. Genetic studies suggest linkage to chromosome 16 in familial cases of true IME.
Myoclonic epilepsies with onset in infancy and childhood are clinically and etiologically heterogeneous. Although genetic factors are thought to play an important role, to date very little is known ...about the etiology of these disorders. We ascertained a large Italian pedigree segregating a recessive idiopathic myoclonic epilepsy that starts in early infancy as myoclonic seizures, febrile convulsions, and tonic-clonic seizures. We typed 304 microsatellite markers spanning the 22 autosomes and mapped the locus on chromosome 16p13 by linkage analysis. A maximum LOD score of 4.48 was obtained for marker D16S3027 at recombination fraction 0. Haplotype analysis placed the critical region within a 3.4-cM interval between D16S3024 and D16S423. The present report constitutes the first example of an idiopathic epilepsy that is inherited as an autosomal recessive trait.
We examined all the official hospital records referring to admissions for acute stroke (AS) (DRG 14) from January 1 to December 31, 1996 in Campania (Italy), a large region with 10% of the Italian ...population. Related healthcare burden and available resources were evaluated. During the study period, a total of 9,003 discharges were reported. We counted 11 neurological care units (NCU) committed to emergency in the region, with 230 hospital beds. The 4,890 admissions in NCU represented 54.3% of the total AS hospitalizations per year. A large number of strokes (45.7%) had no access to specialist assistance and were hospitalized mainly in general wards with a mean hospital stay of 12.7 days, compared with 9.5 days in NCU (p < 0.01). In our region, the number of hospital beds available for neurological emergencies do not meet the demand.
DNA and histone chromatin modifying enzymes play a crucial role in chromatin remodeling in several biological processes. Lysine-specific demethylase 1 (LSD1), the first identified histone ...demethylase, is a relevant player in the regulation of a broad spectrum of biological processes including development, cellular differentiation, embryonic pluripotency and cancer. Here, we review recent insights on the role of LSD1 activity in chromatin regulatory complexes, its functional role in the epigenetic changes during embryonic development, in the establishment and maintenance of stemness and during cancer progression.
•Role of the LSD1 demethylase in the establishment and maintenance of epigenetic signatures of stemness and cancer•LSD1 bound across the genome predominantly at active promoters and enhancers•LSD1 as an emerging target for cancer therapy
The guanine base in nucleic acids is, among the other bases, the most susceptible to being converted into 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) when exposed to reactive oxygen species. In ...double-helix DNA, 8-oxodG can pair with adenine; hence, it may cause a G > T (C > A) mutation; it is frequently referred to as a form of DNA damage and promptly corrected by DNA repair mechanisms. Moreover, 8-oxodG has recently been redefined as an epigenetic factor that impacts transcriptional regulatory elements and other epigenetic modifications. It has been proposed that 8-oxodG exerts epigenetic control through interplay with the G-quadruplex (G4), a non-canonical DNA structure, in transcription regulatory regions. In this review, we focused on the epigenetic roles of 8-oxodG and the G4 and explored their interplay at the genomic level.
Abstract
8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), a major product of the DNA oxidization process, has been proposed to have an epigenetic function in gene regulation and has been associated ...with genome instability. NGS-based methodologies are contributing to the characterization of the 8-oxodG function in the genome. However, the 8-oxodG epigenetic role at a genomic level and the mechanisms controlling the genomic 8-oxodG accumulation/maintenance have not yet been fully characterized. In this study, we report the identification and characterization of a set of enhancer regions accumulating 8-oxodG in human epithelial cells. We found that these oxidized enhancers are mainly super-enhancers and are associated with bidirectional-transcribed enhancer RNAs and DNA Damage Response activation. Moreover, using ChIA-PET and HiC data, we identified specific CTCF-mediated chromatin loops in which the oxidized enhancer and promoter regions physically associate. Oxidized enhancers and their associated chromatin loops accumulate endogenous double-strand breaks which are in turn repaired by NHEJ pathway through a transcription-dependent mechanism. Our work suggests that 8-oxodG accumulation in enhancers–promoters pairs occurs in a transcription-dependent manner and provides novel mechanistic insights on the intrinsic fragility of chromatin loops containing oxidized enhancers-promoters interactions.
Abstract
8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) is one of the major DNA modifications and a potent pre-mutagenic lesion prone to mispair with 2′-deoxyadenosine (dA). Several thousand residues ...of 8-oxodG are constitutively generated in the genome of mammalian cells, but their genomic distribution has not yet been fully characterized. Here, by using OxiDIP-Seq, a highly sensitive methodology that uses immuno-precipitation with efficient anti-8-oxodG antibodies combined with high-throughput sequencing, we report the genome-wide distribution of 8-oxodG in human non-tumorigenic epithelial breast cells (MCF10A), and mouse embryonic fibroblasts (MEFs). OxiDIP-Seq revealed sites of 8-oxodG accumulation overlapping with γH2AX ChIP-Seq signals within the gene body of transcribed long genes, particularly at the DNA replication origins contained therein. We propose that the presence of persistent single-stranded DNA, as a consequence of transcription-replication clashes at these sites, determines local vulnerability to DNA oxidation and/or its slow repair. This oxidatively-generated damage, likely in combination with other kinds of lesion, might contribute to the formation of DNA double strand breaks and activation of DNA damage response.
Growth factor withdrawal inhibits cell cycle progression by stimulating expression of growth-arresting genes through the activation of Forkhead box O transcription factors such as FOXO3a, which binds ...to the FHRE-responsive elements of a number of target genes such as PUMA and GADD45a. Following exposure of cells to growth factors FOXO3a-mediated transcription is rapidly repressed. We determined that repression correlates with activation of PI3K/AKT pathway leading to FOXO3a phosphorylation and release of FOXO3a protein from PUMA and GADD45a chromatin. We show here that Myc significantly and selectively contributes to repression of FOXO-mediated expression of PUMA and GADD45a. We found that in Myc deprived cells inhibition of PUMA and GADD45a following serum stimulation is impaired and that Myc does not interfere with p53 induction of PUMA transcription. We observed that following activation, Myc is rapidly recruited to PUMA and GADD45a chromatin, with a concomitant switch in promoter occupancy from FOXO3a to Myc. Myc recruitment stimulates deacetylation of Histone H3 and H4 and methylation of lysine 9 in H3 (H3K9me2) on both PUMA and GADD45 chromatin. These data highlight a Myc role on cell growth by selectively inhibiting FOXO3a induced transcription of PUMA and GADD45.
8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is the most common marker of oxidative stress and its accumulation within the genome has been associated with major human health issues such as cancer, ...aging, cardiovascular and neurodegenerative diseases. The characterization of the different genomic sites where 8-oxodG accumulates and the mechanisms underlying its formation are still poorly understood. Using OxiDIP-seq, we recently derived the genome-wide distribution of 8-oxodG in human non-tumorigenic epithelial breast cells (MCF10A). Here, we identify a subset of human promoters that accumulate 8-oxodG under steady-state condition. 8-oxodG nucleotides co-localize with double strand breaks (DSBs) at bidirectional and CG skewed promoters and their density correlate with RNA Polymerase II co-occupancy and transcription. Furthermore, by performing OxiDIP-seq in quiescent (G0) cells, we found a strong reduction of oxidatively-generated damage in the majority of 8-oxodG-positive promoters in the absence of DNA replication. Overall, our results suggest that the accumulation of 8-oxodG at gene promoters occurs through DNA replication-dependent or -independent mechanisms, with a possible contribution to the formation of cancer-associated translocation events.
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