Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers in humans. The molecular mechanisms leading to the development of HCC are extremely complicated and consist of prominent genetic, genomic, and epigenetic alterations. This review summarizes the current knowledge of the role of epigenetic aberrations, including changes in DNA methylation, histone modifications, and expression of microRNAs in the pathogenesis of HCC. It also emphasizes that identification of the underlying epigenetic alterations that drive cell transformation and promote development and progression of HCC is crucially important for understanding mechanisms of hepatocarcinogenesis, its detection, therapeutic intervention, and prevention.     

Balo’s concentric sclerosis: Value of magnetic resonance imaging in diagnosis

We report two cases of Balo’s concentric sclerosis that demonstrate the typical magnetic resonance imaging (MRI) findings of concentric rings of demyelination involving the superficial and deep white matter and sparing the cortex. In both cases biopsy was not performed as MRI findings and multi-mode evoked potential studies were consistent with demyelinating illness. The theories regarding the pathogenesis of this peculiar appearance are briefly reviewed.     

HPLC-MS analysis of Schisandra lignans and their metabolites in Caco-2 cell monolayer and rat everted gut sac models and in rat plasma

The absorption profiles of Schisandra chinensis were evaluated using the human Caco-2 cell monolayer and rat everted gut sac models, as well as in rat plasma. By analyzing the chromatographic and MSⁿ characteristics of individual peak acquired by HPLC-DAD-APCI-MSⁿ determination, thirteen lignans were identified as the major in vitro absorbable components of the Schisandra extract. Most of these compounds were also detected and identified in rat plasma after an oral administration of the Schisandra extract, except for angeloyl(tigloyl)gomisin H and angeloyl(tigloyl)gomisin Q, whose structures possess an ester group at the cyclooctadiene ring. In addition, four metabolites, corresponding to the hydroxylation and demethylation products of schisandrin and the hydrolysis derivative of angeloyl(tigloyl)gomisin Q, were tentatively identified. The results demonstrate that Schisandra lignans are the major absorbable components of this crude drug, and hydroxylation, demethylation and hydrolysis are important metabolic transformations of the absorbable lignans.     

The Alimentary Canal of the African Lungfish Protopterus annectens During Aestivation and After Arousal

We describe the structural modifications that occur in the alimentary canal of the African lungfish Protopterus annectens during aestivation and after arousal. With fasting, all gut segments undergo structural modifications. The epithelium covering the intestinal vestibule undergoes bursts of activation at 4 months of aestivation, adopting a more quiescent appearance at 6 months. The ridge area of the spiral intestine shows, at 4 months of aestivation, epithelial disintegration, cell desquamation, cell death, and loss of the freshwater phenotype. Surprisingly, the epithelium adopts a stratified appearance at 6 months of aestivation. Except for epithelial disintegration, the smooth portion of the spiral intestine follows a similar pattern of modifications than the ridge area. The entire epithelium of spiral intestine appears to be renewed during aestivation. The presence of intraepithelial mast cells suggests that inflammation is part of the cellular response to aestivation. After arousal, cell phenotypes are restored in about 6 days, but full structural recovery is not attained during the experimental period (15 days post‐aestivation). Several aspects of the cellular response to fasting are shared by a wide range of animal groups. This commonality agrees with the presence of a character that allows to adjust the structural and functional properties of the gut to food availability and food quality, and to the characteristics of the fasting episodes. Anat Rec, 2012. © 2011 Wiley Periodicals, Inc.     

Programming Antitachycardia Pacing for Primary Prevention in Patients With Implantable Cardioverter Defibrillators: Results From the PROVE Trial

Programming ATP for ICD Patients. Objectives: The PROVE trial was designed to determine if antitachycardia pacing (ATP) is clinically beneficial for primary prevention in patients who have implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT‐Ds). Background: Use of ICDs and CRT‐Ds reduces mortality in patients with ventricular dysfunction and mild to moderate heart failure. However, in studies of the primary prevention population, shock‐only ICDs are predominantly used, without ATP programming for less painful termination of ventricular tachycardia (VT). Methods: We conducted a prospective, nonrandomized, multicenter study using market‐released ICDs and CRT‐Ds. Patients received devices programmed to deliver ATP for VT cycle lengths of 270–330 ms. Follow‐up evaluation was performed at 3, 6, and 12 months. The incidence of VT and the rate of successful termination by ATP were analyzed. Results: Of 830 patients in the study population (men, 73%; mean age, 67.3 ± 12 years), 32% received single‐chamber ICDs, 44% dual‐chamber ICDs, and 24% CRT‐Ds. ATP was attempted for 112 VT episodes in 71 patients, and 103 (92%) of the VT episodes were successfully terminated. Three VT episodes were accelerated by ATP and required termination by ICD shock; 6 episodes terminated spontaneously or by ICD shock. Conclusions: VT is common in patients without a history of this arrhythmia who have received ICDs or CRT‐Ds for primary prevention indications. Programming ICDs for ATP therapy at the time of implantation could potentially terminate most VT episodes and reduce the number of painful shocks for these patients. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1349‐1354, December 2010)     

Role of epigenetic and miR‐22 and miR‐29b alterations in the downregulation of Mat1a and Mthfr genes in early preneoplastic livers in rats induced by 2‐acetylaminofluorene

Carcinogenesis is a multistep sequential process of clonal expansion of initiated cells associated with the accumulation of multiple cancer‐specific heritable phenotypes. The acquisition of these heritable cancer‐specific alterations may be triggered by mutational and/or non‐mutational changes in the genome that affect the regulation of gene expression. Currently, cancer‐specific epigenetically mediated changes in gene expression are regarded as driving events in tumorigenesis. In the present study, we investigated the role of gene‐specific expression changes in the mechanism of rat hepatocarcinogenesis induced by the complete hepatocarcinogen 2‐acetylaminofluorene (2‐AAF). The results of the present study demonstrate significant alterations in gene expression, especially of Mat1a and Mthfr genes, during early stages of rat 2‐AAF‐induced liver carcinogenesis. Both of these genes were downregulated in the livers of 2‐AAF‐treated male rats. Inhibition of Mat1a expression was associated with an increase in histone H3 lysine 27 trimethylation and a decrease in histone H3 lysine 18 acetylation at the gene promoter/first exon region. Additionally, we demonstrate for the first time a critical contribution of miR‐22 and miR‐29b microRNAs in the inhibition of Mat1a and Mthfr gene expression during 2‐AAF‐induced rat hepatocarcinogenesis. The downregulation of Mat1a and Mthfr genes was accompanied by marked functional alterations in one‐carbon metabolism. The results of the present study suggest that downregulation of the Mat1a and Mthfr genes may be one of the main driver events that promote liver carcinogenesis by causing a profound accumulation of subsequent epigenetic abnormalities during progression of the carcinogenic process. © 2011 Wiley Periodicals, Inc.     

Relationship between Thrombophilic Disorders and Type of Severe Early-Onset Hypertensive Disorder of Pregnancy

Objective: To determine whether specific subtypes of early-onset hypertensive disorders of pregnancy (haemolysis, elevated liver enzymes, low platelets [HELLP] syndrome; severe preeclampsia; eclampsia; and fetal growth restriction) differ in increased prevalences of thrombophilic disorders. Design: Cohort study. Setting: Two university hospitals in Amsterdam, the Netherlands. Population: 216 patients participating in a randomized clinical trial with severe and early-onset hypertensive disorders of pregnancy. Methods: More than 3 months after delivery, all patients were invited for a thrombophilia screening protocol, including hereditary thrombophilic disorders (Factor II or V-Leiden mutation, APC-resistance, protein S deficiency), antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant activity), and hyperhomocysteinemia (before and after methionin challenge). Disease expression was classified by HELLP syndrome, severe preeclampsia, or neonatal birth weight ratio below the median (0.65). Univariate and multinomial regression analyses examined the association of disease expression with thrombophilic disorders, and other associated factors (chronic hypertension, smoking, body mass index, positive family history of cardiovascular morbidity, and demographic parameters). Main outcome measures: incidence of thrombophilic disorders in different subtypes of disease. Results: Overall prevalence of thrombophilic disorders in 206 (95%) screened women was 36%. Chronic hypertension was present in 32%, and 34% had a positive family history of cardiovascular morbidity. Multinomial regression analysis showed that hereditary thrombophilia was more frequent among women with infants with a birth weight ratio <0.65 than in women with HELLP syndrome or severe preeclampsia (p = 0.01, OR 5.1 (1.5 to 7.3) and OR 3.4 (1.1 to 10.6), respectively). High body mass index was less frequent in women with HELLP syndrome than in those with severe preeclampsia or fetal growth restriction (p = 0.06, OR 0.5 (0.3 to 0.9) and OR 0.4 (0.2 to 1.0), respectively). Conclusion: In this population, the high prevalence of thrombophilic factors and chronic hypertension was confirmed. There were small differences between groups. Hereditary thrombophilic disorders were associated with fetal growth restriction but not with type of maternal disease, suggesting an effect on placental function. Maternal body mass index was lower in women with HELLP syndrome.     

Interventions for replacing missing teeth: dental implants in fresh extraction sockets (immediate,immediate‐delayed and delayed implants)

Background:  ‘Immediate’ implants are placed in dental sockets just after tooth extraction. ‘Immediate‐delayed’ implants are those implants inserted after weeks up to about a couple of months to allow for soft tissue healing. ‘Delayed’ implants are those placed thereafter in partially or completely healed bone. The potential advantages of immediate implants are that treatment time can be shortened and that bone volumes might be partially maintained thus possibly providing good aesthetic results. The potential disadvantages are an increased risk of infection and failures. After implant placement in postextractive sites, gaps can be present between the implant and the bony walls. It is possible to fill these gaps and to augment bone simultaneously to implant placement. There are many techniques to achieve this but it is unclear when augmentation is needed and which could be the best augmentation technique. Objectives:  To evaluate success, complications, aesthetics and patient satisfaction between ‘immediate’, ‘immediate‐delayed’ and ‘delayed’ implants. To evaluate whether and when augmentation procedures are necessary and which is the most effective technique. Search strategy:  The Cochrane Oral Health Group’s Trials Register (to 2 June 2010), CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE via OVID (1950 – 2 June 2010) and EMBASE via OVID (1980 – 2 June 2010) were searched. Several dental journals were handsearched. Selection criteria:  Randomized controlled trials (RCTs) comparing immediate, immediate‐delayed and delayed implants, or comparing various bone augmentation procedures around the inserted implants, reporting the outcome of the interventions to at least 1 year after functional loading. Data collection and analysis:  Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted independently and in duplicate. Trial authors were contacted for any missing information. Results were expressed as random‐effects models using mean differences for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CIs). The statistical unit of the analysis was the patient. Main results:  Fourteen eligible RCTs were identified but only 7 trials could be included. Four RCTs evaluated implant placement timing. Two RCTs compared immediate versus delayed implants in 126 patients and found no statistically significant differences. One RCT compared immediate‐delayed versus delayed implants in 46 patients. After 2 years patients in the immediate‐delayed group perceived the time to functional loading significantly shorter, were more satisfied and an independent blinded assessor judged the level of the peri‐implant marginal mucosa in relation to that of the adjacent teeth as more appropriate (RR = 1.68; 95% CI 1.04 to 2.72). These differences disappeared 5 years after loading but significantly more complications occurred in the immediate‐delayed group (RR = 4.20; 95% CI 1.01 to 17.43). One RCT compared immediate with immediately delayed implants in 16 patients for 2 years and found no differences. Three RCTs evaluated different techniques of bone grafting for implants immediately placed in extraction sockets. No statistically significant difference was observed when evaluating whether autogenous bone is needed in postextractive sites (1 trial with 26 patients) or which was the most effective augmentation technique (2 trials with 56 patients). Authors’ conclusions:  There is insufficient evidence to determine possible advantages or disadvantages of immediate, immediate‐delayed or delayed implants, therefore these preliminary conclusions are based on a few underpowered trials often judged to be at high risk of bias. There is a suggestion that immediate and immediate‐delayed implants may be at higher risks of implant failures and complications than delayed implants. On the other hand the aesthetic outcome might be better when placing implants just after teeth extraction. There is not enough reliable evidence supporting or refuting the need for augmentation procedures at immediate implants placed in fresh extraction sockets or whether any of the augmentation techniques are superior to the others.     

Role of epigenetic effectors in maintenance of the long-term persistent bystander effect in spleen in vivo

Radiation therapy is a primary treatment modality for brain tumors, yet it has been linked to the increased incidence of secondary, post-radiation therapy cancers. These cancers are thought to be linked to indirect radiation-induced bystander effect. Bystander effect occurs when irradiated cells communicate damage to nearby, non-irradiated 'bystander' cells, ultimately contributing to genome destabilization in the non-exposed cells. Recent evidence suggests that bystander effect may be epigenetic in nature; however, characterization of epigenetic mechanisms involved in bystander effect generation and its long-term persistence has yet to be defined. To investigate the possibility that localized X-ray irradiation induces persistent bystander effects in distant tissue, we monitored the induction of epigenetic changes (i.e. alterations in DNA methylation, histone methylation and microRNA (miRNA) expression) in the rat spleen tissue 24 h and 7 months after localized cranial exposure to 20 Gy of X-rays. We found that localized cranial radiation exposure led to the induction of bystander effect in lead-shielded, distant spleen tissue. Specifically, this exposure caused the profound epigenetic dysregulation in the bystander spleen tissue that manifested as a significant loss of global DNA methylation, alterations in methylation of long interspersed nucleotide element-1 (LINE-1) retrotransposable elements and down-regulation of DNA methyltransferases and methyl-binding protein methyl CpG binding protein 2 (MeCP2). Further, irradiation significantly altered expression of miR-194, a miRNA putatively targeting both DNA methyltransferase-3a and MeCP2. This study is the first to report conclusive evidence of the long-term persistence of bystander effects in radiation carcinogenesis target organ (spleen) upon localized distant exposure using the doses comparable with those used for clinical brain tumor treatments.     

Unusual presentation of ulnar artery aneurysm and dissection with associated anomalous radial artery: appearances on multi-detector row CT angiography

We present a case of ulnar artery aneurysm and dissection associated with a congenitally hypoplastic ipsilateral radial artery. We postulate that the aetiology is due to increased blood flow through the ulnar artery as a consequence of the radial artery anomaly, therefore making the ulnar artery more vulnerable to aneurysm formation and traumatic damage. This might represent a variant of the hypothenar hammer syndrome with associated ulnar artery dissection and recurrent distal embolisation manifesting as Raynaud’s phenomenon. Forearm arterial injuries, treatment and the importance of upper limb arterial anatomical variations are also discussed. To our knowledge, this is the first reported case of its type diagnosed by multi-detector row computed tomography angiography.