Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer

Runt domain transcription factor 3 (RUNX3) is widely regarded as a tumour-suppressor gene inactivated by DNA hypermethylation of its canonical CpG (cytidine-phosphate-guanidine) island (CGI) promoter in gastric cancer (GC). Absence of RUNX3 expression from normal gastric epithelial cells (GECs), the progenitors to GC, coupled with frequent RUNX3 overexpression in GC progression, challenge this longstanding paradigm. However, epigenetic models to better describe RUNX3 deregulation in GC have not emerged. Here, we identify lineage-specific DNA methylation at an alternate, non-CGI promoter (P1) as a new mechanism of RUNX3 epigenetic control. In normal GECs, P1 was hypermethylated and repressed, whereas in immune lineages P1 was hypomethylated and widely expressed. In human GC development, we detected aberrant P1 hypomethylation signatures associated with the early inflammatory, preneoplastic and tumour stages. Aberrant P1 hypomethylation was fully recapitulated in mouse models of gastric inflammation and tumorigenesis. Cell sorting showed that P1 hypomethylation reflects altered cell-type composition of the gastric epithelium/tumour microenvironment caused by immune cell recruitment, not methylation loss. Finally, via long-term culture of gastric tumour epithelium, we revealed that de novo methylation of the RUNX3 canonical CGI promoter is a bystander effect of oncogenic immortalization and not likely causal in GC pathogenesis as previously argued. We propose a new model of RUNX3 epigenetic control in cancer, based on immune-specific, non-CGI promoter hypomethylation. This novel epigenetic signature may have utility in early detection of GC and possibly other epithelial cancers with premalignant immune involvement

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p <.001. Over 24 months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10 ml/min/1.73 m2 decrease), that was most notable in patients with eGFR <30 ml/min/1.73 m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry

Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients

Dental findings and rehabilitation in familial osteodysplasia (Anderson type): a case report

Familial osteodysplasia is a disorder of osteogenesis with an autosomal recessive pattern of inheritance which predominantly affects facial bones. No recent case had been reported, particularly from a dental point of view since the syndrome was first described by Anderson et al (JAMA 1972;220:1687-93). A 23-year-old male with familial osteodysplasia was presented in maxillofacial and dental aspects with clinical and radiological manifestations including malocclusion, abnormal teeth alignment, impacted teeth, shape disturbances including uncompleted coronal formation, root shortening with bulbous form, high angled mandible and elongation of the corpus of mandible. Recognation of the syndromal features prior to any dental intervention is of paramount importance because of increased inclination to spontaneous mandibular fractures. Hence, no surgical intervention was performed for impacted teeth. Following the extractions of severely mobile teeth, a definitive restoration was fabricated as distal-extension removable partial dentures with conus crown telescopic system. The aesthetic and functional outcome was satisfactory for the patient. In conclusion, dentists appear to play an important role in the recognition of familial osteodysplasia, based on maxillofacial and dentoalveolar findings. Awareness of the syndromal features, especially of spontaneous fractures, would detect the limitations for dental interventions and treatment planning

Influence of different surface treatments on push-out bond strengths of fiber-reinforced posts luted with dual-cure resin cement

Objectives: The objective was to evaluate whether fiber postsurface conditioning with air abrasion or erbium:yttrium-aluminum-garnet (Er:YAG) laser would influence the bond strength of dual-cure resin cement to the fiber-reinforced (FRC) posts. Materials and Methods: Twenty-one FRC posts were divided into three groups according to surface treatment methods as follows: An untreated control group air abrasion with Al2O3group, and Er:YAG laser treated group with 150 mJ parameter. Fiber posts were then built up to dual-cure resin cement. Eighteen specimens were set and sectioned perpendicularly along the long axis of the post using a saw. Two disks (thickness of 2 mm) were obtained from each specimen (n = 12). Remaining three posts were stored for scanning electron microscopic evaluation. Push out test was performed on the each specimen and the values were recorded as MPa. The data were analyzed using one-way analysis of variance and Tukey post-hoc tests (P 0.05). Results: The bond strength values for the groups were as follows: Control (15, 28 MPa), air abrasion group (19, 73 MPa), and Er:YAG group (17, 84 MPa). Air abrasion affected the bond strength significantly (P 0.05). Conclusion: Air abrasion attained higher bond strengths when FRC posts were luted to dual-cure resin cement. Additional studies should be designed with different types and parameters of laser devices to understand the effect of these devices on bond strength

Influence of different surface treatments on push-out bond strengths of fiber-reinforced posts luted with dual-cure resin cement

Objectives: The objective was to evaluate whether fiber postsurface conditioning with air abrasion or erbium:yttrium-aluminum-garnet (Er:YAG) laser would influence the bond strength of dual-cure resin cement to the fiber-reinforced (FRC) posts. Materials and Methods: Twenty-one FRC posts were divided into three groups according to surface treatment methods as follows: An untreated control group air abrasion with Al2O3group, and Er:YAG laser treated group with 150 mJ parameter. Fiber posts were then built up to dual-cure resin cement. Eighteen specimens were set and sectioned perpendicularly along the long axis of the post using a saw. Two disks (thickness of 2 mm) were obtained from each specimen (n = 12). Remaining three posts were stored for scanning electron microscopic evaluation. Push out test was performed on the each specimen and the values were recorded as MPa. The data were analyzed using one-way analysis of variance and Tukey post-hoc tests (P 0.05). Results: The bond strength values for the groups were as follows: Control (15, 28 MPa), air abrasion group (19, 73 MPa), and Er:YAG group (17, 84 MPa). Air abrasion affected the bond strength significantly (P 0.05). Conclusion: Air abrasion attained higher bond strengths when FRC posts were luted to dual-cure resin cement. Additional studies should be designed with different types and parameters of laser devices to understand the effect of these devices on bond strength

Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression

Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130F/F GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori-infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130F/F mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression

Coccygectomy with or without periosteal resection

The purpose of this study was to compare the clinical outcomes and wound complications in coccygectomy with or without subperiosteal resection. This retrospective study included 25 patients who underwent coccygectomy. Resection of all mobile coccygeal segments including the periosteum was performed in 11 patients (group 1) and resection was performed subperiostally sparing the periosteum in the remaining 14 patients (group 2). A visual analogue scale was used for pain assessment before and after the surgery both in sitting and standing positions. A questionnaire to evaluate subjective patient satisfaction was also used. The two groups were statistically similar in terms of age, sex, aetiology, duration of symptoms before surgery and follow-up time. Both surgical techniques resulted in a statistically similar clinical outcome. Overall, 84% of patients who underwent coccygectomy benefited from surgery. We observed four wound infections (two superficial and two deep) that caused delayed wound healing in group 1. The rate of infection in group 1 was statistically higher than in group 2. The results of this study suggest that periosteal preservation and closure are related to low risk of infection