Necrotizing periodontitis or medication-related osteonecrosis of the jaw (MRONJ) in a patient receiving Bemcentinib-a case report

Bemcentinib is a newly developed AXL inhibitor that is currently under investigation in phase II trails for the treatment of acute myeloblastic leukemia (AML). Clinical and radiographic findings in this case were very similar to cases of MRONJ in patients receiving Sunitinib or other anti-angiogenetic substances, assuming that Bemcentinib may cause similar oral side effects. We present a male 81-year-old patient with a manifestation of alveolar bone necrosis at the central upper incisors following a 2-month regimen with the AXL-inhibitor Bemcentinib, administered for the treatment of secondary acute myeloblastic leukemia (sAML). Due to the duration of less than 8 weeks, the osteonecrosis was diagnosed as necrotizing periodontitis, but the intraoral clinical and radiographic findings were also compatible with the differential diagnosis of medication-related osteonecrosis of the jaw (MRONJ, stage II). Following to discontinuation of Bemcentinib, the affected bone was surgically revised including the removal of a demarcated bone sequester under preventive antibiotic treatment (metronidazole 400 mg t.i.d.). We hypothesize that Bemcentinib might increase the susceptibility for osteonecrosis of the jaw, probably related to its antiangiogenic effects and the resulting modulation of host immune response. Based on the current observations, it can be assumed that oro-dental health might be significant also prior and during treatment with Bemcentinib for the prevention of MRONJ

Full-length amelogenin influences the differentiation of human dental pulp stem cells

Background: Amelogenin is an extracellular matrix protein well known for its role in the organization and mineralization of enamel. Clinically, it is used for periodontal regeneration and, due to its finding also in predentin and intercellular spaces of dental pulp cells, it has recently been suggested for pulp capping procedures. The aim of this study was to analyse in vitro the effect of the recombinant human full-length amelogenin on the growth and differentiation of human dental pulp stem cells (hDPSCs). Methods: Human DPSCs were treated with a supplement of amelogenin at a concentration of 10 ng/ml, 100 ng/ml and 1000 ng/ml. The groups were compared to the unstimulated control in terms of cell morphology and proliferation, mineralization and gene expression for ALP (alkaline phosphatase), DMP1 (dentin matrix protein-1) and DSPP (dentin sialophosphoprotein). Results: Amelogenin affects hDPSCs differently than PDL (periodontal ligament) cells and other cell lines. The proliferation rate at two weeks is significantly reduced in presence of the highest concentration of amelogenin as compared to the unstimulated control. hDPSCs treated with low concentrations present a downregulation of DMP1 and DSPP, which is significant for DSPP (p = 0.011), but not for DMP1 (p = 0.395). Conclusions: These finding suggest that the role of full-length amelogenin is not restricted to participation in tooth structure. It influences the differentiation of hDPSC according to various concentrations and this might impair the clinical results of pulp capping

Probing pocket depth reduction after non‐surgical periodontal therapy: Tooth‐related factors

Background To investigate tooth-related factors that influence the reduction of probing pocket depths (PPD) after non-surgical periodontal therapy (NST). Methods Seven hundred forty-six patients with a total of 16,825 teeth were included and retrospectively analyzed. PPD reduction after NST was correlated with the tooth-related factors; tooth type, number of roots, furcation involvement, vitality, mobility, and type of restoration; using logistic multilevel regression for statistical analysis. Results NST was able to reduce probing depth overall stratified probing depths (1.20 ± 1.51 mm, p ≤ 0.001). The reduction was significantly higher at teeth with higher probing depths at baseline. At pockets with PPD ≥ 6 mm, PPD remains high after NST. Tooth type, number of roots, furcation involvement, vitality, mobility, and type of restoration are significantly and independently associated with the rate of pocket closure. Conclusions The tooth-related factors: tooth type, number of roots, furcation involvement, vitality, mobility, and type of restoration had a significant and clinically relevant influence on phase I and II therapy. Considering these factors in advance may enhance the prediction of sites not responding adequately and the potential need for additional treatment, such as re-instrumentation or periodontal surgery, to ultimately achieve the therapy end points

Effect of Tension on Human Periodontal Ligament Cells: Systematic Review and Network Analysis

Orthodontic tooth movement is based on the remodeling of tooth-surrounding tissues in response to mechanical stimuli. During this process, human periodontal ligament cells (hPDLCs) play a central role in mechanosensing and mechanotransduction. Various in vitro models have been introduced to investigate the effect of tension on hPDLCs. They provide a valuable body of knowledge on how tension influences relevant genes, proteins, and metabolites. However, no systematic review summarizing these findings has been conducted so far. Aim of this systematic review was to identify all related in vitro studies reporting tension application on hPDLCs and summarize their findings regarding force parameters, including magnitude, frequency and duration. Expression data of genes, proteins, and metabolites was extracted and summarized. Studies’ risk of bias was assessed using tailored risk of bias tools. Signaling pathways were identified by protein-protein interaction (PPI) networks using STRING and GeneAnalytics. According to our results, Flexcell Strain Unit® and other silicone-plate or elastic membrane-based apparatuses were mainly adopted. Frequencies of 0.1 and 0.5 Hz were predominantly applied for dynamic equibiaxial and uniaxial tension, respectively. Magnitudes of 10 and 12% were mostly employed for dynamic tension and 2.5% for static tension. The 10 most commonly investigated genes, proteins and metabolites identified, were mainly involved in osteogenesis, osteoclastogenesis or inflammation. Gene-set enrichment analysis and PPI networks gave deeper insight into the involved signaling pathways. This review represents a brief summary of the massive body of knowledge in this field, and will also provide suggestions for future researches on this topic

The 14-bp deletion polymorphism in the HLA-G gene displays significant differences between ulcerative colitis and Crohn's disease and is associated with ileocecal resection in Crohn's disease

HLA-G is a non-classical MHC class Ib molecule predominantly expressed in cytotrophoblasts and under pathological conditions also in chronically inflamed and in malignant tissues. Recently an increased expression of HLA-G was found in ulcerative colitis (UC), but not in Crohn's disease (CD). The HLA-G gene is located in IBD3, a linkage region for inflammatory bowel disease (IBD). A 14-bp deletion polymorphism (Del+/Del−) within exon 8 of the HLA-G gene might influence transcription activity and is therefore of potential functional relevance. To investigate whether the 14-bp deletion polymorphism is associated with IBD, 371 patients with CD, 257 patients with UC and 739 controls were genotyped. The heterozygous genotype (P = 0.031) and the Del+ phenotype (P = 0.038) were significantly increased, whereas the homozygous Del− phenotype (P = 0.038) was significantly decreased in UC when compared with CD. Thus, the 14-bp deletion polymorphism within the HLA-G gene displayed significant differences between UC and CD. Moreover, a significant increase of the Del+ allele (P = 0.002) and the Del+/Del+ genotype (P = 0.013) and a consecutive decrease of the Del−/− genotype (P = 0.024) were observed in those CD cases positive for ileocecal resection. Thus, a potential effect of the HLA-G gene in IBD may affect both UC and CD. Other polymorphisms linked to the 14-bp deletion polymorphism might also contribute to immunopathogenesis. As there are several partly functional polymorphisms within the promoter region potentially influencing HLA-G expression, further studies in IBD are necessary in the context of differential expression of HLA-G between UC and C

Fluid flow shear stress and tissue remodeling—an orthodontic perspective: evidence synthesis and differential gene expression network analysis

Introduction: This study aimed to identify and analyze in vitro studies investigating the biological effect of fluid-flow shear stress (FSS) on cells found in the periodontal ligament and bone tissue.Method: We followed the PRISMA guideline for systematic reviews. A PubMed search strategy was developed, studies were selected according to predefined eligibility criteria, and the risk of bias was assessed. Relevant data related to cell source, applied FSS, and locus-specific expression were extracted. Based on this evidence synthesis and, as an original part of this work, analysis of differential gene expression using over-representation and network-analysis was performed. Five relevant publicly available gene expression datasets were analyzed using gene set enrichment analysis (GSEA).Result: A total of 6,974 articles were identified. Titles and abstracts were screened, and 218 articles were selected for full-text assessment. Finally, 120 articles were included in this study. Sample size determination and statistical analysis related to methodological quality and the ethical statement item in reporting quality were most frequently identified as high risk of bias. The analyzed studies mostly used custom-made fluid-flow apparatuses (61.7%). FSS was most frequently applied for 0.5 h, 1 h, or 2 h, whereas FSS magnitudes ranged from 6 to 20 dyn/cm2 depending on cell type and flow profile. Fluid-flow frequencies of 1 Hz in human cells and 1 and 5 Hz in mouse cells were mostly applied. FSS upregulated genes/metabolites responsible for tissue formation (AKT1, alkaline phosphatase, BGLAP, BMP2, Ca2+, COL1A1, CTNNB1, GJA1, MAPK1/MAPK3, PDPN, RUNX2, SPP1, TNFRSF11B, VEGFA, WNT3A) and inflammation (nitric oxide, PGE-2, PGI-2, PTGS1, PTGS2). Protein-protein interaction networks were constructed and analyzed using over-representation analysis and GSEA to identify shared signaling pathways.Conclusion: To our knowledge, this is the first review giving a comprehensive overview and discussion of methodological technical details regarding fluid flow application in 2D cell culture in vitro experimental conditions. Therefore, it is not only providing valuable information about cellular molecular events and their quantitative and qualitative analysis, but also confirming the reproducibility of previously published results

Evidence for STAT4 as a Common Autoimmune Gene: rs7574865 Is Associated with Colonic Crohn's Disease and Early Disease Onset

Recent studies demonstrated an association of STAT4 variants with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), indicating that multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 variants on the susceptibility and phenotype of inflammatory bowel diseases (IBD) in a large patient and control cohort. Genomic DNA from 2704 individuals of Caucasian origin including 857 patients with Crohn's disease (CD), 464 patients with ulcerative colitis (UC), and 1383 healthy, unrelated controls was analyzed for seven SNPs in the STAT4 gene (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694, rs10174238). In addition, a detailed genotype-phenotype analysis was performed. Our analysis revealed an association of the STAT4 SNP rs7574865 with overall decreased susceptibility to CD (p = 0.047, OR 0.86 [95% CI 0.74-0.99]). However, compared to CD patients carrying the wild type genotype, the STAT4 SNP rs7574865 was significantly associated with early CD onset (p = 0.021) and colonic CD (p = 0.008; OR = 4.60, 95% CI 1.63-12.96). For two other STAT4 variants, there was a trend towards protection against CD susceptibility (rs7568275, p = 0.058, OR 0.86 [95% CI 0.74-1.00]; rs10174238, p = 0.057, OR 0.86 [95% CI 0.75-1.00]). In contrast, we did not observe any association with UC susceptibility. Evidence for weak gene-gene interaction of STAT4 with the IL23R SNP rs11209026 was lost after Bonferroni correction. Our results identified the STAT4 SNP rs7574865 as a disease-modifying gene variant in colonic CD. However, in contrast to SLE and RA, the effect of rs7574865 on CD susceptibility is only weak

rs1004819 Is the Main Disease-Associated IL23R Variant in German Crohn's Disease Patients: Combined Analysis of IL23R, CARD15, and OCTN1/2 Variants

The IL23R gene has been identified as a susceptibility gene for inflammatory bowel disease (IBD) in the North American population. The aim of our study was to test this association in a large German IBD cohort and to elucidate potential interactions with other IBD genes as well as phenotypic consequences of IL23R variants. Genomic DNA from 2670 Caucasian individuals including 833 patients with Crohn's disease (CD), 456 patients with ulcerative colitis (UC), and 1381 healthy unrelated controls was analyzed for 10 IL23R SNPs. Genotyping included the NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T) and SLC22A5/OCTN2 (-207 G-->C). All IL23R gene variants analyzed displayed highly significant associations with CD. The strongest association was found for the SNP rs1004819 [P = 1.92x10(-11); OR 1.56; 95 % CI (1.37-1.78)]. 93.2% of the rs1004819 TT homozygous carriers as compared to 78% of CC wildtype carriers had ileal involvement [P = 0.004; OR 4.24; CI (1.46-12.34)]. The coding SNP rs11209026 (p.Arg381Gln) was protective for CD [P = 8.04x10(-8); OR 0.43; CI (0.31-0.59)]. Similar, but weaker associations were found in UC. There was no evidence for epistasis between the IL23R gene and the CD susceptibility genes CARD15 and SLC22A4/5. IL23R is an IBD susceptibility gene, but has no epistatic interaction with CARD15 and SLC22A4/5. rs1004819 is the major IL23R variant associated with CD in the German population, while the p.Arg381Gln IL23R variant is a protective marker for CD and UC