Keratocystic odontogenic tumors (KCOTs) are cystic epithelial neoplasias with a high recurrence rate. However, the molecular mechanisms underlying the initiation and progression of KCOTs are still largely unknown. Here, we show that specific ablation of Smad4 in odontoblasts unexpectedly resulted in spontaneous KCOTs in mice. The mutant mice exhibited malformed teeth characterized by fractured incisors and truncated molar roots. These abnormalities were mainly caused by disrupted odontoblast differentiation that led to irregular dentin formation. The cystic tumors arising from the reactivation of epithelial rests of Malassez (ERM), in which Smad4 remained intact, proliferated and formed stratified and differentiated squamous epithelia that exhibited a dramatic upregulation of Hedgehog signaling. Odontoblasts, which are responsive to transforming growth factor beta (TGF-␤)/bone morphogenetic protein (BMP) signals, may produce signal molecules to inhibit the activation of ERM. Indeed, we observed a downregulation of BMP signals from Smad4 mutant odontoblasts to the adjacent Hertwig's epithelial root sheath (HERS). Intriguingly, KCOTs frequently emerged from Smad4-deficient ERM in keratinocytespecific Smad4 knockout mice, suggesting a novel mechanism in which reciprocal TGF-␤/BMP signaling between odontoblasts and HERS was required for tooth root development and suppression of KCOT formation. These findings provide insight into the genetic basis underlying KCOTs and have important implications for new directions in KCOT treatment.

Background: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma have poorer outcomes after functional endoscopic sinus surgery (FESS) and higher recurrence rate. The aim of present study was to investigate the long-term clinical outcomes of extended surgical strategies for patients with recurrent CRSwNP and asthma.Methods: Eighty-one patients with CRSwNP and asthma were enrolled in this 5-year prospective study. They were randomly assigned to undergo FESS, radical endoscopic sinus surgery (RESS), or RESS+Draf 3 surgery. Disease severity and clinical outcomes were evaluated using symptoms scoring, endoscopic scoring system, computed tomography staging system, sinus-specific quality of life scores, tissue and peripheral blood eosinophil percentage, and pulmonary function tests. Baseline, 1-year, 3-year, and 5-year follow-up data were compared among the groups.Results: RESS and RESS+Draf 3 strategies yielded better short-term (1 year) outcomes than did FESS. FESS had a higher short-term recurrence rate, although recurrence rates were similarly high (95.6-96.1%) in all the groups at 5 years postoperatively. RESS and RESS+Draf 3 yielded a lower long-term revision surgery rate and a longer time to recurrence post-surgery than FESS, which was negatively correlated with tissue and peripheral blood eosinophil percentage. Conclusions:CRSwNP with asthma is a systemic disease that inevitably recurs. Radical surgery prolongs recurrence time and improves olfaction, rhinorrhea, and quality of life in the short-term. Combining Draf 3 with RESS did not yield better clinical outcomes than RESS alone; thus, although RESS alone appears to be the best option, these findings need to be confirmed in further studies involving more patients, longer follow-up duration and stricter standardized medication use especially the adequate steroid irrigations.

In mouse, continuous growth of the postnatal incisor is coordinated by two populations of multipotent progenitor cells, the dental papilla mesenchymal cells and dental epithelial stem cells, residing at the proximal end of the incisor, yet the molecular mechanism underlying the cooperation between mesenchymal and epithelial cells is largely unknown. Here, transforming growth factor-b (TGF-b) type II receptor (Tgfbr2) was specifically deleted within the postnatal dental papilla mesenchyme. The Tgfbr2-deficient mice displayed malformed incisors with wavy mineralized structures at the labial side as a result of increased differentiation of dental epithelial stem cells. We found that mesenchymal Tgfbr2 disruption led to upregulated expression of Wnt5a and downregulated expression of Fgf3/10 in the mesenchyme, both of which synergistically enhanced Lrp5/6-b-catenin signaling in the cervical loop epithelium. In accord with these findings, mesenchyme-specific depletion of the Wnt transporter gene Wls abolished the aberrant mineralized structures caused by Tgfbr2 deletion. Thus, mesenchymal TGF-b signaling provides a unifying mechanism for the homeostasis of dental epithelial stem cells via a Wnt signalingmediated mesenchymal-epithelial cell interaction.

SummaryWhether the effect of diabetes on patients with unprotected left main coronary artery (ULMCA) disease differs according to different strategies of revascularization was unknown. This study was conducted to evaluate the impact of diabetes on patients with ULMCA disease treated with either percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG).A total of 922 patients with ULMCA disease who received drug-eluting stent (DES) (n = 465) implantation or underwent CABG (n = 457) were retrospectively analyzed. We compared the effects of these 2 treatments on clinical outcomes (death, myocardial infarction, stroke, repeat revascularization, and the composite of death, myocardial infarction, or stroke), according to diabetic status.During the median follow-up of 7.1 years (interquartile range, 5.3 to 8.2 years), no difference was found between PCI and CABG in the adjusted occurrence of death (P = 0.112) and the composite endpoints of death, myocardial infarction, and stroke (P = 0.235). Significantly higher incidence of repeat revascularization (P < 0.001) was observed in the DES group, whereas the CABG group had a significantly higher rate of stroke (P = 0.001). These trends were consistent in both diabetic and nondiabetic patients. We did not observe significant interactions between treatment outcomes and the presence or absence of diabetes after adjustment for covariates (P interaction = 0.580 for the composite of death, MI and stroke, P interaction = 0.685 for death, P interaction = 0.416 for MI, P interaction = 0.470 for stroke, and P interaction = 0.502 for repeat revascularization).Presence of diabetes was not important for decision-making between CABG and PCI in patients with ULMCA disease. (Int Heart J 2015; 56: 43-48)

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There was a prognostic impact of diabetes mellitus on treatment effects in patients with unprotected LMCA lesions who underwent DES or CABG. For patients with unprotected LMCA lesions, PCI with DES was an acceptable alternative to CABG at risk for higher repeat revascularization in the nondiabetic cohort, whereas in the diabetic cohort PCI with DES was inferior to CABG in terms of both safety and efficacy.

Background: IL-8 is an important chemokine implicated in the pathogenesis of chronic rhinosinusitis (CRS), but little is known about epigenetic regulation of IL8 in the pathogenesis of CRS. Objective: We sought to investigate the relationship between the DNA methylation level in the IL8 proximal promoter and CRS in Han Chinese subjects. Methods: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP; n 5 187), patients with chronic rhinosinusitis without nasal polyps (CRSsNP; n 5 89), and control subjects (n 5 57) were enrolled in 2 independent cohorts. Purified human nasal epithelial cells from each participant were assessed for percentage DNA methylation of CpG sites in the IL8 From the Departments of

BackgroundThis study was performed to determine whether there was any association between abnormal DNA methylation of a thymic stromal lymphopoietin (TSLP) locus and pathogenesis of chronic rhinosinusitis (CRS).MethodsA total of 48 CRS patients with nasal polyps (CRSwNP), 28 CRS patients without nasal polyps (CRSsNP) and 21 control subjects were enrolled into the study; and evaluated for serum total IgE level, olfactory score and nasal resistance. Samples were obtained from nasal polyps of CRSwNP patients, ethmoid mucosae of CRSsNP patients and inferior turbinate (IT) mucosa of control subjects during surgery, and used to isolate purified primary human nasal epithelial cells (HNECs). Genomic DNA was extracted from purified primary HNECs of each subject and DNA methylation ratios for a selected region of the TSLP gene were screened the using MassARRAY EpiTYPER.ResultsA total of 17 CpG units were analyzed; of which two CpG units (CpG3 and 22:23:24) had increased methylation ratios in the CRSwNP patients compared to the CRSsNP and control subjects after correction for false discovery rate (FDR) (Q < 0.1). The methylation ratios at both CpG3 and CpG22:23:24 units were positively correlated with olfactory score (r = 0.41, P = 0.0001; r = 0.25, P = 0.021) and unilateral nasal resistance at 75 Pa (r = 0.24, P = 0.04; r = 0.24, P = 0.036) and 150 Pa (r = 0.34, P = 0.004; r = 0.25, P = 0.031). Total nasal resistance at 75 Pa/150 Pa or serum total IgE levels were not correlated with the methylation ratios at either CpG unit.ConclusionsIncreased DNA methylation at the TSLP locus is likely to be associated with CRSwNP pathogenesis; however these findings need to be confirmed in larger multicentre group studies.