Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling

Head and neck paragangliomas, rare neoplasms of the paraganglia composed of nests of neurosecretory and glial cells embedded in vascular stroma, provide a remarkable example of organoid tumor architecture. To identify genes and pathways commonly deregulated in head and neck paraganglioma, we integrated high-density genome-wide copy number variation (CNV) analysis with microRNA and immunomorphological studies. Gene-centric CNV analysis of 24 cases identified a list of 104 genes most significantly targeted by tumor-associated alterations. The “NOTCH signaling pathway” was the most significantly enriched term in the list (P = 0.002 after Bonferroni or Benjamini correction). Expression of the relevant NOTCH pathway proteins in sustentacular (glial), chief (neuroendocrine) and endothelial cells was confirmed by immunohistochemistry in 47 head and neck paraganglioma cases. There were no relationships between level and pattern of NOTCH1/JAG2 protein expression and germline mutation status in the SDH genes, implicated in paraganglioma predisposition, or the presence/absence of immunostaining for SDHB, a surrogate marker of SDH mutations. Interestingly, NOTCH upregulation was observed also in cases with no evidence of CNVs at NOTCH signaling genes, suggesting altered epigenetic modulation of this pathway. To address this issue we performed microarray-based microRNA expression analyses. Notably 5 microRNAs (miR-200a,b,c and miR-34b,c), including those most downregulated in the tumors, correlated to NOTCH signaling and directly targeted NOTCH1 in in vitro experiments using SH-SY5Y neuroblastoma cells. Furthermore, lentiviral transduction of miR-200s and miR-34s in patient-derived primary tympano-jugular paraganglioma cell cultures was associated with NOTCH1 downregulation and increased levels of markers of cell toxicity and cell death. Taken together, our results provide an integrated view of common molecular alterations associated with head and neck paraganglioma and reveal an essential role of NOTCH pathway deregulation in this tumor type.     

Optimizing acitretin use in patients with plaque psoriasis

Acitretin is one of the systemic agents used for the treatment of psoriasis. Because different acitretin dosages resulted therapeutically successful, there is no general agreement on the optimal dose regimen. To report acitretin efficacy and safety in a real‐life setting, wherein patient‐tailored dose regimen is usually prescribed, a retrospective analysis evaluating charts of all plaque‐type psoriasis patients treated with acitretin from the clinic database was performed. PASI score improvement, as well as PASI 50, 75, 90, and 100 responses were assessed throughout the observational period. Overall, 52% PASI score reduction and a satisfactory safety profile were detected. PASI 50, 75, 90, and 100 response was achieved by 53%, 48%, 28%, and 14%, respectively. Treatment consisted on a mean daily acitretin dose of 25.01 mg. The initial dose was increased (51.2% of cases) or decreased (48.8%) prescribing a mean daily dose of 29.8 mg and 20.02 mg, respectively. This study proposed a dose regimen customized on clinical response and patient's needs, to optimized acitretin benefit.     

Effectiveness of systemic amoxicillin/metronidazole as an adjunctive therapy to full-mouth scaling and root planing in the treatment of aggressive periodontitis: a systematic review and meta-analysis

Background: The systemic use of combined amoxicillin and metronidazole (AMX/MET) as an adjunctive treatment to full‐mouth scaling and root planing (FMSRP) has been proposed for the treatment of generalized aggressive periodontitis; however, its effectiveness and clinical safety remain to be defined. The purpose of the present meta‐analysis is to assess the effectiveness of FMSRP + AMX/MET compared to FMSRP alone. Methods: An electronic search of eight databases and a hand‐search of 10 international dental journals were conducted through September 11, 2011. Gain in clinical attachment level (CAL), reduction in probing depth (PD), secondary outcomes, and adverse events were analyzed. A random‐effect model was used to pool the extracted data. The weighted mean difference (MD) with 95% confidence interval (CI) was calculated for continuous outcomes, whereas risk difference (RD) with 95% CI was used for dichotomous data; heterogeneity was assessed with the χ²‐based Cochran Q test and I² statistic. The level of significance was set at P <0.05. Results: After the selection process, six randomized clinical trials were included. Results of the meta‐analysis showed significant CAL gain (MD, 0.42; 95% CI, 0.23 to 0.61; P <0.05) and PD reduction (MD, 0.58; 95% CI, 0.39 to 0.77; P <0.05) in favor of FMSRP + AMX/MET; moreover, no significant RD was found in the occurrence of adverse events (RD, 0.01; 95% CI, ?0.02 to 0.04; P >0.05). Conclusion: The findings of the meta‐analysis seem to support the effectiveness and the clinical safety of FMSRP + AMX/MET; however, future studies are needed to confirm these results.