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Background
Rosacea is a chronic inflammatory skin condition whose etiology has been linked to mast cells and the antimicrobial peptide cathelicidin LL-37. Individuals with refractory disease have demonstrated clinical benefit with periodic injections of onabotulinum toxin, but the mechanism of action is unknown.Objectives
To investigate the molecular mechanism by which botulinum toxin improves rosacea lesions.Methods
Primary human and murine mast cells were pretreated with onabotulinum toxin A or B or control. Mast cell degranulation was evaluated by β-hexosaminidase activity. Expression of botulinum toxin receptor Sv2 was measured by qPCR. The presence of SNAP-25 and VAMP2 was established by immunofluorescence. In vivo rosacea model was established by intradermally injecting LL-37 with or without onabotulinum toxin A pretreatment. Mast cell degranulation was assessed in vivo by histologic counts. Rosacea biomarkers were analyzed by qPCR of mouse skin sections.Results
Onabotulinum toxin A and B inhibited compound 48/80-induced degranulation of both human and murine mast cells. Expression of Sv2 was established in mouse mast cells. Onabotulinum toxin A and B increased cleaved SNAP-25 and decreased VAMP2 staining in mast cells respectively. In mice, injection of onabotulinum toxin A significantly reduced LL-37-induced skin erythema, mast cell degranulation, and mRNA expression of rosacea biomarkers.Conclusions
These findings suggest that onabotulinum toxin reduces rosacea-associated skin inflammation by directly inhibiting mast cell degranulation. Periodic applications of onabotulinum toxin may be an effective therapy for refractory rosacea and deserves further study. 相似文献Objective
To compare perioperative and long-term outcomes in patients undergoing hemiarch and aggressive arch replacement for acute type A aortic dissection (ATAAD).Methods
From 1996 to 2017, we compared outcomes of hemiarch (n = 322) versus aggressive arch replacements (zones 2 and 3 arch replacement with implantation of 2-4 arch branches, n = 150) in ATAAD. Indications for aggressive arch were arch aneurysm >4 cm or intimal tear in the aortic arch that was not resectable by hemiarch replacement, or dissection of arch branches with malperfusion.Results
Patients in the aggressive arch group were significantly younger (mean age: 57 vs 61 years old) and had significantly longer hypothermic circulatory arrest, cardiopulmonary bypass, and aortic crossclamp times. There were no significant differences in perioperative outcomes between hemiarch and aggressive arch groups, including 30-day mortality (5.3% vs 7.3%, P = .38) and postoperative stroke rate (7% vs 7%, P = .96). Over 15 years, Kaplan–Meier survival was similar between hemiarch and aggressive arch groups (log-rank P = .55, 10-year survival 70% vs 72%). Given death as a competing factor, incidence rates of reoperation over 15 years (2.1% vs 2.0% per year, P = 1) and 10-year cumulative incidence of reoperation (14% vs 12%, P = .89) for arch and distal aorta pathology were similar between the 2 groups.Conclusions
Both hemiarch and aggressive arch replacement are appropriate approaches for select patients with ATAAD. Aggressive arch replacement should be considered for an arch aneurysm >4 cm or an intimal tear at the arch unable to be resected by hemiarch replacement, or dissection of the arch branches with malperfusion. 相似文献Methods: In this study, Wnt4 gene overexpression and knockdown were performed in PINK1 mutant PD transgenic Drosophila, and the protective effect of Wnt4 gene on PD transgenic Drosophila and its possible mechanism were explored. The Wnt4 gene was screened in the previous experiment; And by using the PD transgenic Drosophila model of the MHC-Gal4/UAS system, the PINK1 gene could be specifically activated in the Drosophila muscle tissue.
Results: In PINK1 mutation transgenic fruit flies, the Wnt4 gene to study its implication on PD transgenic fruit flies’ wing normality and flight ability. We found that overexpression of Wnt4 gene significantly reduced abnormality rate of PD transgenic Drosophila and improved its flight ability, and then, increased ATP concentration, enhanced mitochondrial membrane potential and normalized mitochondrial morphology were found. All of these findings suggested Wnt4 gene may have a protective effect on PD transgenic fruit flies. Furthermore, in Wnt4 gene overexpression PD transgenic Drosophila, down-regulation autophagy and apoptosis-related proteins Ref(2)P, Pro-Caspase3, and up-regulation of Beclin1, Atg8a, Bcl2 protein were confirmed by Western Blotting.
Conclusion: The results imply that the restoring of mitochondrial function though Wnt4 gene overexpression in the PINK1 mutant transgenic Drosophila may be related to autophagy and/or apoptosis. 相似文献
Objective
To assess the impact of focality and location of positive surgical margins (PSM) on long-term outcomes after radical prostatectomy (RP) for prostate cancer (PCa), including biochemical recurrence (BCR), metastasis and overall mortality.Patients and Methods
From a total of 2796 cases of RP between 1993 and 2007 in our single hospital, 476 cases with PSMs were identified and included in this study. PSM location was categorized into apex, peripheral, and bladder neck. Survival was estimated using the Kaplan-Meier method. Cox proportional hazard regression models were used to analyze the impact of PSM focality and location status on oncologic survival.Results
Of these 476 cases with PSMs, 335 (70.4%) cases were with single focal (sF) PSMs and 141 (29.6%) cases were with multifocal (mF) PSMs. Furthermore, 406 (85.3%) cases were found to have single location (sL) PSMs, and 70 (14.7%) cases were with multilocation (mL) PSMs. The median follow-up was 12.9 years. mF-PSMs and mL-PSMs showed significant impact on increased BCR risk on univariate analysis, and mL-PSMs remained significant on multivariate analysis (P = .048). Furthermore, the combination of multifocality and multilocation showed added prognostic value on predicting BCR-free survival, but not on metastasis-free survival or overall survival.Conclusion
The presence of mF-PSMs and mL-PSMs, and especially the combination of both, demonstrated significant impact on BCR prognosis. Patients with apex sLsF-PSMs were less likely to have BCR when compared with all those with non-apex sLsF-PSMs. These results should be considered when evaluating patients for adjuvant therapy. 相似文献- Download : Download high-res image (331KB)
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Background
Pure mucinous breast cancer (PMBC) is a rare pathologic type of breast cancer, the prognostic factors of which have not been clearly defined. This study aimed to analyze the prognostic markers and distribution of 21-gene recurrence score (RS) in patients with PMBC.Patients and Methods
Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, a retrospective analysis of PMBC cases was conducted. Multivariate analyses were used to evaluate the indicators for prognosis and the correlations between RS and traditional clinicopathologic characteristics. Disease was subdivided into 4 molecular phenotypes using estrogen receptor (ER) status and tumor grade.Results
Of the 8048 patients, most had ER-positive and node-negative tumors. Multivariate analysis revealed that molecular phenotype as well as age, race, tumor size, and lymph node status was an independent prognostic factor for patients with PMBC (P < .05). The 5-year breast cancer–specific survival of patients among different phenotypes was significantly different (97.9% for ER-positive and grade I tumor, 96.9% for ER-positive and grade II-III tumor, 96% for ER-negative and grade I tumor, 90.1% for ER-negative and grade II-III tumors, P < .001). The proportions of patients categorized into low, intermediate, and high RS risk group were 64.9%, 31.9%, and 3.2%, respectively. Grade, progesterone receptor status, and age were identified as independent variables associated with RS.Conclusion
PMBC had favorable biological features and relatively good prognosis. Molecular phenotype as well as age, race, tumor size, and lymph node status were independent prognostic markers. Furthermore, age, progesterone receptor status, and grade could independently predict RS. 相似文献- Download : Download high-res image (201KB)
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