Larsenlong2017

The pathogenesis of rosacea is incompletely understood. Signaling neuropeptides, including PACAP, a regulator of vasodilation and edema, are upregulated in rosacea skin. Here, we evaluated PACAP38-induced rosacea features and examined whether a 5-HT

receptor agonist could reduce these features.

A total of 35 patients with erythematotelangiectatic rosacea received an intravenous infusion of 10 pmol/kg/minute of PACAP38 followed by an intravenous infusion of 4 mg sumatriptan or placebo (saline) on two study days in a double-blind, randomized, placebo-controlled, and cross-over trial.

PACAP38 increased facial skin blood flow by 90%, dilated the superficial temporal artery by 56%, and induced prolonged flushing and facial edema. Compared with placebo, sumatriptan reduced PACAP38-induced facial skin blood flow for 50 minutes (P= 0.023), constricted the superficial temporal artery for 80 minutes (P= 0.010), and reduced duration of flushing (P= 0.001) and facial edema (P < 0.001).

We established a clinical experimental model of rosacea features and showed that sumatriptan was able to attenuate PACAP38-induced rosacea flushing and edema. Findings support a key role of PACAP38 in rosacea flushing pathogenesis. It remains unknown whether PACAP38 inhibition can improve rosacea.

The trial was registered at ClinicalTrials.govNCT03878784 in March2019.

The trial was registered at ClinicalTrials.govNCT03878784 in March 2019.Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer characterized by high invasiveness, early metastases, and high mortality. Because of the lack of suitable animal models, most functional studies are performed using cell lines, some of which lack classical neuroendocrine growth characteristics. Here, we scrutinized the molecular characteristics of classical MCC and variant MCC cell lines by differential gene expression and the respective epigenetic regulation by microRNAs and DNA methylation. Cutaneous squamous cell carcinoma cell lines were used for comparison. The most striking observation was a lower expression of epithelial-mesenchymal transition-related genes in classical MCCs, which was accompanied by higher expression of the epithelial-mesenchymal transition-regulating microRNA clusters miR-200c-141 and miR-183-96-182 and hypomethylation of the respective microRNA loci. selleck chemical Experimental expression of the MCC lineage factor ATOH1 in variant MCCs resulted in an increased expression of miR-200c-141 paralleled by a reduction of genes associated with epithelial-mesenchymal transition, thus demonstrating a connection between neuroendocrine characteristics and the lack of epithelial-mesenchymal transition. Together, our observations not only reinforce concerns about the use of variant MCCs as proper MCC representatives, but also suggest variant MCCs as cells locked in an intermediate state between neuroendocrine and epithelial differentiation.Gynecological cancers are characterized by a high mortality rate when chemoresistance develops. Autophagy collaborates with apoptosis and participates in homeostasis of chemoresistance. Recent findings supported that crosstalk of necrotic, apoptotic and autophagic factors, and chemotherapy-driven hypoxia, oxidative stress and ER stress play critical roles in chemoresistance in gynecological cancers. Meanwhile, current studies have shown that autophagy could be regulated by and cooperate with metabolic regulator, survival factors, stemness factors and specific post-translation modification in chemoresistant tumor cells. Meanwhile, non-coding RNA and autophagy crosstalk also contribute to the chemoresistance. Until now, analysis of individual autophagy factors towards the clinical significance and chemoresistance in gynecological cancer is still lacking. We suggest comprehensive integrated analysis of cellular homeostasis and tumor microenvironment to clarify the role of autophagy and the associated factors in cancer progression and chemoresistance. Panel screening of pan-autophagic factors will pioneer the development of risk models for predicting efficacy of chemotherapy and guidelines for systematic treatment and precision medicine.The natural history of adenoid cystic carcinoma (ACC) is relentless, defined by treatment failure heralded by locoregional recurrence and distant metastatic disease. In this review, we present an update of clinical features, molecular classification, current targeted therapies, immune landscapes and novel treatment targets with their respective clinical trials. The presented results are defined by a lack of overall response rate and limited progression free survival, with restriction to stable disease. In addition, ACC is resistant to immune checkpoint inhibition due to low tumour immunogenicity and lack of PD-L1 expression. Here we present a new prospective research paradigm for ACC, including the potential to target prostate specific membrane antigen (PSMA) and the potential for manipulation of target receptors in the clinic. The presentation of this review aims to promote future research to improve response rates and outcomes for therapeutics undergoing clinical trial in ACC.Cerium dioxide nanoparticles (CeO2 NPs) are ubiquitous in the water environment due to the extensive commercial applications. The complexity of heterogeneous humic acid (HA) plays a significant role in affecting the physicochemical properties of CeO2 NPs in aqueous environments. However, the effects of light intensities and HA fractions on the interaction mechanism between CeO2 NPs and HA are poorly understood. Here, we provided the evidence that both light intensities (>3 E L-1 s-1) and molecular weights (>10 kDa) can effectively affect the interactions between CeO2 NPs and HA. The absolute content of reactive oxygen species (ROS) and quantum yield (Φ) of 3HA* were inhibited when HA (10 mg of C L-1) interacts with CeO2 NPs. However, they were positively correlated with the increasing irradiation time and simulated sunlight intensities. High molecular weights of HA fraction (>100 kDa) restrained the ROS generation and Φ of 3HA* due to surface adsorption between HA and CeO2 NPs blocking reactive sites, competitive absorption for simulated sunlight. Fourier transform infrared and three-dimensional excitation-emission matrix fluorescence spectroscopy confirmed that the carboxylic groups of HA have high complexation capacity with CeO2 NPs. These findings are essential for us to improve the understanding of the impacts of HA on CeO2 NPs under different conditions in natural waters.

Prenatal exposure to heavy metals during critical developmental phases has been implicated in allergic phenotypes. However, few studies have been conducted on the gender-specific association of prenatal heavy metal exposure with atopic dermatitis (AD) in infants.

To examine the gender-specific association of prenatal exposure to multiple heavy metals with AD incidence in 6-month-old infants using data from the Mothers and Children's Environmental Health (MOCEH).

We evaluated 738 mother-child pairs from the MOCEH study, an ongoing prospective birth cohort. The concentrations of three heavy metals (lead, mercury and cadmium) in maternal blood samples were measured during early and late pregnancy. Each quartile of heavy metal concentration was used to consider the possible nonlinear association with AD. For assessing the multi-pollutant model, we constructed the multivariate regression model including all three heavy metals at both early and late pregnancy. Further, the group Lasso model was used to perforreases risk of AD in 6-month-old boys although the strength of association is weak. Further studies are needed to confirm the susceptibility window and gender differences in lead-induced AD.

To compare length of stay (LOS) in neonatal care for babies born extremely preterm admitted to networks participating in the International Network for Evaluating Outcomes of Neonates (iNeo).

Data were extracted for babies admitted from 2014 to 2016 and born at 24 to 28weeks of gestational age (n=28 204). Median LOS was calculated for each network for babies who survived and those who died while in neonatal care. A linear regression model was used to investigate differences in LOS between networks after adjusting for gestational age, birth weight z score, sex, and multiplicity. A sensitivity analysis was conducted for babies who were discharged home directly.

Observed median LOS for babies who survived was longest in Japan (107days); this result persisted after adjustment (20.7days more than reference, 95% CI 19.3-22.1). Finland had the shortest adjusted LOS (-4.8days less than reference, 95% CI -7.3 to -2.3). For each week's increase in gestational age at birth, LOS decreased by 12.1days (95% CI -12.3 to -11.9). Multiplicity and male sex predicted mean increases in LOS of 2.6 (95% CI 2.0-3.2) and 2.1 (95% CI 1.6-2.6) days, respectively.

We identified between-network differences in LOS of up to 3weeks for babies born extremely preterm. Some of these may be partly explained by differences in mortality, but unexplained variations also may be related to differences in clinical care practices and healthcare systems between countries.

We identified between-network differences in LOS of up to 3 weeks for babies born extremely preterm. Some of these may be partly explained by differences in mortality, but unexplained variations also may be related to differences in clinical care practices and healthcare systems between countries.An integrated understanding of the functional capacities of cells in the context of their physical parameters and molecular markers is increasingly demanded in immunologic studies. Regulatory T cells (Tregs) are a subpopulation of T cells involved in immune response modulation and mediating tolerance to self-antigen with their absence leading to a loss of tolerance. Glycoprotein repetitions A predominant (GARP) is a key marker for activated Tregs, but its detection may also be useful in determining the functional capacities of the cell. This study aims to deduce the optimal stimulation period and the impact of protein transport inhibitors (PTIs), commonly used in the detection of intracellular cytokines, on GARP detection. Through flow cytometric analysis we analyzed different cell culture conditions for optimal GARP expression on activated Tregs. Healthy donor PBMCs were stimulated with either Staphylococcal Enterotoxin B (SEB) or PMA/Ionomycin (PMA/Iono), in the presence and absence of PTIs monensin and/or brefeldin A (BFA) and GARP expression was assessed on CD4+ CD25+ FOXP3+ Tregs. The optimal stimulation period for the detection of GARP was highest at 24-h. Furthermore, we determined that GARP expression on Tregs is significantly reduced when cells are treated with the PTIs monensin and/or BFA following PMA/Iono stimulation. This effect was not seen following SEB stimulation. Therefore, due to the effects of PTIs, alternative methods should be considered when performing simultaneous analysis for cytokine expression and GARP expression on Tregs.

The response mediated by CD8

T-cells in the context of infection and vaccination has been thoroughly investigated and represents one of the most important branches that allow for the development of immunity against intracellular pathogens and, thus, the establishment of robust antiviral responses. However, there is a lack of methods to assess antigen-specific CD8

T-cells.

Search for the ideal assays to assess the function of antigen-specific CD8

T-cells.

In the present study a chimeric HLA-A2β2MIg fusion protein was produced, purified, and evaluated in functional CD8

T-cell response studies using samples from Influenza A patients and humanized mice upon adenoviral vaccination.

The HLA-A2β2MIg molecule, bound to immunodominant viral peptides by passive transfer, was able to induce robust antiviral CD8

T-cell responses mediated by IFN-γ. The in vitro IFN-γ release assay using the chimeric HLA-A2β2MIg fusion protein detected bona fide human CD8

T-cells, demonstrating superior production of IFN-γ by human CD8

T-cells induced by Influenza A immunodominant GILGFVFTL peptide.