Pituitary hormone α-MSH promotes tumor-induced myelopoiesis and immunosuppression.

The hypothalamic-pituitary (HP) unit can produce various hormones to regulate immune responses, and some of its downstream hormones or effectors are elevated in cancer patients. We show that the HP unit can promote myelopoiesis and immunosuppression to accelerate tumor growth. Subcutaneous implantation of tumors induced hypothalamus activation and pituitary α-melanocyte-stimulating hormone (α-MSH) production in mice. α-MSH acted on bone marrow progenitors to promote myelopoiesis, myeloid cell accumulation, immunosuppression, and tumor growth through its melanocortin receptor MC5R. MC5R peptide antagonist boosted antitumor immunity and anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Serum α-MSH concentration was elevated and correlated with circulating myeloid-derived suppressor cells in cancer patients. Our results reveal a neuroendocrine pathway that suppresses tumor immunity and suggest MC5R as a potential target for cancer immunotherapy.

Low Level of PALMD Contributes to the Metastasis of Uveal Melanoma.

Uveal melanoma (UM) is a highly aggressive disease. There is an urgent need to develop the metastasis prediction markers of UM. This study aims to detect the key role of PALMD in UM metastasis. Transcriptome sequencing results of 2 sets of UM metastatic samples (GSE22138 and GSE156877) were downloaded from the Gene Expression Omnibus (GEO), and 18 overlapping differentially expressed genes were screened out, including PALMD. PALMD was significantly underexpressed in metastatic UM tissue. Low expression of PALMD was associated with poor prognosis in UM patients. The decreased expression of PALMD promoted the invasion and migration of 92-1 and Mel270 cells, while the high expression of PALMD inhibited the invasion and migration of UM cells. Furthermore, the levels of matrix metallopeptidase (MMP) 2 and MMP9 increased after transfection of siRNAs specifically targeting PALMD, whereas the levels of MMP2 and MMP9 were decreased after PALMD overexpression. However, PALMD did not affect the proliferation of UM cells. In addition, ZNF263 promoted the transcription of PALMD through the putative binding sequence using the JASPAR database, luciferase reporter gene analysis and chromatin immunoprecipitation assay. In summary, the expression of PALMD regulated by ZNF263 plays an important role in UM metastasis.

ZNF667-AS1, a positively regulating MEGF10, inhibits the progression of uveal melanoma by modulating cellular aggressiveness.

Zinc finger protein 667-antisense RNA 1 (ZNF667-AS1) is a member of the C2 H2 zinc finger protein family. However, the exact effect of ZNF667-AS1 in uveal melanoma (UM) progression has not been elucidated. The biological roles of ZNF667-AS1 and MEGF10 were assessed using cell counting kit-8 and flow cytometry. Quantitative reverse-transcription polymerase chain reaction and Western blot analyses were conducted to measure the expression of subjects. ZNF667-AS1 expression was significantly decreased in metastasized UM tissues and its low expression was related to poorer prognosis of UM patients. MEGF10 expression was positively associated with ZNF667-AS1 expression. The inhibitory effect of ZNF667-AS1 overexpression on UM cellular malignant behaviors could be reversed by MEGF10 knockdown, which was re-ascertained by the detection of corresponding protein levels (p53, cyclin D1, Bcl-2, and Bax). In conclusion, ZNF667-AS1 might play an inhibitory role in the development of UM by regulating cellular aggressiveness, which was partially realized by positively regulating MEGF10.

Association between IL-13 +1923C/T polymorphism and asthma risk: a meta-analysis based on 26 case-control studies.

Asthma is a serious and hereditary respiratory disorder affecting all age groups. Interleukin-13 (IL-13) is a central regulator of allergic inflammation. The purpose of the present study was to estimate the relationship between IL-13 +1923C/T polymorphism and asthma susceptibility. Relevant case-control studies published between January 2000 and July 2016 were searched in the online databases. Review Manage (RevMan) 5.3 was used to conduct the statistical analysis. The pooled odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the strength of association. A total of 26 articles were retrieved, including 17642 asthma patients and 42402 controls. Overall, our results found that IL-13 +1923C/T polymorphism was significantly associated with increased risk of asthma under each genetic model (P<0.00001). Subgroup analysis by ethnicity showed that alleles and genotypes of this variant correlated with asthma among Asians and Caucasians, but only TT genotype under the homozygote model in Africans. When stratified by age group, this variant highly correlated with asthma in children and moderately in adults. Furthermore, the TT, CT and CC genotypes in asthma group were all significantly associated with increased IgE levels in sera of asthma patients when compared with controls. Our results suggested that IL-13 +1923C/T polymorphism contributed to the development of asthma. Further case-control studies with more ethnicities are still needed.

Notch signalling suppresses regulatory T-cell function in murine experimental autoimmune uveitis.

Autoimmune uveitis is an intraocular inflammatory disorder in developed countries. Understanding the mechanisms underlying the development and modulation of immune reaction in uveitic eyes is critical for designing therapeutic interventions. Here we investigated the role of Notch signalling in regulatory T-cell (Treg cell) function during experimental autoimmune uveitis (EAU). Using the Foxp3-GFP reporter mouse strain, the significance of Notch signalling for the function of infiltrating Treg cells was characterized in an EAU model. We found that infiltrating Treg cells substantially expressed Notch-1, Notch-2, JAG1 and DLL1 in uveitic eyes. Activation of Notch signalling, represented by expression of HES1 and HES5, was enhanced in infiltrating Treg cells. Treatment with JAG1 and DLL1 down-regulated Foxp3 expression and immunosuppressive activity of isolated infiltrating Treg cells in vitro, whereas neutralizing antibodies against JAG1 and DLL1 diminished Notch ligand-mediated negative effects on Treg cells. To investigate the significance of Notch signalling for Treg cell function in vivo, lentivirus-derived Notch short hairpin RNAs were transduced into in vitro expanded Treg cells before adoptive transfer of Treg cells into EAU mice. Transfer of Notch-1-deficient Treg cells remarkably reduced pro-inflammatory cytokine production and inflammatory cell infiltration in uveitic eyes. Taken together, Notch signalling negatively modulates the immunosuppressive function of infiltrating Treg cells in mouse EAU.

[Comparison of relevant indicators of coagulation and fibrinolysis in patients with varying severity of community-acquired pneumonia].

OBJECTIVE: To compare the relevant indicators of coagulation and fibrinolysis in patients with varying severity of community-acquired pneumonia (CAP). METHODS: A total of 107 CAP hospitalized patients at Department of Respiratory Medicine, Affiliated Hospital, Chengde Medical College from July 2013 to June 2014 were enrolled as pneumonia group while another 52 healthy outpatients served as control group. The levels of routine blood test, coagulation function, procalcitonin and C-reactive protein (CRP) were measured and compared among different groups. All hospitalized CAP patients were divided into low and high-risk groups according to pneumonia severity index (PSI). And all indicators were measured to examine the differences among different groups. RESULTS: The white blood cell count in pneumonia group was significantly higher than that in control group ((9.3 ± 5.1) vs (7.5 ± 2.9) × 10(9)/L, P < 0.05). The red blood cell count, hemoglobin and platelet count in pneumonia group were significantly lower than those in control group ((4.3 ± 0.6) vs (4.8 ± 0.5) × 10(12)/L, (131.1 ± 18.7) vs (144.9 ± 17.4) g/L, (199.3 ± 69.4) vs (237.9 ± 72.5) × 10(9)/L, all P < 0.05). The D-dimer, fibrinogen degradation products (FDPs), fibrinogen (FIB), activated partial thromboplastin time (APTT) and prothrombin time (PT) in pneumonia group were significantly higher than those in control group ((1.86 ± 1.28) vs (0.48 ± 0.38) mg/L, (6.42 ± 3.27) vs (2.17 ± 1.46) mg/L, (3.87 ± 1.17) vs (3.42 ± 0.96) g/L, (35.64 ± 8.34) vs (31.29 ± 11.19) s, (12.21 ± 1.40) vs (11.36 ± 2.19) s, all P < 0.05) while thromboplastin time (TT) was lower than that in control group ((13.43 ± 3.38) vs (16.16 ± 2.89) s, P < 0.05). The levels of D-dimer, FDPs, procalcitonin, CRP, APTT and PT in high-risk group were significantly higher than those in low-risk group ((2.94 ± 1.14) vs (1.16 ± 0.78) mg/L, (8.85 ± 2.82) vs (4.85 ± 2.49) mg/L, (1.72 ± 1.16) vs (0.40 ± 0.51) µg/L, (104.2 ± 61.9) vs (67.4 ± 59.5) mg/L, (38.80 ± 8.41) vs (33.60 ± 7.69) s, (12.64 ± 1.76) vs (11.94 ± 1.03) s, all P < 0.05) while platelet count and TT were lower than those in low-risk group ((172.8 ± 57.1) vs (216.5 ± 71.6) × 10(9)/L, (12.10 ± 2.66) vs (14.28 ± 3.53) s, all P < 0.05). The abnormal rates of procalcitonin, D-dimer and FDPs in high-risk group were significantly higher than those in low-risk group (100% (42/42) vs 86.2% (56/65), 95.2% (40/42) vs 75.4% (49/65), 95.2% (37/42) vs 44.6% (29/65), all P < 0.05). The plasma levels of D-dimer, FDPs, procalcitonin and CRP were well-correlated with index of pneumonia severity (r = 0.636, 0.608, 0.629, 0.250, all P < 0.05). And the plasma level of platelet was negatively correlated with index of pneumonia severity (r = -0.320, P < 0.01). CONCLUSIONS: The red blood cell, hemoglobin and platelets are lower in patients with pneumonia than those in normal subjects. And the patients with pneumonia have coagulation and fibrinolysis disorders. The plasma levels of D-dimer, FDPs, procalcitonin, CRP and platelets are well-correlated with severity of CAP.