Endostatin induces normalization of blood vessels in colorectal cancer and promotes infiltration of CD8+ T cells to improve anti-PD-L1 immunotherapy.

Introduction: The purpose of this study was to evaluate recombinant human endostatin (rHE)-induced normalization of the tumor vasculature in colorectal cancer (CRC) and to evaluate the therapeutic effects of combined treatment with rHE and a programmed death ligand-1 (PD-L1) inhibitor. Methods: A mouse subcutaneous tumorigenesis model was established to evaluate the antitumor effects of endostatin combined with a PD-L1 inhibitor on CRC. Intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DW MRI) was used to evaluate changes in the intratumor microcirculation in response to combined treatment with endostatin and a PD-L1 inhibitor. The infiltration density and function of CD8+ T cells in tumors were evaluated using flow cytometry. Finally, clinical specimens were used to evaluate the expression area of tumor vascular pericytes and CD8+ T cells in tumor tissues. Results: The antitumor effects of endostatin combined with a PD-L1 inhibitor were significantly greater than those of endostatin or a PD-L1 inhibitor alone. On the ninth day of intervention, the endostatin group showed significantly higher pseudo diffusion parameter (D*) and microvascular volume fraction (F) values in tumors than those in the control group or PD-L1 group. After 27 days of intervention, the endostatin groups showed significantly lower levels of vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-ß than those in the control group. Treatment of CD8+ T cells with endostatin for 24 h did not alter the expression levels of markers of reduced T-cell activity. However, endostatin reversed the VEGF-mediated inhibition of the secretion of interferon (IFN)-γ from T cells. The results in CRC clinical samples showed that treatment with endostatin induced significantly higher infiltration of CD8+ T cells compared with treatment that did not include endostatin. Furthermore, the expression area of pericytes was significantly positively related to the infiltration density of CD8+ T cells and overall survival time. Conclusion: Endostatin improved the antitumor effects of PD-L1 inhibitors on CRC, significantly increased the activity of CD8+ T cells, and synergistically improved the tumor treatment effect of the two inhibitors.

[Effects of Astragalus polysaccharide on imiquimod-induced psoriasiform dermatitis in mice and its mechanisms].

Objective: To investigate the effects and mechanisms of Astragalus polysaccharide on improving imiquimod-induced psoriasiform dermatitis in mice. Methods: Forty healthy female C57BL/6 mice were randomly divided into 5 groups, including blank control group, model group, astragalus polysaccharide high-dose group (200 mg/kg), medium-dose group (100 mg/kg) and low-dose group (50 mg/kg), with 8 mice in each group. The mice in model group and astragalus polysaccharide treatment group were treated with 5% imiquimod cream on the back to induce psoriasiform dermatitis. PASI score was monitored, and the secretion of inflammatory factors was determined by ELISA. The secretion of inflammatory factors was closely related to the infiltration of macrophages. The infiltration of macrophages in skin was detected by flow cytometry to further explore the effect of different concentrations of APS on psoriasis. Results: Compared with control group, the PASI score and the serum levels of TNF-α, IL-1ß and IL-6 were increased significantly (P＜0.05), and the infiltration of macrophages in skin tissue was increased significantly in model group (P＜0.05). Compared with model group, the PASI score was decreased significantly (P＜0.05), and the serum levels of TNF-α, IL-1ß and IL-6 were down-regulated significantly in astragalus polysaccharide high-dose and medium-dose groups (P＜0.05). The infiltrating macrophages in skin tissue were decreased significantly in Astragalus polysaccharide high-dose group (P＜0.05). Conclusion: Astragalus polysaccharide improve psoriasiform dermatitis in mice by inhibiting the infiltration of macrophages in skin tissue and decreasing the secretion of TNF-α, IL-1ß and IL-6 in serum.

[Correlation of serum eosinophil cationic protein with the severity of allergic rhinitis in childhood].

OBJECTIVE: To investigate the relationships between the severity of childhood allergic rhinitis (AR) and the peripheral blood eosinophil count, serum eosinophil cationic protein (ECP), total IgE (tIgE), and allergen-specific IgE (sIgE) levels. METHODS: A total of 138 children with AR aged 3 to 17 (9.96 ± 3.78, x() ± s) years old were enrolled in the study. All children had persistent AR sensitized to house dust mites with a clinical history of 3 months to 12 (4.21 ± 2.72) years. The disease severity was evaluated using 10 cm-visual analogue scale (VAS), and the serum levels of ECP, tIgE and sIgE were determined using an ImmunoCAP system. Statistical analysis was conducted with SPSS11.0 software. RESULTS: Among 138 children with AR, the VAS scores for global severity of rhinitis and nasal obstruction symptom were 5.32 ± 2.16 and 4.78 ± 2.45, respectively. Blood eosinophil count was 0.39 [0.24; 0.63] (M[P(25); P(75)]) ×10(9)/ml. Serum levels of ECP and total IgE were 10.60 [3.26; 30.80] µg/L and (2.50 ± 0.53) log kU/L, respectively. Serum levels of allergen-sIgE against Dermatophagoides pteronyssinus and Dermatophagoides farinae were 58.20[24.75; > 100] kUA/L and 54.95 [24.55; > 100] kUA/L, respectively. The VAS scores of nasal obstruction symptom, but not global severity of rhinitis, were positively related to the duration of AR (r = 0.215, P = 0.011) and the levels of serum ECP (r = 0.196, P = 0.022) in bivariate correlation analysis. There was also a significant correlation between the serum ECP level and the blood eosinophil count (r = 0.295, P = 0.000). No relationships of blood eosinophil count, and serum tIgE and sIgE levels with global severity of rhinitis as well as nasal obstruction symptom were found (all P > 0.05). CONCLUSIONS: These results suggested that the severity of nasal obstruction was positively correlated with the duration of rhinitis and the levels of serum ECP in childhood persistent AR due to house dust mites, indicating the disease severity might be related to chronic inflammatory process.

[Comparison of clinical characteristics between patients with non-allergic and allergic rhinitis].

OBJECTIVE: To analyze and compare the differences of clinical characteristics and comorbidities between patients with non-allergic rhinitis (NAR) and allergic rhinitis (AR). METHODS: A total of 556 out-patients were enrolled from January 2010 to June 2011. The chief complaints of the patients included at least two of the following nasal symptoms: nasal congestion, rhinorrhea, sneezing, and nasal itching. Based on the results of the disease history, physical examination and allergen skin prick test, the patients were classified into NAR group (n = 206) and AR group (n = 350). Detailed information including general data, nasal symptoms and signs, accompanied symptoms and comorbidities were obtained by questionnaires. A scoring was adopted to estimate the severity of disease. SPSS 13.0 software was applied for statistical analysis. RESULTS: The mean age of NAR patients (31.8 ± 16.7) was older than that of AR patients (26.3 ± 14.8), and the difference was significant (t = 4.01, P = 0.0001). While there was no significant difference on gender distribution between two groups (χ² = 0.12, P = 0.73). The percentage of nasal congestion was not significantly different between NAR and AR patients (89.8% and 92.0%, respectively; χ² = 0.26, P = 0.611). However, the symptoms of rhinorrhea, sneezing, nasal itching, eyes itching, lachrymation, wheeze and cough were more popular in AR patients than those in NAR patients (all P < 0.05). Moreover, above symptoms (except cough) were more serious in AR patients, and the symptom scores were significantly higher than those in NAR patients (all P < 0.05). Most of patients with NAR (67.0%) and AR (62.9%) were moderate-severe persistent (χ² = 1.25, P = 0.264). Accompanied asthma were more common in patients with AR (12.6%) compared with NAR (2.4%), while hypertension were more common in patients with NAR (7.3%) compared with AR (1.7%), and the differences were significant (both P < 0.05). CONCLUSION: NAR and AR are two different disease entities, which have different clinical characteristics, as well as different comorbidities. Further clinical study should be done on the rhinitis phenotypes.

[Clinical efficacy of subcutaneous and sublingual immunotherapy in mite-sensitized patients with allergic rhinitis].

OBJECTIVE: To investigate the clinical efficacy of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) with standardized house dust mite (HDM) extract for persistent allergic rhinitis (PER). METHODS: Ninety-eight patients with moderate to severe PER caused by HDM and who completed SCIT (Alutard SQ, ALK-Abell¨®) or SLIT (Chanllergen-Df drops, Wolwo Pharma) regimen for two years were enrolled in this open-label controlled study. The patients were divided into two groups: SCIT group consisted of 40 patients aged 7 to 57 years old [(19.0 ± 2.7) years, x(-) ± s], and SLIT group consisted of 58 patients aged 6 to 50 years old [(17.7 ± 3.2) years]. The nasal symptoms (sneezing, rhinorrhea, nasal obstruction and pruritus) were evaluated using a four-point rating scale (from 0 = absent to 3 = severe) as well as 10 cm-visual analogue scale (VAS). Efficacy of SCIT and SLIT was assessed as the mean change from baseline in nasal symptom scores after 2-year course of immunotherapy, and the results were compared. SAS software version 9.1.3 was applied for statistical analysis. RESULTS: Both SCIT and SLIT significantly reduced the individual symptom score of sneezing, rhinorrhea, nasal obstruction and pruritus, and the total nasal symptom scores (including 4-point scale and VAS) after 2-year treatment when compared with the baseline (Z value were -3.14, -3.76, -3.09, -3.48, -4.13; -3.63, -3.21, -2.48, -3.56, -3.98, respectively, all P < 0.05). There was no significant difference in decreased mean score of the individual and total nasal symptoms (4-point scale) between SCIT and SLIT groups (Z value were -0.97, -0.67, -0.36, -0.04, -0.67, respectively, all P > 0.05). However, a significant reduction of VAS score of nasal obstruction was found in SCIT group after 2-year treatment, compared with SLIT group (t = -2.21, P = 0.032). There was no significant difference in decreased VAS score of three other nasal symptoms as well as global rhinitis severity between two immunotherapy groups (t value were -0.57, -1.93, -1.73, -0.99, respectively, all P > 0.05). CONCLUSIONS: Both SCIT and SLIT demonstrated clinical improvement in moderate to severe PER patients sensitized to HDM after two years treatment. It is suggested that SCIT may relieve nasal obstruction significantly; however, the overall clinical efficacy is consistent with SCIT and SLIT.

[Comparison of risk factors between patients with non-allergic rhinitis and allergic rhinitis].

OBJECTIVE: To investigate and describe the differences in age, sex, seasonality distribution, and related environmental factors between patients with non-allergic rhinitis (NAR) and allergic rhinitis (AR). METHODS: One hundred and eleven patients with NAR and 112 patients with AR were enrolled in this study. All patients were first diagnosed in outpatient department between January and August 2010. Questionnaires were distributed to all participants to record the general information, medical history, and the factors relevant to symptom onset. Statistical analysis was performed using a SPSS13.0 software. RESULTS: The proportion of patients with NAR increased with age, compared to patients with AR. The peak age was 21 - 30 years old in patients with NAR, whereas 11 - 20 years old in patients with AR. In adults more than 18 years old, the average age (years, x(-) ± s) of patients with NAR (38.6 ± 14.5) was significantly higher than those with AR (32.8 ± 13.0; t = 2.58, P = 0.024). NAR was more likely to be males before 30 years old, while after 30 years old, it likely to be female predominance. The same case occurred in AR subjects but in their 20 years old. NAR was symptomatically worse in winter (χ(2) = 27.57, P = 0.000), whereas AR worse in spring (χ(2) = 13.75, P = 0.003). The cases of NAR were significantly more than those of AR during the winter season (χ(2) = 12.34, P = 0.000). Among the disease-related environmental factors, living or working place near the traffic artery had 1.94-fold increased risk for development of NAR compared with AR; however, living or working in ground floor or sunshine time less than 2 h per day had 1.77- or 1.91-fold increased risk for development of NAR compared with NAR. Subjects with personal or family history of allergic disease had 2.14 to 4.06-fold increased risk for development of AR compared with NAR. The self-reported predisposing factors in NAR patients were mainly including temperature shift (56.3%), common cold (52.8%), climate change (32.4%), and strong odors (31.1%). However, there were no significant differences in these nonspecific triggers between NAR and AR (all P > 0.05). CONCLUSION: There are significant differences in the distribution of age, sex and seasonality, personal and family history of allergic disease, and some environmental factors relevant to the onset of symptom between patients with NAR and AR.