Clinical significance and role of CXCL16 in anti-neutrophil cytoplasmic autoantibody-associated vasculitis.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a group of potentially life-threatening autoimmune diseases. The kidney and lung are the most common and most severely affected organs. Previous studies have shown that the chemokine ligand CXCL16 and its receptor CXCR6 play an important role in kidney disease. However, whether CXCL16/CXCR6 is involved in the pathogenesis of AAV remains elusive. In this study, the levels of CXCL16 and its specific receptor CXCR6 were investigated. According to kidney outcome, patients were divided into two groups, specifically one with high CXCL16 levels and one with low CXCL16 levels, by cut-off values using receiver operating characteristic (ROC) curves. The clinical parameters and histological features were further compared between the two groups. The ability of CXCL16 to induce neutrophil chemotaxis was analysed using a Transwell migration assay in a coculture system of conditional immortalized human glomerular endothelial cells (ciGEnCs) and neutrophils. We observed that the levels of CXCL16 were significantly increased in the circulation, along with the expression in renal tissue of AAV patients compared to healthy controls (HCs). CXCR6 expression on neutrophils was significantly higher in patients with AAV than in HCs. There were positive correlations between the levels of CXCL16 and serum creatinine, IL-6, CRP, and TNF-α and negative correlations with eGFR. The serum levels of CXCL16 could act as a predictive biomarker of renal outcome in AAV. CXCL16 secretion was upregulated in ciGEnCs treated with AAV serum. CXCL16 released from ciGEnCs contributed to neutrophil migration. Furthermore, neutrophil migration was attenuated by silencing CXCL16 expression via transfection with short hairpin RNA (shRNA) sequences and lentivirus. Taken together, these data suggest that the inhibition of the CXCL16/CXCR6 axis may provide new therapeutic strategies targeting AAV.

Efficacy and safety of recombinant human endostatin during peri-radiotherapy period in advanced non-small-cell lung cancer.

Background: This study aimed to retrospectively investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with radiotherapy in advanced non-small-cell lung cancer (NSCLC). Methods: Patients with unresectable stage III and IV NSCLC who treated with radiotherapy were enrolled. Patients who received Rh-endostatin infusion throughout the whole peri-radiotherapy period formed the Endostar group, and those who received no Rh-endostatin infusion were the control group. Results: The median progression-free survival was 8.0 and 4.4 months (hazard ratio: 0.53; 95% CI: 0.32-0.90; p = 0.019) and median overall survival was 40.0 and 13.1 months (hazard ratio: 0.53; 95% CI: 0.28-0.98; p = 0.045) for the Endostar and control groups, respectively. The Endostar group exhibited a numerically lower rate of radiation pneumonitis relapse, radiation pneumonitis death and pulmonary fibrosis. Conclusion: Rh-endostatin infusion throughout the peri-radiotherapy period enhanced radiosensitivity and showed better survival outcomes and a tendency toward fewer radiation-related pulmonary events in patients with NSCLC.

Recombinant human endostatin (Rh-endostatin/Endostar) combined with chemotherapy has been approved as first-line standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) in China. This study aimed to retrospectively investigate the efficacy and safety of Rh-endostatin combined with radiotherapy in advanced NSCLC. Patients with unresectable stage III and IV NSCLC who treated with radiotherapy were enrolled. Patients who received Rh-endostatin infusion throughout the whole peri-radiotherapy period were the Endostar group, and those receiving no Rh-endostatin infusion were the control group. Results showed that the median progression-free survival was 8.0 and 4.4 months, and median overall survival was 40.0 and 13.1 months, for the Endostar and control groups, respectively. The Endostar group had a lower rate of radiation pneumonitis relapse, radiation pneumonitis death and pulmonary fibrosis. In conclusion, Rh-endostatin infusion throughout the peri-radiotherapy period enhanced radiosensitivity and showed better survival outcomes and a tendency toward fewer radiation-related pulmonary events in patients with NSCLC.

Fingerprint loss during combination therapy using osimertinib and anlotinib: A case report.

WHAT IS KNOWN AND OBJECTIVE: Recent studies prove that epidermal growth factor receptor (EGFR) inhibitors combined with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are more effective than EGFR TKI monotherapy for treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC); however, the adverse effects associated with this treatment require further investigation. We report a case of fingerprint loss secondary to combination therapy using osimertinib (an EGFR TKI that targets mutated EGFR kinases) and anlotinib (a TKI that acts on multiple targets including mutated VEGFR kinases). CASE SUMMARY: A 55-year-old man with stage IV lung adenocarcinoma and an EGFR L858R mutation received a 5-month course of platinum-based chemotherapy and icotinib. This regimen was subsequently switched to osimertinib plus anlotinib to achieve a better tumour response. This therapy led to fingerprint loss, which recovered following discontinuation of anlotinib treatment but subsequently recurred. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first report that describes fingerprint loss during combination therapy using osimertinib and anlotinib.

[Influence of Meteorological Factors on HFMD and Construction of Prediction Model in Sichuan Province].

OBJECTIVE: To analyze the epidemiological characteristics of hand, foot and mouth disease (HFMD) in Sichuan Province from 2013 to 2019. To study the correlation between meteorological factors and the incidence of HFMD and construct a prediction model. METHODS: The HMFD surveillance data and meteorological data from 2013 to 2019 in Sichuan Province were collected through the Chinese Center for Disease Control and Prevention and the China Meteorological data Network. Spearman correlation was used to analyze the relationship between HFMD incidence and meteorological factors. Multiple regression model and support vector regression (SVR) model were used to construct HFMD incidence prediction models respectively. RESULTS: A total of 615 840 cases of HFMD and 81 deaths were reported from 2013 to 2019. The average annual incidence rate was 107.31/105, and the mortality rate was 0.16/106. Spearman correlation analysis showed that the monthly incidence rate of HFMD was correlated with monthly average relative humidity (r=0.342), monthly average temperature (r=0.284), monthly average water vapor pressure (r=0.304) and monthly average days of precipitation (r=0.259). The prediction effect of the SVR model (R2=0.836) was better than the multiple regression model (R2=0.375). The SVR model provided a good fit to the monthly incidence of HFMD from 2013 to 2018, and can predict the peak incidence of HFMD in 2019. CONCLUSION: Relative humidity has the greatest influence on the incidence of HFMD. The fitting value of SVR model is in good agreement with the actual value, which is valuable in predicting the incidence of HFMD in Sichuan Province.

Clinical value of systemic symptoms in IgA nephropathy with ANCA positivity.

Our aim was to evaluate the pathogenic role of anti-neutrophil cytoplasmic antibodies (ANCAs) in patients with IgA nephropathy (IgAN). A total of 2390 patients with biopsy-confirmed IgAN were analyzed retrospectively. Thirty-five IgAN patients with ANCA and 40 IgAN patients without ANCA were enrolled. According to the Birmingham Vasculitis Activity Score (BVAS) items, the ANCA-positive patients were further divided into two subgroups which with or without systemic symptoms. The cumulative renal survival rate was calculated using Kaplan-Meier analysis. Comparisons between groups were made using the log rank test. Among the 35 ANCA-positive patients, 14 (40%) had systemic symptoms. Compared with ANCA-positive patients without systemic symptoms, ANCA-positive patients with systemic symptoms had a shorter duration of disease (1.0 [IQR, 0.3-6.8] vs. 6.0 [IQR, 2.0-21.0], P = 0.011); showed worse renal function with lower levels of eGFR (24.2 [IQR, 11.7-74.9] vs. 100.1 [IQR, 59.6-130.2] mL/min/1.73 m2, P = 0.002), serum albumin (30.4 [IQR, 27.4-34.8] vs. 41.5 [IQR, 35.1-44.4] g/L, P = 0.001), and hemoglobin (96.1 ± 21.5 vs. 118.2 ± 22.4 g/L, P = 0.006); and presented relatively higher incidences of rapidly deteriorating kidney function (28.6 vs. 0.0%, P = 0.039) and moderate-to-severe tubular atrophy (78.6 vs. 23.8%, P = 0.001). Kaplan-Meier analysis had shown that ANCA-positive patients with systemic symptoms had lower cumulative renal survival rate compared with both ANCA-positive patients without systemic symptoms and ANCA-negative patients (log rank = 14.40, P < 0.001). Evaluation of systemic symptoms is a simple, readily available clinical tool to predictive the pathogenic role of ANCA in IgAN.

Sinomenine Attenuates Angiotensin II-Induced Autophagy via Inhibition of P47-Phox Translocation to the Membrane and Influences Reactive Oxygen Species Generation in Podocytes.

BACKGROUND/AIMS: Sinomenine, a pure alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, and sinomenine hydrochloride (SN) has been successfully used for the therapy of rheumatoid arthritis (RA) and kidney diseases. Autophagy is a cytoprotective mechanism used by podocytes and other cells to alleviate the effects of oxidative stress, and angiotensin II (Ang II) significantly promotes podocyte autophagy. However, excessive autophagy may lead to cell death and podocyte depletion. The present study evaluated the effect of SN in podocytes induced by Ang II. METHODS: Podocytes were pretreated with graded concentrations (10(-8) M ∼ 10(-4) M) of SN and then stimulated with Ang II. The LC3B protein and the p47-phox membrane fraction were measured by Western blot. Autolysosomes were assessed by transmission electron microscopy. FACS was used to quantify the ROS produced by podocytes. The translocation of p47-phox to the membrane was investigated by immunofluorescence. RESULTS: The 10(-8) M ∼ 10(-4) M of SN alone did not effect ROS generation or podocyte autophagy. The 10(-8) M and 10(-6) M SN attenuated Ang II-induced autophagy in podocytes. Furthermore, SN decreased the level of ROS generation in Ang II-induced podocytes via inhibition of NOX subunit p47-phox translocation to the membrane. CONCLUSION: The appropriate concentration of SN attenuated Ang II-induced podocyte autophagy through ROS generation, at least in part, by regulating NOX subunit p47-phox translocation to the membrane.

Clinicopathologic Characteristics and Outcomes of Lupus Nephritis With Antineutrophil Cytoplasmic Antibody: A Retrospective Study.

Few studies have analyzed the clinicopathologic characteristics and outcomes of lupus nephritis (LN) patients with antineutrophil cytoplasmic antibody (ANCA). The clinical and renal histopathologic data of 154 patients with biopsy-proven LN from 2011 to 2013 were analyzed retrospectively. The patients were followed up for a median period of 16.8 ±â€Š9.4 months, and their outcomes were analyzed. Multivariate Cox analysis was used to evaluate the independent factors for poor outcomes. Among the 154 LN patients, 26 (16.88%) were seropositive for ANCA. The incidences of alopecia, oral ulcer, photosensitivity and skin lesion, and psychosomatic manifestations in the ANCA-positive group were significantly higher than in the ANCA-negative group (P = 0.007, 0.02, 0.02, and 0.03, respectively). Compared with the ANCA-negative group, the ANCA-positive group had significantly lower levels of complement C3 (P = 0.03). Additionally, the positive rate of antinucleosome antibodies, antihistone antibodies, antimitochondrial antibody M2, and anticardiolipin antibodies were higher significantly in the ANCA-positive patients than in the ANCA-negative patients (P = 0.001, 0.001, 0.03, 0.005, respectively). The ANCA-positive group had a notably higher chronic index than the ANCA-negative group (P = 0.01). During the follow-up, the complete remission rate in the ANCA-negative group was higher than that in the ANCA-positive group (P = 0.01). The cumulative renal survival rate in the ANCA-positive group was significantly lower than in the ANCA-negative group (log-rank = 6.59, P = 0.01). Multivariate Cox analysis revealed that the reduced estimated glomerular filtration rate (HR, 1.02; 95% confidence interval, 1.01 to 1.03; P = 0.005), NLR (HR, 1.20; 95% confidence interval, 1.02 to 1.40; P = 0.03), and ANCA (HR, 3.37; 95% confidence interval, 1.12 to 10.09; P = 0.03) were independent risk factors for patients' renal survival after adjusting for age, sex, crescent formation, and glomerulosclerosis. The study found ANCA in LN patients is not rare, and patients with ANCA present with more severe clinicopathologic injuries. Thus, ANCA is an independent risk factor for poor renal outcomes in LN patients.

IgA nephropathy with anti-neutrophil cytoplasmic antibody seropositivity.

BACKGROUND: There are few reports of IgA nephropathy (IgAN) with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: The authors report the clinical and pathological findings in 14 patients with IgAN and ANCA seropositivity. RESULTS: These retrospective cases consisted of 4 men and 10 women with a mean age of 44.4 ± 12.7 years. ANCA-positivity was documented by EUROBlot kits and indirect immunofluorescence in all patients. The results of EUROBlot kits were positive in 14 patients (12 MPO-ANCA, 2 PR3-ANCA). Indirect immunofluorescence was positive in 14 patients (12 P-ANCA, 2 C-ANCA). Three of 14 IgAN with ANCA-positive patients showed severe clinical manifestations with crescents involving a mean of 56% glomeruli, including heavy proteinuria (mean 24-hour urine protein: 3.8 g/d), hematuria and acute renal failure (mean creatinine: 4.5 ± 3.7 mg/dL). The remaining 11 patients with no crescents showed various degrees of proteinuria (mean 24-hour urine protein: 2.4 ± 2.4 g/d), hematuria and serum creatinine levels (median creatinine: 0.9 (IQR, 0.5 - 1.4) mg/dL). The follow-up period for 10 patients had an average length of 14.0 ± 11.2 months. Among the three patients with crescents who had been treated with steroids and cyclophosphamide, one patient became dialysis dependent at the time of biopsy and remained on dialysis after treatment, another died of acute heart failure, and the last one showed improvement in renal function after treatment and did not develop end-stage renal disease (ESRD) 26 months after renal biopsy. The remaining 7 patients with no crescents were treated with steroids, cyclophosphamide, renin-angiotensin system inhibitors, and/or Traditional Chinese Medicine; 6 had stabilized or improved renal function and one progressed to ESRD with worsening renal function. CONCLUSIONS: These findings suggest not all ANCAs are involved in the pathology of IgAN. In patients with IgAN and ANCAs, identification of pathogenic vs. non-pathogenic ANCAs is recommended.