Malignancy is increased in patients with antineutrophil cytoplasmic antibody-associated vasculitis in China.

OBJECTIVE: It has been reported that in western countries malignancy risk was higher in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with that in the general population. In the current study, we investigated the incidence, spectrum and risk factors of malignancy in Chinese AAV patients. METHODS: AAV patients diagnosed from 1995 to 2021 in Peking University First Hospital with a follow-up more than 12 months were recruited. Standardized incidence ratios (SIR) were calculated to describe the risk of malignancy, adjusted for sex, age and follow-up time. RESULTS: A total of 552 AAV patients were recruited, among which 23 patients had malignancies either preceding or concurrent with AAV diagnosis, and 43 of the remaining 529 patients developed malignancies within 4.3 ± 4.2 years post AAV diagnosis (SIR: 2.24; 95% CI: 1.68-2.99; p < 0.001). Among these 66 patients, twenty different sites of malignancy were observed, lung cancer being most frequent. To get exactly expected malignancies for the calculation of SIR, 529 patients without preceding or concurrent malignancies were included in the following analysis. Lung cancer was still the leading malignancy diagnosis (SIR: 5.01; 95% CI: 3.29-7.62), followed by malignancies in the kidney, bladder, ureter and prostate. Male gender (HR:2.84; 95%CI:1.36-5.96; p = 0.006) and older age (per year, HR:1.04; 95%CI:1.00-1.07; p = 0.038) were significantly associated with increased risk of malignancy. For patients with malignancy developed beyond 5 years after the diagnosis of AAV, a significantly higher malignancy risk was observed in those with a cumulative cyclophosphamide dose over 20.0 g (SIR: 11.54; 95% CI: 4.77-27.93; p < 0.001). Within the first 2 years after the diagnosis of AAV, the risk of malignancy was still significantly higher than that in the general population, but the cumulative cyclophosphamide dose was not significantly associated with malignancy occurrence in this subgroup of patients. CONCLUSIONS: Malignancy risk is higher in Chinese AAV patients than that in the general population, with a different malignancy spectrum from western countries. Both the use of cyclophosphamide and AAV per se might be associated with higher incidence of malignancy occurrence.

High TXNIP expression accelerates the migration and invasion of the GDM placenta trophoblast.

INTRODUCTION: Our previous study has proofed the glucose sensitive gene-thioredoxin-interacting protein (TXNIP) expression was up in the placenta of the patients with gestational diabetes mellitus (GDM), but the pathological mechanisms underlying abnormal TXNIP expression in the placenta of patients with GDM is completely unclear and additional investigations are required to explain the findings we have observed. In the present study, we simulated the high TXNIP expression via introducing the Tet-On "switch" in vitro, approximate to its expression level in the real world, to explore the following consequence of the abnormal TXNIP. METHODS: The expression and localization of TXNIP in the placenta of GDM patients and the health control was investigated via immunofluorescent staining, western blot and RT-qPCR. Overexpression of TXNIP was achieved through transfecting Tet-on system to the human trophoblastic cell line-HTR-8/Svneo cell. TXNIP knockout was obtained via CRISPR-Cas9 method. The cell phenotype was observed via IncuCyte Imaging System and flow cytometry. The mechanism was explored via western blot and RT-qPCR. RESULTS: The expression level of TXNIP in the GDM placenta was nearly 2-3 times higher than that in the control. The TXNIP located at trophoblastic cells of the placenta. When the expression of TXNIP was upregulated, the migration and invasion of the cells accelerated, but cell apoptosis and proliferation did not changed compared with the control group. Furthermore, the size of the TetTXNIP cells became larger, and the expression level of Vimentin and p-STAT3 increased in the TetTXNIP cells. All the changes mentioned above were opposite in the TXNIP-KO cells. CONCLUSIONS: Abnormal expression of TXNIP might be related to the impairment of the GDM placental function, affecting the migration and invasion of the placental trophoblast cells through STAT3 and Vimentin related pathway; thus, TXNIP might be the potential therapeutic target for repairing the placental dysfunction deficient in GDM patients.

A modified renal risk score for Chinese patients with antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: The renal risk score (RRS) is a useful tool to predict end-stage renal disease (ESRD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to validate the predictive performance of RRS and to further modify this model in Chinese AAV patients. METHODS: Two hundred and seventy-two patients diagnosed with AAV confirmed by renal biopsies were retrospectively enrolled from a single center. The RRS was calculated based on 3 categorical variables, i.e., the proportion of normal glomeruli, the proportion of interstitial fibrosis and tubular atrophy (IF/TA), and eGFR at biopsy, classifying these patients into low-, medium-, and high-risk groups. In addition, a modified model was developed based on the RRS and was further validated in another independent cohort of 117 AAV patients. The predictive performance of each model was evaluated according to discrimination and calibration. RESULTS: Patients were classified by the RRS into low- (26.5%), medium- (46.7%), and high-risk (26.8%) groups, with 120-month renal survival rates of 93.3%, 57.2%, and 18.4%, respectively (P < 0.001). The RRS showed good discrimination but less satisfactory calibration. Therefore, a modified model with improved discrimination and calibration was developed in Chinese AAV patients, with eGFR, proportion of normal glomeruli (both as continuous variables), and IF/TA (< 25%, 25-50%, > 50%) included. Internal and external validation of the modified model were performed. Finally, an online risk prediction tool was developed based on the modified model. CONCLUSIONS: The RRS was an independent predictor of ESRD of AAV patients. The modified model could predict the probability of ESRD for AAV patients with improved performance in Chinese AAV patients.

The effects of music therapy on peripherally inserted central catheter in hospitalized children with leukemia.

To explore the effect of music therapy on children with leukemia who have peripherally inserted central catheters (PICC).In this study, we divided 107 patients undergoing PICC into music group (47 cases) and control group (60 cases). The music group received music therapy during PICC, while the control group was given no complementary treatment. The total length of catheterization, the use of sedatives and the changes of pain level and emotion level before and after PICC placement were compared between two groups.Compared with the control group, the total PICC placement time of the music group was significantly shorter (35(30-40) vs. 60(60-60); Z = -8.307; p < 0.001), and the use of sedative medications was also significantly reduced (4.35% (n = 2) vs. 91.84% (n = 45); p < 0.001). Moreover, the pain of catheterization was significantly alleviated. The median difference of pain scores of the music group was significantly less (2(1-3) vs. 5(5-5); p < 0.001). The mood of patients was also improved. The median difference of emotional scores of the music group was significantly more (5(4.75-6) vs. 3(3-3); p < 0.001) than the control group.Music therapy is effective to use in PICC. It can shorten the treatment time, reduce the use of sedative medications, and improve the children's emotion and pain response significantly, which is worth clinical application.

Down-regulated FcγRII expression on plasma cells is associated with the disease activity of ANCA-associated vasculitis.

OBJECTIVES: Inhibitory FcγRIIB/CD32B on B cells are critical for immunity regulation to help maintain peripheral tolerance. Altered FcγRIIB expression on B cells has been observed in several autoimmune diseases, and animal studies have suggested that FcγRIIB on B cells participates in the pathogenesis of ANCA-associated vasculitis (AAV). Here, we investigated the expression of FcγRII (FcγRIIB) on various B cell subsets and the correlation of FcγRII/CD32 expression with disease activity in AAV patients. MATERIAL AND METHODS: Blood samples of patients with AAV in active stage and in remission were collected. FcγRII/CD32 expressions on various B cell subsets of the whole blood were detected by flow cytometry, and their correlation with clinical and pathological data was analysed. RESULTS: The expression of FcγRII/CD32 on plasma cells was significantly lower in AAV patients in active stage than those in both AAV patients in remission and healthy donors. Furthermore, the expression of FcγRII/CD32 on plasma cells negatively correlated with BVAS and percentages of cellular crescents in renal biopsies. CONCLUSIONS: There is a down-regulation of FcγRIIB/CD32B expression on B cells in patients with AAV, which is associated with the disease activity of AAV.

Renal Expression of Annexin A1 Is Associated With the Severity of Renal Injury in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Background: Increasing studies demonstrated the importance of activation of neutrophils in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Previous studies showed that annexin A1 (ANXA1) inhibited the recruitment, transendothelial migration and respiratory burst of neutrophils and induced apoptosis of neutrophils. The current study aimed to investigate the plasma and renal levels of ANXA1 as well as their association with the disease severity in AAV patients. Methods: Thirty-one AAV patients in active stage and 35 AAV patients in remission stage were recruited. The expression of ANXA1 in renal specimens was assessed by immunohistochemistry. The co-localization of ANXA1 with renal intrinsic and infiltrating cells was detected by double immunofluorescence. The plasma levels of ANXA1 were determined by ELISA. The association of plasma and renal levels of ANXA1 with clinicopathological parameters was further analyzed. Results: Plasma levels of ANXA1 were significantly higher in active AAV patients than those in AAV patients in remission as well as healthy controls. The renal expression of ANXA1 was significantly higher in active AAV patients than in healthy controls and disease controls. Double immunofluorescence assay showed that ANXA1 was expressed in glomerular endothelial cells, mesangial cells, podocytes, proximal tubular epithelial cells, neutrophils, monocytes/macrophages and T cells in AAV patients. The mean optical density of ANXA1 in glomeruli was correlated with serum creatinine levels (r = -0.491, P = 0.005) and eGFR (r = 0.492, P = 0.005) at renal biopsy and the proportion of crescents (r = -0.423, P = 0.018) in renal specimens of AAV patients. The expression of ANXA1 in glomeruli of AAV patients achieving complete renal recovery was significantly higher than those achieving partial renal recovery. Conclusion: In AAV patients, the renal expression of ANXA1 was associated with the severity of renal injury.

Increased frequency of IgD-CD27hiCD38hi B cells and its association with the renal involvement in ANCA-associated vasculitis.

BACKGROUND: B cells have been highlighted in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by the identification of activated B cells in granulomatous lesions and the efficacy of B cell depletion in treatment of AAV patients in the current study; we aimed to investigate the frequency of a specific B cell subset, IgD-CD27hiCD38hi B cells in AAV patients, and its association with the disease severity of AAV. METHODS: Blood samples of patients with AAV in active stage and in remission were collected. The frequency of IgD-CD27hiCD38hi B cells was detected by flow cytometry, and its correlation with clinicopathological parameters was analyzed. RESULTS: Our results showed a significant increase of circulating IgD-CD27hiCD38hi B cells in AAV patients in active stage compared with patients in remission and healthy donors, and the frequency of IgD-CD27hiCD38hi B cells correlated with the severity of renal involvement, including serum creatinine, estimated glomerular filtration rate, and percentages of total crescents in renal biopsies. CONCLUSIONS: The results indicated that IgD-CD27hiCD38hi B cells could reflect disease severity of renal involvement in AAV.

Structural optimizations and bioevaluation of N-substituted acridone derivatives as strong topoisomerase II inhibitors.

Previously, an array of N-substituted acridone derivatives have been reported as potent topoisomerase II (topo II) inhibitors, and preliminary structure-activity relationship (SAR) outcomes revealed that the linker between 1-NH and N-methyl piperazine motif of the tricyclic acridone scaffold significantly affected their anti-proliferative potencies. To further explore the SARs of acridone-derived topo II inhibitors, a wider range of novel acridone derivatives were herein synthesized via two rounds of structural optimizations on two validated hits, E17 and E24. Initially, the linker length was optimized, and then influences of N-methyl piperazinyl moiety and disposition of three N atoms on the bioactivity were investigated. As a result, a newly developed topo II inhibitor 6 h was found to be more potent than E17 and E24, thereby serving as a tool compound for the follow-up mechanistic study. Compound 6 h functioned as a strong topo IIα/ß inhibitor, caused obvious DNA damage, and induced apoptosis by triggering the loss of mitochondrial membrane potential (Δψm). Further molecular docking and MD study illustrated the favorable interactions of 6 h with both topo IIα and topo IIß subtypes.

A Unique Topoisomerase II Inhibitor with Dose-Affected Anticancer Mechanisms and Less Cardiotoxicity.

Type II DNA topoisomerase (topo II) is an essential nuclear enzyme and a well-validated anticancer drug target. Previously, we have carried out several rounds of structural optimizations on our in-house topo II inhibitor E17, which was shown to have superior anticancer activity and less risk of multidrug resistance (MDR). Among the newly developed acridone derivatives, 6h displayed significant anticancer efficacy with unique mechanisms of action. At low concentrations, it arrested cancer cell cycles and triggered cell apoptosis, which is similar to the action of the well-known topo II inhibitor VP16. By contrast, 6h showed significant and long-term anti-proliferative activity at relatively high concentrations, with negligible influence on apoptosis. In addition, 6h exhibited no serious cardiotoxicity compared to doxorubicin (DOXO), a widely used topo II-targeting antineoplastic drug in clinic, but with damaging myocardial side effects. Collectively, our present work has supported the therapeutic value of 6h as a promising chemotherapy for cancers.

Central nervous system involvement in patients with antineutrophil cytoplasmic antibody-associated vasculitis: a study of 29 cases in a single Chinese center.

BACKGROUND: In antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), central nervous system (CNS) involvement is relatively uncommon. The current study retrospectively investigated the clinical features and outcomes of AAV patients with CNS involvement. METHODS: A total of 497 AAV patients were retrospectively recruited in our center, twenty-nine of which had CNS involvement. Clinical and radiological manifestations and the outcomes of these patients were analyzed. RESULTS: The predominant symptom was sensorimotor impairment. According to the MRI findings, twenty-four patients had cerebral ischemic lesions, four patients had hemorrhagic lesions, and one patient had pituitary mass. With a median follow-up of 25 (range 9-45) months, 23 of 24 patients with cerebral ischemic lesions responded to induction therapy, and symptoms were ameliorated. The remaining one died from acute myocardial infarction 2 months after the diagnosis of cerebral ischemic lesions. Compared with patients without CNS involvement, patients with CNS involvement had significantly higher level of Birmingham Vasculitis Activity Score (23.5 ± 5.3 versus 18.8 ± 6.5, P < 0.01) and significantly higher proportion of peripheral nervous system involvement (58.6% versus 14.6%, P < 0.01). However, we did not found significant difference of patients' survival between those with and without CNS involvement. CONCLUSION: CNS involvement in Chinese patients with AAV was mainly manifested as cerebral ischemic lesions. Compared with patients without CNS involvement, patients with CNS involvement had a significantly more active disease of AAV, and significantly higher proportion of peripheral nervous system involvement.Key Points• CNS involvement in Chinese patients with AAV was mainly manifested as cerebral ischemic lesions.• Patients with CNS involvement had a significantly more active disease of AAV.

Monoclonal immunoglobulin mediates complement activation in monoclonal gammopathy associated-C3 glomerulonephritis.

BACKGROUND: C3 glomerulonephritis (C3GN) is a rare disease caused by inherited or acquired complement alternative pathway (CAP) dysregulation, which could also be secondary to monoclonal gammopathy of undetermined significance (MGUS). Herein, we described a patient presenting with C3GN and monoclonal gammopathy, and the pathogenic association between the two diseases was further explored in vitro. CASE PRESENTATION: A 76-year-old Chinese man presented with low serum C3 level, haematuria and nephrotic syndrome, and experienced rapid worsening of renal function over a period of 10 months. His serum and urine immunofixation electrophoresis both revealed a monoclonal IgGλ. A bone marrow puncture showed plasma cell dyscrasias with the highest plasma cell count of 5.25%. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence, a membranoproliferative pattern on light microscopy and electron dense deposits in sub-epithelial, intramembranous, sub-endothelial and mesangial regions by electron microscopy. The patient was positive for C3 nephritic factor (C3NeF) activity and anti-CFH autoantibodies, and all became negative during disease remission. The anti-CFH autoantibodies purified from the patient's plasma exchange fluids were proven to be a monoclonal IgGλ, and could inhibit CFH binding to C3b and accelerate the formation of C3 convertase indirectly by interfering with the formation-impeding activity of CFH. No deficiency of candidate genes, especially variants in CFH, was detected in our patient. Based on the pathological and laboratory findings, the diagnosis of monoclonal gammopathy of renal significance (MGRS)-associated C3GN was finally made. CONCLUSIONS: This is the first demonstration that intact monoclonal immunoglobulin (IgGλ) could act as an anti-CFH antibody and lead to MGRS-associated C3GN by activating the CAP.

MicroRNA­4500 suppresses tumor progression in non­small cell lung cancer by regulating STAT3.

Research has revealed that microRNA (miR)­4500 is downregulated in non­small cell lung cancer (NSCLC), and miR­4500 suppresses tumor growth by targeting lin­28 homolog B and NRAS proto­oncogene, GTPase. In the present study, it was reported that signal transducer and activator of transcription 3 (STAT3) may function as a novel target gene for miR­4500 in NSCLC. The experiments conducted in the present study confirmed that the miR­4500 expression was decreased in NSCLC tissues and cells compared with adjacent normal tissues and a normal lung cell line. miR­4500 suppressed the cell proliferation, migration, invasion and promoted apoptosis of the human NSCLC cell lines A549 and H1975. Expression of STAT3 was negatively correlated with miR­4500 expression in vivo. A luciferase reporter assay suggested that miR­4500 directly targeted the 3' untranslated region of STAT3. The tumor inhibition effect of small interfering RNA STAT3 in A549 and H1975 lines may be partially impaired by a miR­4500 inhibitor. The results of the present study suggests that miR­4500 may be a tumor suppressor and a potential therapeutic target in NSCLC.

Upregulated microRNA­671­3p promotes tumor progression by suppressing forkhead box P2 expression in non­small­cell lung cancer.

In the present study, the expression of microRNA (miR)­671­3p in non­small­cell lung cancer (NSCLC) was detected via reverse transcription­quantitative polymerase chain reaction analysis, and its role in cell proliferation, apoptosis, migration and invasion was investigated via Cell Counting Kit­8, colony formation, flow cytometry, Transwell and scratch assays, respectively. It was observed that the expression of miR­671­3p was upregulated in NSCLC tissues and cell lines (A549 and H1975). Treatment with miR­671­3p inhibitors suppressed cell proliferation, migration and invasion, and increased apoptosis in vitro, suggesting that miR­671­3p functions as an oncogene in NSCLC. In addition, forkhead box P2 (FOXP2) has been reported to be a tumor suppressor that is downregulated in several types of cancer, and its low expression was confirmed in NSCLC tissues and cell lines in the current study via western blotting. The results of the luciferase reporter assay also demonstrated that miR­671­3p targeted directly the 3'­untranslated region of FOXP2. Furthermore, overexpression of FOXP2 in A549 and H1975 cell lines suppressed the growth, migration and invasion, and promoted apoptosis, whereas these effects were reversed by transfection with miR­671­3p mimics, suggesting that miR­671­3p promoted tumor progression via regulating FOXP2. Taken together, the results reported in the present study implied that miR­671­3p may be a potential therapeutic target in NSCLC.

Myeloperoxidase-ANCA-positive granulomatosis with polyangiitis is a distinct subset of ANCA-associated vasculitis: A retrospective analysis of 455 patients from a single center in China.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA) directed to proteinase 3 (PR3) used to be considered the serologic marker for granulomatosis with polyangiitis (GPA). However, patients with myeloperoxidase (MPO)-ANCA positive GPA have been increasingly reported. The aim of this study was to analyze the clinical and pathological characteristics and outcome of Chinese patients with MPO-ANCA positive GPA. METHODS: The clinical and renal histology data, renal outcomes, response to treatment, relapse and mortality were compared between patients with MPO-ANCA positive GPA and MPO-ANCA positive microscopic polyangiitis (MPA) as well as proteinase 3 (PR3)-ANCA positive GPA. RESULTS: 455 patients with ANCA-associated vasculitis (AAV) were recruited in this study. 276/455 patients were classified as MPO-ANCA positive MPA, 4/455 patients were classified as PR3-ANCA positive MPA, 124/455 were MPO-ANCA positive GPA and 51/455 were PR3-ANCA positive GPA. Compared with MPO-ANCA positive MPA patients, MPO-ANCA positive GPA patients had significantly higher level of BVAS and milder renal lesion at diagnosis. The probability of developing ESRD was significantly higher in patients with MPO-ANCA positive MPA than MPO-ANCA positive GPA. MPO-ANCA positive GPA patients were likely to have relapse than MPO-ANCA positive MPA patients. Compared with PR3-ANCA positive GPA patients, MPO-ANCA positive GPA patients had significantly higher proportion of female, less constitutional symptoms and milder renal lesion at diagnosis. CONCLUSIONS: Patients with MPO-ANCA positive GPA should be regarded as a unique subset of AAV. This subset of AAV patients had relatively milder renal injury. Although ANCA specificities play an important role in differentiating AAV, taking the disease type together to classify AAV may be more rational.

Identification of Compounds Targeting Hepatitis B Virus Core Protein Dimerization through a Split Luciferase Complementation Assay.

The capsid of the hepatitis B virus is an attractive antiviral target for developing therapies against chronic hepatitis B infection. Currently available core protein allosteric modulators (CpAMs) mainly affect one of the two major types of protein-protein interactions involved in the process of capsid assembly, namely, the interaction between the core dimers. Compounds targeting the interaction between two core monomers have not been rigorously screened due to the lack of screening models. We report here a cell-based assay in which the formation of core dimers is indicated by split luciferase complementation (SLC). Making use of this model, 2 compounds, Arbidol (umifenovir) and 20-deoxyingenol, were identified from a library containing 672 compounds as core dimerization regulators. Arbidol and 20-deoxyingenol inhibit the hepatitis B virus (HBV) DNA replication in vitro by decreasing and increasing the formation of core dimer and capsid, respectively. Our results provided a proof of concept for the cell model to be used to screen new agents targeting the step of core dimer and capsid formation.

Myeloperoxidase influences the complement regulatory activity of complement factor H.

Objective: The interaction between neutrophils and activation of alternative complement pathway plays a critical role in the pathogenesis of ANCA-associated vasculitis (AAV). MPO, which can be released from ANCA-stimulated neutrophils, was recently demonstrated to be capable of activating the alternative complement pathway. Here we aimed to investigate the interaction between MPO and factor H (FH), a key regulator of the alternative pathway, and its effect on the functional activities of FH. Methods: Detection of FH and MPO on neutrophil extracellular traps (NETs) induced by serum from AAV patients and in kidney biopsies of AAV patients was performed by immunostaining. In vitro binding between MPO and FH was examined by ELISA and surface plasmon resonance. The influence of MPO on the complement regulatory activity of FH was further assessed. Results: FH deposited and co-localized with MPO in NETs. In kidney biopsies from AAV patients, MPO was closely adjacent to FH in glomerular capillaries. We demonstrated that MPO binds to FH with an apparent nanomolar affinity and identified short consensus repeats 1-4 of FH as the major binding sites. In terms of functional analysis, MPO inhibited the interaction between FH and C3b and the decay-accelerating activity of FH. The fluid phase and surface cofactor activities of FH upon C3b inactivation were inhibited by MPO. Conclusion: Our findings indicate that MPO binds to FH and influences the complement regulatory activity of FH. MPO-FH interaction may participate in the pathogenesis of AAV by contributing to activation of the alternative complement pathway.

Persistent hematuria in patients with antineutrophil cytoplasmic antibody-associated vasculitis during clinical remission: chronic glomerular lesion or low-grade active renal vasculitis?

BACKGROUND: Whether persistent hematuria in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) during clinical remission reflects active disease or chronic glomerular injury is uncertain. This study aimed to investigate the significance of persistent hematuria during clinical remission in a large cohort of AAV patients. METHODS: A cohort of 219 AAV patients in complete clinical remission after induction therapy at our center was retrospectively studied, and their clinical and laboratory data as well as long-term outcomes were analyzed. RESULTS: A total of 80 out of 219 patients had persistent hematuria during clinical remission of AAV. Compared with patients without hematuria during remission, the slope of eGFR decline in patients with persistent hematuria was significantly higher during the long-term follow-up [3.6 (IQR 1.2, 7.2) vs. 1.5 (IQR 0.2, 4.0) mL/min/1.73 m2/year, P < 0.001]. Among the 80 patients with persistent hematuria during remission, there was little difference between those with fast and slow decline of eGFR, as divided by either median or interquartile range of the slope of eGFR decline. We also compared patients without hematuria who had a slope of eGFR decline that was lower than the median level of the slope of eGFR decline with those with persistent hematuria, and found that patients with hematuria had significantly lower levels of CRP and ESR at baseline and higher levels of ANCA at remission. CONCLUSIONS: Among the AAV patients who achieved clinical remission after immunosuppressive therapy, those with persistent hematuria are not rare and may reflect either chronic renal damage or low-grade active renal disease.

Sweroside eradicated leukemia cells and attenuated pathogenic processes in mice by inducing apoptosis.

Acute myeloid leukemia (AML), characterized by extremely heterogeneous molecular and biologic abnormalities, is an aggressive hematologic malignancy, hampering the research and development of effective targeted treatment modalities. Sweroside (SWE), an iridoid glycoside, is isolated from Lonicera japonIca. It has diverse biological activities, but little is known in human leukemia. Here, our study showed the potential of sweroside as an effective agent against human leukemia using in vitro and in vivo approaches. Sweroside treatment obviously reduced the cell viability in human leukemia cell lines and primary human leukemia cells. S and G2/M cell-cycle arrest were induced by sweroside, associated with the down-regulation of Cyclin D1, cyclin-dependent kinase 4 (CDK4), CDC2 and CDC25 as well as the up-regulation of p53 and p21. In addition, apoptosis was highly induced by sweroside both in vitro and in vivo through enhancement of cleaved Caspase-3 and poly (ADP-ribosyl) transferase (PARP). Consistently, anti-apoptotic molecule of B cell CLL/lymphoma 2 (Bcl-2) was impeded by sweroside, while pro-apoptotic signal of Bcl-2-associated X protein (Bax) was elevated. In vivo, HL-60-bearing tumor growth was considerably inhibited by sweroside, which was related to proliferation suppression and apoptosis induction. Our study highlighted the therapeutic potential of sweroside, and provided new insights into the molecular mechanism of sweroside chemosensitization in human leukemia.

Clinicopathological significance of oestrogen receptor expression in non-small cell lung cancer.

Objective To investigate the expression and clinicopathological significance of the oestrogen receptor (ER) in non-small cell lung cancer (NSCLC). Methods ER expression was examined by immunohistochemical staining of tumour tissue and adjacent normal lung tissue from 67 NSCLC patients. The relationships between ER expression and clinicopathological features were analysed. Results A higher percentage of NSCLC tissues (28/67, 41.79%) than adjacent normal lung tissues (10/55, 18.18%) were ER positive. ER expression correlated with tumour differentiation but not with gender, age, tumour histological type, tumour size, lymph node metastasis, or clinical TNM staging. The median survival times of patients with ER-positive ( n = 28) and -negative ( n = 39) tumours were 36 and 27 months, respectively. The 1-, 3-, and 5-year survival rates were higher for patients with ER-positive tumours than for patients with ER-negative tumours. Conclusion ER expression could be a useful prognostic biomarker and therapeutic target for patients with NSCLC.

The Prevalence and Management of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis in China.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). Myeloperoxidase (MPO) and proteinase 3 (PR3) are the main antigens for ANCA. AAV is a common multisystem autoimmune disease and most of the studies on AAV have been conducted in Western countries. Nowadays in China many efforts are made to investigate this disease. SUMMARY: This review highlights the progress in the prevalence, management and outcomes of AAV in Chinese patients. With respect to the prevalence of AAV, though there are no precise data, AAV is not rare in the Chinese population. In Chinese patients with AAV there is a striking preponderance of MPA, and MPO-ANCA is much more common than PR3-ANCA. Even in patients with GPA there is a predominance of MPO-ANCA over PR3-ANCA. Propylthiouracil-induced AAV and ANCA-negative pauci-immune glomerulonephritis are stated in this review as well. With respect to the management of AAV, glucocorticoids in combination with cyclophosphamide remain the mainstay of induction therapy. Besides, we describe predictors of different outcomes in Chinese patients, including mortality, relapse, treatment resistance and end-stage renal disease. KEY MESSAGES: AAV is not rare in the Chinese population. The disease spectrum and subtypes of ANCA are different between patients with AAV in China and Western countries. The treatment strategy for AAV in China is in consistency with that in Western countries. Predictors of different clinical outcomes are provided. FACTS FROM EAST AND WEST: Treatment options for AAV are shared between the East and West, with corticosteroid combined with cyclophosphamide being the standard regimen for inductive therapy and switching to azathioprine after remission. The major cause of death in treated patients is infection related to immunosuppressive therapy within the first year after diagnosis, and this rate might be higher in China than in Western countries. Western studies demonstrated the efficacy and safety of rituximab for induction of remission in cases with relatively mild disease and maintenance therapy, but this agent is rarely used in China.