High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes.

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.

ExsgRNA: reduce off-target efficiency by on-target mismatched sgRNA.

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing technology has been widely used to facilitate efficient genome editing. Current popular sgRNA design tools only consider the sgRNA perfectly matched to the target site and provide the results without any on-target mismatch. We suppose taking on-target gRNA-DNA mismatches into consideration might provide better sgRNA with similar binding activity and reduced off-target sites. Here, we trained a seq2seq-attention model with feedback-loop architecture, to automatically generate sgRNAs with on-target mismatches. Dual-luciferase reporter experiment showed that multiple sgRNAs with three mismatches could achieve the 80% of the relative activity of the perfect matched sgRNA. Meanwhile, it could reduce the number of off-target sites using sgRNAs with on-target mismatches. Finally, we provided a freely accessible web server sgRNA design tool named ExsgRNA. Users could submit their target sequence to this server and get optimal sgRNAs with less off-targets and similar on-target activity compared with the perfect-matched sgRNA.

Optical Information Transmission and Multimode Fluorescence Anticounterfeiting of Ca2-xMgxGe7O16:Mn2.

Multimode emission of Mn2+ for multimode fluorescence anticounterfeiting is achieved by cation site and interstitial occupancy in Ca2-xMgxGe7O16. The rings in Ca2-xMgxGe7O16 have a significant distortion for Mn2+ ions to enter the ring interstitials with a luminescence center at 665 nm, which is supported by XRD refinement results and first-principles calculations. The interstitial Mn2+ ion has good thermal stability with an activation energy of 0.36 eV. Surprisingly, these two luminescence centers, the cation site Mn and the interstitial Mn, have an obvious afterglow, and the disappearing afterglow will reappear by heating or irradiating with the 980 nm laser. The afterglow is significantly enhanced, as MnO2 is used as the manganese source, which is explained in detail by the thermal luminescence spectrum. Finally, Ca2-xMgxGe7O16:Mn2+ fully demonstrates its excellent prospects in fluorescent anticounterfeiting, information encryption, and optical information storage.

Chromosome 1 instability in multiple myeloma: Aberrant gene expression, pathogenesis, and potential therapeutic target.

Multiple myeloma (MM), the terminally differentiated B cells malignancy, is widely considered to be incurable since many patients have either developed drug resistance or experienced an eventual relapse. To develop precise and efficient therapeutic strategies, we must understand the pathogenesis of MM. Thus, unveiling the driver events of MM and its further clonal evolution will help us understand this complicated disease. Chromosome 1 instabilities are the most common genomic alterations that participate in MM pathogenesis, and these aberrations of chromosome 1 mainly include copy number variations and structural changes. The chromosome 1q gains/amplifications and 1p deletions are the most frequent structural changes of chromosomes in MM. In this review, we intend to focus on the genes that are affected by chromosome 1 instability: some tumor suppressors were lost or down regulated in 1p deletions, and others that contributed to tumorigenesis were upregulated in 1q gains/amplifications. We have summarized their biological function as well as their roles in the MM pathogenesis, hoping to uncover potential novel therapeutical targets and promote the development of future therapeutic approaches.

Good pregnancy outcomes in lupus nephritis patients with complete renal remission.

BACKGROUND: The aim of this study was to investigate pregnancy outcomes and risk factors in patients with lupus nephritis (LN). METHODS: A total of 158 pregnancies in 155 women with LN were divided into a remission group and a control group according to whether they achieved complete renal remission (CRR) prior to pregnancy. The adverse pregnancy outcomes and risk factors were retrospectively analyzed. RESULTS: In the remission group, 130 LN patients with 133 pregnancies (two twin pregnancies) delivered 127 live births; 25 LN patients with 25 pregnancies delivered 19 live births in the control group. Compared with the control group, the remission group had significantly lower incidence of LN relapse, fetal loss and premature birth. For LN patients in the remission group, a CRR duration <18 months [odds ratio (OR) 11.24, 95% confidence interval (CI) 2.95-42.80, P < 0.001] and anti-C1q antibody positivity before pregnancy (OR 7.2, 95% CI 1.38-37.41, P = 0.019) were independent risk factors for LN relapse; anti-phospholipid antibody positivity (OR 9.32, 95% CI 1.27-68.27, P = 0.028) and prednisone dosage during pregnancy ≥12.5 mg/day (OR 3.88, 95% CI 1.37-10.99, P = 0.011) were independent risk factors for fetal loss and premature birth, respectively; and age >30 years was an independent risk factor for preeclampsia and premature birth. CONCLUSION: LN patients with a CRR duration greater than 18 months were associated with good pregnancy outcomes and lower LN relapse. Age, anti-C1q and anti-phospholipid antibodies, and prednisone dosage during pregnancy were risk factors for adverse pregnancy outcomes.

Long-term follow-up of autologous peripheral blood hematopoietic stem cell transplantation for refractory lupus nephritis-a series study of 20 patients.

BACKGROUND: Autologous hematopoietic cell transplantation (ASCT) improves immunologic homeostasis in autoimmune diseases. ASCT-treated refractory lupus nephritis (LN) has been reported. Nevertheless, the long-term outcome of patients with refractory LN after ASCT remains unknown. This study reports the outcomes of 20 refractory lupus patients with 10-year of follow-up after receiving ASCT. METHODS: Twenty-two patients with LN refractory to immunosuppressive therapy were enrolled. Twenty patients were examined closely and two cases died within 100 days after ASCT. Hematopoietic cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of intravenous cyclophosphamide, rabbit antithymocyte globulin, methylprednisolone, and G-CSF. All immunosuppressive therapies were discontinued at the start of mobilization and corticosteroids were tapered rapidly after ASCT. RESULTS: Data was collected from 22 patients with refractory LN treated by ASCT. 59% were female, duration of lupus before ASCT was 46 (33-71) months, and median duration of follow-up after ASCT was 89.5 (56-108) months. 20 long-term followed up patients had an average follow-up time of 92 months (63.25-109.5). Eighteen patients achieved complete remission, one patient reached partial remission, one patient without remission started peritoneal dialysis at month 12, and one patient received short-term renal replacement therapy before ASCT started hemodialysis at 84 months after transplantation. Nine patients relapsed 10 times during the follow-up, and three patients received rituximab. Two patients relapsed during pregnancy after complete response and the Apgar scores of infants were 9 and 10, respectively. All nine patients received glucocorticoids and immunosuppressive medication after relapse and responded again. The 10-year overall survival, 10-year disease-free survival rate, and 10-year renal survival were 100%, 35%, and 90%, respectively. The rate of relapse was 45%. Complications included hypocytosis, infection, B-type insulin resistance syndrome, and monoclonal immunoglobulinemia. CONCLUSION: This study suggests ASCT is effective and safety in treating refractory LN and is beneficial to improve their long-term outcomes.

An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation.

Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) (∼360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region. Specifically, rs6426749-G allele can bind transcription factor TFAP2A, which efficiently elevates the enhancer activity and increases LINC00339 expression. Downregulation of LINC00339 significantly increases the expression of CDC42 in osteoblast cells, which is a pivotal regulator involved in bone metabolism. Our study provides mechanistic insight into how a noncoding SNP affects osteoporosis by long-range interaction, a finding that could indicate promising therapeutic targets for osteoporosis.

Modeling circRNA expression pattern with integrated sequence and epigenetic features demonstrates the potential involvement of H3K79me2 in circRNA expression.

MOTIVATION: CircRNAs are an abundant class of non-coding RNAs with widespread, cell-/tissue-specific patterns. Previous work suggested that epigenetic features might be related to circRNA expression. However, the contribution of epigenetic changes to circRNA expression has not been investigated systematically. Here, we built a machine learning framework named CIRCScan, to predict circRNA expression in various cell lines based on the sequence and epigenetic features. RESULTS: The predicted accuracy of the expression status models was high with area under the curve of receiver operating characteristic (ROC) values of 0.89-0.92 and the false-positive rates of 0.17-0.25. Predicted expressed circRNAs were further validated by RNA-seq data. The performance of expression-level prediction models was also good with normalized root-mean-square errors of 0.28-0.30 and Pearson's correlation coefficient r over 0.4 in all cell lines, along with Spearman's correlation coefficient ρ of 0.33-0.46. Noteworthy, H3K79me2 was highly ranked in modeling both circRNA expression status and levels across different cells. Further analysis in additional nine cell lines demonstrated a significant enrichment of H3K79me2 in circRNA flanking intron regions, supporting the potential involvement of H3K79me2 in circRNA expression regulation. AVAILABILITY AND IMPLEMENTATION: The CIRCScan assembler is freely available online for academic use at https://github.com/johnlcd/CIRCScan. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Transcriptional profiling of Microtus fortis responses to S. japonicum: New sight into Mf-Hsp90α resistance mechanism.

AIMS: Schistosomiasis is a parasitic disease with a chronic debilitating character caused by parasitic flatworms of the genus Schistosoma. The main disease-causing species of Schistosoma in China is S. japonicum. M fortis has been proved to be a nonpermissive host of S. japonicum. Mf-HSP90α (Microtus fortis heat shock protein 90alpha), the homologue of HSP90α, display anti-schistosome effect in vitro and in vivo. In the current study, in order to investigate the mechanism of anti-schistosome effect of Mf-HSP90α, we conducted RNA-Seq to obtain the transcriptome profile of M. fortis liver infected with S. japonicum at different time points. METHODS AND RESULTS: By mapping the differential expressed genes (DEGs) to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), we found that the JAK2/STAT1 pathway was highly enriched with an elevated level of IL-10 and HSP90α. We then checked the IL-10-JAK2/STAT1-HSP90α pathway, and found that this pathway was activated in the infected mice with S. japonicum. The expression of the molecules in this pathway was elevated on the 10th day after infection and gradually decreased on the 20th day. CONCLUSIONS: The IL-10-JAK2/STAT1-HSP90α axis was associated with the anti-schistosome effect of Mf-HSP90α, and targeting IL-10-JAK2/STAT1-HSP90α axis might be a novel therapeutic strategy for developing resistance to S. japonicum infection.

Long-term renal outcomes and related risk factors of familial systemic lupus erythematosus patients with lupus nephritis
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AIMS: To investigate the renal pathological characteristics, renal outcomes and risk factors in lupus nephritis (LN) patients qualified as familial systemic lupus erythematosus (SLE). MATERIALS AND METHODS: Patients with biopsy-proven LN of familial SLE were enrolled. The clinical, laboratory, and pathological data of familial patients were analyzed and compared with those of sporadic SLE patients. The renal prognosis and risk factors were also assessed. RESULTS: 68 biopsy-proven familial SLE patients with LN were investigated. They were 17 males and 51 females with an average onset age of 25.4 years. The proportion of males in the familial group was higher than that in the sporadic group (p = 0.008). LN class IV was the most common class. Significantly, a higher amount of fibrotic crescents (p = 0.001) was observed in the sporadic group, while other renal lesions were comparable. With a median follow-up of 51.7 months in 48 familial SLE patients, 14.6% patients progressed to end-stage renal disease (ESRD). The 5-year cumulative renal survival rate from ESRD was 82.8%. Serum creatinine at biopsy (HR 2.359, p = 0.01) was the independent risk factor of renal outcomes. A serum creatinine level > 1.7 mg/dL predicted progression to ESRD (p = 0.015). CONCLUSION: Renal insufficiency at biopsy of familial SLE patients predicted poor renal outcome. Most renal laboratory and pathological features between familial and sporadic SLE were broadly similar.
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Risk factors for infectious complications of ANCA-associated vasculitis: a cohort study.

BACKGROUND: Severe infections are common complications of immunosuppressive treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with renal involvement. We investigated the clinical characteristics and risk factors of severe infection in Chinese patients with AAV after immunosuppressive therapy. METHODS: A total of 248 patients with a new diagnosis of ANCA-associated vasculitis were included in this study. The incidence, time, site, and risk factors of severe infection by the induction therapies were analysed. Multivariate Cox proportional hazards models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). RESULTS: A total of 103 episodes of severe infection were identified in 86 (34.7%, 86/248) patients during a median follow-up of 15 months. The incidence of infection during induction therapy was 38.5% for corticosteroids (CS), 39.0% for CS+ intravenous cyclophosphamide (IV-CYC), 33.8% for CS+ mycophenolate mofetil and 22.5% for CS + tripterygium glycosides, 76 (73.8%) infection episodes occurred within 6 months, while 66 (64.1%) occurred within 3 months. Pneumonia (71.8%, 74/103) was the most frequent type of infection, and the main pathogenic spectrum included bacteria (78.6%), fungi (12.6%), and viruses (8.7%). The risk factors associated with infection were age at the time of diagnosis (HR = 1.003, 95% CI = 1.000-1.006), smoking (HR = 2.338, 95% CI = 1.236-4.424), baseline secrum creatinine (SCr) ≥5.74 mg/dl (HR = 2.153, 95% CI = 1.323-3.502), CD4+ T cell< 281 µl (HR = 1.813, 95% CI = 1.133-2.900), and intravenous cyclophosphamide regimen (HR = 1.951, 95% CI =1.520-2.740). Twelve (13.9%) patients died of severe pneumonia. CONCLUSION: The infection rate during induction therapy was high in patients with AAV. Bacterial pneumonia was the main type of infection encountered. Age at the time of diagnosis, smoking, baseline SCr ≥5.74 mg/dl, CD4+ T cell< 281 µl, and IV-CYC therapy were identified as risk factors for infection.

Etiology and Outcome of Crescentic Glomerulonephritis From a Single Center in China: A 10-Year Review.

BACKGROUND: The disease spectrum of crescentic glomerulonephritis (GN) has been described in only a few previous studies, and detailed epidemiologic data from China are unavailable to date. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 528 patients with biopsy-proven crescentic GN in 2003 to 2013 from a single center. PREDICTOR: Crescentic GN was classified into 3 types according to immunofluorescence findings: type I was defined as linear deposition of immunoglobulins along the glomerular basement membrane; type II, as glomerular deposition of immune complex; and type III, as pauci-immune deposition. OUTCOMES: Demographic, clinical, and serologic characteristics. RESULTS: Of 528 cases identified, 208 (39.4%) were men, with a mean age of 37.6±16.4 (SD) years at kidney biopsy. 61 (11.6%) patients had type I crescentic GN, 331 (62.7%) had type II (lupus nephritis, 34.3%; immunoglobulin A [IgA] nephropathy, 17.4%), and 136 (25.8%) had type III. Proportions of patients with acute kidney injury (AKI), acute kidney diseases and disorders without AKI, and chronic kidney disease were 86.9%, 0%, and 13.1% for type I; 42.0%, 19.6%, and 38.4% for type II; and 84.6%, 2.9%, and 12.5% for type III crescentic GN, respectively. Serum antineutrophil cytoplasmic antibodies were detected in 11 (18.0%) patients with type I, 15 (4.5%) with type II, and 117 (86.0%) with type III. Anti-glomerular basement membrane antibodies were found in 60 (98.4%) patients with type I, 3 (0.9%) with type II, and 5 (3.7%) with type III. 5-year cumulative renal survival rates for patients with types I, II, and III were 17.6%, 70.1%, and 44.3%, respectively. LIMITATIONS: Retrospective study, single-center experience. CONCLUSIONS: Lupus nephritis may be the most common type of crescentic GN in China, followed by pauci-immune crescentic GN and IgA nephropathy. Almost half the patients presented with AKI, whereas 28.8% of cases showed chronic kidney disease. Clinical manifestations and outcomes varied according to crescentic GN type. The distinction between subtypes based on immunofluorescence and serologic findings has important implications for therapy and outcome.

4.1N is involved in a flotillin-1/ß-catenin/Wnt pathway and suppresses cell proliferation and migration in non-small cell lung cancer cell lines.

The membrane-cytoskeletal protein 4.1N has recently been proposed as a tumor suppressor in a number of cancers of epithelial origin, including non-small-cell lung cancer (NSCLC). However, the molecular mechanism associated with 4.1N tumor suppression remains has not been thoroughly characterized. In this study, 4.1N was shown to directly interact with the lipid raft marker flotillin-1 through its FERM and U2 domains in several different NSCLC cell lines using immunoprecipitation, co-immunoprecipitation and pull-down assays. Moreover, 4.1N silencing/overexpression experiments in paired 95C/95D cells that are of homologous origin but varying endogenous 4.1N expression (high expression in 95C cells, low expression in 95D cells) indicated that 4.1N is involved in the suppression of cell proliferation and migration through a flotillin-1/ß-catenin/Wnt pathway. Taken together, the findings of this study help to elucidate the novel tumor suppressor role of 4.1N in NSCLC.

Long-term outcome of mycophenolate mofetil treatment for patients with microscopic polyangiitis: an observational study in Chinese patients.

This study aimed to retrospectively analyze the long-term outcome of mycophenolate mofetil (MMF) therapy for microscopic polyangiitis (MPA) with mild to moderate renal involvement in Chinese patients. Thirty-four MPA patients (24 females, 10 males, aged 44.7 ± 17 years, BVAS score 13.8 ± 3.2, SCr 2.2 ± 1.1 mg/dl) with SCr < 5 mg/dl and who received glucocorticoids plus MMF therapy for inducing and maintaining remission were included in this study. The remission and relapse rates, patient and renal survival rates and adverse events were retrospectively analyzed. We found that 31 (91.2 %) of 34 patients achieved remission and were continuously treated with glucocorticoids plus MMF for maintaining remission. The median duration of MMF treatment was 24 months (IQR 15-53 months) and follow-up time was 86 months (IQR 29-124 months). During the follow-up, 7 (22.6 %) patients relapsed, one patient died, and one patient progressed into end-stage renal disease. The 5-year patient and renal survival rates were 92.8 and 95.2 %, respectively. 11 (32.4 %) patients suffered 16 adverse events, 13 of which were pulmonary infection. In conclusion, glucocorticoids plus MMF regimen as induction and maintenance therapy could achieve high remission rate and good long-term renal survival in MPA patients with mild to moderate renal involvement. Prospective controlled trials with a large sample size are needed to confirm the efficacy of MMF in this population.

Long-term outcomes in antineutrophil cytoplasmic autoantibody-positive eosinophilic granulomatosis with polyangiitis patients with renal involvement: a retrospective study of 14 Chinese patients.

BACKGROUND: The clinic-pathological features and outcomes of Chinese patients with antineutrophil cytoplasmic autoantibody (ANCA)-positive eosinophilic granulomatosis with polyangiitis (EGPA) and renal involvement have not been studied. METHODS: Fourteen EGPA patients with renal involvement were included. All patients underwent renal biopsy. Clinic-pathological features and outcomes were retrospectively analyzed. RESULTS: The most common initial symptom of EGPA was asthma (57.1 %), followed by hemoptysis (21.4 %), gross hematuria (14.3 %), and arthritis (7.1 %). All patients had positive serum ANCA (anti-MPO in 12, anti-PR3 in 2). Elevated eosinophils (median 15 %, range 10-45 %) were found in all patients. The median serum IgE level was 463 g/L (range 200-1000 g/L). All patients presented with renal dysfunction, with a median SCr of 5.4 mg/dL (range 1.47-11 mg/dL), seven patients (50 %) required initial renal replacement therapy. Thirteen patients showed hematuria and proteinuria (median 1.1 g/24 h, range 0.5-7.8 g/24 h). Renal biopsy showed pauci-immune segmental necrotizing glomerulonephritis with crescents in 13 patients and acute interstitial nephritis in one patient. Twelve patients (85.7 %) showed renal interstitial eosinophil infiltration, among whom three had eosinophilic granuloma. Among seven patients (71.4 %) who required initial dialysis, 5 discontinued dialysis, one died, one received maintenance dialysis after glucocorticoids plus immunosuppressive for induction treatment. Twelve patients were followed up for a median of 43.5 months (range 6-83 months), during follow-up, two patients progressed to end-stage renal disease, nine had chronic kidney disease with eGFR < 60 mL/min, and two patients had normal eGFR. CONCLUSIONS: Renal involvement in ANCA-positive EGPA could be severe and showed varied renal histology. Although intensive immunosuppressive therapy effectively improved the renal function, the long-term renal survival was poor. Early diagnosis and treatment are essential to improve long-term renal survival.

Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.

BACKGROUND: Treatment of lupus nephritis (LN) remains challenging. OBJECTIVE: To assess the efficacy and safety of a multitarget therapy consisting of tacrolimus, mycophenolate mofetil, and steroid compared with intravenous cyclophosphamide and steroid as induction therapy for LN. DESIGN: 24-week randomized, open-label, multicenter study. (ClinicalTrials.gov: NCT00876616). SETTING: 26 renal centers in China. PATIENTS: Adults (aged 18 to 65 years) with biopsy-proven LN. INTERVENTION: Tacrolimus, 4 mg/d, and mycophenolate mofetil, 1.0 g/d, versus intravenous cyclophosphamide with a starting dose of 0.75 (adjusted to 0.5 to 1.0) g/m2 of body surface area every 4 weeks for 6 months. Both groups received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy. MEASUREMENTS: The primary end point was complete remission at 24 weeks. Secondary end points included overall response (complete and partial remission), time to overall response, and adverse events. RESULTS: After 24 weeks of therapy, more patients in the multitarget group (45.9%) than in the intravenous cyclophosphamide group (25.6%) showed complete remission (difference, 20.3 percentage points [95% CI, 10.0 to 30.6 percentage points]; P < 0.001). The overall response incidence was higher in the multitarget group than in the intravenous cyclophosphamide group (83.5% vs. 63.0%; difference, 20.4 percentage points [CI, 10.3 to 30.6 percentage points]; P < 0.001), and the median time to overall response was shorter in the multitarget group (difference, -4.1 weeks [CI, -7.9 to -2.1 weeks]). Incidence of adverse events did not differ between the multitarget and intravenous cyclophosphamide groups (50.3% [91 of 181] vs. 52.5% [95 of 181]). LIMITATION: The study was limited to 24 weeks of follow-up. CONCLUSION: Multitarget therapy provides superior efficacy compared with intravenous cyclophosphamide as induction therapy for LN. PRIMARY FUNDING SOURCE: National Basic Research Program of China, National Key Technology R&D Program.

Pathological spectrums and renal prognosis of severe lupus patients with rapidly progressive glomerulonephritis.

The objectives of the study were to investigate the pathological features and renal prognosis of severe lupus patients with rapidly progressive glomerulonephritis. One hundred and one cases of biopsy-proven severe LN with rapidly progressive glomerulonephritis (RPGN) were analyzed in this retrospective study. Another 200 severe LN patients without RPGN were randomly enrolled as a control group. Their clinicopathological data and long-term outcome were compared. There were 76 females and 25 males with an average age of 31.9 ± 14.2 years followed for a median period of 4 years. Compared with controls, patients with RPGN had shorter LN duration (p = 0.008), higher level of creatinine (p < 0.001), severe anemia (p = 0.037), heavier hematuria (p < 0.001), severe tubular injury parameters [NAG (p < 0.001), RBP (p < 0.001), C3 (p < 0.001)], higher scores of AI (p = 0.001) and CI (p = 0.004), higher proportions of glomerular sclerosis (0.033) and crescents (p < 0.001), severe tubulointerstitial lesions (p < 0.001) and interstitial inflammation (p < 0.001), lower rate of complete remission (33.9 vs 68.2 %) and higher rate of treatment failure (46.8 vs 7.9 %). The 3-, 5- and 10-year cumulative renal survival rates of RPGN and non-RPGN patients were 65.1 versus 53.9 versus 42.9 and 96.9 versus 94.9 versus 91.7 %, respectively. Multivariate analysis revealed that SCr concentration and the proportion of crescents were the most important risk factors for end-stage renal disease (ESRD) in severe LN with RPGN (p < 0.001). In conclusion, RPGN occurred in 3.6 % of LN and is associated with severe renal manifestations, serious sclerotic and crescentic glomeruli lesions, severe tubulointerstitial inflammation, atrophy and fibrosis, prominent leukocyte infiltration and worse treatment response. Multivariate analysis revealed that SCr concentration and the proportion of crescents were the most important risk factors for ESRD. 57.1 % of severe LN patients with RPGN might progress to ESRD within 10 years.

Resveratrol induces human K562 cell apoptosis, erythroid differentiation, and autophagy.

Resveratrol (Res) is a naturally occurring phytoalexin with apoptotic and inducing-glob effects in leukemic cells, but the potential induction of erythroid differentiation in cells is not fully understood. Here, we investigated the effects of Res on human erythro-megakaryoblastic leukemia cell line K562. Among the treated cells, proliferation was inhibited and the occurrence of cell apoptosis and cell death were detected. Erythroid differentiation assay was explored, and we found that Res could increase the expression of glycophorin A (GPA), HBA1, HBB, and γ-globin genes and enforced the expression of GPA, CD71, and Band3 proteins. Res also induced K562 cell autophagy when the concentration of Res was increased up to 50 or 100 µM. Our findings suggested that Res possesses the potency not only inducing apoptosis but also inducing erythroid differentiation and autophagy in K562 cells. These results provide that Res may be a therapeutic candidate for chronic myelogenous leukemia treatment.

Clinicopathological characteristics and outcomes of pediatric patients with systemic small blood vessel vasculitis.

BACKGROUND: Systemic small blood vessel vasculitis (SSV) is uncommon among pediatric patients, and the predictive value of the new histopathological classification for SSV in terms of renal outcomes in these patients is unknown. METHODS: The study cohort comprised 38 pediatric patients and 285 adult patients with SSV who were treated in a medical center between 1993 and 2012. RESULTS: Children accounted for 11.8 % of all patients with SSV diagnosed during the study period. In contrast to the adult patients, the pediatric patients were predominantly female (73.7 vs. 51.9 %; P < 0.05). The prevalence of skin purpura was higher and pulmonary symptoms were less common among pediatric patients than among adult ones (36.8 vs. 13.7 %, P < 0.01 and 26.3 vs. 46.0 %, P < 0.05, respectively). Subtype was correlated with the baseline levels of serum creatinine and treatment response among patients with SSV and was found to have a tendency to predict end-stage renal disease (ESRD) among pediatric patients (hazard ratio 2.273, P < 0.01). The probability of progressing to ESRD was highest in pediatric patients with the sclerotic glomerulonephritis subtype, followed by the mixed, crescentic and focal glomerulonephritis subtypes (in descending order of probability) (P < 0.01). CONCLUSIONS: Estimated histopathological classification has a prognostic value for renal outcome and response to therapy in children with SSV.