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Previous studies have suggested a potential association between sleep and telomere length (TL), but its genetic basis remains unclear. In this study, we aimed to explore the genetic correlation and potential causal association between TL and insomnia.The genome-wide association study (GWAS) datasets of TL and insomnia-related traits were used, including insomnia, snoring, daytime dozing and napping. Based on the polygenic risk scores (PRS) of TL, linear regression and linkage disequilibrium score (LDSC) regression were used to preliminarily explore the association between TL and insomnia parameters in the UK Biobank cohort. Then, we investigated the causal association between TL and insomnia by mendelian randomization (MR) analysis and colocalization analysis.In the UK Biobank cohort, the association between TL and insomnia was observed in the female samples (t = 2.968, P = 3.00 × 10Our study found no evidence for causal association between insomnia and TL in individuals of European ancestry. We detected a candidate gene associated with both insomnia and TL, providing novel clues for understanding the roles of this association.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma and most of the patients presented localized disease. Combined modality therapy (CMT), namely chemotherapy combined with radiotherapy, has been recommended for patients with early-stage ENKTL. However, the optimal CMT has not been fully clarified. This study reports the efficacy and toxicity of sequential P-GEMOX (pegaspargase, gemcitabine and oxaliplatin) and radiotherapy in a large Chinese cohort comprising of 202 patients diagnosed with early-stage ENKTL from six medical centers. The observed best overall response rate was 96.0% and 168 (83.2%) patients achieved complete remission. With a median follow-up of 44.1 months, the 3-year progression-free survival (PFS) and overall survival (OS) were 74.6% and 85.2%, respectively. Multivariate analysis suggested that extensive primary tumor (PFS, hazard ratio [HR] 3.660, 95%CI 1.820-7.359, P

RATIONALE & AIMS: Healthy dietary patterns have been associated with a lower risk of chronic kidney disease (CKD). We aimed to investigate the association of a fully food-based diet quality score assessed by the Lifelines Diet Score (LLDS) with either incident CKD or eGFR decline in the general population.METHODS: For this study, data from a prospective general population-based Lifelines cohort in the Northern Netherlands was used. Diet was assessed with a 110-item food frequency questionnaire at baseline. The LLDS, based on international evidence for diet-disease relations at the food group level, was calculated to assess diet quality. For the analysis, the score was divided into tertiles. Logistic regression was performed to evaluate the association of the LLDS at baseline with either incident CKD (eGFR RESULTS: A total of 78 346 participants free of CKD at baseline were included. During a mean (SD) follow-up of 3.6 ± 0.9 years, 2071 (2.6%) participants developed CKD and 7611 (9.7%) had a ≥20% eGFR decline. Participants in the highest tertile of LLDS had a lower risk of incident CKD (fully adjusted OR 0.83, [95% CI: 0.72-0.96]) and ≥20% eGFR decline (fully adjusted OR 0.80, [95% CI: 0.75-0.86]), compared with those in the lowest tertile. Similar dose-response associations were observed in continuous LLDS.CONCLUSIONS: Higher adherence to a high-quality diet was associated with a lower risk of incident CKD or ≥20% eGFR decline in the general population.

Background The early clinical diagnosis of spinal infections in elderly patients with recessive or atypical symptoms is difficult. Klebsiella aerogenes is a common opportunistic bacterium that can infect the respiratory tract, urinary tract, and even the central nervous system. However, whether it can infect the lumbar spine has not been previously described. Case presentation In this paper, we report the case of a 69-year-old female patient with osteoporosis who was initially diagnosed with hemolytic anemia. Later, she was diagnosed with K. aerogenes infection of the lumbar spine based on imaging combined with blood culture and metagenome next-generation sequencing (mNGS) detection. After precise medication, the lumbar degeneration was improved. Conclusions Bacterial infection should therefore be considered in cases of lumbar degenerative disease in middle-aged and elderly patients.

Current prognostic scoring systems based on clinicopathologic variables are inadequate in predicting the survival and treatment response of extranodal natural killer/T-cell lymphoma (ENKTL) patients undergoing nonanthracyline-based treatment. We aimed to construct a classifier based on single-nucleotide polymorphisms (SNPs) for improving predictive accuracy and guiding clinical decision making. Data from 722 patients with ENKTL from international centers were analyzed. A 7-SNP–based classifier was constructed using LASSO Cox regression in the training cohort (n = 336) and further validated in the internal testing cohort (n = 144) and in 2 external validation cohorts (n = 142 and n = 100). The 7-SNP–based classifier showed good prognostic predictive efficacy in the training cohort and the 3 validation cohorts. Patients with high- and low-risk scores calculated by the classifier exhibited significantly different progression-free survival (PFS) and overall survival (OS) (all P < .001). The 7-SNP–based classifier was further proved to be an independent prognostic factor by multivariate analysis, and its predictive accuracy was significantly better than clinicopathological risk variables. Application of the 7-SNP–based classifier was not affected by sample types. Notably, chemotherapy combined with radiotherapy significantly improved PFS and OS vs radiotherapy alone in high-risk Ann Arbor stage I patients, whereas there was no statistical difference between the 2 therapeutic modalities among low-risk patients. A nomogram was constructed comprising the classifier and clinicopathological variables; it showed remarkably better predictive accuracy than either variable alone. The 7-SNP–based classifier is a complement to existing risk-stratification systems in ENKTL, which could have significant implications for clinical decision making for patients with ENKTL.

Advanced natural killer/T cell lymphoma (NKTL) has demonstrated poor prognosis with currently available therapies. Here, we report the efficacy of anti-programmed death 1 (PD-1) antibody with the P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) regimen in advanced NKTL. Nine patients underwent six 21-day cycles of anti-PD-1 antibody (day 1), pegaspargase 2000 U/m2 (day 1), gemcitabine 1 g/m2 (days 1 and 8) and oxaliplatin 130 mg/m2 (day 1), followed by anti-PD-1 antibody maintenance every 3 weeks. Programmed death-ligand 1 (PD-L1) expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing (NGS) analysis. Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) and computed tomography or magnetic resonance imaging. Eight patients exhibited significant responses, comprising of seven complete remissions and one partial remission (overall response rate: 88.9%). After a median follow-up of 10.6 months, 6/9 patients (66.7%) remained in complete remission. The most common grade 3/4 adverse events were anemia (33.3%), neutropenia (33.3%), and thrombocytopenia (33.3%); all of which were manageable and resolved. Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression (5/6, 83.3%). NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy. Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D, TET2, and BCORL1 might indicate a poor response to immunochemotherapy. In conclusion, the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL. PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.

BackgroundLow-grade chronic inflammation may contribute to the pathogenesis of polycystic ovary syndrome (PCOS). Interleukin-15 (IL-15) is a proinflammatory cytokine involved in the development of chronic inflammation leading to obesity-associated metabolic syndrome. However, the concentration of IL-15 in follicular fluid of patients with PCOS has yet been evaluated.ObjectivesThe aim of this study is to evaluate the expression level of IL-15 in both patients with PCOS and PCOS mice model and investigate the functional effect of IL-15 on ovarian granulosa cells.MethodsThe level of IL-15 in follicular fluid (FF) was measured using cytokine array and enzyme linked immunosorbent assay (ELISA) in two cohorts from 23 PCOS patients and 18 normo-ovulatory controls. PCOS mice model was induced by subcutaneously implanted with letrozole pellet for 21 days. The expression level of IL-15 in serum, ovarian, and subcutaneous adipose tissue in PCOS mice model was measured by ELISA, real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and immunofluorescence. The effect of IL-15 on the proliferation and apoptosis of the KGN cells and mouse ovarian granulosa cells (GCs) were detected by CCK-8 assay and flow cytometry, respectively. Transcript expression of 17α-hydroxylase17,20-lyase (CYP17A1), cytochrome P450 family 19 subfamily A member 1(CYP19A1), FSH receptor (FSHR), steroidogenic acute regulatory protein (StAR), and proinflammatory cytokine were quantified using RT-PCR. The protein level and phosphorylation level of p38 MAPK and JNK are detected by Western blot. Concentration of dehydroepiandrosterone sulfate (DHEAS) and progesterone (P)were measured by ELISA.ResultsIL-15 expression in follicular fluid of patients with PCOS was significantly elevated compared with the control group, and similar results were observed in the ovarian and subcutaneous adipose tissue of PCOS mice models. Furthermore, the elevated FF IL-15 levels have a positive correlation with the serum testosterone levels. FSHR co-localized with IL-15 indicating that IL-15 production originate from ovarian granulose cells. IL-15 treatment inhibited proliferation and promoted apoptosis of KGN cells and mouse GCs. Moreover, IL-15 upregulated the transcription levels of CYP17A1, IL-1b and Ifng KGN cells. Similar results were observed in mouse GCs except concentration of DHEAS was higher in IL-15 treatment. IL-15 promoted p38 MAPK and JNK phosphorylation in KGN cells, treating KGN cells with p38 MAPK inhibitor SP600125 and JNK inhibitor SB203580 could reverse the effect of IL-15 on the proliferation and function of KGN cells.ConclusionThe results indicate that IL-15 is involved in the pathogenesis of PCOS potentially by affecting survival, the inflammation state and steroidogenesis of granulosa cells. The practical significance of this association between IL-15 and the pathogenesis of PCOS needs further investigation.

Background Adult patients with T‐cell lymphoblastic lymphoma (T‐LBL) are treated with high‐intensity chemotherapy regimens, but the response rate is still unsatisfactory because of frequent drug resistance. We aimed to investigate the potential mechanisms of drug resistance in adults with T‐LBL. Methods Gene expression microarray was used to identify differential mRNA expression profiles between chemotherapy‐resistant and chemotherapy‐sensitive adult T‐LBL tissues. Real‐time PCR and immunohistochemistry were performed to detect the expression of bromodomain‐containing protein 2 (BRD2) and c‐Myc in fresh‐frozen T‐LBL tissues from 85 adult patients. The Ras pull‐down assay was performed to monitor Ras activation. Chromatin immunoprecipitation assays were used to analyze the binding of E2F transcription factor 1 (E2F1)/BRD2 to the RAS guanyl releasing protein 1 (RasGRP1) promoter region. The drug resistance effect and mechanism of BRD2 were determined by both in vivo and in vitro studies. Results A total of 86 chemotherapy resistance‐related genes in adult T‐LBL were identified by gene expression microarray. Among them, BRD2 was upregulated in chemotherapy‐resistant adult T‐LBL tissues and associated with worse progression‐free survival and overall survival of 85 adult T‐LBL patients. Furthermore, BRD2 suppressed doxorubicin (Dox)‐induced cell apoptosis both in vitro and in vivo. The activation of RasGRP1/Ras/ERK signaling might contribute to the Dox resistance effect of BRD2. Besides, OTX015, a bromodomain and extra‐terminal (BET) inhibitor, reversed the Dox resistance effect of BRD2. Patient‐derived tumor xenograft demonstrated that the sequential use of OTX015 after Dox showed superior therapeutic effects. Conclusions Our data showed that BRD2 promotes drug resistance in adult T‐LBL through the RasGRP1/Ras/ERK signaling pathway. Targeting BRD2 may be a novel strategy to improve the therapeutic efficacy and prolong survival of adults with T‐LBL.

Cytosine and adenine base editors are promising new tools for introducing precise genetic modifications that are required to generate disease models and to improve traits in pigs. Base editors can catalyze the conversion of C→T (C>T) or A→G (A>G) in the target site through a single guide RNA. Injection of base editors into the zygote cytoplasm can result in the production of offspring with precise point mutations, but most F0 are mosaic, and breeding of F1 heterozygous pigs is time-intensive. Here, we developed a method called germinal vesicle oocyte base editing (GVBE) to produce point mutant F0 porcine embryos by editing the maternal alleles during the GV to MⅡ transition. Injection of cytosine base editor 3 (BE3) mRNA and X-linked Dmd -specific guide RNAs into GV oocytes efficiently edited maternal Dmd during in vitro maturation and did not affect the maturation potential of the oocytes. The edited MⅡ oocytes developed into blastocysts after parthenogenetic activation (PA) or in vitro fertilization (IVF). However, BE3 may reduce the developmental potential of IVF blastocysts from 31.5%±0.8% to 20.4%±2.1%. There 40%–78.3% diploid PA blastocysts had no more than two different alleles, including up to 10% embryos that had only C>T mutation alleles. Genotyping of IVF blastocysts indicated that over 70% of the edited embryos had one allele or two different alleles of Dmd . Since the male embryos had only a copy of Dmd allele, all five (5/19) F0 male embryos are homozygous and three of them were Dmd precise C>T mutation. Nine (9/19) female IVF embryos had two different alleles including a WT and a C>T mutation. DNA sequencing showed that some of them might be heterozygous embryos. In conclusion, the GVBE method is a valuable method for generating F0 embryos with maternal point mutated alleles in a single step.

Renal arteriolar microangiopathic lesions may occur in immunoglobulin A nephropathy (IgAN), but their role in disease progression remains unclear. We sought to understand the prevalence and character of microangiopathic lesions in IgAN and their role in disease progression.A retrospective cohort study.In this study, we enrolled a Chinese cohort with 944 adult patients with IgAN who had been followed up for at least 1 year.Renal arteriolar microangiopathic lesions.Composite kidney end point event defined as a50% reduction in estimated glomerular filtration rate, end-stage kidney disease, or death.All kidney biopsies were independently reviewed by 2 investigators. Renal arteriolar microangiopathic lesions were detected using light microscopy. Multivariable Cox regression analysis was used to test the association between microangiopathic lesions and the outcomes.Overall, 194 (20.6%) patients had renal arteriolar microangiopathic lesions. Patients with microangiopathic lesions presented with higher blood pressures, more severe proteinuria, and lower estimated glomerular filtration rates (all P0.001) than patients without microangiopathic lesions. After a median follow-up of 4.2 years, 75 (38.7%) patients with microangiopathic lesions and 83 (11.1%) patients without these lesions reached the composite kidney end point (P0.001). In a multivariable Cox regression model adjusting for clinical and pathologic variables available at the time of biopsy, the presence of microangiopathic lesions was an independent risk factor for kidney failure (HR, 1.95; 95% CI, 1.34-2.83; P0.001). Renal vascular sclerosis (arterial intimal fibrosis or arteriolar hyalinosis) was not a risk factor for kidney disease progression (P = 0.5).A single Chinese center's experience, retrospective study, most patients were not tested for hemolytic markers (for example, haptoglobin level, lactate dehydrogenase level, and schistocytes).Renal arteriolar microangiopathic lesions are frequent in IgAN and their presence is independently associated with progression to kidney failure. If confirmed in other patient cohorts, such lesions could be considered for inclusion in formal classification schemes of IgAN.

Patients with classical Hodgkin lymphoma (cHL) who do not achieve complete remission (CR) after second-line chemotherapy have poor clinical outcomes. Besides, conventional salvage chemotherapy regimens have an unsatisfactory CR rate. The present retrospective study reports the efficacy and toxicity of the GVD (gemcitabine, vinorelbine, liposomal doxorubicin) regimen with or without programmed cell death 1 (PD-1) inhibitor for patients with cHL who failed first-line treatment. A total of 103 patients with cHL (GVD+PD-1 group, n = 27; GVD group, n = 76) with response assessment based on positron emission tomography were included. The GVD+PD-1 group tended to have a higher CR rate than GVD group (85·2% vs. 65·8%, P = 0·057) and had a better event-free survival (EFS) (P = 0·034). Subgroup analysis showed that patients with low-risk second-line International Prognostic Score might benefit from the addition of PD-1 inhibitor (GVD+PD-1 vs. GVD, 100·0% vs. 64·7%, P = 0·028) and had better EFS than GVD alone (P = 0·016). Further analysis demonstrated that PD-1 consolidation therapy might provide an EFS benefit (P = 0·007). The toxicity of the GVD+PD-1 regimen was comparable to the GVD regimen, except for higher rates of hypothyroidism and autoimmune pneumonitis, which were manageable. In conclusion, combining a PD-1 inhibitor with a GVD regimen could be a potentially effective second-line therapy for patients with cHL.

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare but devastating event. Intravenous high-dose methotrexate (HD-MTX) is recommended as CNS prophylaxis, but the optimal timing and dose has not been elucidated. Here, we report a multicenter analysis of prophylactic HD-MTX administration for DLBCL. Two hundred eighty-four patients receiving HD-MTX either concurrent with each induction chemotherapy cycle (n = 221) or at the end of induction therapy (EOI, n = 63) were included. Patients with CNS-IPI scoring 4-6, and/or testicular involvement, and/or double/triple hit lymphoma, were stratified into the high-risk group and the others into the moderate-risk group. Concurrent HD-MTX was associated with increased risk of grade 3/4 treatment-related toxicity (OR,1.49; P = 0.006) and subsequent chemotherapy delays (OR, 1.87; P = 0.003) in multivariate analysis. With a median follow-up of 36.0 months, no significant difference in CNS relapse rate was identified between the concurrent and EOI groups (3.2% vs 4.8%, P = 0.34), even in the high-risk group. Analysis on systemic MTX dose suggested that high-dose MTX (≥ 2 g/m

Background We aimed to establish a predictive prognostic risk-stratification model for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. Methods The data of 1406 primary DLBCL patients from the Sun Yat-Sen University Cancer Center were analysed to establish a nomogram prognostic index (NPI) model for predicting overall survival (OS) based on pre-treatment indicators. An independent cohort of 954 DLBCL patients from three other hospitals was used for external validation. Results Age, performance status, stage, lactate dehydrogenase, number of extranodal sites, BCL2, CD5 expression, B symptoms and absolute lymphocyte and monocyte count were the main factors of the NPI model and could stratify the patients into four distinct categories based on their predicted OS. The calibration curve demonstrated satisfactory agreement between the predicted and actual 5-year OS of the patients. The concordance index of the NPI model (0.794) was higher than the IPI (0.759) and NCCN-IPI (0.750), and similar results were obtained upon external validation. For CD5 + DLBCL patients, systemic treatment with high-dose methotrexate was associated with superior OS compared to R-CHOP-based immunochemotherapy alone. Conclusions We established and validated an accurate prediction model, which performed better than IPI and NCCN-IPI for prognostic stratification of DLBCL patients.

Objective: The main objective of the present study is to evaluate the psychometric properties of the Chinese version of Beliefs about Medicines Questionnaire-specific among asthma patients; and to assess the association between patients’ belief and adherence to inhaled corticosteroid therapy. Methods: A cross-sectional survey was carried out in the asthma clinic of Zhongshan Hospital, to Fudan University (Shanghai, China) between April 2016 and March 2018. The Beliefs about Medicines Questionnaire-specific was translated into Chinese according to international guidelines. Internal consistency, test–retest reliability, and confirmatory factor analysis were calculated to validate the Beliefs about Medicines Questionnaire-specific. The relationship between the adherence and the belief subscale were assessed using Kruskal–Wallis test. Results: Two hundred and seventeen patients were recruited in this study. The Beliefs about Medicines Questionnaire-specific was deemed reliable based on the results of Cronbach’s alpha coefficient and test–retest intraclass correlation coefficient (ICC, ICC= 0.759). Confirmatory factor analysis showed acceptable model fit for the two-factor model. Patients’ compliance was closely related to their belief about inhaled corticosteroid. The adherence rates were highest for the accepting groups, and lowest for the skeptical groups. Higher adherence was significantly associated with higher necessity-concerns differential (p = .001) and lower concern (p = .004). Conclusions: The Chinese version of the Beliefs about Medicines Questionnaire-specific can be used as a reliable tool by the clinicians to identify beliefs and behaviors of individual to improve adherence in Chinese patients.

Background and aims Presence of the metabolic syndrome (MetS) importantly contributes to excess mortality in kidney transplant recipients (KTRs). However, it is unclear which dietary factors drive the adverse role of MetS in KTRs. We aimed to define a dietary pattern that maximally explained the variation in MetS components, and to investigate the association between this MetS-related dietary pattern (MetS-DP) and all-cause mortality in KTRs. Methods and results We included 429 adult KTRs who had a functioning graft ≥1 year. A MetS-DP was constructed using habitual dietary intake derived from a 177-item food frequency questionnaire. We used reduced rank regression (RRR), and defined the six components of MetS (waist circumference, systolic blood pressure, diastolic blood pressure, serum triglycerides, HbA1c, and HDL cholesterol) as response variables and 48 food groups as predictor variables. We evaluated the association between the MetS-DP and all-cause mortality using multivariable Cox regression analysis. The MetS-DP was characterized by high intakes of processed meat and desserts, and low intakes of vegetables, tea, rice, fruits, milk, and meat substitutes. During a mean follow-up of 5.3±1.2 years, 63 KTRs (14.7%) died. Compared to the lowest tertile of the Mets-DP score, those with the greatest adherence had a more than 3-fold higher risk of all-cause mortality (hazard ratio [HR]=3.63; 95% confidence interval [CI], 1.70-7.74, P Conclusions We identified a MetS-related dietary pattern which was independently associated with all-cause mortality in KTRs. The association between this dietary pattern and all-cause mortality was mediated by MetS. Clinical trial reg. no NCT02811835. Clinical Trial Notation Jun 23, 2016, Clinical trial reg. no. NCT02811835, Clinical-Trials.gov .

We constructed a prognostic score for persons with diffuse large B-cell lymphoma (DLBCL) based on infiltrating immune cells. Data of 956 consecutive subjects were retrieved from the Gene Expression Omnibus database and assigned to training (GSE10846, n = 305) or validation (GSE87371 n = 206 and GSE117556 n = 445 combined) cohorts. Proportions of non-lymphoma cells in the sample were inferred using the ESTIMATE algorithm. An immune risk score was constructed comprised of eight types of non-lymphoma immune cells calculated using the CIBERSORT algorithm. Five-year survival of subjects with an immune risk score ≤ 0·45 in the training cohort was better than that of subjects with a score > 0·45 (hazard ratio [HR] = 3·99; 95% confidence interval [CI] = 2·74, 5·82; P < 0·001). HR in the validation cohort was HR = 2·17 (1·47, 3·21; P < 0·001). Enrichment analyses indicated correlations with genes controlling immune-related biological processes and pathways. A nomogram comprised of the immune risk score and most covariates including age, lactate dehydrogenase concentration (LDH), lymphoma-type (germinal centre B cell [GCB] versus non-GCB), Eastern Cooperative Oncology Group performance status (ECOG-PS) and rituximab therapy had a C-statistic of 0·76 compared with C-statistics of 0·69 and 0·69 for the International Prognostic Index (IPI) and Revised International Prognostic Index (R-IPI). These data indicate the immune risk score is an accurate, independent survival predictor in persons with DLBCL.

Rationale & Objective: Glomerular C4d (C4dG) as an indicator of the lectin pathway of complement activation in immunoglobulin A nephropathy (IgAN) has been associated with more severe kidney damage. Recent studies have suggested that vascular lesions in IgAN biopsy specimens with complement deposition are also associated with disease progression. We aimed to study the clinical significance of arteriolar C4d (C4dA) in IgAN kidney biopsy tissue.Study Design: Retrospective cohort study.Setting & Participants: Kidney biopsy specimens from 126 adults with IgAN diagnosed by Oxford classification criteria were stained using immunohistochemistry and classified according to C4dG and C4dA deposition. Additionally, vascular lesions including acute and chronic microangiopathy, arteriolar hyalinosis, and arterial intima fibrosis were characterized.Predictor: C4dA.Outcome: Progressive kidney disease, defined as a decline in estimated glomerular filtration rate by >= 50% or occurrence of kidney failure.Analytical Approach: The association of C4dA and C4dG with baseline clinical and histologic characteristics, as well as progressive kidney disease, were assessed with survival analysis using multivariable Cox regression analysis.Results: C4dA was identified in 21 (17%) patients and was associated with mean arterial pressure, arterial intima fibrosis, and chronic microangiopathy. C4dA was also significantly associated with C4dG and both were associated with progressive kidney disease. In regression analysis, C4dA remained significantly associated with progressive kidney disease after adjusting for other significant predictors, including baseline estimated glomerular filtration rate, mean arterial pressure, and the presence of crescents.Limitations: Findings based on the retrospective evaluation of a single center's experience, limited number of events, a small number of patients with a broad range of kidney disease stages, and use of immunohistochemistry rather than immunofluorescence to detect C4d.Conclusions: C4dA is a potential biomarker for disease progression in IgAN. It should be further investigated in larger cohorts to determine the value of C4dA in improving prediction of IgAN disease progression.

No specific dietary patterns have been established that are linked with loss of kidney function. We aimed to identify an estimated glomerular filtration rate-based dietary pattern (eGFR-DP) and to evaluate its association with eGFR decline and chronic kidney disease (CKD) incidence in the general population. We included 78,335 participants from the Lifelines cohort in the Northern Netherlands. All participants had an eGFR &gt, 60 mL/min/1.73 m2 at baseline and completed a second visit five years later. The eGFR-DP was constructed at baseline using a 110-item food frequency questionnaire by reduced rank regression, stratified by sex. Logistic regression was performed to evaluated the association between the eGFR-DP score and either a &ge, 20% eGFR decline or incident CKD. Among women, eGFR-DP were characterized by high consumption of egg, cheese, and legumes and low consumption of sweets, white meat, and commercially prepared dishes. In men, eGFR-DP were characterized by high consumption of cheese, bread, milk, fruits, vegetables, and beer and low consumption of white and red meat. A higher eGFR-DP score was associated with a lower risk of a &ge, 20% eGFR decline (OR 4th vs. 1st quartile, women: 0.79 [95% CI: 0.73&ndash, 0.87], men: 0.67 [0.59&ndash, 0.76]). The association between the eGFR-DP score and CKD incidence was lost upon adjustment for baseline eGFR. Our results provide support for dietary interventions to prevent kidney function decline in the general population.

Objective To investigate the pregnancy outcomes for patients with stage 3–4 chronic kidney disease (CKD) and the effects of pregnancy on kidney function. Methods Clinical data of pregnant women with CKD in the Peking University First Hospital between January 1st 2005 and October 1st 2016 were retrospectively analysed. The pregnancy outcomes of patients with different stages of CKD were compared. Patients with stage 3–4 CKD were followed up by telephone interview, and non-pregnant patients with stage 3–4 CKD were selected using the propensity score method to analyse the effects of pregnancy on kidney function. Results A total of 293 women with 300 pregnancies met the study criteria. There were 30 cases of stage 3–4 CKD. The incidence of adverse pregnancy outcomes of patients with stage 3–4 CKD was significantly higher than that with stage 1 CKD. The mean postpartum follow-up time of pregnant patients with CKD was 49.0 ± 33.1 months. A total of 26 cases of stage 3–4 CKD were followed up. During the follow-up period, 8 patients progressed to ESRD. A total of 28 non-pregnant patients with stage 3–4 CKD were selected as the control group. The results of multivariate analysis revealed that pregnancy did not increase the risk of deterioration of kidney function. Conclusion Patients with stage 3–4 CKD in early pregnancy had a significantly increased risk of adverse pregnancy outcomes. Pregnancy itself did not seem to accelerate kidney disease progression in patients with stage 3–4 CKD.

Preoperative lymph node (LN) status is important for the treatment of bladder cancer (BCa). Here, we report a genomic-clinicopathologic nomogram for preoperatively predicting LN metastasis in BCa. In the discovery stage, 325 BCa patients from TCGA were involved and LN-status-related mRNAs were selected. In the training stage, multivariate logistic regression analysis was used to developed a genomic-clinicopathologic nomogram for preoperative LN metastasis prediction in the training set (SYSMH set, n = 178). In the validation stage, we validated the nomogram using two independent sample sets (SYSUCC set, n = 142; RJH set, n = 104) with respect to its discrimination, calibration and clinical usefulness. As results, we identified five LN-status-related mRNAs, including ADRA1D, COL10A1, DKK2, HIST2H3D and MMP11. Then, a genomic classifier was developed to classify patients into high- and low-risk groups in the training set. Furthermore, a nomogram incorporating the five-mRNA-based classifier, image-based LN status, transurethral resection (TUR) T stage, and TUR lymphovascular invasion (LVI) was constructed in the training set, which performed well in the training and validation sets. Decision curve analysis demonstrated the clinical value of our nomogram. Thus, our genomic-clinicopathologic nomogram shows favorable discriminatory ability and may aid in clinical decision-making, especially for cN-patients. Keywords: Genomics, Lymphatic metastasis, Nomogram, Urinary bladder neoplasms

Ovarian cancer is the leading cause of cancer death among gynecological malignancies. The high mortality rate has not been significantly reduced despite advances in surgery and chemotherapy. Gene therapy shows therapeutic potential, but several key issues must be resolved before clinical application. To minimize toxicity in noncancerous tissues, tumor-specific ligands are conjugated to vectors to increase the selectivity of drug delivery. The expression pattern of follicle-stimulating hormone (FSH) receptor in normal and cancer tissues provides an opportunity for highly selective drug delivery in ovarian cancer. Furthermore, tumor-specific promoters can conditionally regulate therapeutic gene expression in tumor or normal tissues. The mucin 16 (MUC16) promoter might be a potential tool to drive ovarian cancer-localized gene expression since MUC16/CA125 is overexpressed in most ovarian carcinomas. Here, we screened the possible MUC16 promoter sequences and constructed MUC16 promoter-driven gro-α shRNA plasmid vectors. The vectors were specifically delivered into ovarian cancer cells via FSH peptide-conjugated nanoparticles. The predicted promoter sequence with TAAA repeats showed high transcriptional activity. The nanoparticle complex containing MUC16 promoter-driven gro-α shRNA and FSH peptides had the ability to decrease gro-α protein secretion in ovarian cancer cells and block tumor growth without obvious toxic effects in a nude mouse model bearing ovarian cancer. Our study provides a novel gene delivery system using a MUC16 promoter trigger and FSH peptide-mediated active targeting in ovarian cancer, and this system may be a promising strategy for specific genetic therapeutic delivery.

Peripheral T-cell lymphoma (PTCL) is characterized by an aggressive clinical behavior. Chidamide has been approved for the treatment of relapsed/refractory (R/R) PTCL in China. We compared the efficacy of chidamide-contained regimens with chemotherapy (ChT) in R/R PTCL. Based on the second-line treatments, patients were divided into three groups, including ChT, ChT combined with chidamide (chidamide + ChT) and chidamide combined with or without other targeted agents (targeted therapy) group. Chidamide + ChT group had a better progression-free survival (PFS) compared with targeted therapy group (p = 0.013), and showed a trend towards superior PFS compared with ChT group (p = 0.079). Among patients with high second-line International Prognostic Index (IPI) (3-5), chidamide+ChT group had a longer PFS than ChT group(p = 0.018), and PFS in targeted therapy group was not inferior to that in chidamide+ChT group (p = 0.200). Among patients younger than 60 years, chidamide+ChT group demonstrated a PFS benefit over targeted therapy group (p = 0.010). Among CD30-negative patients, PFS was superior in the chidamide+ChT group compared with ChT group (p0.001). Conversely, results observed above were absent in patients with low second-line IPI or patients older than 60 years or CD30-positive patients. Overall, the combination of chidamide and ChT may be an effective treatment strategy for R/R PTCL.

Summary Castleman disease (CD) is a rare lymphoproliferative disorder. To assess the clinical features, outcomes, and prognostic factors of this disease, we retrospectively analyzed 185 HIV-negative CD patients from four medical centers in southern China. The median age was 37 years. 121 patients (65.4%) were classified as unicentric CD (UCD) and 64 patients (34.6%) were classified as multicentric CD (MCD). The histology subtype was hyaline-vascular for 132 patients (71.4%), plasma cell for 50 patients (27%) and mixed type for 3 patients (1.6%). The 5-year overall survival (OS) of 185 CD cases was 80.3%. All UCD patients underwent surgical excision, while the treatment strategies of MCD patients were heterogeneous. The outcome for UCD patients was better than MCD patients, with 5-year OS rates of 93.6% and 51.2%, respectively. In further analysis of the MCD subgroup, a multivariate analysis using a Cox regression model revealed that age, splenomegaly and pretreatment serum albumin level were independent prognostic factors for OS. This multicenter study comprising the largest sample size to date suggested that MCD is a distinct entity from UCD with a significantly worse outcome. Older age (≥40 years), splenomegaly and hypoalbuminemia were risk factors for poorer MCD prognosis. This article is protected by copyright. All rights reserved.

// Feifei Huang 1, 2, * , Jie Chen 2, 3, * , Xun Liu 4, * , Feng Han 5, * , Qingqing Cai 6 , Guicheng Peng 7 , Kun Zhang 1, 2 , Weiqing Chen 8 , Jingfeng Wang 1, 2 , Hui Huang 1, 2 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 2 Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China 3 Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China 4 Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China 5 Department of Ultrasound, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China 6 Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Sun Yat-Sen University, Guangzhou, China 7 Department of Internal Medicine, Dongguan Hengli Hospital, Dongguan, China 8 Department of Biostatistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Hui Huang, email: huanghui765@hotmail.com Jingfeng Wang, email: sysmwjf@163.com Keywords: cigarette smoking, hypertension, renal function deterioration, homocysteine Received: September 27, 2015 Accepted: November 02, 2016 Published: November 11, 2016 ABSTRACT Elevated homocysteine (HCY) and smoking are both important risk factors for hypertensive patients. However, whether they have crossing effect on renal function deterioration of hypertensive patients and what is the underlying mechanism are unclear. In the present study, 3033 participants diagnosed as essential hypertension with estimated glomerular filtration rate (eGFR)> 30 ml/min/1.73 m 2 from southern China were enrolled in this cross-sectional study. We collected the demographic and clinical data. In addition, the mediation effects were analyzed. The results showed that, comparing with non-smokers, smokers had significant higher levels of HCY (13.10 (11.20−16.87) vs. 11.00 (8.90−13.40) umol/L, P < 0.001) and lower eGFR (79.71 (66.83−91.05) vs. 82.89 (69.80−95.85) ml/min/1.73m 2 , P < 0.001). HCY levels and smoking were independently associated with decreased eGFR. Meanwhile, eGFR levels were significantly negatively correlated with HCY ( P < 0.001), and this correlation might be stronger in current smokers. Current smoker consuming over 20 cigarettes per day would accelerate early renal function deterioration (OR = 1.859, P = 0.019). The mediation effects analysis further showed that the association between smoking and renal function deterioration was mediated by HCY. And elevated HCY was accounted for 56.94% of the estimated causal effect of smoking on renal function deterioration in hypertensive patients. Our findings indicated that cigarette smoking was associated with renal function deterioration in hypertensive patients, and the association between cigarette smoking and renal function deterioration was probably mediated by elevated HCY. Therefore, HCY-lowering therapy may be beneficial for renal function deterioration in hypertensive smoking patients.

// Weijing Feng 1, 2, * , Kun Zhang 1, 2, * , Yu Liu 3, * , Jie Chen 1, 4, * , Qingqing Cai 5 , Yinyin Zhang 1, 2 , Mongheng Wang 6 , Jingfeng Wang 1, 2 , Hui Huang 1, 2 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 2 Laboratory of RNA and Major Diseases of Brain and Heart, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 3 Department of Cardiology, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China 4 Department of Radiation Oncology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China 5 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China 6 Department of Physiology, Georgia Regents University, Augusta, GA, USA * These authors have contributed equally to this work Correspondence to: Hui Huang, email: huanghui765@hotmail.com Keywords: vascular smooth muscle cells, osteogenic switching, vascular calcification, angiotensin II, apocynin Received: January 27, 2016 Accepted: October 19, 2016 Published: November 08, 2016 ABSTRACT Vascular calcification (VC) is a significant risk factor for cardiovascular morbidity and mortality. We recently reported that apocynin had benefits for preventing cardiovascular diseases. However, whether apocynin could attenuate VC is unknown. Here, we investigated the role of apocynin in VC and its underlying mechanisms. 163 participants with high or normal ankle–brachial index (ABI) were enrolled in this study for analyzing the demographic and biochemical data. In vitro, vascular smooth muscle cells (VSMCs) were exposed to calcification medium containing b-glycerophosphate and angiotensin II (Ang II) for 24 hours. The results showed that serum level of Ang II was significantly increased in patients with high ABI (P

BACKGROUND: Although the interregional disparity in chronic kidney disease (CKD) prevalence has been reported globally, little is known about differences in CKD prevalence within a region. We aimed to study the intraregional distribution of renal function in the Northern Netherlands and identify determinants of geographical differences in renal function.METHODS: We included 143,735 participants from the Lifelines population-based cohort in the Northern Netherlands. Spatial analysis was performed to identify regional clusters of lower eGFR (cold spots) and higher eGFR (hot spots) at the postal code level, without and with adjustment for clinical risk factors. Multivariate logistic regression was used to identify the contribution of neighborhood-level health-related behaviors, socioeconomic status, and environmental factors (air pollution parameters, urbanity) to regional clustering of lower eGFR.RESULTS: Significant spatial clustering of renal function was found for eGFR as well as for early stage renal function impairment (eGFRCONCLUSIONS: Significant intraregional clustering of renal function, early renal function impairment and CKD were observed in the Northern Netherlands even after adjustment for renal function-related clinical risk factors. Environmental (air pollution), neighborhood-level socioeconomic factors and diet are determinants of intraregional renal function distribution. Spatial analysis might be a useful adjunct to guide public health strategies for the prevention of CKD.

Background Hydroxychloroquine (HCQ), a well-known immunomodulator, has recently been found to be a promising and safe anti-proteinuric agent for treating IgA nephropathy (IgAN). We aimed to compare the efficacy and safety of HCQ and corticosteroid treatment in patients with IgAN. Methods This is a case-control study. Ninety-two patients with IgAN who received HCQ in addition to routine renin-angiotensin-aldosterone system inhibitors (RAASi) therapy were included. Ninety-two matched historical controls who received corticosteroids were selected by propensity score matching. The clinical data over 6 months were compared. Results Baseline proteinuria levels were comparable between the HCQ and corticosteroid groups (1.7 [1.2, 2.3] vs. 1.8 [1.3, 2.5] g/d, p = 0.96). The percentage reduction in proteinuria at 6 months was smaller in the HCQ group than in the corticosteroid group (− 48.5% [− 62.6, − 31.4] vs. -62.9% [− 81.1, − 34.9], p = 0.006). The time averaged proteinuria within the 6 months of observation was comparable for the HCQ and corticosteroid groups (1.1 [0.8, 1.5] vs. 1.1 [0.5, 1.8] g/d, p = 0.48). The cumulative frequency of patients with a 50% reduction in proteinuria during the study was also comparable between the two groups (52.2% vs. 62.0%, p = 0.25). However, six of the 92 (6.5%) patients suffered from severe adverse events (SAEs) in the corticosteroid group, while no SAEs were observed in the HCQ group (6.5% vs. 0%, p = 0.03). Conclusions The antiproteinuric effect of HCQ might be slightly inferior to that of corticosteroids over 6 months in patients with IgAN who were deemed to be candidates for HCQ and not corticosteroids treatment. However, HCQ treatment was safer than corticosteroid treatment.

Background: The development of nanoparticle drug delivery systems with targeted ligands has the potential to increase treatment efficiency in ovarian cancer. Methods: We developed a 21-amino acid peptide, YTRDLVYGDPARPGIQGTGTF (L-FP21) conjugated to polyethylenimine (PEI) and methoxy polyethylene glycol (mPEG) to prepare a nanoparticle drug vehicle to target follicle-stimulating hormone receptor (FSHR) in ovarian cancer. At the same time, we optimized the ligand of the nanoparticle vehicle using D-peptides, which consist of D-amino acids (D-FP21). Nanoparticle vehicles carrying the therapeutic gene plasmid growth-regulated oncogene alpha (pGRO-α) short hairpin RNA (shRNA) (FP21-PEG-PEI/pGRO-α) were prepared for further investigation. Results: Compared with L-FP21, D-FP21 exhibited improved biological stability and higher uptake rate for FSHR-expressing ovarian cancer cells. The cytotoxicity of the L, D-FP21-PEG-PEI/pGRO-α complexes were significantly lower than that of the PEI/pGRO-α complex. The nanoparticle drug with the targeted ligand showed higher transfection efficiencies and improved anti-proliferation effects for ovarian cancer cells than that without the targeted ligand (mPEG-PEI/pGRO-α). Furthermore, an in vivo evaluation of an antitumor assay indicated that D-FP21-PEG-PEI/pGRO-α inhibited the growth of tumor spheroids considerably more than L-FP21-PEG-PEI/pGRO-α; their tumor inhibition rates were 58.5% and 33.3%, respectively. Conclusions: D-FP21-PEG-PEI/plasmid DNA is a safe and efficient gene delivery vehicle for ovarian cancer targeted therapy.

There is a paucity of literature available as to the relationship between different levels of each metabolic syndrome (MetS) component and decreased GFR. In the present study, we aimed to demonstrate whether MetS always plays a critical role in decreased GFR.A cross-sectional study was conducted between February 2010 and September 2012, with 75,468 adults enrolled undergoing measurements of blood pressure as well as tests of blood and urine samples. Univariate and multivariable logistic regression analyses were performed to estimate the odds ratio (OR) with 95% confidence intervals (CI), and the chi-square test was used for categorical variables and described as a percentage.Of the 75,468 participants, 350 (0.5%) subjects met criteria for the decreased GFR, with a mean age of 48.79 ± 13.76 years. After adjustment for age, diastolic blood pressure and high-density lipoprotein were inversely related to decreased estimated glomerular filtration rate (eGFR) in multivariable analyses, with an OR (95% CI) of 0.57 (0.39-0.84) and 0.41 (0.24-0.72), respectively. The prevalence rate of CKD in critical group was 0.73% (154 of 21,127) and 0% (0 of 370) in noncritical group. In analysis stratified by the type of MetS components, the differences in noncritical group and the reference group were not statistically significant (χ(2 )=( )1.349, p 0.05).MetS does not always play a critical role in decreased GFR, with different levels of individual components of MetS exerting idiosyncratic effects in decreased eGFR. In fact, patients with abnormal body mass index, high triglycerides, and elevated fasting plasma glucose would not have impact on decreased GFR.

Although human papillomavirus (HPV) infection is a major cause leading to the development of cervical intraepithelial neoplasia (CIN), the relationship between genital microbiome and HPV persistence/clearance is not well established. Loop electrosurgical excision procedure (LEEP) is one of standard treatments of CIN 2/3 globally, yet little is known about how the LEEP influence genital microbiota. We conducted a prospective study of 26 patients with CIN2/3 who underwent analysis of cervical microbiome before and after 3 months of LEEP treatment. Cervical swabs were collected, and microbiomes were analyzed by 16S ribosomal RNA gene sequencing. A decrease of cervical microbial diversity was observed after 3 months of LEEP treatment. Notably, a significant shift from community type of a Prevotella-containing and lack of a consistent dominant species to lactobacillus iners dominated microbiome correlated with LEEP. Particularly, Leptotrichia and clostridium were further decreased after LEEP treatment (P = 0.049 and P = 0.002, respectively). Our results suggest that the cervical microbiome is altered after LEEP treatment in patients with CIN2/3. Further studies with larger sample sizes are needed to validate these findings.

Background The programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis. Methods We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical (IHC) assay. The expression of anaplastic lymphoma kinase (ALK), CD5, CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein–Barr virus (EBV)-encoded RNAs (EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan–Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis. Results Of the 204 patients, 100 (49.0%) were PD-L1-positive in tumor cells and 44 (21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like (GCB) subtype than in the GCB subtype (P = 0.02 and P = 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment (P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression (r = − 0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival (OS) rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells (P = 0.02). PD-L1 expression in tumor cells was an independent risk predictor for OS (P

Faithful repair of DNA double-strand breaks in mammalian oocytes is essential for meiotic maturation and embryonic development. In the present study we investigated the roles of Roscovitine and Trichostatin A (TSA) in DNA damage recovery during invitro maturation of porcine oocytes. Etoposide was used to trigger DNA damage in oocytes. When these DNA-damaged oocytes were treated with 2μM Roscovitine, 50nM TSA or both for 22h, first polar body extrusion and blastocyst formation in all treated groups were significantly improved compared with the etoposide-only group. The most significant improvement was observed when Roscovitine was present. Further immunofluorescent analysis of γH2A.X, an indicator of DNA damage, indicated that DNA damage was significantly decreased in all treated groups. This observation was further supported by analysing the relative mRNA abundance of DNA repair-related genes, including meiotic recombination 11 homolog A (MRE11A), breast cancer type 1 susceptibility protein (BRCA1), Recombinant DNA Repair Protein 51 (RAD51), DNA-dependent protein kinase catalytic subunit (PRKDC) and X-ray cross complementing gene 4 (XRCC4). Compared with the etoposide-only group, the experimental group with combined treatment of Roscovitine and TSA showed a significant decrease of all genes at germinal vesicle and MII stages. The Roscovitine-only treatment group revealed a similar tendency. Together, these results suggest that Roscovitine and TSA treatments could increase the capacity of oocytes to recover from DNA damage by enlisting DNA repair processes.

Human papillomaviruses (HPVs) including high-risk (HR) and low-risk (LR) subtypes have distinguishable variation on both genotypes and phenotypes. The co-infection of multiple HR-HPVs, headed by HPV16, is common in cervical cancer in female. Recently accumulating reports have focused on the interaction between virus and host, particularly the role of human microRNAs (miRNAs) in anti-viral defense by targeting viral genome. Here, we found a well-conserved target site of miRNAs in the genomes of most HR-HPVs, not LR-HPVs, by scanning all potential target sites of human miRNAs on 24 HPVs of unambiguous subtypes of risk. The site is targeted by two less common human miRNAs, miR-875 and miR-3144, and is located in E6 oncogene open reading frame (ORF) and overlap with the first alternative splice exon of viral early transcripts. In validation tests, miR-875 and miR-3144 were identified to suppress the target reporter activity markedly and inhibit the expression of both synthetically exogenous E6 and endogenous E6 oncogene. High level of two miRNAs can inhibit cell growth and promote apoptosis in HPV16-positive cervical cancer cells. This study provides a promising common target of miRNAs for most HR-HPVs and highlights the effects of two low expressed human miRNAs on tumour suppression.

Background and aims Full blockade of renin-angiotensin-aldosterone system (RAAS) is believed to decrease morbidity and mortality of patients with chronic kidney disease. In non-dialysis patients, combined RAAS blockade with two different RAAS blockers causes more adverse events without improving survival, but its role in maintenance dialysis patients is still unclear. We conducted a systematic review and mediation analysis to investigate the efficacy and safety of combined RAAS blockade in dialysis patients. Methods Comprehensive search was conducted in PubMed, EMBASE, Web of Science and Cochrane Library database to June 2017 to identify relevant studies. Studies comparing combined with single RAAS blockade and reporting all-cause death, cardiovascular death, hypotension or hyperkalemia in dialysis patients were included. Effect sizes were calculated with randomized effects model and summarized as odd ratios (OR). Results A total of 9 studies with 13,050 dialysis patients were included. Compared with single blockade, combined blockade significantly reduced all-cause mortality (OR 0.71, 95% confidence interval 0.54–0.93, p = 0.01), while cardiovascular mortality remained unchanged (0.85, 0.45–1.59, p = 0.61). Combined blockade tended to increase odd of hypotension but not odd of hyperkalemia (1.54, 1.00–2.38, p = 0.05; 0.89, 0.76–1.05, p = 0.17). Further mediation analysis indicated that hypotension might exert a suppression effect on the survival benefit of angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker treatment on cardiovascular mortality. Conclusions Combined RAAS blockade might be a promising treatment in dialysis patients to further reduce mortality if blood pressure was well controlled.

Dysregulated NF-κB signaling is critical for lymphomagenesis, however, the expression and clinical relevance of NF-κB subunit p50 in diffuse large B-cell lymphoma have not been evaluated. In this study, we analyzed the prognostic significance and gene expression signatures of p50 nuclear expression as a surrogate for p50 activation in 465 patients with de novo diffuse large B-cell lymphoma. We found that p50(+) nuclear expression, observed in 34.6% of diffuse large B-cell lymphoma, predominantly composed of activated B-cell-like subtype, was an independent adverse prognostic factor in patients with activated B-cell-like diffuse large B-cell lymphoma. It was also an adverse prognostic factor in patients with wild-type TP53 independent of the activated B-cell-like and germinal center B-cell-like subtypes, even though p50 activation correlated with significantly lower levels of Myc, PI3K, phospho-AKT, and CXCR4 expression and less frequent BCL2 translocations. In contrast, in germinal center B-cell-like diffuse large B-cell lymphoma patients with TP53 mutations, p50(+) nuclear expression correlated with significantly better clinical outcomes, and decreased p53, Bcl-2, and Myc expression. Gene expression profiling revealed multiple signaling pathways potentially upstream the p50 activation through either canonical or noncanonical NF-κB pathways, and suggested that immune suppression, including that by the immune checkpoint TIM-3 and that through leukocyte immunoglobulin-like receptors, but not antiapoptosis and proliferation, may underlie the observed poorer survival rates associated with p50(+) nuclear expression in diffuse large B-cell lymphoma. In conclusion, these data show that p50 is important as a unique mechanism of R-CHOP-resistance in activated B-cell-like diffuse large B-cell lymphoma and in patients without TP53 mutations. The results also provide insights into the regulation and function of p50 in diffuse large B-cell lymphoma and its cross talk with the p53 pathway with important therapeutic implications.

We retrospectively compared outcomes of patients with relapsed/refractory non-Hodgkin lymphoma (NHL) who underwent stem cell transplantation (SCT) with stable disease or better following a novel combination of lenalidomide and rituximab (LR) treatment and did not undergo SCT in a phase I/II clinical trial. We retrospectively compared outcomes of patients who underwent SCT with that of patients who had stable disease or better following LR treatment and did not undergo SCT. Twenty-two patients enrolled in LR clinical trial and undergone SCT were identified, 13 with mantle cell lymphoma (MCL) and nine with large B-cell lymphoma (LBCL). All patients who underwent SCT achieved complete response. In the MCL subset, there were no significant differences between SCT and non-SCT groups except that non-SCT patients were older and had a higher mantle-cell international prognostic index score. There was no difference between SCT-group and non-SCT-group in response duration (P=0.3), progression-free survival (PFS) (P=0.304) and overall survival (OS) (P=0.87). In LBCL subgroup, there were no significant differences between two groups except that non-SCT group had a higher international prognostic index score. Patients with LBCL who underwent SCT had significantly longer response duration (P=0.001), PFS (P=0.000), and OS (P=0.003) than the non-SCT group. The novel therapeutic combination offers a bridge to SCT in patients with relapsed/refractory aggressive B-cell NHL.

The aims of this study were to assess depression and type D personality in parents of children with leukemia in southern China and to investigate the associations between parents' depression and type D personality, social support, coping style, and demographic characteristics.Parents (n=231) of children with leukemia (study group) and parents (n=261) of children with acute respiratory/digestive infections (control group) were recruited from five hospitals in southern China. Children's clinical characteristics and parents' demographic characteristics, depression, type D personality, coping styles, and social support were collected with self-report questionnaires.Parents of children with leukemia, especially mothers, reported higher levels of depression accompanied by a higher prevalence of type D personality, more negative coping styles, and less subjective social support, but received more objective social support than controls (P0.05). The depression in parents in the study group was positively correlated with type D personality and negative coping style, but negatively correlated with social support and positive coping styles (P0.05). Multivariate logistic regression analyses showed that type D personality (OR=5.64, P0.001), lower social support (OR=2.38, P=0.020), and less positive coping (OR=3.32, P=0.003) were independently associated with depression in parents of children with leukemia. As for demographic characteristics, female, lower education level, unemployed, and paying medical expenses at one's own expenses were independent predictors of depression in parents of children with leukemia.Depression and type D personality were remarkably prevalent in parents of children with leukemia in southern China. Type D personality and multiple social factors were associated with depression in parents of children with leukemia.

The practical application of elevated carbohydrate antigen 125 (CA125) to predict clinical outcome in chronic heart failure (CHF) is under debate. The mechanism for this CA125 elevation remains unknown. We hypothesize that mechanical stress on mesothelial cells initiates CA125 synthesis.A total of 191 patients suffering from edema and/or dyspnea were enrolled. 109 patients were diagnosed as CHF, and 82 patients without CHF were assigned as control group. Echocardiography, CA125, N-terminal pro-brain natriuretic peptide (NT-proBNP), and other biochemical parameters were measured. All enrolled patients underwent heart function classification.Patients with serous cavity effusion (SCE) demonstrated higher serum CA125 than patients without SCE (82.91 (61.90-103.92) vs. 44.98 (29.66-60.30) U/mL, P0.001). In the absence of SCE, CA125 levels in CHF patients were slightly higher than non-CHF patients (52.37 (34.85-69.90) vs. 35.15 (23.81-46.49) U/mL, P=0.017). Additionally, compared with non-CHF patients, CHF patients had higher levels of high-sensitivity C-reactive protein (hsCRP) and lower superoxide dismutase (SOD). In all enrolled patients, CA125 levels were negatively correlated with SOD concentrations (r=-0.567, P0.001), and positively correlated with hsCRP levels (r=0.608, P0.001). Receiver operating characteristic curve analysis showed that CA125 was better in predicting SCE than NT-proBNP, while NT-proBNP was more suitable for predicting CHF than CA125. The in vitro study demonstrated that MUC16, the CA125 coding gene, was up-regulated by mechanical stretch on human mesothelial cell line (MeT-5A).CA125 elevation in CHF was associated with SCE. Mechanical extension of mesothelial cells from SCE plays an important role in CA125 increase.

The interactions of sodium balance and response of renin–angiotensin–aldosterone system are important for maintaining the hemodynamic stability in physiological conditions. However, the influence of short-term sodium intake intervention in the response of renin–angiotensin system (RAS) on hypertensive patients is still unclear. Thus, we conducted a clinical trial to investigate the effects of short-term sodium intake intervention on the response of RAS in hypertensive patients. One hundred twenty-five primary Chinese hypertensive patients were divided into high, moderate, and low sodium groups by 24-hour urinary sodium excretion (UNa+). All the patients received a 10-day dietary sodium intake intervention with standardized sodium (173.91mmol/day) and potassium (61.53mmol/day). Blood pressure, urinary sodium, urinary potassium, plasma sodium, potassium, creatinine, the levels of plasma renin activity, plasma angiotensin II concentrations (AT-II), and plasma aldosterone concentrations were detected before and after the intervention. Before the intervention, no differences were found in blood pressure and RAS among 3 groups. After standardized dietary sodium intake intervention, both UNa+ excretion and systolic pressure decreased in high-sodium group, while they increased in moderate and low-sodium groups. Intriguingly, there were no changes in the levels of plasma renin activity, AT-II, and plasma aldosterone concentrations among 3 groups during the intervention. The present study demonstrated that the influenced sodium excretion and blood pressure by short-term sodium intake intervention were independent of RAS quick response in Chinese hypertensive patients.

This study aimed to identify the prognostic factors for primary fallopian tube carcinoma.A retrospective analysis was conducted of the patients treated with primary surgery and adjuvant chemotherapy at the Obstetrics and Gynecology Hospital of Fudan University from February 2003 to December 2010. Cox proportional hazards model was used for univariate and multivariate survival analysis.Included in this study were 101 patients with a median follow-up of 64 months and a mean age of 57 years. Latzko triad symptom of abdominal pain, vaginal bleeding or discharge, and palpable pelvic mass was reported in 14 patients, and elevated CA 125 (≥ 35 U/mL) was found in 63. Four patients were classified as grade 1, 31 were grade 2, and 66 were grade 3. The distribution of International Federation of Gynecology and Obstetrics stage was 33 at stage I, 28 at stage II, 39 at stage III, and 1 at stage IV. Ninety patients underwent optimal tumor debulking in which residual tumor was no larger than 1 cm, and 67 patients received no fewer than 6 cycles of postoperative chemotherapy with paclitaxel and carboplatin (TP)-based regimen. Recurrence occurred in 44 patients after a median of 20 months (range, 1-72 months). The 5-year overall survival rate was 67.7%, and the 5-year disease-free survival was 57.4%. Multivariate analysis revealed that International Federation of Gynecology and Obstetrics stage (I-II) [hazard ratio (HR), 2.670; 95% confidence interval (CI), 1.316-5.418; P = 0.007 vs HR, 2.716; 95% CI, 1.416-5.211; P = 0.003], pelvic lymphadenectomy (HR, 0.274; 95% CI, 0.136-0.555; P0.001 vs HR, 0.449; 95% CI, 0.227-0.888; P = 0.021), and cycles (≥ 6) of chemotherapy (HR, 0.480; 95% CI, 0.246-0.937; P = 0.031 vs HR, 0.521; 95% CI, 0.276-0.985; P = 0.045) might serve as independent predictors of both overall survival and disease-free survival.Preoperative diagnosis of fallopian tube carcinoma is difficult due to the silent course of this neoplasm. Comprehensive surgical staging including pelvic lymphadenectomy followed by adequate cycles of chemotherapy is an important strategy to improve patients' prognosis.

Prophylactic antiviral therapy is essential for lymphoma patients with high baseline HBV DNA who undergo cytotoxic chemotherapy. However, there are limited data on the optimal options. The present study was designed to compare the efficacy of prophylactic lamivudine (LAM) with lamivudine plus adefovir dipivoxil (LAM+ADV) in preventing hepatitis B virus (HBV) reactivation in lymphoma with, pre-chemotherapy HBV DNA load ≥2000 IU/ml. We retrospectively analyzed the medical records of 86 lymphoma patients with baseline HBV DNA load ≥2000 IU/ml during chemotherapy and received LAM or LAM+ADV as prophylaxis between January 1, 2008 and November 30, 2014 at Sun Yat-sen University Cancer Center, China. Sixty-five patients received LAM and 21 received LAM+ADV. The rate was significantly lower in the LAM+ADV group compared with the LAM group for HBV reactivation (23.8% vs 55.4%; p = 0.012), while no difference was observed between the two groups in patients for HBV-related hepatitis (21.3% vs 33.3%; p = 0.349), and chemotherapy disruption (10.9% vs 19.0%; p = 0.337). In a multivariate analysis of factors associated with HBV reactivation in these patients, LAM+ADV treatment and HBeAg negative were the independent protective factors. Therefore, LAM+ADV should be considered for antiviral prophylaxis in lymphoma patients with pre-chemotherapy HBV DNA load ≥2000 IU/ml. Further study is warranted to confirm these findings.

One possible reason for the relapse and refractoriness of extranodal natural killer/T-cell (NK/T) lymphoma (ENKL) is resistance to a CHOP-like regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). To evaluate the outcome of first-line EPOCH chemotherapy (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) for ENKL, 34 patients, including 30 with nasal ENKL (88.2%) and four with extranasal ENKL (11.8%), were studied. Involved-field radiation therapy (IFRT) was administered to patients with localized nasal focus after chemotherapy. Thirty-three cases were eligible for response evaluation. The response rate (RR) was 60.6% (20/33) with a complete remission (CR) rate of 45.5% (15/33). For patients with localized nasal ENKL, the CR rate was 57.7% (15/26). The 3-year progression-free survival and overall survival rates were 53.6% and 69.0%, respectively. After initial EPOCH chemotherapy followed by IFRT, the CR rate was 75.0% and the 3-year overall survival rate was 75.0%. However, patients with disseminated and extranasal disease responded poorly. These results indicate that EPOCH followed by IFRT yields promising outcomes for patients with localized nasal ENKL.

Increasing evidence has suggested that dysregulation of certain microRNAs (miRNAs) may contribute to tumorigenesis. microRNA-125b (miR-125b) was implicated to have close relationship with cell proliferation and differentiation, and downregulation of miR-125b was observed in various types of cancers. However, the biological function of miR-125b in bladder tumorigenesis is still unknown. In our study, we showed that the expression of miR-125b was significantly decreased in bladder cancer tissues and four bladder cancer cell lines. Moreover, miR-125b could suppress bladder cancer cells to form colonies in vitro and to develop tumors in nude mice. E2F3, which was critical for G1/S transition and was overexpressed in most of poor-differentiated bladder cancers, was identified as a target of miR-125b by luciferase assay. The E2F3 mRNA and protein expression levels were detected in bladder cancer tissues and cell lines, and interestingly, inverse correlations between miR-125b and E2F3 protein level were found in bladder cancer tissues and four E2F3 nonamplified cell lines. Introduction of miR-125b could reduce the expression of E2F3 protein but not the E2F3 mRNA. In addition, we observed that transfection of miR-125b could inhibit the expression of Cyclin A2, one of the E2Fs-responsive genes involved in G1/S transition. These results suggest that miR-125b may regulate G1/S transition through the E2F3-Cyclin A2 signaling pathway. Taken together, miR-125b may act as a tumor suppressor in bladder urothelium, and downregulation of miR-125b may contribute to the tumorigenesis of bladder cancer.

Hepatitis B virus (HBV) reactivation is a well-known complication in cancer patients receiving cytotoxic chemotherapy, resulting in varying degrees of liver damage. The objective of this study was to investigate the efficacy of lamivudine for the prevention of HBV reactivation in non-Hodgkin's lymphoma (NHL) patients undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT).Thirty-two patients with NHL who were HBV surface antigen (HBsAg)-positive were enrolled in this pilot study. They were divided into two groups: 20 patients received prophylactic oral lamivudine 100 mg/day before, and until at least 6 months after transplantation. The historical control group comprised 12 patients who received high-dose chemotherapy and AHSCT without lamivudine. The incidence and severity of hepatitis due to HBV reactivation, as well as other adverse clinical outcomes, were compared between the two groups.Most baseline clinical characteristics were similar in the two groups, except for HBV e-antigen (HBeAg)-positive status (85% in the lamivudine group vs 33.3% in the control group, p = 0.006) and the type of AHSCT. There was a lower incidence of hepatitis due to HBV reactivation in the lamivudine group than in the control group (10 vs 50%, p = 0.030), less severe hepatitis (0 vs 25%, p = 0.009), and lower mortality (0 vs 25%, p = 0.236). An HBV variant with tyrosine methionine aspartate aspartate (YMDD) mutation was detected in one patient in the lamivudine group (5%) after administration of lamivudine for 9 months. No significant adverse events were associated with the use of prophylactic lamivudine, and hematopoietic reconstitution was not affected by the intervention.Prophylactic lamivudine may reduce the incidence and severity of chemotherapy-related HBV reactivation and hepatitis-related mortality in HBsAg-positive NHL patients receiving high-dose chemotherapy and AHSCT. Additional randomized, multicenter trials are warranted.

Radiotherapy is widely applied for treatment of esophageal squamous cell carcinoma (ESCC). The Rad51-related protein XRCC3 plays roles in the recombinational repair of DNA double-strand breaks to maintain chromosome stability and repair DNA damage. The present study aimed to investigate the effect of XRCC3 on the radiotherapy response of ESCC and the underlying mechanisms of the roles of XRCC3 in ESCC radiosensitivity. XRCC3 expression in ESCC cells and tissues was higher than that in normal esophageal epithelial cells and corresponding adjacent noncancerous esophageal tissue. High XRCC3 expression was positively correlated with resistance to chemoradiotherapy in ESCC and an independent predictor for short disease-specific survival of ESCC patients. Furthermore, the therapeutic efficacy of radiotherapy in vitro and in vivo was substantially increased by knockdown of XRCC3 in ESCC cells. Ectopic overexpression of XRCC3 in both XRCC3-silenced ESCC cells dramatically enhanced ESCC cells' resistance to radiotherapy. Moreover, radiation resistance conferred by XRCC3 was attributed to enhancement of homologous recombination, maintenance of telomere stability, and a reduction of ESCC cell death by radiation-induced apoptosis and mitotic catastrophe. Our data suggest that XRCC3 protects ESCC cells from ionizing radiation-induced death by promoting DNA damage repair and/or enhancing telomere stability. XRCC3 may be a novel radiosensitivity predictor and promising therapeutic target for ESCC.

// Zijun Y. Xu-Monette 1,* , Meifeng Tu 2,* , Kausar J. Jabbar 1 , Xin Cao 1 , Alexandar Tzankov 3 , Carlo Visco 4 , Qingqing Cai 1 , Santiago Montes-Moreno 5 , Yuji An 1 , Karen Dybkaer 6 , April Chiu 7 , Attilio Orazi 8 , Youli Zu 9 , Govind Bhagat 10 , Kristy L. Richards 11 , Eric D. Hsi 12 , William W.L. Choi 13 , J. Han van Krieken 14 , Jooryung Huh 15 , Maurilio Ponzoni 16 , Andres J.M. Ferreri 16 , Xiaoying Zhao 17 , Michael B. Moller 18 , John P. Farnen 19 , Jane N. Winter 20 , Miguel A. Piris 5 , Roberto N. Miranda 1 , L. Jeffrey Medeiros 1 and Ken H. Young 1,21 1 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Peking University Cancer Hospital and Institute, Beijing, China 3 University Hospital, Basel, Switzerland 4 San Bortolo Hospital, Vicenza, Italy 5 Hospital Universitario Marques de Valdecilla, Santander, Spain 6 Aalborg University Hospital, Aalborg, Denmark 7 Memorial Sloan-Kettering Cancer Center, New York, NY, USA 8 Weill Medical College of Cornell University, New York, NY, USA 9 The Methodist Hospital, Houston, TX, USA 10 Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA 11 University of North Carolina School of Medicine, Chapel Hill, NC, USA 12 Cleveland Clinic, Cleveland, OH, USA 13 University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China 14 Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands 15 Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea 16 San Raffaele H. Scientific Institute, Milan, Italy 17 Zhejiang University School of Medicine, Second University Hospital, Hangzhou, China 18 Odense University Hospital, Odense, Denmark 19 Gundersen Lutheran Health System, La Crosse, WI, USA 20 Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 21 The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, Texas, USA * These authors made equal contributions to this work Correspondence to: Ken H. Young, email: // Keywords : ABC, BCL2, CD5, diffuse large B-cell lymphoma, NF-κB Received : December 29, 2014 Accepted : January 02, 2015 Published : March 08, 2015 Abstract CD5 is a pan-T-cell surface marker and is rarely expressed in diffuse large B-cell lymphoma (DLBCL). Large-scale studies of de novo CD5 + DLBCL are lacking in Western countries. In this study by the DLBCL Rituximab-CHOP Consortium, CD5 was expressed in 5.5% of 879 DLBCL patients from Western countries. CD5 + DLBCL was associated with higher frequencies of >1 ECOG performance status, bone marrow involvement, central nervous system relapse, activated B-cell–like subtype, Bcl-2 overexpression, and STAT3 and NF-κB activation, whereas rarely expressed single-stranded DNA-binding protein 2 (SSBP2), CD30 or had MYC mutations. With standard R-CHOP chemotherapy, CD5 + DLBCL patients had significantly worse overall survival (median, 25.3 months vs . not reached, P < .0001) and progression-free survival (median, 21.3 vs. 85.8 months, P < .0001) than CD5 – DLBCL patients, which was independent of Bcl-2, STAT3, NF-κB and the International Prognostic Index. Interestingly, SSBP2 expression abolished the prognostic significance of CD5 expression, suggesting a tumor-suppressor role of SSBP2 for CD5 signaling. Gene-expression profiling demonstrated that B-cell receptor signaling dysfunction and microenvironment alterations are the important mechanisms underlying the clinical impact of CD5 expression. This study shows the distinctive clinical and biological features of CD5 + DLBCL patients in Western countries and underscores important pathways with therapeutic implications.

WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription; however, its role in bladder cancer remains largely unknown. Our study investigated the role of WDR5 in bladder cancer and demonstrated that WDR5 was upregulated in bladder cancer tissues and elevated WDR5 protein levels positively correlated with advanced tumor stage and poor survival. Through gain or loss of function, we demonstrated that WDR5 promoted proliferation, self-renewal and chemoresistance to cisplatin in bladder cancer cells in vitro and tumor growth in vivo. Mechanistically, WDR5 regulated various functions in bladder cancer by mediating the transcription of cyclin B1, cyclin E1, cyclin E2, UHMK1, MCL1, BIRC3 and Nanog by histone H3 lysine 4 trimethylation. Therefore, we have discovered that WDR5 plays an important role in bladder cancer suggesting that WDR5 is a potential biomarker and a promising target in the treatment of bladder cancer.

Background The impact of the various elements of metabolic syndrome (MetS) on chronic kidney disease (CKD) has been conflicting. Therefore, in the present study we aimed to examine the association of MetS and its components with decreased glomerular filtration rate (GFR). Methods A total of 75,468 urban workers who underwent annual health examinations under the auspices of the local governments between March 2010 and September 2012 at the health examination center of Xuzhou center hospital were enrolled in the cross-sectional survey. Decreased GFR was defined as an estimated GFR

Background We previously identified platelet-activating factor receptor (PAFR) as being overexpressed in ovarian cancer and found that its ligand PAF evoked EGFR phosphorylation using the phospho-antibody microarray. Epidermal growth factor receptor (EGFR) are also overexpressed in ovarian cancer and contribute to the growth of ovarian cancer cells. Here, we investigated the mechanisms of crosstalk between PAFR and EGFR signaling in ovarian cancer cells to further determine whether the interaction between PAFR and EGFR synergistic contribute to the progression of ovarian cancer. Methods Expression and localization of PAFR in several ovarian cancer cell lines were assessed by Western blot, realtime-PCR and immunofluorescence. The ovarian cancer cells were stimulated with PAF or PAF and in some experiments also pharmacological inhibitors. Phosphorylation of proteins in signaling pathways were measured by Western blot. HB-EGF concentrations of the supernatant from stimulated ovarian cancer cells were measured by enzyme-linked immunosorbent assay. Results Our data show that PAF increases EGFR phosphorylation through PAFR in a time- and dose- dependent manner in SKOV-3 ovarian cancer cells. This transactivation is dependent on phospholipase C-β and intracellular calcium signaling. This pathway is also Src tyrosine kinase- and metalloproteinase- dependent. PAF triggers EGFR activation through the increased heparin-binding EGF-like growth factor (HB-EGF) release in metalloprotease-dependent manner. Several studies involving EGFR transactivation through G-protein coupled receptor (GPCR) have demonstrated EGFR-dependent increase in ERK1/2 phosphorylation. Yet in SKOV-3 cells, PAF treatment also increases ERK1/2 phosphorylation in a EGFR-independent manner. Conclusions The results suggest that in SKOV-3 ovarian cancer cells, PAF transactivates EGFR and downstream ERK pathways, thus diversifying the GPCR-mediated signal. The crosstalk between PAFR and EGFR suggests a potentially important signaling linkage between inflammatory and growth factor signaling in ovarian cancer cells.