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Roadside air pollution is one of the serious air pollution problems in urban areas. Even though roadside air pollution has been reported to cause adverse human health impacts, the spatial distribution of roadside air pollution in a large urban agglomeration has yet to be fully assessed. This study aimed to analyse roadside fine particulate matter (PM _2.5 ) pollution and the population exposure in 11 cities in the Pearl River Delta (PRD) region of China. We developed satellite-retrieval algorithms with dark target method, vector support machine model and random forest model to retrieve the spatial distribution of PM _2.5 at an ultra-high-spatial-resolution (30 m) based on 30 m Landsat-8 L1 data. Our results show that the retrieved PM _2.5 had a promising consistency with PM _2.5 measurements at general and roadside stations ( R ^2 = 0.86; RMSE = 7.72 µ g m ^−3 ). Moreover, on average, the roadside PM _2.5 in Dongguan, Foshan, and Guangzhou was relatively higher (up to 107.60 µ g m ^−3 ) whereas that in Hong Kong was relatively lower (up to 30.40 µ g m ^−3 ). The roadside PM _2.5 pollution typically occurred in roads for motorized vehicles i.e. motorway, trunk, primary and secondary road. Our results also show that roadside PM _2.5 was up to 17% higher in holidays than in workdays in all the PRD cities except Hong Kong that showed roadside PM _2.5 higher in workdays than in holidays. The population-weighted PM _2.5 decreased with increasing distances from roads in every PRD city, and population-weighted PM _2.5 was estimated to be up to 22% higher at roadsides than at distances of 1500 m away from roads. This study pinpointed the seriousness of roadside air pollution in the PRD region.

Objective: To explore the mechanism underlying the inhibitory effect of quercetin against testicular oxidative damage induced by a mixture of 3 commonly used phthalates (MPEs) in rats., Methods: Forty male Sprague-Dawley rats were randomly divided into control group, MPEs exposure group, and MPEs with low-, median- and high-dose quercetin treatment groups. For MPEs exposure, the rats were subjected to intragastric administration of MPEs at the daily dose of 900 mg/kg for 30 consecutive days; Quercetin treatments were administered in the same manner at the daily dose of 10, 30, and 90 mg/kg. After the treatments, serum levels of testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), and testicular malondialdeyhde (MDA), catalase (CAT) and superoxide dismutase (SOD) were detected, and testicular pathologies of the rats were observed with HE staining. The expressions of nuclear factor-E2-related factor 2 (Nrf2), Kelch-like ECH2 associated protein 1 (Keap1) and heme oxygenase 1 (HO-1) in the testis were detected using immunofluorescence assay and Western blotting., Results: Compared with the control group, the rats with MPEs exposure showed significant reductions of the anogenital distance, weight of the testis and epididymis, and the coefficients of the testis and epididymis with lowered serum testosterone, LH and FSH levels ( P < 0.05). Testicular histological examination revealed atrophy of the seminiferous tubules, spermatogenic arrest, and hyperplasia of the Leydig cells in MPEs-exposed rats. MPEs exposure also caused significant increments of testicular Nrf2, MDA, SOD, CAT and HO-1 expressions and lowered testicular Keap1 expression ( P < 0.05). Treatment with quercetin at the median and high doses significantly ameliorated the pathological changes induced by MPEs exposure ( P < 0.05)., Conclusion: Quercetin treatment inhibits MPEs-induced oxidative testicular damage in rats possibly by direct scavenging of free radicals to lower testicular oxidative stress and restore the regulation of the Nrf2 signaling pathway.

Since the discovery of circulating hepatitis B virus (HBV) RNA in the peripheral blood of patients with chronic hepatitis B in 1996, a growing number of studies have focused on clarifying the biological characteristics and clinical application value of serum HBV RNA. This consensus mainly summarizes the research progress of serum HBV RNA existing profiles, quantitative detection methods, and current clinical applications. In order to better apply this indicator for the clinical management of patients with chronic HBV infection, recommendations on quantitative detection target regions, detection results, and clinical applications are put forward.

Objective: To explore the role of parental reproductive age on the risk of overweight and obesity in offspring. Methods: The participants were derived from physical examination data of students aged 6-18 years in seven provinces in China, and questionnaire survey was used to collect demographic characteristics and lifestyle information of the students and their parents. A total of 41 567 children with complete data were included. According to the restricted cubic spline curve, maternal reproductive age was divided into three categories, 14-23, 24-28, and 29-38 years, and paternal reproductive age was divided into 14-23, 24-30, and 31-42 years. Multivariate logistic regression model was used to analyze the association between parental reproductive age and parental nutritional status and the risk of overweight and obesity in offspring. Results: The mean age of 41 567 children was (10.6±3.2) years, and the mean paternal and maternal age were (27.9±4.4) years and (25.8±4.0) years, respectively. The detection rate of overweight and obesity was 23.4%. After adjusting factors of children diet and behaviors, the OR (95% CI )of offspring overweight and obesity in groups of fathers aged 24-30 years and mothers aged 24-28 years was 1.11 (1.04-1.18) and 1.16 (1.08-1.24), respectively. When none parents were overweight and obese, the difference of obesity risk was not statistically significant. When both parents were overweight and obese, the OR (95% CI )of offspring overweight and obesity in groups of fathers aged 24-30 years and mothers aged 14-28 years old was 1.27 (1.00-1.62) and 1.33 (1.07-1.65) respectively. Conclusion: Parental reproductive age and parental overweight and obesity status may both increase the risk of overweight and obesity in offspring, with a significant interaction effect.

Background: Visfatin acts as an oncogenic factor in numerous tumors through a variety of cellular processes. Visfatin has been revealed to promote cell migration and invasion in gastric cancer (GC). Snai1 is a well-known regulator of EMT process in cancers. However, the relationship between visfatin and snai1 in GC remains unclear. The current study aimed to explore the role of visfatin in GC., Methods: The RT-qPCR and western blot analysis were used to measure RNA and protein levels, respectively. The cell migration and invasion were tested by Trans-well assays and western blot analysis., Results: Visfatin showed upregulation in GC cells. Additionally, Visfatin with increasing concentration facilitated epithelial-mesenchymal transition (EMT) process by increasing E-cadherin and reducing N-cadherin and Vimentin protein levels in GC cells. Moreover, endogenous overexpression and knockdown of visfatin promoted and inhibited migratory and invasive abilities of GC cells, respectively. Then, we found that snai1 protein level was positively regulated by visfatin in GC cells. In addition, visfatin activated the NF-κB signaling to modulate snai1 protein expression. Furthermore, the silencing of snai1 counteracted the promotive impact of visfatin on cell migration, invasion and EMT process in GC., Conclusion: Visfatin facilitates cell migration, invasion and EMT process by targeting snai1 via the NF-κB signaling, which provides a potential insight for the treatment of GC.

Survival for patients with advanced gastric cancer (GC) remains poor. Systemic chemotherapy which has reached a plateau stays the standard first-line (1L) treatment for advanced human epidermal growth-factor receptor 2 (HER2)-negative GC. To maximize the benefit of 1L treatment, the concept of maintenance treatment is constantly being explored. In advanced HER2-negative GC, current clinical guidelines do not recommend a standard maintenance therapy strategy. In addition to the monotherapy maintenance with fluorouracil after 4-6 cycles of 1L chemotherapy, some agents that are active against novel targets have been evaluated in clinical trials for maintenance treatment. Whereas most of these trials do not reach their primary endpoints, they open new horizons for the 1L treatment of advanced HER2-negative GC. Therefore, we reviewed the clinical trials in the field of maintenance treatment in advanced HER2-negative GC and discussed some of the problems in clinical trials.

Background: The purpose of this study is to explore the association of CYP3A5, ABCB1, and CYP2C8 polymorphisms with the risk of developing early kidney impairment in Chinese liver transplant recipients receiving tacrolimus., Methods: CYP3A5, ABCB1, and CYP2C8 polymorphisms were genotyped in the Chinese liver transplant recipients in the study receiving tacrolimus for at least 2 years by polymerase chain reaction and high-resolution melting method. Serum cystatin C and urine microprotein (α1-microglobulin, microalbumin, transferrin, and immunoglobulin) of liver transplant recipients were used to determine both the status of early renal injury and the lesion part., Results: We documented 3 genotypes of CYP3A5 and ABCB1 and only 2 genotypes of CYP2C8 in our cohort. The levels of cystatin C and all 4 indicators of the urine microprotein in the recipient group were significantly higher than those in the control group (P < .05). The concentrations of transferrin differed significantly in each CYP3A5 genotype group (P < .05). Based on diverse CYP2C8 genotypes, we divided all the recipients into 2 groups: CYP2C8*1*1 group and CYP2C8*3*1 group. The concentrations of α1-microglobulin and cystatin C differed significantly between the 2 groups (P < .05). For CYP2C8*3, the positive predictive value is 68.5% and negative predictive value is 70.2%. For CYP3A5*3, the positive predictive value is 55.3% and negative predictive value is 60.4%., Conclusions: CYP2C8*3 and CYP3A5*3 appear to be predictive of risk of tacrolimus-induced early renal impairment. CYP3A5*3 was associated with the risk of early renal glomerular lesion, while CYP2C8*3 was associated with the risk of the tubulointerstitial injury. ABCB1 polymorphisms (both C3435T and C1236T) were not associated with the early renal injury in liver transplant recipients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to identify the potential risk factors of acute rejection after deceased donor kidney transplantation in China., Methods: Adult kidney transplantations from deceased donors in our center from February 2004 to December 2015 were enrolled for retrospective analysis. All deceased donations complied with China's Organ Donation Program. No organs from executed prisoners were used. The incidence of clinical and biopsy-proved acute rejection was assessed with the Kaplan-Meier method, and the Cox proportional hazard model was used for multivariate analysis., Results: One-year, 2-year, 3-year and 5-year incidences of acute rejection were 12.4%, 14.2%, 14.8%, and 17.1%, respectively. Multivariate analysis demonstrated that longer pre-transplant dialysis duration (hazard ratio [HR] 1.009 per month; 95% confidence interval, 1.003-1.015; P = .003), positive pre-transplant panel reactive antibody (PRA) (positive vs negative HR 3.266; 1.570-6.793; P = .023), and increasing HLA mismatches (≥4 vs < 4 HR 2.136; 1.022-4.465; P = .044) increased the risk of acute rejection, while tacrolimus decreased acute rejection risk compared to cyclosporine (HR 0.317; 0.111-0.906; P = .032)., Conclusion: Longer pre-transplant dialysis duration, HLA mismatch, and positive pre-transplant PRA increase the risk of acute rejection, while tacrolimus helps prevent acute rejection compared to cyclosporine in deceased donor kidney transplantation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The aim of the study was to investigate the effect of immunosuppression therapy early after kidney transplantation, particularly exposure of mycophenolic acid (MPA) and calcineurin inhibitor (CNI), on posttransplantation de novo HLA antibody production., Methods: A single-center retrospective cohort study was performed at the First Affiliated Hospital of Sun Yat-sen University, enrolling the kidney transplant or pancreas-kidney transplant recipients who had surgery between January 2010 and February 2016., Results: A total of 214 recipients were included in the study with a median follow-up period of 1.06 years. A total of 30 recipients (14.0%) were positive in HLA antibody detection posttransplant with a median follow-up period of 1.46 years. Ten recipients (4.7%) lost their allograft function during follow-up, and 6 of them (60%) developed de novo HLA antibody after graft failure. Multivariate analysis showed that acute rejection significantly increased the risk of de novo HLA antibody (hazard ratio [HR], 2.732). Intensified MPA dosing therapy reduced the risk by 59.8% (HR, 0.402); low-dose CNI therapy increased the risk by 33.3% (HR, 1.333), and the effect of extremely low-dose CNI therapy was even larger (HR, 2.242)., Conclusion: The risk of de novo HLA antibody can be decreased by reducing the risk of acute rejection. A tendency was seen in low-dose CNI therapy to increase the risk of de novo HLA antibody, but intensified MPA dosing therapy may provide an umbrella protection effect by reducing the risk. Prospective study was required to confirm the effects., (Copyright © 2018. Published by Elsevier Inc.)

The aim of this study was to determine distinctive risk factors for graft survival of living-related and deceased donor kidney transplantation (KTx)., Methods: Consecutive 536 living-related and 524 deceased donor kidney transplant recipients from February 2014 to December 2015 in a single center were enrolled for retrospective analysis. Graft survival was assessed with the Kaplan-Meier method, and the Cox proportional hazard model was used to determine independent risk factors of allograft survival., Results: One-, 3-, and 5-year graft survival rates were 98.8%, 98.5%, and 97.2%, respectively, in living-related donor KTx and were 94.9%, 91.3%, and 91.3%, respectively, in deceased donor KTx (log-rank, P < .001). Multivariate analysis demonstrated that risk factors for graft survival in living-related donor KTx were pretransplant dialysis duration (hazard ratio [HR], 1.023 per month; P = .046), delayed graft function (HR, 5.785; P = .02), and acute rejection (HR, 2.706; P = .04); risks factors in deceased donor KTx were recipient age (HR, 1.066 per year; P = .004), recipient history of diabetes mellitus (HR, 3.011; P = .03), pretransplant positive panel reactive antibody (HR, 3.353; P = .02), and donor history of hypertension (HR, 2.660; P = .046)., Conclusion: Distinctive risk factors for graft survival of living-related and deceased donor KTx were found., (Copyright © 2018. Published by Elsevier Inc.)

Background: Refractory infectious wounds on renal transplantation (RT) recipients significantly prolong hospital stay, increase medical costs, and threaten allograft survival. Vacuum sealing drainage (VSD) therapy is a new technique for managing wounds based on the principle of application of controlled negative pressure. The aim of this study was to summarize the efficacy and safety of VSD therapy in the management of refractory infectious wounds following RT., Materials and Methods: This is a retrospective study of a cohort of 661 consecutive patients who received renal transplants over a period of 3 years in which the data were collected and analyzed retrospectively., Results: Out of the 661 patients, 16 (2.4%) developed refractory wound infection following RT. Nineteen organisms were identified by culture from all patients, including 10 patients infected with 1 or more bacteria, 2 patients with fungal infection, and 4 patients with both. Specifically, mucormycosis was demonstrated in 4 patients, pan-resistant Klebsiella pneumoniae in 2 patients, and Acinetobacter baumannii in 2 patients. All 16 patients were treated with VSD therapy for a median of 37 days (range, 6-111 days). The number of VSD sets used ranged from 4 to 28 sets (mean, 11.1 sets). A combination of antibiotics, debridement, and VSD therapy lead to 100% (16 of 16) wound healing. No VSD-relevant adverse events were observed., Conclusions: VSD therapy is an effective and safe adjunct to conventional treatment modalities for the management of refractory wound infection following RT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Glomerulonephritis recurrence has emerged as one of the leading causes of allograft loss. We aimed to investigate the effect of living-related and deceased donation on the incidence of renal allograft glomerulonephritis and its effect on renal allograft survival., Methods: Adult renal allograft recipients with primary glomerulonephritis were enrolled. Transplantation date was from Feb 2004 to Dec 2015. Exclusion criteria included combined organ transplantation, structural abnormality, diabetic nephropathy, hypertension nephropathy, obstructive nephropathy, and primary uric acid nephropathy. The incidence of biopsy-proven allograft glomerulonephritis was compared between the living-related donor group and the deceased donor group. Graft survival was assessed with Kaplan-Meier method, and Cox proportional hazard model was used to evaluate the effect of posttransplant glomerulonephritis on graft outcome., Results: There were 525 living-related donor kidney transplant recipients (LRKTx) and 456 deceased donor kidney transplant recipients (DDKTx) enrolled. The incidence of IgA nephropathy was 8.8% in the LRKTx group and 1.3% in the DDKTx group (P < .001); the incidence of focal segmental glomerulosclerosis (FSGS) was 3.8% in the LRKTx group and 1.5% in the DDKTx group (P = .03). FSGS increased the risk of graft failure compared with non-FSGS (hazard ratio [HR], 3.703 [1.459-9.397]; P = .006). IgA nephropathy increased the risk of graft failure by over 5 times 5 years after kidney transplantation compared with non-IgA nephropathy, but it did not affect early allograft survival (HR for ≥5 years, 6.139; 95% CI, 1.766-21.345; P = .004; HR for <5 years, 0.385 [0.053-2.814]; P = .35)., Conclusions: Higher incidence of IgA nephropathy and FSGS in renal allograft was observed in living-related donor kidney transplantation compared with deceased donor kidney transplantation. De novo or recurrent IgA nephropathy and FSGS impaired long-term renal allograft survival., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To compare the clinical outcome of kidney transplantation from living-related and deceased donors., Patients and Methods: Consecutive adult kidney transplants from living-related or deceased donors from February 2004 to December 2015 in a single center were enrolled for retrospective analysis. Estimated glomerular filtration rate (eGFR) was compared with linear mixed models controlling the effect of repeated measurement at different time points., Results: There were 536 living-related and 524 deceased donor kidney transplants enrolled. The 1-year, 3-year, and 5-year graft survival rates were 98.8%, 98.5% and 97.2% in living-related kidney transplantation (KTx), and 94.9%, 91.3% and 91.3% in deceased donor KTx (log-rank, P < .001). A significantly higher incidence of delayed graft function (DGF) was observed in deceased donor KTx (20.6% vs 2.6%, P < .001). eGFR in deceased donor KTx was significantly higher than that in living-related KTx (68.0 ± 23.7 vs 64.7 ± 17.9 mL/min/1.73 m 2 at 1 year postoperation, 70.1 ± 23.3 vs 64.3 ± 19.3 mL/min/1.73 m 2 at 2 years postoperation, and 72.5 ± 26.2 vs 65.2 ± 20.4 mL/min/1.73 m 2 at 3 years postoperation; P < .001). The donor age was significantly higher in living-related KTx group (47.5 ± 11.0 vs 31.1 ± 14.4 years, P < .001)., Conclusion: Living-related graft survival is superior to deceased graft survival at this center, while better 5-year renal allograft function is obtained in deceased donor KTx patients, which may be attributable to the higher age of living-related donors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Increasing evidences suggest that inflammatory microenvironment has a crucial role in prostate cancer (PCa) progression; however, the underlying mechanisms are unclear. Here, we used the inflammation-associated prostate cellular transformation model to screen out a crucial microRNA, miR186, which was significantly downregulated in the transformed cells and effectively rescued the transformed phenotype. On stimulation of inflammatory cytokines, the activated nuclear factor kappa B (NF-κB)/p65 was able to induce miR186 expression through binding to its promoter in non-transformed cells, whereas this pathway was lost in transformed cells. Interestingly, Twist1, which is a reported downstream target of miR186, was responsible for the loss of NF-κB/p65-miR186 pathway. Twist1 downregulated miR186 expression in a novel negative feedback loop binding to the E-box and simultaneously recruiting Dnmt3a, which facilitated the site-specific CpG methylation of the miR186 promoter, thereby blocked the transcriptional activity of NF-κB/p65 and the responsiveness of miR186 to inflammatory signals. The high level of Twist1 triggered this feedback loop that underlies the epigenetic switch, which was essential for maintaining transformed and advanced PCa state. Finally, our clinical data confirmed that the CpG methylation and miR186 expression levels were closely related with inflammation-associated human PCa progression.

What Is Known and Objective: Tacrolimus is a widely used immunosuppressive drug with marked pharmacokinetic variability partly due to CYP3A5 polymorphism. Our study aimed to investigate the dynamic effects of CYP3A5 genotypes on dose requirement and trough concentration (C 0 ) of tacrolimus in renal transplant recipients., Methods: A total of 194 Chinese renal transplant recipients received oral tacrolimus twice daily. Whole-blood C 0 of tacrolimus were measured on the 3rd day, 7th day, 14th day, 1st month, 3rd month and 6th month post-transplantation. CYP3A5 genotypes were determined and the recipients were categorized as CYP3A5 expressers (CYP3A5*1 allele carriers) and non-expressers (homozygous CYP3A5*3). The correlated serum creatinine, haematocrit and albumin were also detected., Results: The allele frequencies for CYP3A5*1/*1, *1/*3 and *3/*3 were 7·7%, 44·8% and 47·4%, respectively. There were no significant variability in serum creatinine, haematocrit and albumin values between CYP3A5 expressers and non-expressers. Larger doses were administered to CYP3A5 expressers than to non-expressers after surgery except the initial dose. C 0 were much lower in CYP3A5 expressers than in non-expressers on the 3rd day, 7th day, 14th day and 1st month post-transplantation (P < 0·01); however, no significant differences were found on the 3rd and 6th months post-transplantation. All of the dose-adjusted C 0 in CYP3A5 expressers were significantly lower than non-expressers (P < 0·01). Less of the recipients achieving target C 0 (4-8 ng/mL) were found in CYP3A5 expressers than in non-expressers after initial dose (35·7% vs. 50%). Meanwhile, CYP3A5 non-expressers were detected having higher C 0 (>8 ng/mL) during 3 months post-transplantation. Besides, the proportions in the two groups both increased gradually over time and up to 91·8% and 94% on the 6th month, respectively., What Is New and Conclusion: There are no significant differences in serum creatinine, haematocrit and albumin values between CYP3A5 expressers and non-expressers. CYP3A5 expressers have decreased dose-adjusted tacrolimus C 0 when compared to non-expressers. Dose-adjusted C 0 of tacrolimus increases in a time-dependent manner in both groups., (© 2016 John Wiley & Sons Ltd.)

The salvage radiation or surgery is the main choice for recurrent nasopharyngeal cancer now. However the recurrent tumor becomes radiation insensitive and meanwhile,morbidity and mortality become higher.Recently the endoscopic salvage surgery has been developed;the collective evidence from a number of such studies suggests that endoscopic nasopharyngectomy is a safe and effective procedure for the treatment of rNPC.This article reviewed related researches about the feasibility,methods, and current situation of endoscopic salvage surgery., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Background: Calcineurin inhibitor-associated chronic nephrotoxicity threatens the prognosis of liver transplant recipients. This study aimed to study the mechanisms involved by identifying the cytokine profiles in tacrolimus (Tac)-induced nephrotoxicity., Methods: We enrolled 125 living-donor liver transplant recipients. All of the recipients had normal serum cystatin (Cys) C and urine microalbumin before transplantation. They received a Tac-based immunosuppressive regimen (Tac + mycophenolate mofetil + prednisone) thereafter. Patients were grouped according to Cys-C results (measured a mean 3.55 ± 1.89 years after transplantation) as a measure of renal injury: the early renal damage group was Cys-C >1 mg/L, and normal renal function was Cys-C ≤1 mg/L. Serum levels of 10 cytokines and chemokines, as well as urine proteins including α1 microglobulin, microalbumin, transferrin, and immunoglobulin G, were compared between groups., Results: In the early renal damage group, the concentration of interferon-γ-induced protein (IP) 10 was higher and monocyte chemotactic protein (MCP) 1 was lower compared with the group with normal renal function (P = .027 and .048, respectively). Multivariate logarithmic regression analysis showed that IP-10 and MCP-1 were independently correlated with renal damage., Conclusions: High level of IP-10 and low level of MCP-1 may be involved in renal injury and therefore may indicate poor prognosis. IP-10 could be a target for renal injury treatment after liver transplantation. Further studies with larger sample sizes are recommended to validate the study results., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Acute promyelocytic leukemia (APL) cells exhibit disrupted regulation of cell death and differentiation, and therefore the fate of these leukemic cells is unclear. Here, we provide the first evidence that a small percentage of APL cells undergo a novel cell death pathway by releasing extracellular DNA traps (ETs) in untreated patients. Both APL and NB4 cells stimulated with APL serum had nuclear budding of vesicles filled with chromatin that leaked to the extracellular space when nuclear and cell membranes ruptured. Using immunofluorescence, we found that NB4 cells undergoing ETosis extruded lattice-like structures with a DNA-histone backbone. During all-trans retinoic acid (ATRA)-induced cell differentiation, a subset of NB4 cells underwent ETosis at days 1 and 3 of treatment. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly elevated at 3 days, and combined treatment with TNF-α and IL-6 stimulated NB4 cells to release ETs. Furthermore, inhibition of autophagy by pharmacological inhibitors or by small interfering RNA against Atg7 attenuated LC3 autophagy formation and significantly decreased ET generation. Our results identify a previously unrecognized mechanism for death in promyelocytes and suggest that ATRA may accelerate ET release through increased cytokines and autophagosome formation. Targeting this cellular death pathway in addition to conventional chemotherapy may provide new therapeutic modalities for APL.

Aims: The aim of this study was to investigate the efficacy and safety of a transient intensified enteric-coated mycophenolate sodium (EC-MPS) dosing regimen with low exposure of calcineurin inhibitors (CNIs) in Chinese de novo kidney transplantation., Methods: In a 6-month prospective study, a total of 97 recipients were enrolled and assigned to either an intensified EC-MPS dosing (IS) regimen or a standard EC-MPS dosing (SD) regimen. The area under the curve (AUC) of MPA was assessed at week 1 post transplant. The incidences of acute rejection, patient and graft survival, renal allograft function and adverse events were analysed., Results: The IS regimen displayed a trend of acute rejection risk reduction (IS 2.7% vs. SD 13.3%, p = 0.061) and allograft function improvement (IS 62.8 ± 14.0 ml/min per 1.73 m(2) vs. SD 56.6 ± 18.3 ml/min per 1.73 m(2) , p = 0.084) after 6-month follow-up. MPA-AUC0-12 h was substantially higher in the intensified EC-MPS group than the standard EC-MPS group, though without a significant difference (71.4 ± 41.7 vs. 53.0 ± 27.0 mg·h/l, p = 0.107). The IS regimen did not increase the incidence of adverse effects (IS 54.1% vs. 45.0%, p = 0.39), including diarrhoea or leucopenia., Conclusions: The intensified EC-MPS dosing regimen maintaining low-dose CNIs in this study may be beneficial for Chinese adult de novo kidney transplant recipients in terms of acute rejection and allograft function and is safe within 6 months post transplant., (© 2016 John Wiley & Sons Ltd.)

Porcine reproductive and respiratory syndrome virus (PRRSV) causes one of the most economically devastating and pandemic porcine diseases. Previous study has shown that MARC-145 cells pretreated with recombinant IFN-β (rIFN-β) couldn't develop cytopathic effect (CPE) of PRRSV. However, up to date, it is not clear whether MARC-145 cells post-treated with rIFN-β could develop CPE of PRRSV. The present work showed that the MARC-145 cells didn't develop the CPE at 120 hr post-infection (p.i.) with low-dose of PRRSV when the cells were pre-treated with rIFN-β (Group 1), post-treated with rIFN-β at 4 hr p.i. (Group 2), or post-treated with rIFN-β at 8 hr p.i. (Group 3), while the MARC-145 cells could develop CPE when the cells were infected with high-dose PRRSV and then treated with rIFN-β at 24 hr p.i.. Furthermore, the indirect immunofluorescence assay confirmed that there were a few N protein-positive cells in the high-dose infected cells in Group 1, Group 2 and Group 3, while there were no N protein-positive cells in the low-dose infected cells in all rIFN-β treatment groups. In addition, the numbers of N protein-positive cells in high-dose infected cells (MOI = 10) in Group 1 were lower than that in Group 2 and Group 3. The results above demonstrated that both pre-treatment with rIFN-β and an earlier post-treatment with rIFN-β could inhibit the PRRSV replication and could clear the low-dose infected PRRSV, which indicated that the rIFN-β had efficient antiviral activities when the cells have been infected with PRRSV.

Background: BK virus (BKV) nephropathy (BKVN) is an increasingly recognized cause of kidney allograft loss and is thought to be related to the newer, more potent immunosuppressive agents. However, the risk factors for different types of BKV infection under the impact of intensive monitoring and reduction of maintenance immunosuppression are not well understood., Methods: Quantitative BKV DNA surveillance in plasma/urine and cytological testing in urine were performed regularly within the first year post-transplantation in 229 kidney recipients. Patients with BK viremia and BKVAN treated with immunosuppression reduction were monitored for BKV every 3-6 months. All the patients were followed up for a minimum of 5 years to exclude later development of BKVAN. Potential variables were compared and analyzed using logistic regression model multivariate analysis to assess and rank the BKV infection-related factors., Results: Seventy-eight (34.1%) patients had decoy cells, 99 (43.2%) BK viruria, 38 (16.6%) BK viremia, and 7 (3.1%) BKVAN. Risk for decoy cells, BK viruria, and viremia, and BKVAN in univariate analyses were higher with tacrolimus (Tac) and deceased kidney donation. Multivariate analysis showed that Tac ([HR, 2.7; P = .008], [HR, 2.3; P = .016], [HR, 2.9; P = .032]) and deceased kidney donation ([HR, 2.5; P = .004], [HR, 2.6; P = .002], [HR, 2.1; P = .071]) were risk factors for BK decoy cells, BK viruria, and viremia, respectively. BKVAN was inclined to the patients with the combination of Tac and mycophenolate mofetil and longer BKV clearance time., Conclusions: Tac and deceased kidney donation are independent risk factors for BKV infection under the impact of therapeutic drug monitoring., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The serine/threonine kinase AKT is generally accepted as a promising anticancer therapeutic target. However, the relief of feedback inhibition and enhancement of other survival pathways often attenuate the anticancer effects of AKT inhibitors. These compensatory mechanisms are very complicated and remain poorly understood. In the present study, we found a novel 2-pyrimidyl-5-amidothiazole compound, DC120, as an ATP competitive AKT kinase inhibitor that suppressed proliferation and induced apoptosis in liver cancer cells both in vitro and in vivo. DC120 blocked the phosphorylation of downstream molecules in the AKT signal pathway in dose- and time-dependent manners both in vitro and in vivo. However, unexpectedly, DC120 activated mammalian target of rapamycin complex 1 (mTORC1) pathway that was suggested by increased phosphorylation of 70KD ribosomal protein S6 kinase (P70S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). The activated mTORC1 signal was because of increase of intracellular Ca(2+) via Ca(2+)/calmodulin (CaM)/ signaling to human vacuolar protein sorting 34 (hVps34) upon AKT inhibition. Meanwhile, DC120 attenuated the inhibitory effect of AKT on CRAF by decreasing phosphorylation of CRAF at Ser259 and thus activated the mitogen-activated protein kinase (MAPK) pathway. The activation of the mTORC1 and MAPK pathways by DC120 was not mutually dependent, and the combination of DC120 with mTORC1 inhibitor and/or MEK inhibitor induced significant apoptosis and growth inhibition both in vitro and in vivo. Taken together, the combination of AKT, mTORC1 and/or MEK inhibitors would be a promising therapeutic strategy for liver cancer treatment.

Breast cancer is the most common type of cancer among women worldwide, and metastasis represents the most devastating stage of the disease. Recent studies have revealed that microRNAs (miRNA) have critical roles to regulate cancer cell invasion and metastasis. Here we present evidence to show the role of miR-182 in breast cancer metastasis. miR-182 is upregulated in the malignant cell line variants of both human MCF10 and mouse 4T1 series. Ectopic expression of miR-182 enhanced breast cancer cell motility and invasiveness, whereas miR-182 inhibition resulted in opposite changes. In nude mice, miR-182 led to increased pulmonary colonization of cancer cells. We further demonstrated that miR-182 directly targets MIM (Missing in Metastasis), which suppresses metastasis by inhibiting ras homolog family member A (RhoA) activity and stress fiber formation in breast cancer cells. Restoring MIM expression completely blocked the pro-metastasis function of miR-182, while RhoA inhibition reversed the phenotypes of both miR-182 overexpression and MIM knockdown. In breast tumor samples, miR-182 induction is linked to downregulation of MIM, RhoA activation and poor prognosis. Hence, our data delineates the molecular pathway by which miR-182 promotes breast cancer invasion and metastasis, and may have important implication for the treatment of metastatic cancers.

The structure and development of collapsed layers of the haustorium were studied in Santalum album Linn. Through light and transmission electron microscopy, it was shown that the collapsed layers originated from starch-containing cells when the haustorium developed an internal gland, thickened gradually and ultimately developed into the mantle, which, combined with the sucker, buckled the host root. We report on the presence of inter-collapsed layers for the first time. These layers develop after penetration into the host and are located between the intrusive tissues and the vascular meristematic region, gradually linking the collapsed layers and remains around the sucker. The proliferation of cells in the meristematic region and the 'host tropism' of cortical layers contribute to pressure within the haustorium and result in development of the collapsed layers. Besides, starch-containing cells that turn into collapsed layers are vulnerable to pressure as they lack a large vacuole, have uneven cell wall thickness and a loose cell arrangement. We proposed that the functions of collapsed layers are to efficiently assure that cell inclusion and energy concentrate at the inner meristematic region and are recycled to affect penetration, reinforce the physical connection between the sandalwood haustorium and host root, and supply space for haustorial development., (© 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.)

Natural killer (NK) cells are important in host to eliminate circulating tumour cells (CTCs) in turn preventing the development of tumour cells into metastasis but the mechanisms are very poorly defined. Here we find that the expression level of miR-296-3p is much lower in the non-metastatic human prostate cancer (PCa) cell line P69 than that in the highly metastatic cell line M12, which is derived from P69. We demonstrate that miR-296-3p directly targets and inhibits the expression of intercellular adhesion molecule 1 (ICAM-1) in the malignant M12. The data from clinical tissue microarrays also show that miR-296-3p is frequently upregulated and ICAM-1 is reversely downregulated in PCa. Interestingly, ectopic expression of miR-296-3p in P69 increases the tolerance to NK cells whereas knockdown of miR-296-3p in M12 reduces the resistance to NK cells, which both phenotypes can be rescued by re-expression or silencing of ICAM-1 in P69 and M12, respectively. These results are also manifested in vivo by the decrease in the incidence of pulmonary tumour metastasis exhibited by knockdown of miR-296-3p in M12 when injected into athymic nude mice via tail vein, and consistently down-expression of ICAM-1 reverses this to increase extravasation of CTCs into lungs. Above results suggest that this newly identified miR-296-3p-ICAM-1 axis has a pivotal role in mediating PCa metastasis by possible enhancing survival of NK cell-resistant CTC. Our findings provide novel potential targets for PCa therapy and prognosis.

Background: Published data on the association between GSTM1 and GSTT1 polymorphisms and risk of anti-tuberculosis drug-induced liver injury (ATDILI) are inconclusive., Objective: To derive a more precise estimation of the relationship, a meta-analysis on this topic was performed., Design: PubMed, Medline, EMBASE and Chinese national knowledge infrastructure were searched for studies on the association of GSTM1 and GSTT1 polymorphisms with risk of ATDILI. Summary odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were calculated., Results: The GSTM1 null genotype was associated with increased risk of ATDILI (OR(random-effects) 1.50, 95%CI 1.15-1.95). When stratifying for study population and median number of cases, statistically significant results were observed in the Chinese population (OR(random-effects) 1.45, 95%CI 1.12-1.92) and in studies with case numbers > 57 (OR(fixed-effects) 1.60, 95%CI 1.31-1.97). No statistically significant association was observed between GSTT1 null genotype or GSTM1/GSTT1 interaction and risk of ATDILI., Conclusion: The meta-analysis suggests that GSTM1 null genotype may be associated with an increased risk of ATDILI, particularly among the Chinese population. The GSTT1 null genotype or GSTM1/GSTT1 interaction may not affect susceptibility to ATDILI.

Background and Objective: A number of studies have evaluated the association between cytochrome P450 2E1 (CYP2E1) RsaI/PstI polymorphism and the risk of anti-tuberculosis drug-induced liver injury (ATDILI). However, the results were inconsistent. We conducted a meta-analysis to clarify the role of this polymorphism in ATDILI., Design: Two authors independently searched the PubMed, Medline, EMBASE and Chinese National Knowledge Infrastructure databases for studies on the association of CYP2E1 RsaI/PstI polymorphism with risk of ATDILI. Summary odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were calculated., Results: The combined results showed that the CYP2E1 c1/c1 genotype was associated with increased ATDILI risk compared to variant genotypes (c1/c2+c2/c2) (OR 1.36, 95%CI 1.09-1.69). When stratifying for study population, statistically significant results were observed in Chinese (OR 1.47, 95%CI 1.12-1.92) and Korean populations (OR 1.85, 95%CI 1.04-3.30). In comparison with CYP2E1 c1/c2 or c2/c2 with rapid/intermediate acetylators, the risk of ATDILI increased from 1.88 (95%CI 1.14-3.09) for CYP2E1 c1/c1 with rapid/intermediate acetylators to 6.44 (95%CI 3.47-11.97) for CYP2E1 c1/c1 with slow acetylators., Conclusion: This meta-analysis suggests that CYP2E1 RsaI/PstI polymorphism may affect susceptibility to ATDILI, particularly among Chinese and Korean populations.

TCR specific antibodies may modulate the TCR engagement with antigen-MHC complexes, and in turn regulate in vivo T cell responses to alloantigens. Herein, we found that in vivo administration of mAbs specific for mouse TCRβ (H57-597), TCRα or CD3 promptly reduced the number of CD4(+) and CD8(+) T cells in normal mice, but H57-597 mAb most potently increased the frequency of CD4(+) Foxp3(+) Treg cells. When mice were injected with staphylococcal enterotoxin B (SEB) superantigen and H57-597 mAb, the expansion of SEB-reactive Vβ8(+) T cells was completely abrogated while SEB-nonreactive Vβ2(+) T cells remained unaffected. More importantly, transient H57-597 mAb treatment exerted long-lasting effect in preventing T cell responses to alloantigens, and produced long-term cardiac allograft survival (>100 days) in 10 out of 11 recipients. While Treg cells were involved in maintaining donor-specific long-term graft survival, T cell homeostasis recovered over time and immunity was retained against third party allografts. Moreover, transient H57-597 mAb treatment significantly prolonged survival of skin allografts in naïve recipients as well as heart allografts in skin-sensitized recipients. Thus, transient modulation of the TCRβ chain by H57-597 mAb exhibits potent, long-lasting therapeutic effects to control alloimmune responses., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Aim: To investigate whether the p38α mitogen-activated protein kinases (MAPK) is involved in bone morphogenetic protein (BMP)-2-induced odontoblastic differentiation of human dental pulp cells (HDPCs)., Methodology: Recombinant retrovirus encoding shRNA against p38α MAPK was constructed to investigate the role of p38α MAPK on BMP-2-induced odontoblastic differentiation of HDPCs. HDPCs were transfected with retrovirus expressing sh-p38α. Activation of p38α MAPK was detected by Western blot. The effects of p38α MAPK on BMP-2-induced odontoblastic differentiation of HDPCs were measured by alkaline phosphatase (ALP) activity, and the expression of odontoblastic markers was identified by quantitative real-time polymerase chain reaction analysis. The effect of SD-282, a p38a-specific inhibitor, on BMP-2-induced odontoblastic differentiation was also investigated., Results: BMP-2 dose- and time-dependently upregulated phosphorylation of p38α of HDPCs. Compared with BMP-2-treatment group, gene knock-down of p38α MAPK significantly inhibited ALP activity and the formation of mineralized nodules in HDPCs. Moreover, suppression of p38α MAPK repressed the odontoblastic differentiation in HDPCs. Consistently, inhibition of p38α by SD-282 also decreased odontoblastic differentiation., Conclusions: p38α MAPK is involved in BMP-2-induced odontoblastic differentiation of HDPCs., (© 2011 International Endodontic Journal.)

An elevated DNA-repair capacity in cancer cells leads to radiation resistance and severely limits the efficacy of radiation therapy. Activation of Akt is tightly associated with resistance to radiotherapy, and Mre11 protein has important role during the repair of DNA double-strand breaks (DSBs). In this report, our results showed that inhibition of Akt activity impaired the repair of DSBs in CNE2 cells, whereas activated Akt promoted the repair of DSBs in HeLa cells. Knockdown of Mre11 also impaired the process of DSB repair in both these two cell lines. More importantly, we found that Akt could regulate Mre11 expression. Inhibition of Akt activity by small interfering RNA or LY294002 efficiently downregulated the Mre11 expression in CNE2 cells, and transfection with myr-Akt plasmid in HeLa cells upregulated the Mre11 expression. In addition, luciferase reporter analysis revealed that Mre11 reporter activity increased after transfection with myr-Akt1 plasmids, and this myr-Akt1-induced transcriptional activity was blocked in the presence of LY294002. Further study showed GSK3β/β-catenin/LEF-1 pathway was involved in this regulation. Knockdown of β-catenin or LEF-1 led to the downregulation of Mre11, whereas overexpression of β-catenin led to upregulation of Mre11. The chromatin immunoprecipitation assay assay showed β-catenin/LEF-1 heterodimer could directly bind to the promoter of Mre11 in vivo. And the luciferase activity of the pGL3-Mre11 and pGL3-Lef increased in HeLa cells following β-catenin plasmid co-transfected, but was abolished when the LEF-1-binding conserved sequences of Mre11 promoter were mutated. These results together support Akt can upregulate the expression of Mre11 through GSK3β/ β-catenin/LEF pathway to elevate DSB-repair capacity in cancer cells.

MTRX1011A is a humanized anti-CD4 antibody with an amino acid substitution (N434H) to improve its binding to the neonatal Fc receptor (FcRn). Pharmacokinetic/pharmacodynamic (PK/PD) data in baboons suggest that the increased binding to FcRn reduces the nonspecific elimination rate (K(el)) of MTRX1011A by ~50% but does not affect its PK-PD relationship. The human PK/PD data of MTRX1011A from a phase I study in patients with rheumatoid arthritis (RA) were compared with those previously reported for TRX1, its predecessor antibody, using population PK-PD modeling. The results suggest a comparable PK-PD relationship and no significant difference between the K(el) values of the two antibodies. However, the results may have been confounded by the differences in the clinical populations in which the two antibodies were studied and the presence of preexisting immunoglobulin M (IgM) antibodies in the RA sera that recognize N434H in MTRX1011A. This study highlights the challenges in translating from animal studies to human application the effects of FcRn-directed mutations on the PK of monoclonal antibodies.

Horizontal gene transfer (HGT) is the probable origin of new genes. Identification of HGT-introduced genes would be helpful to the understanding of the genome evolution and the function prediction of new genes. In this study, a method using support vector machine (SVM) was used to distinguish horizontally transferred genes and non-horizontally transferred genes of mammalian herpesviruses based on the atypical composition identification, with accuracy higher than 95% within a reasonable length of time by using just a common PC. This identified 302 putative horizontally transferred genes, 171 genes being identified for the first time. Although most putative transferred genes are of unknown function, many genes have been discovered or predicted to encode glycoproteins or membrane proteins.

Antibody-drug conjugates (ADCs) are potent cytotoxic drugs linked to antibodies through chemical linkers, and allow specific targeting of drugs to neoplastic cells. The expression of CD22 is limited to B-cells, and we show that CD22 is expressed on the vast majority of non-Hodgkin's lymphomas (NHLs). An ideal target for an ADC for the treatment of NHL would have limited expression outside the B-cell compartment and be highly effective against NHL. We generated an ADC consisting of a humanized anti-CD22 antibody conjugated to the anti-mitotic agent maytansine with a stable linker (anti-CD22-MCC-DM1). Anti-CD22-MCC-DM1 was broadly effective in in vitro killing assays on NHL B-cell lines. We did not find a strong correlation between in vitro potency and CD22 surface expression, internalization of ADC or sensitivity to free drug. We show that anti-CD22-MCC-DM1 was capable of inducing complete tumor regression in NHL xenograft mouse models. Further, anti-CD22-MCC-DM1 was well tolerated in cynomolgus monkeys and substantially decreased circulating B-cells as well as follicle size and germinal center formation in lymphoid organs. These results suggest that anti-CD22-MCC-DM1 has an efficacy, safety and pharmacodynamic profile that support its use as a treatment for NHL.

The monoclonal antibodies (mAbs) against ractopamine (Rac) were prepared and their properties identified by indirect competitive enzyme-linked immunoabsorbant assay (ELISA). The IC(50) of mAbs was 2.7 ng ml(-1) towards Rac or 9.3 ng ml(-1) towards Rac-glucuronides and no cross-reactivity (CR) towards other competitors except dobutamine (CR: 3.76%). Based on the mAbs, the Rac-kit (kit) and Rac-strip (strip) were developed to detect Rac residues in swine urine. The strip and kit assay could be performed within 5-10 min and 2 h, respectively, allowing the analysis of urine samples without the need for sample clean-up. The detection limits were 1 ng ml(-1) for kit and 3 ng ml(-1) with the unaided eye, and 0.2 ng ml(-1) with the Strip Reader for strip. The correlation coefficients (R(2)) were 0.988 for kit in the range 0-128.0 ng ml(-1), and 0.987 for strip in the range 0-10.8 ng ml(-1). Comparing the gas chromatography-mass spectrometry (GC-MS) with the kit or strip in swine urine spiked with Rac standards, the differences ranged from 1.4% to 4.5% for kit and 1.0% to 4.7% for strip. However, the differences were greater than 54% for the kit and 55% for the strip test for the analysis of urine from swine treated with Rac. The results obtained from GC-MS using hydrolysed urine samples were generally in good agreement with those obtained from strip or kit using non-hydrolysed urine samples.

Economists have long argued that a fishery that maximizes its economic potential usually will also satisfy its conservation objectives. Recently, maximum economic yield (MEY) has been identified as a primary management objective for Australian fisheries and is under consideration elsewhere. However, first attempts at estimating MEY as an actual management target for a real fishery (rather than a conceptual or theoretical exercise) have highlighted some substantial complexities generally unconsidered by fisheries economists. Here, we highlight some of the main issues encountered in our experience and their implications for estimating and transitioning to MEY. Using a bioeconomic model of an Australian fishery for which MEY is the management target, we note that unconstrained optimization may result in effort trajectories that would not be acceptable to industry or managers. Different assumptions regarding appropriate constraints result in different outcomes, each of which may be considered a valid MEY. Similarly, alternative treatments of prices and costs may result in differing estimates of MEY and their associated effort trajectories. To develop an implementable management strategy in an adaptive management framework, a set of assumptions must be agreed among scientists, economists, and industry and managers, indicating that operationalizing MEY is not simply a matter of estimating the numbers but requires strong industry commitment and involvement.

The c-Jun NH2-terminal kinase (JNK) pathway represents one subgroup of MAP kinases that are activated primarily by cytokines and exposure to environmental stress. Autophagy is a protein-degradation system characterized by the formation of double-membrane vacuoles termed autophagosomes. Autophagy-related gene beclin 1 plays a key role in autophagosome formation. However, the relationships between activation of JNK pathway, autophagy induction and Beclin 1 expression remain elusive. In this study, we used human cancer cell lines CNE2 and Hep3B to investigate the role of JNK-mediated Beclin 1 expression in ceramide-induced autophagic cell death. Ceramide-treated cells exhibited the characteristics of autophagy (that is, acidic vesicular organelle formation and the LC3-II generation). JNK was activated in these two cell lines exposed to ceramide and the phosphorylation of c-Jun also increased. In the meantime, we found that ceramide upregulated Beclin 1 expression in cancer cells. The upregulation of Beclin 1 expression could be blocked by SP600125 (a specific inhibitor of JNK) or a small interfering RNA (siRNA) directed against JNK1/2 or c-Jun. Chromatin immunoprecipitation and luciferase reporter analysis revealed that c-Jun was involved in the regulation of beclin 1 transcription in response to ceramide treatment. In addition, inhibition of JNK activity by SP600125 could inhibit autophagy induction by ceramide. Furthermore, Beclin 1 knockdown by siRNA also inhibited ceramide-mediated autophagic cell death. JNK-mediated Beclin 1 expression was also observed in topotecan-induced autophagy. These data suggest that activation of JNK pathway can mediate Beclin 1 expression, which plays a key role in autophagic cell death in cancer cells.

The pathogenesis of human H5N1 influenza remains poorly understood and controversial. 'Cytokine storm' has been hypothesized to be the main cause of the severity of this disease. However, the significance of this hypothesis has been called into question by a recent report, which demonstrates that inhibition of the cytokine response did not protect against lethal H5N1 influenza infection in mice. Here we showed discrepant findings in two adult H5N1 autopsies and a fetus obtained at autopsy which also raise doubt about this hypothesis. Antigens of 10 cytokines/chemokines which were found to be significantly elevated in previous H5N1-infected patients and in vitro experiments, and mRNA of eight of these, were absent from the lungs of a pregnant woman and her fetus. In contrast, antigens of seven cytokines/chemokines and mRNA of six of these were found to be increased in the lungs of a male autopsy. The cells expressing these cytokines and chemokines were identified as type II pneumocytes, bronchial epithelial cells, macrophages and vascular endothelial cells. Levels of cytokines and chemokines in the serum of the male case were also significantly higher than those of infectious (infection other than by H5N1) and non-infectious controls. In comparison with results from our previous study, it appeared that the male case had increased cytokine/chemokine expression but reduced viral load, while the pregnant female had diminished cytokine/chemokine expression but a significantly increased viral load in the lungs. These disparate findings in these two cases suggest that 'cytokine storm' alone could not be a sufficient explanation for the severe lung injury of this newly emerging disease., ((c) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

A comprehensive phylogenetic analysis of 45 herpesviruses was performed based on whole-genome sequences. We used 4 methods, namely the alignment of conserved gene sequences (excluding 5 herpesviruses), compositional vector tree (CVTree) method, local homology analysis, and gene content analysis. The obtained results showed good consistency between the phylogenetic trees prepared by these methods and likewise, the obtained classification of the herpesviruses was consistent with their current taxonomic designation. The herpesviruses with the ambiguous classification or not assigned in the family or with the newly published genomes were also phylogenetically classified.

Objective: Yunnan Province, located in southwest China, is one of the poorest province in China. The maternal mortality ratio (MMR) is about twice the national average (56.2/100,000 live births), and in remote mountainous regions, the rate is five times higher. This study aimed to examine the progress in reduction of maternal mortality in the 1990s and early 2000s and the factors associated with this reduction in Yunnan., Design: A population-based, longitudinal, ecological correlation study., Setting: A remote province of China with a proportionately large indigenous population., Population: Populations at county, prefecture and provincial level., Methods: Using maternal mortality data collected at the province, prefecture/region and county levels, trend and time series analyses and multivariate linear regression analyses were performed using SPSS (Version 13)., Main Outcome Measure: MMR and its change over time., Results: MMR declined substantially in the 1990s at a rate of 3.0% per year. Utilisation of prenatal and obstetric care increased and was significantly correlated with the declining trend in MMR. Hospital delivery was a strong predictor of MMR, independent of social and economic development. Both low income and illiteracy were significantly associated with increased MMR., Conclusions: Declines in maternal mortality in Yunnan over the past 14 years appear to reflect health, social and economic interventions implemented in the 1990s. The association of hospital delivery with maternal mortality may be due to the effective management of severe pregnancy and birth complications. Low income and illiteracy were associated with MMR but primarily through their impact on the use of prenatal and obstetric care.

It has been shown that acetylcholinesterase (AChE) expression was induced during apoptosis and the anti-sense oligonucleotides and siRNA of AChE may prevent apoptosis in various cell types. However, the mechanisms underlying AChE upregulation remain elusive. We demonstrated here that c-Jun NH2-terminal kinase (JNK) could mediate AChE expression. In this study, both etoposide and excisanin A, two anticancer agents, induced apoptosis in colon cancer cell line SW620 as determined by Annexin V staining, the cleavage of caspase-3 and the proteolytic degradation of poly (ADP-ribose) polymerase (PARP). The results showed that both the agents upregulated AChE in SW620 cells. In the meantime, JNK was also activated and the expression and phosphorylation of c-Jun increased in SW620 cells exposed to the two agents. The induced AChE mRNA and protein expression could be blocked by SP600125, a specific inhibitor of SAPK/JNK, and small interfering RNA directed against JNK1/2. Transfection with adenovirus-mediated dominant negative c-Jun also blocked the upregulation of AChE expression. Together, these results suggest that AChE expression may be mediated by the activation of JNK pathway during apoptosis through a c-Jun-dependent mechanism.

Human differentially expressed in chondrocytes (DEC), mouse stimulated with retinoic acid and rat split and hairy related proteins constitute a structurally distinct class of the basic helix-loop-helix proteins. DEC1 is abundantly expressed in tumors and protects against apoptosis induced by serum starvation. In this study, we report that DEC1 antiapoptosis is achieved by inducing survivin, an antiapoptotic protein. In paired tumor-normal tissues, survivin and DEC1 exhibited a paralleled expression pattern. Tetracycline-induced expression of DEC1 in stable lines proportionally increased the expression of survivin. In reporter assays, DEC1 transactivated the survivin promoter but repressed the DEC2 promoter. In contrast to the repression, the activation was delayed and varied depending on serum concentrations and cycle blockers. Studies with reporter mutants located, in the survivin promoter, two Sp1 sites that supported DEC1 transactivation. Electrophoretic mobility shift assay and chromatin immunoprecipitation detected the presence of DEC1 in the survivin promoter. These findings establish that the survivin gene is a transcription target of DEC1, and induction of survivin is at least in part responsible for DEC1 antiapoptosis.

Agents stabilizing G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase or telomerase-independent mechanism and could therefore act as antitumor agents. In this study, we found that quindoline derivatives interacted preferentially with intramolecular G-quadruplex structures and were novel potent telomerase inhibitors. Treatment with quindoline derivatives reproducibly inhibited telomerase activity in human leukemia K562 cells and colon cancer SW620 cells. N'-(10H-Indolo [3,2-b] quinolin-11-yl)-N, N-dimethyl-propane-1,3-diamine (SYUIQ-5), (one of quindoline derivatives), when added to K562 and SW620 cell culture at nonacute cytotoxic concentrations, increased time of population doublings of K562 and SW620 cells, induced a marked cessation in cell growth and cellular senescence phenotype after 35 and 18 days, respectively. Growth cessation was accompanied by a shortening of telomere length, and induction of p16, p21 and p27 protein expression. However, another compound SYUIQ-7 with greater IC(50) for telomerase had no obvious cellular effect in nonacute cytotoxic concentrations. These results indicate that quindoline derivatives as novel potent G-quadruplex interactive agents induce senescence and telomere shortening in cancer cells and therefore are promising agents for cancer treatment.

The full-length cDNA of genomic segment A of three infectious bursal disease viruses, two attenuated strains (HZ2 and JD1) and one virulent field strain (ZJ2000), was amplified in a single step by reverse transcription-polymerase chain reaction, cloned into pGEM-T Easy Vector, and sequenced. The full length of cloned segment A contains 3259 nucleotides, which includes two partially overlapping open reading fragments (ORFs) ORF1 and ORF2, flanked by 5' and 3' noncoding regions. These strains shared high sequence identity with each other either at the nucleotide or deduced amino acid level. Strains HZ2 and JD1 were highly related to two attenuated strains, CEF94 and P2, whereas ZJ2000 was closely related to two other virulent strains, Cu-1 and Harbin. Substitutions of four amino acids at positions 253, 279, 284, and 330, a common feature of attenuated and most virulent strains, were also observed in these three strains. Two major hydrophilic peaks were conserved in the three strains; however, there are two amino acid substitutions at positions 280 (N to S) and 290 (M to L) in the second minor hydrophilic peak for all three strains, which might have a critical influence on antigenicity. Two amino acid substitutions near the VP2-VP4 cleavage site were identified in virulent strain JZ2000, which might be involved in increasing the virulence of the virus. Phylogenetic analyses indicated that these three Chinese strains are most closely related to some European virulent strains but are distinct from very virulent infectious bursal disease virus and variant strains.

Polymerase chain reaction was performed to screen Bacillus thuringiensis isolates for cryI, cryIII, and cryV genes with cryI-, cryIII-, and cryV-specific primers respectively. The results indicated that, in the 56 Bt isolates examined, 7 isolates contain cryI gene, 2 isolates contain cryIII gene, and 21 isolates contain both cryI and cryV genes. The cryV gene was located by Southern hybridization in the large plasmid of about 150 MD molecular mass.

The terminal globular domain of the paramyxovirus hemagglutinin-neuraminidase (HN) glycoprotein spike has a number of conserved residues that are predicted to form its neuraminidase (NA) active site, by analogy to the influenza virus neuraminidase protein. We have performed a site-directed mutational analysis of the role of these residues in the functional activity of the Newcastle disease virus (NDV) HN protein. Substitutions for several of these residues result in a protein lacking both detectable NA and receptor recognition activity. Contribution of NA activity, either exogenously or by coexpression with another HN protein, partially rescues the receptor recognition activity of these proteins, indicating that the receptor recognition deficiencies of the mutated HN proteins result from their lack of detectable NA activity. In addition to providing support for the homology-based predictions for the structure of HN, these findings argue that (i) the HN residues that mediate its NA activity are not critical to its attachment function and (ii) NA activity is required for the protein to mediate binding to receptors.

The effects of lanthanum and calcium ions on electron transport, dichlorephenol indophenol (DCIP) photoreduction, and oxygen evolution activities in chloroplast from cucumber (Cucumis satives L.) were determined. The lanthanum inhibited the whole electron chain-transport activity of chloroplast. DCIP photoreduction and oxygen evolution activities of the photosystem I (PSII) also decrease after treatment with La3+. But the diminished activities of PSII and chloroplast caused by La3+ could be reversed by Ca2+ and even became higher than the control level. The concentration analysis of related protein complexes to photoelectron transport in chloroplast included that La3+ induced the concentration of chlorophyll protein complexes increasing but caused some nonchlorophyll protein complexes to decompose partially. This increasing effect of La3+ on chlorophyll protein complexes results in the improvement of chlorophyll content, which will improve the absorption of photoelectron and energy transport in the process of photosynthesis.