Down-regulation of Sphk2 suppresses bladder cancer progression.

Bladder cancer is the second most common urological malignancy around the world and is by far the most frequent urological malignancy in China. The abnormal expression of sphingosine kinase 2 (SphK2) is associated with tumor progression and a poor patient survival rate, however, the effect of SphK2 on the bladder cancer cells remains unclear. The aim of the paper was to study the expression of SphK2 in bladder cancer and the role of SphK2 on the cell proliferation, metastasis, and apoptosis in bladder cancer in vitro. Our results showed that SphK2 is up-regulated in bladder cancer tissues compared with the corresponding adjacent non-neoplastic tissues, and the expression level of SphK2 was significantly higher in human bladder cancer cells in comparison with normal bladder epithelial cells. Silencing of SphK2 could inhibit the proliferation ability of T24 cells in vitro. In addition, SphK2 knockdown could induce a significant increase in the number of apoptotic cells. Furthermore, the transwell assay also showed significant cell migration inhibition in SphK2 siRNA transfectant compared with cell lines transfected with NC. Thus, this study suggested that SphK2 inhibition may provide a promising treatment for bladder cancer patients.

Predictive value of high residual platelet reactivity by flow cytometry for outcomes of ischemic stroke patients on clopidogrel therapy.

High residual platelet reactivity (HRPR) assessed by multiple tests has been associated with worse clinical outcomes. However, the clinical impact of HRPR assessed by flow cytometry is unknown. The aim of this study was to validate the predictive value of HRPR measured by flow cytometry for clinical outcomes in ischemic stroke patients during clopidogrel therapy. Overall, 198 consecutive patients with ischemic stroke taking clopidogrel underwent platelet function testing on flow cytometer including adenosine diphosphate (ADP)-induced platelet aggregation (PAg) and platelet activation markers (CD62P, CD63, and PAC-1). Poor outcome was defined as poor prognosis and ischemic events during 12-month follow-up. By receiver operating characteristic curve analysis, residual platelet reactivity assessed by flow cytometry was able to distinguish between patients with and without poor outcomes, when platelet inhibition was evaluated with ADP-PAg (area under the curve [AUC], .77; 95% confidence interval [CI], .69-.84; P < .001), CD62P (AUC, .73; 95% CI, .64-.81; P < .001), CD63 (AUC, .72; 95% CI, .64-.80; P < .001), and PAC-1 (AUC, .70; 95% CI, .62-.78; P < .001). The prevalence of HRPR was 25.8% for ADP-PAg, 32.8% for CD62P, 41.4% for CD63, and 56.1% for PAC-1. The multiple logical regression analysis demonstrated that HRPR was an independent predictor of poor outcomes (ADP-PAg: odds ratio [OR] 13.03, 95% CI 5.66-29.98, P < .001; CD62P: OR 8.55, 95% CI 3.94-18.57, P < .001; CD63: OR 8.74, 95% CI 3.89-19.64, P < .001; PAC-1: OR 4.23, 95% CI 1.98-9.08). In conclusion, HRPR, assessed by flow cytometry, is able to detect ischemic stroke patients at increased risk of 12-month poor outcomes on clopidogrel treatment.

[Analysis of the diagnosis and treatment of desmoplastic small round cell tumor].

OBJECTIVE: To explore the clinical diagnostic features and treatment of desmoplastic small round cell tumor (DSRCT), and to improve the understanding and management of this tumor. METHODS: The clinicopathological data of nine patients treated in our hospital from October 2004 to June 2014 were retrospectively analyzed and a review of the literature was made. The clinical manifestations, pathological characteristics, diagnosis and differential diagnosis, treatment and prognosis of this tumor were summarized and analyzed. RESULTS: Nine patients with DSRCT, 5 males and 4 females, with an average age of 21 years (range 8-56 years) were included in this study. Ultrasound examination revealed irregular low-density mass shadow in the abdominal cavity. CT examination found that 6 cases had abdominal and retroperitoneal multiple solid tumor nodules, uneven density, and visible low density fluid area. Postoperative pathological examination revealed that the tumor cells were small, mostly elliptic, gathered to form clear structure of nests with clear irregular boundaries. The central portion of large tumor nests often showed necrosis. Scattered fibroblasts and large amount of hyalinization of collagen fibers were seen in the interstitial tissue around the nests. Six patients received laparotomy surgery, however, all failed to resect the tumor completely. Three patients received postoperative chemotherapy, i. e. two cases had carboplatin and paclitaxel chemotherapy, and one case of chemotherapy regimen not specified. Two patients had radiation and chemotherapy (no concrete plan was available). Another case was lost to follow-up. Two of the three patients without surgery received chemotherapy with CAP (cyclophosphamide+adriamycin+carboplatin) and total rectal lesions, pelvic and inguinal lymph nodes, ilium metastases radiation therapy. Another one patient received EP regimen (DDP+VP16) which was then changed into a TP chemotherapy alone. Eight of the nine cases died shortly after surgery, and only one patient treated with chemotherapy alone was still alive after 11 months of follow-up. CONCLUSIONS: Desmoplastic small round cell tumor is a very rare, special type of soft tissue tumor, with very poor prognosis. This tumor may be preliminarily diagnosed according to the imaging characteristics and detection of tumor markers, however, final diagnosis is made by pathology. Surgery is the priority of treatment, combined with complementary radiation and chemotherapy.

Association between genetic polymorphisms of cytochrome P450 2C19 and the risk of cerebral ischemic stroke in Chinese.

BACKGROUND: Cytochrome P450 (CYP) 2C19 is a very important drug metabolizing enzyme. Although the single nucleotide polymorphisms (SNPs) of CYP2C19 G681A and G636A have been suggested that they may increase the incidence of cardiovascular events, the relationship between SNPs in CYP2C19 and cerebral ischemic stroke (CIS) are unclear. The aim of this study was to investigate the correlation between the distribution of G681A and G636A polymorphisms in CYP2C19 gene and the risk of CIS in Chinese. METHODS: The peripheral blood DNA was extracted from 299 patients with CIS and 295 healthy controls. The genotyping was conducted using the polymerase chain reaction-restriction fragment length polymorphism. The sampled sequencing was applied to verify the correctness of genotyping results. Both the genotype and allele distributions were compared in patients with CIS and healthy controls. RESULTS: The frequencies of CYP2C19 681AA (11.7% vs. 2.7%; P = 0.000), 636AA (4.0% vs. 0.7%; P = 0.007), 636AG (7.0% vs. 2.2%; P = 0.038) genotype, CYP2C19 681A (30.9% vs. 20.8%; P = 0.000) and 636A (13.0% vs. 5.8%; P = 0.000) allele in the CIS group are significantly higher than those in the controls. The frequencies of CYP2C19 681AA (16.7% vs. 8.6%; P = 0.036), CYP2C19 636AA (7.0% vs. 2.2%; P = 0.038) genotype, CYP2C19 681A (36.4% vs. 27.6%; P = 0.023) and CYP2C19 636A (17.5% vs.10.3%; P = 0.010) allele in the recurrent stroke group are significantly higher than those in the first onset group. Multivariate logistic regression analysis of risk factors for cerebral ischemic stroke and recurrent stroke respectively suggests that the CYP2C19 681AA genotype may be an independent risk factor for CIS (OR = 6.179, 95% CI: 2.285 ~ 16.708; P = 0.000) and recurrent stroke (OR = 2.305, 95% CI: 1.121 ~ 4.743; P = 0.023). CONCLUSIONS: The AA genotype and A allele of CYP2C19 G681A may be related to the occurrence and recurrence of cerebral ischemic stroke.

Meta-analysis of studies on the association between the NF-κB1-94ins/del ATTG promoter polymorphism and cancer.

Nuclear factor-kappa B (NF-κB), a cell survival signal, is involved in carcinogenesis. Polymorphism of NF-κB1 is associated with cancer by several studies. This study aims to perform a comprehensive meta-analysis of studies and determine the association between the NF-κB1-94ins/del ATTG promoter polymorphism and cancer. Twenty-five case-control studies (7,281 cases and 10,039 controls) were included. We used odds ratios (ORs) to assess the strength of the association, and 95 % confidence intervals (CIs) to identify precision of the estimate. Overall, NF-κB1-94ins/del ATTG promoter polymorphism was significantly associated with decreased susceptibility to cancer in overall population under homozygote (for DD vs. WW: OR = 0.74, 95 % CI = 0.58-0.96), recessive (for DD vs. WD+WW: OR = 0.82, 95 % CI = 0.69-0.99), dominant (for DD+WD vs. WW: OR = 0.84, 95 % CI = 0.71-1.00), and allele (for D vs. W: OR = 0.88, 95 % CI = 0.78-0.98) model. Subgroup analysis for ethnicity found that NF-κB1-94ins/del ATTG promoter polymorphism was significantly associated with decreased susceptibility to cancer in Asians (for DD vs. WW: OR = 0.54, 95 % CI = 0.40-0.74; for WD vs. WW: OR = 0.75, 95 % CI = 0.69-0.81; for DD vs. WD+WW: OR = 0.70, 95 % CI = 0.55-0.90; for DD+WD vs. WW; OR = 0.66, 95 % CI = 0.56-0.78; for D vs. W: OR = 0.75, 95 % CI = 0.65-0.86), but the association was not found in Caucasians. The findings suggest that NF-κB1-94ins/delATTG promoter polymorphism is significantly associated with decreased susceptibility to cancer in overall and Asian population.

Evidence that TMEM67 causes polycystic kidney disease through activation of JNK/ERK-dependent pathways.

TMEM67 mutations are associated with severe autosomal recessive polycystic kidney disease (ARPKD) in both humans and animals. However, the molecular mechanisms underlying the pathogenesis of PKD caused by TMEM67 mutations remain to be determined. We have investigated the possible signalling pathways involved in the pathogenesis of PKD. Overexpression of TMEM67 in human embryonic kidney (HEK293) cells triggered the activation of overall tyrosine phosphorylated proteins, extracellular signal-regulated kinase (ERK) and c-jun N-terminal KINASE (JNK). Activation was suppressed by pharmacological inhibitors of ERK or JNK. Activation of the mammalian target of rapamycin (mTOR) or p70s kinase (S6K) did not occur, although elevated phosphorylation of eIF4E-binding protein 1 (4E-BP1), a target of S6K, was seen. In animal studies, activation of a variety of signalling molecules was linked to ERK, JNK and 4E-BP1. Significant induction of phosphorylation of tyrosine phosphorylated proteins, ERK and 4E-BP1, at different postnatal ages was detected in mutant kidneys of B6C3Fe a/a-bpck mice, a cystic renal disease mouse model caused by TMEM67 loss of function mutation. Based on these in vitro and in vivo observations, we propose that TMEM67 mutations cause PKD through ERK- and JNK-dependent signalling pathways, which may provide novel insight into the therapy of polycystic kidney diseases.

[Toll-like receptor 4 expression of human peripheral blood mononuclear cells treated by recombinant hIFN-α-2b-BCG and its role of immune activation].

OBJECTIVE: To examine the toll-like receptor 4 (TLR4) expression of human peripheral blood mononuclear cells (hPBMC) treated with recombinant bacillus Calmette-Guérin (rBCG) and its role of immune activation. METHODS: hPBMC was treated with recombinant human interferon (hIFN)-α-2b-BCG (rBCG) or wild BCG (wBCG) in vitro and the TLR4 expression detected by flow cytometry. The TLR4 functional blocking antibodies were applied for intervening the TLR4 signaling pathway of hPBMC. Then rBCG, wBCG, hIFN-α-2b and phosphate-buffered solution (PBS) were used to stimulate the hPBMC of blocking and non-blocking groups. The changes of human tumor necrosis factor-alpha (hTNF-α), human interleukin-12 (hIL-12) and hIFN-γ between the blocking and non-blocking groups by ELISA. RESULTS: The expression of TLR4 in hPBMC treated with rBCG or wBCG were stronger than that treat with PBS (all P < 0.05). In TLR4 non-blocking groups the expressions of hTNF-α and hIFN-γ were rBCG group > wBCG group > hIFN-α-2b group > PBS group, the expressions of hIL-12 was hIFN-α-2b group > PBS group > rBCG group > wBCG group (all P < 0.05). Application of TLR4 functional blocking antibodies to intervene hPBMC 48 h, comparing the changes in rBCG group, wBCG group, hIFN-α-2b group and PBS group, the expressions of hIFN-γ in TLR4 blocking groups (27.3 ± 1.2, 20.6 ± 0.9, 20.3 ± 0.8, 18.4 ± 0.7)were significantly inhibited than those in non-blocking groups (84.6 ± 1.3, 34.0 ± 1.0, 24.9 ± 0.9, 22.9 ± 0.7) (all P < 0.05). The expressions of hTNF-α in TLR4 blocking groups (1431 ± 28, 1032 ± 21, 104 ± 6, 109 ± 4) were significantly inhibited than those in non-blocking groups (1553 ± 28, 1065 ± 31, 343 ± 6, 299 ± 4) (all P < 0.05). The expressions of hIL-12 in TLR4 blocking groups (0.646 ± 0.005, 0.592 ± 0.015, 0.638 ± 0.008, 0.595 ± 0.019) were significantly inhibited than those in non-blocking groups (1.120 ± 0.012, 0.946 ± 0.015, 1.254 ± 0.011, 1.112 ± 0.024) (all P < 0.05). CONCLUSION: rBCG regulates the secretion of Th1 cytokines through the TLR4 signaling pathway.

[Stage I testis teratoma in adults: treatment options and recurrence factors].

OBJECTIVE: To study the clinical outcomes of stage I testis teratoma, including pure teratoma, and to provide information on the treatment options for this disease. METHODS: We retrospectively analyzed 27 cases of orchiectomy for stage I testis teratoma, excluding epidermoid cyst, and investigated its recurrence associated with treatment methods and clinicopathological factors. RESULTS: Four of the 27 cases relapsed, all in the orchiectomy group and confined to the retroperitoneal region, 3 with and the other 1 without risk factors, but with no death. No recurrence was found in those treated by orchiectomy followed by chemotherapy with bleomycin, etoposide and platinum (BEP). The total rate of recurrence was 15.8%. No severe side effects were observed in the 9 patients undergoing adjuvant BEP chemotherapy. CONCLUSION: Risk factors may increase the recurrence rate of stage I testis teratoma, while postoperative adjuvant chemotherapy can reduce it, including that of pure teratoma, though surveillance policy remains the most popular option after orchiectomy.

Oridonin Promotes Apoptosis and Restrains the Viability and Migration of Bladder Cancer by Impeding TRPM7 Expression via the ERK and AKT Signaling Pathways.

BACKGROUND: Oridonin is a powerful anticancer compound found in Rabdosia rubescens. However, its potential impact on bladder cancer remains uninvestigated. In this work, we aimed to detect the anticancer effect of oridonin on bladder cancer and explore the molecular mechanisms involved. METHODS: The anticancer activity of oridonin was assessed in vitro with a CCK8 assay, an annexin V-FITC apoptosis analysis, and colony formation and Transwell migration assays which were performed with the human bladder cancer cell line T24. Levels of apoptosis-related proteins, melastatin transient receptor potential channel 7 (TRPM7), and signaling molecules were examined in oridonin-treated T24 cells by western blotting or RT-PCR. Oridonin anticancer efficacy was further validated in vivo with a T24 xenograft mouse model. RESULTS: Oridonin repressed the proliferative, colony-forming, and migratory capacities of T24 cells, triggered extensive apoptosis in vitro, and retarded tumor growth in vivo. Moreover, oridonin treatment significantly increased expression levels of p53 and cleaved caspase-3 and reduced expression of TRPM7, p-AKT, and p-ERK. CONCLUSION: Oridonin exhibited outstanding antiproliferative and antimigratory effects on bladder cancer, and these effects were at least partially associated with targeting of TRPM7 through inactivation of the ERK and AKT signaling pathways. These findings provide insight for the clinical application of oridonin in bladder cancer prevention.

Progress in studies on pathological changes and future treatment strategies of obesity-associated female stress urinary incontinence: a narrative review.

With the increasing prevalence of obesity worldwide, obesity-related female stress urinary incontinence (FSUI) has become a key health problem. Recent studies indicated that FSUI is primarily caused by obesity-related pathological changes, such as fat droplet deposition, and results in pelvic floor nerve, vascular, and urethral striated muscle injury. Meanwhile, treatments for obesity-associated FSUI (OA-FSUI) have garnered much attention. Although existing OA-FSUI management strategies, including weight loss, pelvic floor muscle exercise, and urethral sling operation, could play a role in symptomatic relief; they cannot reverse the pathological changes in OA-FSUI. The continued exploration of safe and reliable treatments has led to regenerative therapy becoming a particularly promising area of researches. Specifically, micro-energy, such as low-intensity pulsed ultrasound (LIPUS), low-intensity extracorporeal shock wave therapy (Li-ESWT), and pulsed electromagnetic field (PEMF), have been shown to restore the underlying pathological changes of OA-FSUI, which might be related by regulation endogenous stem cells (ESCs) to restore urine control function ultimately in animal experiments. Therefore, ESCs may be a target for repairing pathological changes of OA-FSUI. The aim of this review was to summarize the OA-FSUI-related pathogenesis, current treatments, and to discuss potential therapeutic options. In particular, this review is focused on the effects and related mechanisms of micro-energy therapy for OA-FSUI to provide a reference for future basically and clinical researches.

SRD5A2 V89L polymorphism and prostate cancer risk: a meta-analysis.

BACKGROUND: Increasing studies investigating the association between steroid 5-alpha reductase type II gene polymorphism at codon 89 (SRD5A2 V89L) and susceptibility to prostate cancer (PCa) confer inconsistent results. To precisely estimate the relationship with more statistical power, a meta-analysis was performed. METHODS: A comprehensive search was conducted to identify all case-control studies investigating such an association. Odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the size effect. RESULTS: Twenty-five eligible reports were identified including 8,615 cases/9,089 controls in 33 comparisons. In overall analysis, no significant associations were found in all genetic models. Subgroup analyses by ethnicity revealed that small excess PCa risks were observed in dominant model (OR, 1.11; 95% CI, 1.03-1.19 for (LL + VL) vs. VV; P < 0.01; P(heterogeneity) = 0.49) and L allele frequency comparison (OR, 1.09; 1.03-1.15 for L allele frequency; P < 0.01; P(heterogeneity) = 0.07) in Europeans. Meanwhile, SRD5A2 V89L polymorphism was significantly associated with an increased PCa risk in men aged < or =65 under the co-dominant (OR, 1.70; 95% CI, 1.09-2.66 for LL vs. VV; P = 0.02; P(heterogeneity) = 0.31) and recessive (OR, 1.75; 95% CI, 1.14-2.68 for LL vs. (VV + VL); P = 0.01; P(heterogeneity) = 0.12) models. However, no significant associations were found in Asians and Africans. CONCLUSIONS: Our study suggests SRD5A2 V89L polymorphism could play a low-penetrant role in PCa risk among Europeans and individuals younger than 65 years. Additional well-designed studies are warranted to validate these findings.

Monitoring of CD95 and CD38 expression in peripheral blood T lymphocytes during active human cytomegalovirus infection after orthotopic liver transplantation.

AIM: The aim of the present study was to quantitatively monitor the response of CD95 molecules expressed on CD3(+) T cells (CD95(+)CD3(+) cells) and CD38 molecules expressed on CD8(+) T cells (CD38(+)CD8(+) cells) to ganciclovir treatment after orthotopic liver transplant (OLT) in recipients with active human cytomegalovirus (HCMV) infection. METHODS: Blood samples were collected from 20 liver transplanted recipients with active HCMV infection and 24 recipients without HCMV infection. CD95(+)CD3(+) cells and CD38(+)CD8(+) cells were quantitatively detected with QuantiBRITE bead methods by dual-color flow cytometry analysis during the post-transplantation period. RESULTS: CD95(+)CD3(+) cells and CD38(+)CD8(+) cells were not significantly different among different ages of healthy adults (P > 0.05). CD95(+)CD3(+) cells and CD38(+)CD8(+) cells were drastically increased in the active HCMV infection group compared with that in the stable group or in the healthy group (P < 0.001), and then they were gradually decreased within the next several weeks after ganciclovir treatment when compared with active HCMV infection recipients (P < 0.001). CONCLUSIONS: The present study showed that CD38(+)CD8(+) T cells can be an appropriate immunological marker for early detection and antiviral therapeutic monitoring of HCMV infection. The evaluation of CD95 molecule levels may be used routinely in clinical practice to assess the level of immunosuppression.

[Effect of recombinant hIFN-alpha-2b-BCG on mouse bladder tumor MB49 cells in vitro].

OBJECTIVE: To investigate the antitumor effect of recombinant IFN-alpha-2b-BCG on mouse bladder cancer MB49 cells in vitro, and to explore its antitumor mechanisms. METHODS: MB49 cells were co-cultured with recombinant BCG or wild BCG, and than were examined by light and transmission electron microscopy. The cell growth was assessed by MTT assay, and apoptosis rate and MHC-I of the MB49 cells was detected by flow cytometry using AO and Hoechst33258 fluorescence immunostaining. RESULTS: The hIFN-alpha-2b-BCG-treated tumor cells showed slow growth, detachment of some cells, and various degree of degeneration. Light microscopy revealed organelle disorganization, chromatin aggregation, nuclear pyknosis, and cytolysis in some cells. Cellular membrane bulged and some bubbles were seen under fluorescence microscope using AO staining. Hoechst33258 assay also depicted frequent apoptosis in the tumor cells. The MTT assay showed that rBCG more actively than the wild BCG inhibited the proliferation of MB49 cells. The apoptosis rate of the recombinant BCG group was 19.7% and 46.6% at the time point of 24 h and 48 h, respectively, significantly higher than 10.8% and 20.9%, respectively, in the wild BCG group. The results of flow cytometry indicated that both types of BCG enhanced the expression of MHC-I in the MB49 cells, but more effective in the recombinant BCG group. CONCLUSION: The recombinant hIFN-alpha-2b-BCG has more strong immuno-modulatory properties, anti-tumor effect on MB49 cells and induces apparent cytotoxicity in the bladder cancer cells in vitro.

Retraction: Graphene oxide/DNA-decorated electrode for the fabrication of microRNA biosensor.

[This retracts the article DOI: 10.1039/C5RA12373A.].

Control of precerebellar neuron development by Olig3 bHLH transcription factor.

The rhombic lip (RL) is the neuroepithelium immediately adjacent to the roof plate of the fourth ventricle, and it gives rise to various brainstem and cerebellar cell types. Our study shows that the bHLH (basic helix-loop-helix) transcription factor Olig3 is expressed in the progenitors of RL, and ablation of Olig3 significantly affects the development of RL. In Olig3-/- caudal RL, the expression level of Math1 in the dorsal interneuron 1 (dI1) domain is reduced, and the formation of four mossy-fiber nuclei is compromised; dI2-dI3 neurons are misspecified to dI4 interneurons, and the climbing-fiber neurons (inferior olive nucleus) are completely lost. In addition, the formation of brainstem (nor)adrenergic centers and first-order relay visceral sensory neurons is also dependent on Olig3. Therefore, Olig3 plays an important role in the fate specification and differentiation of caudal RL-derived neurons.

Recombinant bacillus Calmette-Guérin (BCG) expressing interferon-alpha 2B enhances human mononuclear cell cytotoxicity against bladder cancer cell lines in vitro.

PURPOSE: The proper induction of cellular immunity is required for effective bacillus Calmette-Guérin (BCG) immunotherapy of bladder cancer. It has been known that BCG stimulation of human peripheral blood mononuclear cells (PBMC) leads to the generation of effector cells cytotoxic to bladder cancer cells in vitro. To improve BCG therapy, we previously developed human interferon (IFN)-alpha 2B secreting recombinant (r) BCG (rBCG-IFN-alpha). We demonstrated that rBCG-IFN-alpha augmented T helper type 1 (Th1) cytokine IFN-gamma production by PBMC. In this study, we further investigated whether rBCG-IFN-alpha could also enhance PBMC cytotoxicity toward bladder cancer cells. MATERIALS AND METHODS: PBMC were prepared from healthy individuals, left alone or stimulated with rBCG-IFN-alpha or control MV261 BCG, and used as effector cells in (51)Cr-release assays. Human bladder cancer cell lines T24, J82, 5637, TCCSUP, and UMUC-3 were used as target cells. To determine the role of secreted rIFN-alpha as well as endogenously expressed IFN-gamma and IL-2 in inducing the cytotoxicity, PBMC were stimulated with rBCG-IFN-alpha in the presence of neutralizing antibodies to IFN-alpha, IFN-gamma or IL-2. To determine the role of natural killer (NK) and CD8(+) T cells in inducing the cytotoxicity, both cell types were isolated after BCG stimulation of PBMC and used as effector cells in (51)Cr-release assays. RESULTS: Non-stimulated PBMC showed basal levels of cytotoxicity against all target cell lines tested. MV261 BCG increased the PBMC cytotoxicity by 1.8- to 4.2-fold. rBCG-IFN-alpha further increased the PBMC cytotoxicity by up to 2-fold. Elevated production of IFN-gamma and IL-2 by PBMC was observed after rBCG-IFN-alpha stimulation. Blockage of IFN-alpha, IFN-gamma or IL-2 by neutralizing antibodies during rBCG-IFN-alpha stimulation reduced or abolished the induction of PBMC cytotoxicity. Both NK and CD8(+) T cells were found to be responsible for the enhanced PBMC cytotoxicity induced by rBCG-IFN-alpha with the former cell type being more predominant. CONCLUSIONS: rBCG-IFN-alpha is an improved BCG agent that induces enhanced PBMC cytotoxicity against bladder cancer cells in vitro. This rBCG strain may serve as an alternative to BCG for the treatment of superficial bladder cancer.

HER2 codon 655 polymorphism and breast cancer risk: a meta-analysis.

To evaluate the association between HER2 codon 655 polymorphism and breast cancer risk in this meta-analysis. A comprehensive search was performed to identify all case-control studies investigating such association. Statistical analyses were conducted with software MIX 1.54. Twenty eligible reports, including 10,642 cases/11,259 controls, were identified. In overall analysis, the Val allele frequency in cases was significantly higher than that in controls (OR = 1.0921, 95% CI: 1.0013-1.191, P = 0.0466), while no associations were found in both recessive and dominant models. In subgroup analysis, HER2 codon 655 polymorphism was weakly associated with breast cancer risk in recessive (OR = 2.4624, 95% CI: 1.0619-5.7104, P = 0.0357), dominant (OR = 1.2781, 95% CI: 1.0353-1.5779, P = 0.0225), and co-dominant genetic models (OR = 1.2947, 95% CI: 1.0682-1.5693, P = 0.0085) in Asian population, respectively. Meanwhile, the susceptibility to breast cancer in people aged < or =45 was significantly increased in both recessive (OR = 2.2408; 95% CI: 1.2876-3.8998, P = 0.0043), and dominant models (OR = 1.2902, 95% CI: 1.1035-1.5085, P = 0.0014). No significant associations were observed in Caucasian, European, and Family history subgroups. So our analyses suggest HER2 codon 655 Val allele is weakly associated with an increased risk of breast cancer, and SNP at HER2 codon 655 could be considered as a susceptibility biomarker for breast cancer for Asian females or women age 45 years or younger.

Synergistic effects of alpha-1,2-fucosyltransferase, DAF, and CD59 in suppression of xenogenic immunological responses.

BACKGROUND: Previous studies showed that alpha-1,2-fucosyltransferase (HT), decay accelerating factor (DAF), and CD59 have an inhibitory effect on the immunological rejection of xenogenic transplantation. METHODS: To investigate their possible synergistic effects in suppression of heterogeneic transplantation, we produced transgenic mouse lines expressing human HT, DAF, and/or CD59 by the standard pronuclear injection approach. PCR and Southern blot were used to identify the transgenic founder lines. Flow cytometry confirmed the high-level expression of HT, DAF, or CD59 in the transgenic mice. RESULTS: The deposition of IgM, C3c, or C9 in the cardiac vascular endothelial cells of the HT, HT/CD59, and/or DAF multiple positive transgenic mice was markedly decreased. The survival time and function of the hearts of the co-transgenic mice were significantly longer and higher than that of the single HT-positive transgenic mice (P < 0.05). CONCLUSION: The mice co-expressing HT/DAF or HT/CD59 could resist the hyperacute rejection better than those expressing HT alone. It is feasible to use HT and C-reactive proteins co-transgenic tissues to resist hyperacute rejection and xenograft rejection.

Temporal evolution of soluble Fas and Fas ligand in patients with orthotopic liver transplantation.

AIM: The aim of this study was to analyze the expression levels of plasma soluble Fas (sFas) and soluble Fas ligand (sFasL) in patients with orthotopic liver transplantation (OLT) procedures routinely performed without venovenous bypass. METHODS: The sFas and sFasL were analyzed in the blood of 20 consecutive patients who underwent transplantation. Blood samples were drawn from the radial artery at serial time points before, during, and after surgery. Plasma levels of sFas and sFasL were detected by Enzyme Linked-Immuno-Sorbent Assay. Plasma aspartate transaminase (AST) and alanine transaminase (ALT) were assayed by routine clinical chemistry testing. RESULTS: Marked elevation of plasma AST and ALT were detected at the reperfusion and postoperation time points (P<0.001), with a peak on the first postoperative day. The mean plasma concentration of sFas and sFasL remained unchanged from preoperative to anhepatic phase (T1 to T3) (P> or =0.268). The sFas and sFasL concentrations were significantly higher at 15 and 60 min after reperfusion compared to the preoperative value (P< or =0.048). Postoperatively, sFas and sFasL concentration were decreased to preoperative levels on the first postoperative day (P> or =0.127). CONCLUSION: The sFas and sFasL seem to be involved in reperfusion injury during OLT. The understanding of Fas may provide new insights into the mechanisms of ischemia/reperfusion injury during OLT.