D Rhamnose ß-hederin Reverses NAP1L5-mediated Adriamycin Resistance in Breast Cancer.

Context: The persistent use of anticancer medicines can cause multidrug resistance in many tumors and serious cytotoxicity for healthy cells, including adriamycin (ADR), a treatment for breast cancer (BC). Cell resistance to ADR in patients with recurrent advanced BC can occur. Creating effective treatments that can grapple with multidrug resistance is still challenging. Traditional Chinese medicine (TCM) may offer a solution in D Rhamnose beta-hederin (DRß-H), an oleanane type of triterpenoid saponin. Objective: The study intended to assess the ability of DRß-H to inhibit the ADR resistance of two BC-lineage cell lines, MCF-7 and SUM-1315, and to explore the causal link between DRß-H and the reversal of chemoresistance. Design: The research team performed a cell biology study. Setting: The study took place at laboratory in China. Outcome Measures: The research team: (1) assessed cell viability and the migration and invasion the cell lines; (2) investigated the molecular mechanism and identified the downstream targets of DRß-H, and (3) comprehensively examined the expression pattern, underlying functions, and evident prognostic significance of NAP1L5 in BC by gathering the online information available. Results: DRß-H can inhibit the viability of the MCF-7/ADR and SUM-1315/ADR cancer cells in a dosage-dependent manner. NAP1L5 might be the main target of DRß-H in reversing ADR resistance. Its expression decreased in BC cells, and the more advanced the BC was, the lower the NAP1L5 expression was. Conclusion: DRß-H at nontoxic concentrations was related to ADR resistance in BC through its downstream target NAP1L5. NAP1L5 is potentially a preferable prognostic marker for BC.

Metformin exhibits antiproliferation activity in breast cancer via miR-483-3p/METTL3/m6A/p21 pathway.

Evidence suggests that metformin might be a potential candidate for breast cancer treatment. Yet, its relevant molecular mechanisms remain to be fully investigated. We found that metformin could suppress the N6-methyladenosine (m6A) level in breast cancer cells significantly. The latter has an essential role in breast cancer progression and is newly considered as a therapeutic target. In this study, we measured the m6A level by m6A colorimetric analysis and dot blot assay. We then performed qRT-PCR, western blot, MeRIP, dual-luciferase reporter assay, and others to explore the m6A-dependent pathway associated with metformin. In vivo effect of metformin was investigated using a mouse tumorigenicity model. In addition, breast cancer and normal tissues were used to determine the role of METTL3 in breast cancer. Metformin could reduce the m6A level via decreasing METTL3 expression mediated by miR-483-3p in breast cancer. METTL3 is known to be able to promote breast cancer cell proliferation by regulating the p21 expression by an m6A-dependent manner. Metformin can take p21 as the main target to inhibit such effect. To specify, this study exhibited that metformin can inhibit breast cancer cell proliferation through the pathway miR-483-3p/METTL3/m6A/p21. Our findings suggest that METTL3 may be considered as a potential therapeutic target of metformin for breast cancer.

Bioinformatics analysis of potential therapeutic targets among ARHGAP genes in breast cancer.

GTPase activating proteins (RhoGAPs) serve significant roles in multiple aspects of tumor biology. Genes encoding RhoGAPs (ARHGAP), which switch off Rho-like GTPases, are responsible for breast cancer biogenesis. However, the identification of suitable and novel biomarkers for precision treatment and prognosis remains challenging. The present study aimed to evaluate the expression of ARHGAP family genes in breast cancer and investigate the survival data using the Oncomine, Kaplan-Meier Plotter, bcGenExMiner and cBioPortal online databases. The results demonstrated low expression of ARHGAP6, 7, 10, 14, 19, 23 and 24 and high expression of ARHGAP9, 11, 15, 18 and 30 in patients with breast cancer compared with that in healthy individuals. The survival analysis revealed that low expression levels of ARHGAP6, 7 and 19 were associated with poor relapse-free survival (RFS) and overall survival (OS), whereas high expression levels of ARHGAP9, 15 and 30 were associated with preferable RFS and OS. Metastatic relapse data demonstrated that higher expression of ARHGAP9, 15, 18, 19, 25 and 30 were associated with better prognosis and increased expression of ARHGAP11A and 14 exerted negative effects on patient prognosis. The overlapping genes ARHGAP9, 15, 19 and 30 obtained from these bioinformatics analysis tools exhibited significant association with clinical parameters including age, the presence of estrogen receptor, progesterone receptor and epidermal growth factor receptor-2, Scarff-Bloom-Richardson grade and Nottingham prognostic index. In conclusion, bioinformatics analysis revealed that ARHGAP9, 15, 19 and 30, but not other ARHGAP family genes may be promising targets with prognostic value and biological function for precision treatment of breast cancer.

Bioinformatics analysis of dysregulated microRNAs in exosomes from docetaxel-resistant and parental human breast cancer cells.

Background: Resistance to docetaxel is a major obstacle to effective treatment of breast cancer. Exosomal microRNAs (miRNAs) have recently been introduced in cell-to-cell transmission of chemoresistance between heterogeneous populations of tumor cells with diverse drug sensitivity. However, a systematic evaluation of the exosomal miRNA signature remains largely unclear. Method: miRNA expression profiles in exosomes from docetaxel-resistant (D/exo) and parental sensitive breast cancer cells (S/exo) were assessed using microarray. Bioinformatics analysis was performed to predict target genes of the dysregulated miRNAs and to uncover their potential roles in chemoresistance formation. Signaling pathways, gene ontology terms, transcription factors, protein-protein interactions, and hub genes were also constructed. Results: The selected exosomal miRNAs could modulate target genes responsible for MAPK, TGF-beta, Wnt, mTOR, and PI3K/Akt signaling pathways. Function enrichment analysis revealed the involvement of target genes in transcription regulation, protein phosphorylation, kinase activity, and protein binding. Enriched transcription factors including SP1, SP4, and EGR1 were obtained and a protein-protein interaction network was established. The hub genes for up-expressed and down-expressed exosomal miRNAs such as CCND1 and PTEN were identified. Conclusion: This bioinformatics study provides a comprehensive view of the function of dysregulated exosomal miRNAs, and may help us to understand exosome-mediated resistance transmission and overcome docetaxel resistance in future breast cancer therapy.

MicroRNA-222 promotes drug resistance to doxorubicin in breast cancer via regulation of miR-222/bim pathway.

Resistance to doxorubicin (DOX) is the most common clinical problem in breast cancer therapy, and the underlying molecular mechanism remains to be investigated. MicroRNAs (miRNAs) exhibit important regulatory functions in various malignant tumors including breast cancer. The aim of the present study was to find the relationship between miR-222 and DOX resistance. We found that miR-222 was highly expressed in patients' serum and DOX-resistant cell line MCF-7-R and that miR-222 could promote proliferation and migration of breast cancer cells. Our results also showed that inhibition of miR-222 in MCF-7-R significantly increased Bcl-2 interacting mediator (Bim) expression both in mRNA and protein levels by using quantitative real-time PCR (qRT-PCR) and Western blot. MTT and flow cytometry suggested that lower expressed miR-222 enhanced apoptosis and decreased IC50 of MCF-7-R cells. Conversely, in MCF-7 cells transfected with miR-222 mimics, up-regulation of miR-222 was associated with decreased Bim level accompanied by less apoptosis and higher IC50 Moreover, miR-222 inhibitors reversed DOX resistance via miR-222-Bim-caspase pathway. Collectively, these data first elucidated that miR-222 could function as an oncogene and was able to reduce the sensitivity of breast cancer cells to DOX through miR-222-Bim-caspase pathway, which provided a potential target to increase DOX sensitivity in clinical breast cancer treatment.

Bioinformatics analysis revealing prognostic significance of RRM2 gene in breast cancer.

Background: Ribonucleotide reductase M2 subunit (RRM2) plays vital roles in many cellular processes such as cell proliferation, invasiveness, migration, angiogenesis, senescence, and tumorigenesis. However, the prognostic significance of RRM2 gene in breast cancer remains to be investigated. Methods:RRM2 expression was initially evaluated using the Oncomine database. The relevance between RRM2 level and clinical parameters as well as survival data in breast cancer was analyzed using the Kaplan-Meier Plotter, PrognoScan, and Breast Cancer Gene-Expression Miner (bc-GenExMiner) databases. Results:RRM2 was overexpressed in different subtypes of breast cancer patients. Estrogen receptor (ER) and progesterone receptor (PR) were negatively correlated with RRM2 expression. Conversely, the Scarff-Bloom-Richardson (SBR) grade, Nottingham prognostic index (NPI), human epidermal growth factor receptor-2 (HER-2) status, nodal status, basal-like status, and triple-negative status were positively related to RRM2 level in breast cancer samples with respect to normal tissues. Patients with increased RRM2 showed worse overall survival, relapse-free survival, distant metastasis-free survival, disease-specific survival, and disease-free survival. RRM2 also exerted positive effect on metastatic relapse event. Besides, a positive correlation between RRM2 and KIF11 genes was confirmed. Conclusion: Bioinformatics analysis revealed that RRM2 might be used as a predictive biomarker for prognosis of breast cancer. Further studies are needed to more precisely elucidate the value of RRM2 in evaluating breast cancer prognosis.

Bioinformatics analysis of prognostic value of TRIM13 gene in breast cancer.

Background: Tripartite motif 13 (TRIM13) plays a significant role in various biological processes including cell growth, apoptosis, transcriptional regulation, and carcinogenesis. However, the prognostic significance of TRIM13 gene in breast cancer treatment remains largely unclear. Methods: We performed a bioinformatics analysis of the clinical parameters and survival data as it relates to TRIM13 in breast cancer patients using several online databases including Oncomine, bcGenExMiner, PrognoScan, and UCSC Xena. Results: We found that TRIM13 was lower-expressed in different subtypes of breast cancer with respect to normal tissues. Estrogen receptor and progesterone receptor status were positively correlated with TRIM13 level; whereas, the Scarff-Bloom-Richardson grade, Nottingham prognostic index, nodal status, basal-like status, and triple-negative status were negatively related to TRIM13 expression in breast cancer patients with respect to normal individuals. Lower TRIM13 expression correlated with worse distant metastasis free survival, relapse free survival, disease specific survival, and metastatic relapse free survival. We also confirmed a positive correlation between TRIM13 and RAB11FIP2 gene expression. Conclusion: Bioinformatics analysis revealed that TRIM13 may be adopted as a promising predictive biomarker for prognosis of breast cancer. More in-depth experiments and clinical trials are needed to validate the value of TRIM13 in breast cancer treatment.

Analysis of miRNA signature differentially expressed in exosomes from adriamycin-resistant and parental human breast cancer cells.

A major cause of failure in chemotherapy is drug resistance of cancer cells. Exosomes have been introduced to spread chemoresistance through delivering miRNAs. However, a systematic evaluation of the exosomal miRNA expression profiles responsible for chemoresistance is still lacking. In the present study, miRNA signature differentially expressed in exosomes derived from adriamycin-resistant (A/exo) and parental breast cancer cells (S/exo) were analyzed by microarray and the results were confirmed by PCR. A total of 309 miRNAs were increased and 66 miRNAs were decreased significantly in A/exo compared with S/exo. Specifically, 52 novel miRNAs with increased expression levels >16.0-fold in A/exo were identified. After prediction of target genes for 13 of 52 selected novel miRNAs, pathway analysis, gene ontology (GO) terms, and protein-protein interactions (PPIs) were constructed. The results implied that these selected exosomal miRNAs inhibited target genes involved in transcriptional misregulation in cancer, MAPK, and Wnt signaling pathways. Functional enrichment analysis demonstrated that the target genes were mainly responsible for protein phosphorylation, transcription regulation, molecular binding, and kinase activity. In summary, the current bioinformatics study of exosomal miRNAs may offer a new understanding into mechanisms of chemoresistance, which is helpful to find potential exosomal miRNAs to overcome drug insensitivity in future breast cancer treatment.

D Rhamnose ß-Hederin against human breast cancer by reducing tumor-derived exosomes.

D Rhamnose ß-hederin (DRß-H), a novel oleanane-type triterpenoid saponin isolated from the traditional Chinese medicinal plant Clematis ganpiniana, has been demonstrated to be effective against various types of tumor. However, the exact role of DRß-H on breast cancer remains largely unresolved. In the present study, it was observed that DRß-H exhibited anti-proliferative and pro-apoptotic activity in human breast cancer cells (MCF-7/S). DRß-H was able to inhibit exosome secretion, and the level of exosomes was positively associated with cell growth after absorption and internalization by target breast cancer cells. By analyzing the miRNA profiles of exosomes and MCF-7/S, it was identified that several miRNAs were detected exclusively in exosomes. Knockdown of the top five exosomal miRNAs and an MCF-7/S proliferation assay indicated that exosomal miR-130a and miR-425 may enhance MCF-7/S cell viability. Target gene prediction and pathway analysis revealed the involvement of miR-130a and miR-425 in pathways associated with malignant cell proliferation. These results demonstrated that DRß-H inhibited MCF-7/S cell growth through reducing exosome release.

d Rhamnose ß-hederin reverses chemoresistance of breast cancer cells by regulating exosome-mediated resistance transmission.

d Rhamnose ß-hederin (DRß-H), an active component extracted from the traditional Chinese medicinal plant Clematis ganpiniana, has been reported to be effective against breast cancer. Recent studies have also indicated that the isolated exosomes (D/exo) from docetaxel-resistant breast cancer cells MCF-7 (MCF-7/Doc) were associated with resistance transmission by delivering genetic cargo. However, the relevance of D/exo during DRß-H exposure remains largely unclear. In the present work, exosomes were characterized by morphology and size distribution. We reinforced the significant role of D/exo in spreading chemoresistance from MCF-7/Doc to recipient sensitive cells after absorption and internalization. DRß-H could reduce the formation and release of D/exo. Next, we demonstrated that DRß-H was able to reverse docetaxel resistance and that D/exo was responsible for DRß-H-mediated resistance reversal. We also found that DRß-H could decrease the expressions of several most abundant miRNAs (miR-16, miR-23a, miR-24, miR-26a, and miR-27a) transported by D/exo. Target gene prediction and pathway analysis showed the involvement of these selected miRNAs in pathways related to treatment failure. Our results suggested that DRß-H could reduce D/exo secretion from MCF-7/Doc cells and induce the reduction in resistance transmission via D/exo.

Potential Effects of Interleukins on the Pathogenesis of Systemic Onset Juvenile Idiopathic Arthritis.

BACKGROUND: To analyze the correlation of cytokines with clinical inflammatory indexes in systemic onset juvenile idiopathic arthritis (SOJIA). METHODS: A total of 30 active SOJIAs, 30 remission SOJIAs, and 20 normal controls were enrolled. The clinical inflammatory indexes such as tender joints counts, swelling joints counts, C-reactive protein, erythrocyte sedimentation rate, visual analogue scale (VAS), and disease activity score 28 (DAS28) were detected. The serum cytokines interleukin (IL)-17, IL-6, IL-21, interferon (IFN)-γ, and IL-4 levels were determined with enzyme-linked immunosorbent assay method. The correlation coefficients between these cytokines and two clinical indexes (VAS and DAS28) in the active SOJIA group were calculated with the Spearman's method. RESULTS: The serum IL-17 and IL-6 levels in active SOJIA group were significantly increased compared with those in the remission SOJIA group and control group (p < 0.05), and the serum IL-21, IFN-γ, and IL-4 levels showed no obvious difference. In the active SOJIA group, the Spearman coefficients between IL-17 and DAS28, IL-17 and IL-6, IL-6 and DAS28, and between IL-17 and VAS were 0.686 (p = 0.000), 0.833 (p = 0.000), 0.633 (p = 0.000), and 0.524 (p = 0.003), respectively. There was no correlation between cytokines of IL-21, IFN-γ, and IL-4 and the clinical indexes of DAS28 and VAS. Furthermore, in the other two groups, none of the five cytokines exhibited an association with DAS28 or VAS. CONCLUSION: IL-6 and IL-17 were significantly correlated with DAS28 and VAS, and they might be considered as therapeutic targets for the treatment of SOJIA.

Effects of intermedin on dorsal root ganglia in the transmission of neuropathic pain in chronic constriction injury rats.

Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. The P2X3 receptor plays a crucial role in facilitating pain transmission. Intermedin (IMD), which is also known as adrenomedullin 2 (AMD2) is a newly discovered hormone that is a member of the calcitonin/calcitonin gene-related peptide family. The present research investigates the effects of IMD on pain transmission in neuropathic pain states as mediated by P2X3 receptors in dorsal root ganglia (DRG). Chronic constriction injury (CCI) rats were used as the neuropathic pain model. Adult male Sprague-Dawley rats were randomly assigned to five groups as follows: blank control group (Control), sham operation group (Sham), CCI rats treated with saline group (CCI+NS), CCI rats treated with IMD1-53 group (CCI+IMD1-53 ), and CCI rats treated with IMD inhibitor IMD14-47 group (CCI+IMD14-47 ). The mechanical withdrawal threshold (MWT) was tested by the von Frey method, and the thermal withdrawal latency (TWL) was tested via automatic thermal stimulus instruments. Changes in the expression of P2X3 receptors and IMD in CCI rat L4/L5 DRG were detected using immunohistochemistry, reverse transcription-polymerase chain reaction, and Western blotting. After treatment with intrathecal injection (i.t.), mechanical and thermal hyperalgesia in the CCI+IMD1-53 group was maintained, but MWT and TWL in the CCI+IMD14-47 groups increased. The expression levels of P2X3 receptors and IMD in L4/L5 DRG in the CCI+NS and CCI+IMD1-53 groups were significantly increased compared with those in the Control group or the Sham group. After application of IMD14-47 in CCI rats, there was a decrease in the expression levels of P2X3 receptors and IMD in L4/L5 DRG. The phosphorylation of p38 and ERK1/2 in L4/L5 DRG in the CCI+NS group and the CCI+IMD1-53 group was stronger than that in the Control group or the Sham group; however, the phosphorylation of p38 and ERK1/2 in the CCI+IMD14-47 group was much lower than that in the CCI+NS group or the CCI+IMD1-53 group. Our findings indicate that IMD might increase the sensitization effects of IMD on P2X3 receptors to alleviate chronic neuropathic pain injury. The IMD agonist IMD1-53 might enhance nociceptive responses mediated by P2X3 receptors in neuropathic pain, and the IMD inhibitor IMD14-47 could inhibit the sensitization of the P2X3 receptor in chronic neuropathic pain injury.

Atopy in children with systemic onset juvenile idiopathic arthritis (SoJIA) is associated with a worse outcome.

CONTEXT: Atopy and systemic onset juvenile idiopathic arthritis (SoJIA) are two potential outcomes of a dysregulated immune system. Although rare, SoJIA causes 60% of the morbidity of JIA patients which exhibit a wide heterogeneity of prognosis and treatment. Co-morbidities can complicate the responses to therapy. OBJECTIVE: To study the influence of co-existing atopy on the prognosis of SoJIA. MATERIALS AND METHODS: Patients diagnosed with SoJIA between Jan 2006 and Sep 2010 were screened, enrolled in this prospective cohort study, and followed for 2 years. Management of SoJIA patients was assessed by ACR Pedi30/50/70 criteria, laboratory variables, and systemic feature score. RESULTS: At disease onset, 61 SoJIA patients (34 male and 27 female) were enrolled and were divided into SoJIA patients with atopy (n = 27) or those without atopy (n = 34). Atopic group at disease onset had significantly higher numbers of affected joints, ferritin levels and IgE serum levels than the non-atopic group. At 3 and 6 months, fewer SoJIA patients with atopy reached the ACR Pedi50 criteria (p < 0.02). During the 2 years of follow-up time, the number of infections and the number of flares were significantly higher in the SoJIA with atopy group (p < 0.01). CONCLUSION: Atopy may exert an adverse influence on SoJIA, as patients with atopy had a more active disease at diagnosis and poorer outcome. This prospective study showed that the TH1/TH2 hypothesis was too simplistic to explain the interaction between atopy and SoJIA.

GSTT1 genetic polymorphism and susceptibility to childhood acute lymphoblastic leukemia: a meta-analysis.

Glutathione S-transferase T1 (GSTT1) genetic polymorphism has been considered as a risk factor for developing malignant diseases including acute lymphoblastic leukemia; however, the results from previous studies are inconsistent. We performed a meta-analysis of 16 published studies to investigate the association between GSTT1 null variant and risk of acute lymphoblastic leukemia in childhood. Between-study heterogeneity was assessed using the I (2) statistic method. Odds ratios (ORs) with corresponding 95 % confidence intervals (95 %CI) were pooled to assess the association. Those 16 studies were from 14 publications and included a total of 2,424 cases and 3,447 controls. Meta-analysis of a total of 16 studies showed that GSTT1 null variant was significantly associated with risk of childhood acute lymphoblastic leukemia (fixed-effect OR = 1.22, 95 %CI 1.07-1.39, P = 0.003, I (2) = 35 %). Subgroup analysis showed that GSTT1 null variant was significantly associated with risk of childhood acute lymphoblastic leukemia in Asians (fixed-effect OR = 1.47, 95 %CI 1.16-1.85, P = 0.001, I (2) = 0 %). However, there was no obvious association in both Caucasians (random-effect OR = 1.07, 95 %CI 0.83-1.38, P = 0.59, I (2) = 53 %) and Africans (random-effect OR = 0.99, 95 %CI 0.31-3.10, P = 0.98, I (2) = 72 %). Therefore, the GSTT1 null variant is significantly associated with susceptibility to childhood acute lymphoblastic leukemia in Asians.

Dynamic random access memory devices based on bismuth sulfide nanoplates prepared from a single source precursor.

Semiconducting bismuth sulfide (Bi2S3) nanoplates with unique highly oriented {001} surfaces were prepared on a large scale using a novel organic precursor Bi(DTCA)3 (DTCA = carbazole-9-carbodithioic acid). The as-prepared Bi2S3 nanoplates were dispersed in dimethyl sulfoxide (DMSO) and spin-coated onto an indium tin oxide (ITO) coated glass substrate. With a simple ITO/Bi2S3/Al stacked structure, the fabricated sandwich-like memory device demonstrates dynamic random access memory (DRAM) characteristics with a maximum ON/OFF current ratio up to 10(6) and a long retention time. It is suggested that the volatile nature of the memory device comes from the Schottky contact between the Bi2S3 nanoplates and the Al electrodes.

Tetrandrine suppresses LPS-induced astrocyte activation via modulating IKKs-IkappaBalpha-NF-kappaB signaling pathway.

Astrocyte activation has been implicated in the pathogenesis of many neurological diseases. These reactive astrocytes are capable of producing a variety of proinflammatory mediators and potentially neurotoxic compounds, such as nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta). In this study, we examined the suppressive effects of Tetrandrine (TET) on astrocyte activation induced by lipopolysaccharide (LPS) in vitro. We found that TET decreased the release of NO, TNF-alpha, IL-6 and IL-1beta in LPS-activated astrocytes. Also mRNA expression levels of inducible nitric oxide synthase (iNOS), macrophage inflammatory protein-1alpha (MIP-1alpha) and vascular cell adhesion molecule-1 (VCAM-1) were inhibited in TET pretreated astrocytes. Such suppressive effects might be resulted from the inhibition of nuclear factor kappa B (NF-kappaB) activation through downregulating IkappaB kinases (IKKs) phosphoration, which decreased inhibitor of nuclear factor-kappaB-alpha (IkappaBalpha) phosphoration and degradation. Our results suggest that TET acted to regulate astrocyte activation through inhibiting IKKs-IkappaBalpha-NF-kappaB signaling pathway.

Tetrandrine suppresses lipopolysaccharide-induced microglial activation by inhibiting NF-kappaB pathway.

AIM: Microglial activation has been implicated in many neurological diseases. In this study, we examined the effects of tetrandrine (TET), a major pharmacologically-active compound of Chinese herb Stephania tetrandra S Moore on microglial activation. METHODS: The microglia pretreated with or without TET were activated by lipopolysaccharide (LPS) in vitro. Nitric oxide (NO) release, superoxide anion (O2-) generation, as well as TNF-alpha and interleukin-6 (IL-6) production by microglia were measured afterwards. Electrophoretic mobility shift assay was performed to determine whether NF-kappaB activity in microglia was affected by TET treatment. RESULTS: We found that TET inhibited the LPS-induced activation of microglia by decreasing the production of NO and O2-, consequently affecting the release of TNF-alphaand IL-6 in LPS-induced microglial activation. Such suppressive effect was accompanied by inhibiting transcription factor NF-kappaB activation. CONCLUSION: Our results suggest that TET might modulate LPS-induced microglial activation by inhibiting the NF-kappaB-mediated release of inflammatory factors.

IL-12/IFN-gamma/NO axis plays critical role in development of Th1-mediated experimental autoimmune encephalomyelitis.

The importance of the IL-12/IFN-gamma/nitric oxide (NO) axis in the pathogenesis of autoimmune diseases remains controversial. In parallel experiments, we explored the role of the IL-12/IFN-gamma/NO axis in the development of MOG 35-55-induced experimental autoimmune encephalomyelitis (EAE) in mice lacking IL-12, IFN-gamma receptor (IFN-gammaR) and inducible nitric oxide synthase (NOS2), respectively. In comparison with wide-type control mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice displayed more severe clinical signs of EAE both in remission and at subsequent relapse. Given the relatively low IFN-gamma production in IL-12-/- mice and the lack of IFN-gamma/IFN-gammaR signaling pathway in IFN-gammaR-/- mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice with EAE exhibited low NO production. This correlated negatively with MOG 35-55-induced T cell proliferation. Both ED1-positive macrophages and CD4-positive T cells were increased in spinal cords from IL-12-/-, IFN-gammaR-/- and NOS2-/- compared to control mice. In vitro experiments demonstrate that spleen mononuclear cells from IL-12-/-, IFN-gammaR-/- and NOS2-/-mice with EAE present stronger migration capacity when compared to control mice. These results reveal that the IL-12/IFN-gamma/NO axis plays a critical role in the development of MOG 35-55-induced EAE, possibly over failing NO production.

[Efficacy of selective continuous transarterial infusion chemotherapy on advanced pancreatic cancer].

BACKGROUND & OBJECTIVE: Advanced pancreatic cancer is mainly treated by chemotherapy with poor prognosis. This study was designed to evaluate clinical efficacy and application of selective continuous transarterial infusion chemotherapy in treating patients with advanced pancreatic cancer. METHODS: Twenty patients with advanced pancreatic cancer were treated by selective continuous transarterial infusion chemotherapy. The interventional treatment was performed with Seldinger technique,12 patients received percutaneous femoral artery cannulization and catheter retention, 8 received percutaneous left subclavian artery port-catheter system implantation. Chemotheraputic drugs were continuously infused when the catheter was selectively placed in turner feeding artery. Nine patients were treated with pirarubicin (THP)/adriamycin (ADM) plus hydroxycamptothecin (HCPT),and 5-fluorouracil (5-FU)/calcium folinate (CF) regimen,and 11 were treated with gemcitabine (GEM) plus carboplatin (CBP),and 5-FU/CF regimen. Treatment regimens were repeated every 4-6 weeks with each cycle of 4 days. Tumor response rate,clinical benefit response (CBR),and survival time were observed. RESULTS: Objective response rate was 10% with 1 case of complete remission (CR), and 1 case of partial remission (PR), CBR was 70% (14/20), 6-,and 9-month survival rates were 58.8%,and 39.2%. Median survival time for all patients was 8.8 months. No complication related to cannulization was found. CONCLUSION: Selective continuous transarterial infusion chemotherapy is safe,and has good efficacy in treating patients with advanced pancreatic cancer, it may prolong survival time of patients.