BackgroundConventional chemotherapy and radiotherapy for the treatment of lymphoma have notable drawbacks, and passive immunotherapy using a monoclonal antibody is restricted to CD20-positive B cell lymphoma. Therefore, new treatment types are urgently required, especially for T cell lymphoma. One type of new antitumour therapy is the use of active immunotherapeutic agents, such as agonists of the Toll-like receptors (TLRs), which facilitate the induction of prolonged antitumour immune responses.MethodsWe have synthesised a novel TLR7 agonist called SZU-101 and investigated the systemic antitumour effect on a murine model of T cell lymphoma in vivo.ResultsHere, we report that the intratumoural administration of SZU-101 enhanced the effectiveness of a conventionally used chemotherapeutic agent, doxorubicin (DOX). SZU-101 administration improved tumour clearance in a murine model of T cell lymphoma. The novel combination of intratumourally administered SZU-101 and DOX generated strong cytokine production and enhanced the cytotoxic T lymphocyte response, leading to the eradication of both local and distant tumours in tumour-bearing mice.ConclusionsThese findings suggested that combined active immunotherapy can be developed as a promising treatment for T cell lymphoma, which may further improve the effectiveness of the current standard cyclophosphamide, DOX, vincristine and prednisone (CHOP) therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0121-9) contains supplementary material, which is available to authorized users.
The resistance genes Lr9, Lr24, Lr25, Lr29, Lr35 and Lr37, which were not previously utilised in Hungary, have been incorporated into four Martonvásár winter wheat cultivars using markerassisted selection with PCR-based markers. In the course of a backcross programme, the genes were transferred into Martonvásár wheat varieties and various BC generations were produced. Work aimed at pyramiding resistance genes is currently underway in Martonvásár, and plants containing the gene combinations Lr9 ? Lr24, Lr9 ? Lr25 and Lr9 ? Lr29 are now available. From the BC 2 F 4 generation of the 'Mv Emma'*3/'R.L.6010' combination ('R.L.6010' is the donor of the Lr9 gene) 287 lines were tested for leaf rust resistance in an artificially inoculated nursery. A co-dominant primer combination was designed to identify both resistant and susceptible offsprings. The results of resistance tests and molecular marker detection agreed in most cases. Designated leaf rust resistance genes were identified with molecular markers in wheat varieties and breeding lines. The Lr26 and Lr34 resistance genes occur frequently in the Martonvásár gene pool, and the presence of the Lr37 gene has also been detected in a number of Hungarian genotypes.
Adult-plant resistance (APR) is an effective means of controlling powdery mildew in wheat. In the present study, 406 simple-sequence repeat markers were used to map quantitative trait loci (QTLs) for APR to powdery mildew in a doubled-haploid (DH) population of 181 lines derived from the cross Bainong 64xJingshuang 16. The DH lines were planted in a randomized complete block design with three replicates in Beijing and Anyang during the 2005-06 and 2007-08 cropping seasons. Artificial inoculations were carried out in Beijing using the highly virulent Blumeria graminis f. sp. tritici isolate E20. Disease severities on penultimate leaves were scored twice in Beijing whereas, at Anyang, maximum disease severities (MDS) were recorded following natural infection. Broad-sense heritabilities of MDS and areas under the disease progress curve were 0.89 and 0.77, respectively, based on the mean values averaged across environments. Composite interval mapping detected four QTLs for APR to powdery mildew on chromosomes 1A, 4DL, 6BS, and 7A; these were designated QPm.caas-1A, QPm.caas-4DL, QPm.caas-6BS, and QPm.caas-7A, respectively, and explained 6.3 to 22.7% of the phenotypic variance. QTLs QPm.caas-4DL and QPm.caas-6BS were stable across environments with high genetic effects on powdery mildew response, accounting for 15.2 to 22.7% and 9.0 to 13.2% of the phenotypic variance, respectively. These results should be useful for the future improvement of powdery mildew resistance in wheat.
Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the α,β-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/β-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer.
Background: The global burden of hepatitis B virus (HBV) infection in terms of morbidity and mortality is immense. Novel treatments that can induce a protective immune response are urgently needed to effectively control the HBV epidemic and eventually eradicate chronic HBV infection. Methods:We designed and evaluated an HBV therapeutic vaccine consisting of a novel Toll-like receptor 7 (TLR7) agonist T7-EA, an Alum adjuvant and a recombinant HBsAg protein. We used RNA-seq, ELISA and hTLR7/8 reporting assays to characterize T7-EA in vitro and real-time PCR to evaluate the tissue-retention characteristics in vivo. To evaluate the adjuvant potential, we administrated T7-EA intraperitoneally in a formulation with an Alum adjuvant and HBsAg in normal and HBV mice, then, we evaluated the HBsAg-specific immune responses by ELISA and Elispot assays.Results: T7-EA acted as an hTLR7-specific agonist and induced a similar gene expression pattern as an unmodified TLR7 ligand when Raw 264.7 cells were exposed to T7-EA; however, T7-EA was more potent than the unmodified TLR7 ligand. In vivo studies showed that T7-EA had tissue-retaining activity with stimulating local cytokine and chemokine expression for up to 7 days. T7-EA could induce Th1-type immune responses, as evidenced by an increased HBsAgspecific IgG2a titer and a T-cell response in normal mice compared to mice received traditional Alum-adjuvant HBV vaccine. Importantly, T7-EA could break immune tolerance and induce persistent HBsAg-specific antibody and T-cell responses in an HBV mouse model. Conclusions:T7-EA might be a candidate adjuvant in a prophylactic and therapeutic HBV vaccine.
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