Mathewswaller0171

The efficacy and safety of Epstein-Barr virus (EBV)-specific antigen peptide-activated cytotoxic T lymphocytes (CTLs) in the treatment of refractory or recurrent angioimmunoblastic T-cell lymphoma (AITL) was determined in this prospective one-arm clinical study. Seven males and two females were enrolled with a median age of 70 years. The tumor stages were all stage III and IV. All patients had group B symptoms and IPI scores of 3 to 5 points. All patients received chemotherapy before CTLs infusion which the median chemotherapy cycle was three. The diseases states before CTLs included five cases of disease progression (PD), two cases of recurrence (R), and two cases with residual lesions after chemotherapy. Eight patients received HLA-haploidentical EBV-specific CTLs, and one patient chose autologous CTLs. The number of transfused cells was 1.67 to 2.38 × 1010 for one course of CTLs therapy. One patient was treated with three courses of CTLs, three patients were treated with two courses of CTLs, and five patients were treated with one course of CTLs. During the infusion, eight patients had fever, one patient had rash, and no graft-vs-host diseases were observed. The EBV-DNA decreased by more than two orders of magnitude in six patients, and the response rate was 66.7%. Two patients of PD status achieved complete remission (CR), one patient of PD status achieved partial remission, two patients with residual lesions after chemotherapy achieved CR, and four patients had no response. The objective remission rate was 55.6%. After the median follow-up of 14.5 months, five patients died, and three patients were completely relieved while one patient was lost during follow-up. The 3-year overall survival was 44.4% and 3-year progression-free survival was 33.3%. EBV-specific antigen peptide-activated CTLs showed positive effect in certain patients with refractory and recurrent AITL with high clinical safety. © 2020 John Wiley & Sons Ltd.Polyphenols exert pharmacological actions through protein-mediated mechanisms and by modulating intracellular signalling pathways. We recently showed that a gut-microbial metabolite of ellagic acid named urolithin C is a glucose-dependent activator of insulin secretion acting by facilitating L-type Ca2+ channel opening and Ca2+ influx into pancreatic β-cells. However, it is still unknown whether urolithin C regulates key intracellular signalling proteins in β-cells. Here, we report that urolithin C enhanced glucose-induced extracellular signal-regulated kinases 1/2 (ERK1/2) activation as shown by higher phosphorylation levels in INS-1 β-cells. Interestingly, inhibition of ERK1/2 with two structurally distinct inhibitors led to a reduction in urolithin C effect on insulin secretion. Finally, we provide data to suggest that urolithin C-mediated ERK1/2 phosphorylation involved insulin signalling in INS-1 cells. Together, these data indicate that the pharmacological action of urolithin C on insulin secretion relies, in part, on its capacity to enhance glucose-induced ERK1/2 activation. Therefore, our study extends our understanding of the pharmacological action of urolithin C in β-cells. More generally, our findings revealed that urolithin C modulated the activation of key multifunctional intracellular signalling kinases which participate in the regulation of numerous biological processes. © 2020 Société Française de Pharmacologie et de Thérapeutique.NF-κB signaling pathway is important for linking inflammation and tumorigenesis. Here, we characterized a NF-κB-signaling-activation induced long intergenic non-coding RNA in hepatocellular carcinoma (HCC), LINC00665 that contributes to the enhanced cell proliferation of HCC cells both in vitro and in vivo. LINC00665 physically interacts with the double-stranded RNA (dsRNA)-activated protein kinase (PKR) and enhances its activation, and maintains PKR protein stability by blocking ubiquitin/proteasome-dependent degradation, thus resulting in a positive feedback regulation of NF-κB signaling in HCC cells. Notably, HCC patients with higher LINC00665 have poorer outcomes in clinic CONCLUSION Our findings indicate that LINC00665 is involved in the NF-κB signaling activation in HCC cells and inflammatory LINC00665/PKR/NF-κB loop plays important oncogenic roles in hepatic cancer progression and may be a potential therapeutic target. This article is protected by copyright. All rights reserved.INTRODUCTION We investigated the mechanisms underlying immobilization-induced muscle pain in rats. METHODS In rat skeletal muscle, pressure pain threshold (PPT) of the gastrocnemius muscle was measured, and nerve growth factor (NGF) level, peripheral nerve fiber density, macrophage number, and interleukin-1β (IL-1β) mRNA expression were examined. An NGF receptor inhibitor was injected intramuscularly to assess the relationship between PPT and NGF levels. RESULTS Immobilization resulted in a decrease in PPT and increases in NGF level, C-fiber density, M1 macrophage number, and IL-1β mRNA expression. Injection of NGF receptor inhibitor reversed the decrease in PPT. DISCUSSION NGF upregulation may be a major contributor to immobilization-induced muscle pain. The increases in C-fiber density, M1 macrophage number, and IL-1β mRNA expression may be related to immobilization-induced muscle pain. © 2020 Wiley Periodicals, Inc.The gaseous plant hormone ethylene induces the ripening of climacteric fruit, including apple (Malus domestica). Another phytohormone, auxin, is known to promote ethylene production in many horticultural crops, but the regulatory mechanism remains unclear. Here, we found that auxin application induces ethylene production in apple fruit prior to the stage of commercial harvest, when they are not otherwise capable of ripening naturally. The expression of MdARF5, a member of the auxin response factor transcription factor (TF) family involved in the auxin signaling pathway, was enhanced by treatment with the synthetic auxin naphthaleneacetic acid (NAA). Further studies revealed that MdARF5 binds to the promoter of MdERF2, encoding a TF in the ethylene signaling pathway, as well as the promoters of two 1-aminocyclopropane-1-carboxylic acid synthase (ACS) genes (MdACS3a and MdACS1) and an ACC oxidase (ACO) gene, MdACO1, all of which encode key steps in ethylene biosynthesis, thereby inducing their expression. We also observed that auxin-induced ethylene production was dependent on the methylation of the MdACS3a promoter. Our findings reveal that auxin induces ethylene biosynthesis in apple fruit through activation of MdARF5 expression. This article is protected by copyright. All rights reserved.Tricin (3´,5´-dimethoxylated flavone) is a predominant flavonoid amongst monocots but occurs only in isolated and unrelated dicot lineages. Although tricin biosynthesis has been intensively studied in monocots, it remained largely elusive in tricin-accumulating dicots. We investigated a subgroup of cytochrome P450 (CYP) 75B subfamily flavonoid B-ring hydroxylases (FBHs) from two tricin-accumulating legumes, Medicago truncatula and alfalfa (M. sativa), by phylogenetic, molecular, biochemical and mutant analyses. Five Medicago cytochrome P450 CYP75B FBHs are phylogenetically distant from other legume CYP75B members. Among them, MtFBH-4, MsFBH-4 and MsFBH-10 were expressed in tricin-accumulating vegetative tissues. In vitro and in planta analyses demonstrated that these proteins catalyze 3´- and 5´-hydroxylations critical to tricin biosynthesis. A key amino acid polymorphism, T492G, at their Substrate Recognition Site 6 domain is required for the novel 5´-hydroxylation activities. M. truncatula mtfbh-4 mutants were tricin-deficient, indicating that MtFBH-4 is indispensable for tricin biosynthesis. Our results revealed that these Medicago legumes had acquired the tricin pathway through molecular evolution of CYP75B FBHs subsequent to speciation from other non-tricin-accumulating legumes. Moreover, their evolution is independent from that of grass-specific CYP75B apigenin 3´-hydroxylases/chrysoeriol 5´-hydroxylases dedicated to tricin production and Asteraceae CYP75B flavonoid 3´,5´-hydroxylases catalyzing the production of delphinidin-based pigments. This article is protected by copyright. All rights reserved.AIMS PDGFRB rearrangement defines a unique group of myeloid/lymphoid neoplasms with frequent eosinophilia and high sensitivity to tyrosine kinase inhibitors. This genetic abnormality is also rarely reported in Philadelphia-like B-lymphoblastic leukemia (B-ALL). PDGFRB rearrangement was initially thought to only occur in cases with 5q31-33 rearrangement by conventional cytogenetics; however, there are reported cases with cryptic rearrangements, suggesting the need for a broader screening strategy. METHODS AND RESULTS We performed FISH for PDGFRB rearrangement in 197 patients, including 70 B-ALL, 10 myeloid neoplasms with 5q31-33 rearrangements, and 117 with eosinophilia (≥0.5 x 109 /L in peripheral blood or ≥ 5% in bone marrow), and identified PDGFRB rearrangement in 4/197 (2.0%) cases. In an attempt to identify clinicopathologic and genetic features that may have a stronger association with PDGFRB rearrangement, we analyzed 13 patients with confirmed PDGFRB rearrangements, including 10 myeloid neoplasms and 3 B-ALL. Of the 10 patients with myeloid neoplasms, eosinophilia was present in 8, monocytosis in 2, 5q31-33 rearrangement in 7, and abnormal bone marrow morphology in all. All patients with myeloid neoplasms showed an excellent response to imatinib including a patient in blast crisis. The three B-ALL patients presented de novo, showed no eosinophilia, had complex karyotype including 5q31-33 rearrangement, and had clinically aggressive courses with ultimate patient demise. CONCLUSIONS These findings suggest a higher yield for the identification of PDGFRB rearrangement may result from an index of suspicion on patients with eosinophilia, monocytosis, bone marrow features of a myeloid neoplasm, 5q31-33 rearrangement, and patients with Philadelphia-like B-ALL. This article is protected by copyright. All rights reserved.BACKGROUND Healthcare professionals (HCPs) play an important role in discussing weight with children and their parents but report barriers such as lack of training and supports. These barriers are especially prevalent within specialized populations such as children with autism spectrum disorder (ASD). To address this, a Knowledge Translation Casebook on positive weight-related conversations was developed by a research team at a Canadian paediatric hospital. The purpose of the current pre-implementation pilot study was to explore initial acceptability and adoption of the Casebook into clinical settings. METHODS An interactive, multimodal education workshop was created to provide HCPs with knowledge and training on how to have positive weight-related conversations with children and parents. Two workshops were conducted using the same curriculum but delivered either in-person or online. Participants were drawn from a team of clinicians at a teaching hospital whose care focuses on medication management for clientded to foster the uptake of best practices in weight-related conversations into clinical practice. © 2020 John Wiley & Sons Ltd.