Search

Although chemotherapy using CHOP-based protocol induces remission in most cases of canine multicentric high-grade B-cell lymphoma (mhBCL), some cases develop early relapse during the first induction protocol. In this study, we examined the gene expression profiles of canine mhBCL before chemotherapy and investigated their associations with early relapse during the first whole CHOP-based protocol. Twenty-five cases of mhBCL treated with CHOP-based protocol as first induction chemotherapy were included in this study. Sixteen cases completed the first whole CHOPbased protocol without relapse (S-group), and nine developed relapse during the chemotherapy (R-group). RNA-seq was performed on samples from neoplastic lymph nodes. Differentially expressed genes (DEGs) were extracted by the comparison of gene expression profiles between S- and R-groups, and the differences in the expression levels of these genes were validated by RTqPCR. Extracted 179 DEGs included the genes related to chemokine CC motif ligand, T-cell receptor signaling pathway, and PD-L1 expression and PD-1 checkpoint pathway. We focused on chemokine CC motif ligand, and CCL4 was confirmed to be significantly downregulated in the R-group (P=0.039). We also focused on the genes related to T-cell signaling pathway, and CD3E (P=0.039), ITK (P=0.023), and LAT (P=0.023) genes were confirmed to be significantly upregulated in the R-group. The current results suggest that both changes in tumor cells and the interactions between tumor cells and immune cells are associated with the efficacy of the chemotherapy for first remission induction. [ABSTRACT FROM AUTHOR]

Celastrol, a bioactive molecule extracted from the Tripterygium wilfordii plant, has been shown to exhibit anti-inflammatory properties. However, its mechanism of action has not been fully elucidated. Here, we show that celastrol suppresses humoral immune responses and autoimmunity by disabling a protein complex consisting of copper metabolism MURR1 domain–containing (COMMD) 3 and COMMD8 (COMMD3/8 complex), a signaling adaptor for chemoattractant receptors. Having demonstrated the involvement of the COMMD3/8 complex in a mouse model of rheumatoid arthritis, we identified celastrol as a compound that covalently bound to and dissociated the COMMD3/8 complex. Celastrol inhibited B cell migration, reduced antibody responses, and blocked arthritis progression, recapitulating deficiency of the COMMD3/8 complex. These effects of celastrol were abolished in mice expressing a celastrol-resistant mutant of the COMMD3/8 complex. These findings establish that celastrol exerts immunosuppressive activity by targeting the COMMD3/8 complex. Our study suggests that the COMMD3/8 complex is a potentially druggable target in autoimmune diseases and points to celastrol as a lead pharmacologic candidate in this capacity. Targeting B cell migration in arthritis: COMMD3 and COMMD8, members of the copper metabolism MURR1 domain–containing (COMMD) protein family, form a heterodimer essential for chemoattractant-mediated B cell migration during induction of humoral immune responses. By screening a compound library for molecules capable of disrupting the COMMD3/8 complex, Shirai et al. identified the Chinese herbal medicine celastrol as a potent inhibitor of COMMD3 association with COMMD8. In a mouse model of rheumatoid arthritis, celastrol treatment initiated at the onset of arthritis prevented disease progression. Celastrol's ability to disrupt the COMMD3/8 complex and inhibit arthritis was lost when cysteine 170 of COMMD3 was replaced with alanine. These findings reveal a molecular mechanism for the anti-arthritic activity of celastrol and identify the COMMD3/8 complex as a potential drug target in B cell-dependent autoimmune diseases. —IRW [ABSTRACT FROM AUTHOR]

Approximately 60–70% of EWSR1-negative small blue round cell sarcomas harbour a rearrangement of CIC, most commonly CIC-DUX4. CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX4 fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX4 pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo. Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS. [ABSTRACT FROM AUTHOR]

Canine histiocytic sarcoma (CHS) is a malignant tumor derived from macrophages and dendritic cells. Since effective chemotherapy is needed for CHS cases, we conducted this prospective study to evaluate the efficacy and adverse events of vincristine treatment as a rescue therapy for this disease. We administered vincristine to nine CHS cases that acquired resistance to lomustine or nimustine. Complete remission was achieved in one dog, partial remission in two dogs, stable disease in five dogs, and progressive disease in one dog. The median progression-free survival was 21 days (range: 7-71 days). Severe adverse effect was observed in one dog (Grade 3 thrombocytopenia). It is essential to establish novel effective treatments for CHS.

Non-neoplastic bone marrow disorders are main causes of non-regenerative anemia in dogs. Despite the high incidence of the diseases, their molecular pathophysiology has not been elucidated. We previously reported that Miniature Dachshund (MD) was a predisposed breed to be diagnosed with non-neoplastic bone marrow disorders in Japan, and immunosuppressive treatment-resistant MDs showed higher number of platelets and morphological abnormalities in peripheral blood cells. These data implied that treatment-resistant MDs might possess distinct pathophysiological features from treatment-responsive MDs. Therefore, we conducted transcriptomic analysis of bone marrow specimens to investigate the pathophysiology of treatment-resistant MDs. Transcriptomic analysis comparing treatment-resistant MDs and healthy control dogs identified 179 differentially expressed genes (DEGs). Pathway analysis using these DEGs showed that "Wnt signaling pathway" was a significantly enriched pathway. We further examined the expression levels of DEGs associated with Wnt signaling pathway and confirmed the upregulation of AXIN2 and CCND2 and the downregulation of SFRP2 in treatment-resistant MDs compared with treatment-responsive MDs and healthy control dogs. This alteration implied the activation of Wnt signaling pathway in treatment-resistant MDs. The activation of Wnt signaling pathway has been reported in human patients with myelodysplastic syndrome (MDS), which is characterized by dysplastic features of blood cells. Therefore, the results of this study implied that treatment-resistant MDs have distinct molecular pathological features from treatment-responsive MDs and the pathophysiology of treatment-resistant MDs might be similar to that of human MDS patients.