Using two specific anti-peptide antibodies (WH-66 and WH-412) against tryptophan hydroxylase (TPH or WH), a single principle band from the midbrain raphe area was seen (approximately 49 kDa) in immunoblots. Densitometric comparison of the immunoreactivity of the 49 kDa band was greater (50-75%) in immunoblots of midbrain raphe samples from adrenalectomized (ADX) rats given dexamethasone (DEX) in their drinking water (10 mg/liter) for 12-96 hr. No difference from ADX brains was seen in the 49 kDa band after only 4 hr of exposure to DEX in the drinking water. Immunocytochemical staining with WH-66 of sections from rat brainstem showed specific cellular staining in all of the serotonergic raphe nuclei but not in substantia nigra or locus coeruleus. More cellular staining of WH-66-immunoreactive (WH-66-IR) cells was observed in the dorsal and median raphe nuclei in ADX rats given DEX for 72 hr, especially in the perikarya and in the primary dendrites. Quantification of staining per cell soma with an automatic image analyzer indicates that amount of WH-66-IR in neurons from both the lateral wing subdivision of the dorsal raphe nucleus and in the supralemniscal nucleus, B-9, was 80% higher in the ADX+DEX compared to ADX animals. Interestingly, morphometric analysis of these same cells showed a corresponding increase of 37-80% in somal area. It is suggested that a part of the increase in TPH/WH staining may be a consequence of cellular hypertrophy due to DEX treatment of the ADX rats.
BackgroundCytogenetic aberrations and gene mutations have long been regarded as independent prognostic markers in AML, both of which can lead to misexpression of some key genes related to hematopoiesis. It is believed that the expression level of the key genes is associated with the treatment outcome of AML.MethodsIn this study, we analyzed the clinical features and molecular aberrations of 560 newly diagnosed non-M3 AML patients, including mutational status of CEBPA, NPM1, FLT3, C-KIT, NRAS, WT1, DNMT3A, MLL-PTD and IDH1/2, as well as expression levels of MECOM, ERG, GATA2, WT1, BAALC, MEIS1 and SPI1.ResultsCertain gene expression levels were associated with the cytogenetic aberration of the disease, especially for MECOM, MEIS1 and BAALC. FLT3, C-KIT and NRAS mutations contained conversed expression profile regarding MEIS1, WT1, GATA2 and BAALC expression, respectively. FLT3, DNMT3A, NPM1 and biallelic CEBPA represented the mutations associated with the prognosis of AML in our group. Higher MECOM and MEIS1 gene expression levels showed a significant impact on complete remission (CR) rate, disease free survival (DFS) and overall survival (OS) both in univariate and multivariate analysis, respectively; and an additive effect could be observed. By systematically integrating gene mutational status results and gene expression profile, we could establish a more refined system to precisely subdivide AML patients into distinct prognostic groups.ConclusionsGene expression abnormalities contained important biological and clinical informations, and could be integrated into current AML stratification system.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1279-4) contains supplementary material, which is available to authorized users.
Severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) strongly hampered the broad clinical applicability of chimeric antigen receptor T cell (CAR-T) therapy. Vascular endothelial activation has been suggested to contribute to the development of CRS and ICANS after CAR-T therapy. However, therapeutic strategies targeting endothelial dysfunction during CAR-T therapy have not been well studied yet. Here, we found that tumor necrosis factor α (TNFα) produced by CAR-T cells upon tumor recognition and interleukin 1β (IL1β) secreted by activated myeloid cells were the main cytokines in inducing endothelial activation. Therefore, we investigated the potential effectiveness of TNFα and IL1β signaling blockade on endothelial activation in CAR-T therapy. The blockade of TNFα and IL1β with adalimumab and anti-IL1β antibody respectively, as well as the application of focal adhesion kinase (FAK) inhibitor, effectively ameliorated endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Moreover, adalimumab and anti-IL1β antibody exerted synergistic effect on the prevention of endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Our results indicate that TNFα and IL1β blockade might have therapeutic potential for the treatment of CAR-T therapy-associated CRS and neurotoxicity.
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