Purpose: Fms-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase (RTK) for which activating mutations have been identified in a proportion of acute myelogenous leukemia (AML) patients and associated with poor clinical prognosis. Given the relevance of FLT3 mutations in AML, we investigated the activity of CHIR-258, an orally active, multitargeted small molecule, with potent activity against FLT3 kinase and class III, IV, and V RTKs involved in endothelial and tumor cell proliferation in AML models. Experimental Design: CHIR-258 was tested on two human leukemic cell lines in vitro and in vivo with differing FLT3 mutational status [MV4;11 cells express FLT3 internal tandem duplications (ITD) versus RS4;11 cells with wild-type (WT) FLT3]. Results: Antiproliferative activity of CHIR-258 against MV4;11was f24-fold greater compared with RS4;11, indicating more potent inhibition against cells with constitutively activated FLT3 ITD. Dose-dependent down modulation of receptor phosphorylation and downstream signaling [signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase] in MV4;11 cells with CHIR-258 confirmed the molecular mechanism of action. Target modulation of phospho-FLT3, phospho-STAT5, and phospho-ERK in MV4;11 tumors was achieved at biologically active doses of CHIR-258. Tumor regressions and eradication of AML cells from the bone marrow were shown in s.c. and bone marrow engraftment leukemic xenograft models. Tumor responses were characterized by decreased cellular proliferation and positive immunohistochemical staining for active caspase-3 and cleaved poly(ADP-ribose) polymerase, suggesting cell death was mediated in part via apoptosis. Conclusions: Our data indicate that CHIR-258 may be an effective therapy in FLT3-associated AML and warrants clinical trials.
Surface electromyography (sEMG) studies have indicated that chronic low back pain (cLBP) involves altered electromyographic activity and morphological structure of the lumbar multifidus (LM) beyond pain perception; however, most studies have evaluated the superficial lumbar multifidus. It is difficult to record electromyography (EMG) signals from the deep multifidus (DM) to determine the neuromuscular activation patterns, making it difficult to determine the relationship between functional and structural changes in cLBP. We developed a novel method to record intramuscular EMG signals in the DM based on the sEMG system and fine-wire electrodes. We measured EMG signals of the DM in 24 cLBP patients and 26 pain-free healthy controls to identify changes in neuromuscular activation. We also used ultrasound to measure DM muscle thickness, cross-sectional area, and contraction activity to identify potential relationships between EMG activity and structural damage. cLBP patients had decreased average EMG and root mean square, but increased median frequency and mean power frequency. Average EMG was positively correlated with contractile activity, but not statistically correlated with noncontractile anatomical abnormalities. Our results suggest that cLBP alters the neuromuscular activation patterns and morphological structure of the contractile activity of the DM, providing insights into the mechanisms underlying pain perception.
Palbociclib, a highly selective CDK4/6 inhibitor, has been shown to be a novel anti-tumor agent that suppresses breast cancer cell proliferation. However, its anti-metastasis activity remains controversial. In the present study, we evaluated whether palbociclib prevented breast cancer cell metastasis and revealed its regulatory mechanism. We found that palbociclib inhibited migration and invasion in the breast cancer cells MDA-MB-231 and T47D. The epithelial-mesenchymal transition (EMT) markers, vimentin and Snail, were down-regulated with palbociclib treatment. Moreover, we revealed that this inhibition was mediated by the c-Jun/COX-2 pathway. COX-2 was decreased after palbociclib treatment. The production of PGE2 was also reduced along with COX-2. Additionally, our data showed that c-Jun, a crucial transcriptional regulator of COX-2, was down-regulated by palbociclib. We found that palbociclib weakened the COX-2 promoter binding activity of c-Jun and prevented its translocation from the cytoplasm to cell nuclei. Bioluminescence imaging and tail intravenous injection were used to evaluate the anti-metastasis effect of palbociclib in vivo. The data demonstrated that palbociclib reduced breast cancer metastasis to the lung. These results therefore demonstrated that the anti-metastasis activity of palbociclib is mediated via the c-Jun/COX-2 signaling pathway by inhibiting EMT in breast cancer cells.
The morbidity associated with atopic diseases and immune dysregulation disorders such as asthma, food allergies, multiple sclerosis, atopic dermatitis, type 1 diabetes mellitus, and inflammatory bowel disease has been increasing all around the world over the past few decades. Although the roles of non-biological environmental factors and genetic factors in the etiopathology have been particularly emphasized, they do not fully explain the increase; for example, genetic factors in a population change very gradually. Epidemiological investigation has revealed that the increase also parallels a decrease in infectious diseases, especially parasitic infections. Thus, the reduced prevalence of parasitic infections may be another important reason for immune dysregulation. Parasites have co-evolved with the human immune system for a long time. Some parasite-derived immune-evasion molecules have been verified to reduce the incidence and harmfulness of atopic diseases in humans by modulating the immune response. More importantly, some parasite-derived products have been shown to inhibit the progression of inflammatory diseases and consequently alleviate their symptoms. Thus, parasites, and especially their products, may have potential applications in the treatment of autoimmune diseases. In this review, the potential of parasite-derived products and their analogs for use in the treatment of atopic diseases and immune dysregulation is summarized.
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