Anthelmintic drug niclosamide enhances the sensitivity of chronic myeloid leukemia cells to dasatinib through inhibiting Erk/Mnk1/eIF4E pathway.

Chronic myeloid leukemia (CML) responds well to BCR-ABL tyrosine kinase inhibitors (TKI), but becomes resistant to TKIs after it progresses to blast phase (BP). Here we show that niclosamide, a FDA-approved anthelmintic drug, enhances the sensitivity of BP-CML cells to dasatinib (2nd generation of BCR-ABL TKI) through inhibiting Erk/Mnk1/eIF4E signaling pathway. Niclosamide dose-dependently inhibits proliferation and induces apoptosis in a panel of CML cell lines. It also selectively targets BP-CML CD34 stem/progenitor cells through inducing apoptosis, inhibiting colony formation and self-renewal capacity while sparing normal bone marrow (NBM) counterparts. In addition, combination of niclosamide and dasatinib is synergistic in CML cell lines and BP-CML CD34 cells. Importantly, niclosamide inhibits phosphorylation of Erk, Mnk1 and eIF4E in CML cells. Overexpression of phosphomimetic but not nonphosphorylatable form of eIF4E reverses the inhibitory effects of niclosamide, suggesting that eIF4E inhibition is required for the action of niclosamide in CML. Compared to NBM, the increased levels of eIF4E and its activity in CML CD34 cells might explain the selective toxicity of niclosamide in CML versus NBM. We further show that dasatinib time-dependently induces eIF4E phosphorylation. The combination of eIF4E depletion and dasatinib results in similar effects as the combination of niclosamide and dasatinib, suggesting that niclosamide enhances dasatinib through targeting eIF4E. Our work is the first to demonstrate that niclosamide is a potential drug to overcome resistance to BCR-ABL TKI treatment in BP-CML. Our findings also suggest the therapeutic value of Erk/Mnk/eIF4E in CML treatment.

FOXG1 improves mitochondrial function and promotes the progression of nasopharyngeal carcinoma.

Forkhead­box gene 1 (FOXG1) has been reported to serve an important role in various malignancies, but its effects on nasopharyngeal cancer (NPC) remain unknown. Thus, the present study aimed to investigate the specific regulatory relationship between FOXG1 and NPC progression. Tumor tissues and matching para­carcinoma tissues were obtained from patients with NPC. Small interfering (si)RNA­FOXG1 and pcDNA3.1­FOXG1 were transfected into SUNE­1 and C666­1 cells to knockdown and overexpress FOXG1 expression, respectively. FOXG1 expression was detected using reverse transcription­quantitative PCR and immunohistochemistry. Cell proliferation was detected using MTT and 5­ethynyl­20­deoxyuridine assays. Transwell invasion assay, wound healing assay and flow cytometry were used to detect cell invasion, migration and apoptosis, respectively. Western blotting was conducted to detect the expression levels of mitochondrial markers (succinate dehydrogenase complex flavoprotein subunit A, heat shock protein 60 and pyruvate dehydrogenase), epithelial­mesenchymal transition (EMT) related proteins (N­cadherin, Snail and E­cadherin) and apoptosis­related proteins [Bax, Bcl­2, poly(ADP­ribose) polymerase 1 (PARP), cleaved PARP, cleaved caspase­3, cleaved caspase­8, cleaved caspase­9, caspase­3, caspase­8 and caspase­9]. The mitochondrial membrane potential was detected via flow cytometry, while the ATP/ADP ratio was determined using the ADP/ATP ratio assay kit. The present results demonstrated that FOXG1 expression was upregulated in NPC tissues and cells, and was associated with distant metastasis and TNM stage. Moreover, knockdown of FOXG1 inhibited the proliferation, migration, invasion, EMT and mitochondrial function of SUNE­1 cells, as well as promoted cell apoptosis, while the opposite results were observed in C666­1 cells. In conclusion, FOXG1 enhanced proliferation, migration and invasion, induced EMT and improved mitochondrial function in NPC cells. The current findings provide an adequate theoretical basis for the treatment of NPC.

Gut-Brain-Skin Axis in Psoriasis: A Review.

INTRODUCTION: Psoriasis is a common skin disease, with chronic inflammation and a complex etiology. It has long been recognized that chronic skin conditions and mental health disorders are often co-morbid. Thus, the concept of the gut-brain-skin axis emphasized in mental health disorders may also regulate the health of skin. RESULTS: The gut microbiota has been found to be the bridge between the immune system and nervous system. By leveraging clinical cases and animal models of psoriasis, an important communication pathway has been identified along the gut-brain-skin axis that is associated with the modulation of neurotransmitters from the microbiota. Furthermore, mammalian neurotransmitters, including dopamine, serotonin, or γ-aminobutyric acid (GABA), can be produced and/or consumed by several types of bacteria. Other studies suggest that manipulating these neurotransmitters by bacteria may have an effect on host physiology, and the levels of neurotransmitter can be altered by microbiota-based interventions. CONCLUSIONS: Nonetheless, it is unknown whether or not the manipulation of neurotransmitter levels by bacteria can affect the occurrence and development of psoriasis. Notably, preliminary experiments found that oral consumption of probiotics improves the clinical symptoms in patients with psoriasis, perhaps correlated with the gut microbiome-mediated crosstalk between the immune system and the nervous system by secreting neurotransmitters in psoriasis. In this review, the communication along the gut-brain-skin axis is discussed.

Automatic Recognition of Laryngoscopic Images Using a Deep-Learning Technique.

OBJECTIVES/HYPOTHESIS: To develop a deep-learning-based computer-aided diagnosis system for distinguishing laryngeal neoplasms (benign, precancerous lesions, and cancer) and improve the clinician-based accuracy of diagnostic assessments of laryngoscopy findings. STUDY DESIGN: Retrospective study. METHODS: A total of 24,667 laryngoscopy images (normal, vocal nodule, polyps, leukoplakia and malignancy) were collected to develop and test a convolutional neural network (CNN)-based classifier. A comparison between the proposed CNN-based classifier and the clinical visual assessments (CVAs) by 12 otolaryngologists was conducted. RESULTS: In the independent testing dataset, an overall accuracy of 96.24% was achieved; for leukoplakia, benign, malignancy, normal, and vocal nodule, the sensitivity and specificity were 92.8% vs. 98.9%, 97% vs. 99.7%, 89% vs. 99.3%, 99.0% vs. 99.4%, and 97.2% vs. 99.1%, respectively. Furthermore, when compared with CVAs on the randomly selected test dataset, the CNN-based classifier outperformed physicians for most laryngeal conditions, with striking improvements in the ability to distinguish nodules (98% vs. 45%, P < .001), polyps (91% vs. 86%, P < .001), leukoplakia (91% vs. 65%, P < .001), and malignancy (90% vs. 54%, P < .001). CONCLUSIONS: The CNN-based classifier can provide a valuable reference for the diagnosis of laryngeal neoplasms during laryngoscopy, especially for distinguishing benign, precancerous, and cancer lesions. LEVEL OF EVIDENCE: NA Laryngoscope, 130:E686-E693, 2020.