MYB-activated models for testing therapeutic agents in adenoid cystic carcinoma.

OBJECTIVE: There are no effective systemic therapies for adenoid cystic cancer (ACC) and lack of tumor lines and mouse models have hindered drug development.We aim to develop MYB-activated models for testing new therapeutic agents. MATERIALS AND METHODS: We studied new ACC patient-derived xenograft (PDX) models and generated a matched cell line from one patient. In addition, we generated a genetically-engineered MYB-NFIB mouse model (GEMM) that was crossed with Ink4a+/-/Arf+/- mice to study tumor spectrum and obtain tumor lines. Using human and murine ACC-like tumor lines, we analyzed MYB expression by RNA-Seq and immunoblot and tested efficacy of new MYB inhibitors. RESULTS: We detected MYB-NFIB transcripts in both UFH1 and UFH2 PDX and observed tumor inhibition by MYB depletion using shRNA in vivo. We observed rapid loss of MYB expression when we cultured UFH1 in vitro, but were able to generate a UFH2 tumor cell line that retained MYB expression for 6 months. RNA-Seq expression detected an ACC-like mRNA signature in PDX samples and we confirmed an identical KMT2A/MLL variant in UFH2 PDX, matched cell line, and primary biopsy. Although the predominant phenotype of the MYB-NFIB GEMM was B-cell leukemia, we also generated a MYB-activated ACC-like mammary tumor cell line. We observed tumor inhibition using a novel MYB peptidomimetic in both human and murine tumor models. CONCLUSIONS: We generated and studied new murine and human MYB-activated tumor samples and detected growth inhibition with MYB peptidomimetics. These data provide tools to define treatment strategies for patients with advanced MYB-activated ACC.

Rhamnazin attenuates inflammation and inhibits alkali burn-induced corneal neovascularization in rats.

The purpose of our study was to determine whether rhamnazin inhibits corneal neovascularization in the rat alkali burn model, and alleviates the inflammatory response of the cornea. Rhamnazin inhibited the proliferation of HUVEC cells in a dose-dependent manner, and it also inhibited the migration and luminal formation of HUVEC cells. 20 µM rhamnazin eye drops were applied to an animal model of corneal alkali burn neovascularization 4 times a day for 14 days. The corneal neovascularization in the rhamnazin group was obviously less than that in the PBS control group. In the rhamnazin group, the inflammatory index of the cornea decreased gradually over time, whereas the inflammatory index of the PBS group decreased only slightly with time. The corneal CNV area in the PBS group was significantly larger than that in the rhamnazin group. The expression level of VEGF protein of the rhamnazin group was lower than that in the PBS group, and the expression level of PEDF was significantly higher than that of the PBS group. Rhamnazin downregulated the expression of VEGFR2 protein and decreased the expression levels of p-STAT3, p-MAPK and p-Akt proteins. This study provides a new idea for the study of the molecular mechanism of corneal neovascularization.

Altered intrinsic brain activities in patients with acute eye pain using amplitude of low-frequency fluctuation: a resting-state fMRI study.

OBJECTIVE: Many previous studies have reported that pain symptoms can lead to significant brain function and anatomical changes, whereas the intrinsic brain activity changes in acute eye pain (EP) patients remain unknown. Using the amplitude of low-frequency fluctuation (ALFF) method, this study aimed to evaluate the spontaneous brain activity alterations and their relationships with clinical features in acute EP patients. PARTICIPANTS AND METHODS: A total of 20 patients with EP (15 males and 5 females) and 20 healthy controls (HCs; 15 males and 5 females) closely matched in age, sex, and education underwent resting-state functional magnetic resonance imaging scans. The ALFF method was applied to assess spontaneous brain activity changes. The ALFF values of the EP patients were distinguished from those of the HCs using a receiver operating characteristic curve. Pearson's correlation analysis was used to investigate the relationships between the mean ALFF signal values from many brain regions and the clinical features in EP patients. RESULTS: Compared with the HCs, acute EP patients had significantly lower ALFF in the left and right precentral/postcentral gyrus and left precuneus. In contrast, acute EP patients showed higher ALFF values in the right and left parahippocampal gyri and left caudate. However, no relationship was observed between the mean ALFF signal values from the different areas and clinical manifestations in the acute EP patients. CONCLUSION: We demonstrated that acute EP patients showed abnormal intrinsic brain activities in the precentral/postcentral gyrus and limbic system, which might provide useful information for explaining neural mechanisms in EP patients.

Abnormal regional spontaneous neural activity in visual pathway in retinal detachment patients: a resting-state functional MRI study.

OBJECTIVE: The aim of the study was to investigate changes of brain neural homogeneity in retinal detachment (RD) patients using the regional homogeneity (ReHo) method to understand their relationships with clinical features. MATERIALS AND METHODS: A total of 30 patients with RD (16 men and 14 women), and 30 healthy controls (HCs) (16 men and 14 women) closely matched in age and sex were recruited. Resting-state functional magnetic resonance imaging scans were performed for all subjects. The ReHo method was used to investigate the brain regional neural homogeneity. Patients with RD were distinguished from HCs by receiver operating characteristic curve. The relationships between the mean ReHo signal values in many brain regions and clinical features in RD patients were calculated by Pearson correlation analysis. RESULTS: Compared with HCs, RD patients had significantly decreased ReHo values in the right occipital lobe, right superior temporal gyrus, bilateral cuneus and left middle frontal gyrus. Moreover, we found that the mean ReHo signal of the bilateral cuneus showed positive relationships with the duration of the RD (r=0.392, P=0.032). CONCLUSION: The RD patients showed brain neural homogeneity dysfunction in the visual pathway, which may underline the pathological mechanism of RD patients with acute vision loss. Besides, the ReHo values can reflect the progress of the RD disease.