Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer.

BACKGROUND: Effective treatment for patients with advanced thyroid cancer is lacking. Metabolism reprogramming is required for cancer to undergo oncogenic transformation and rapid tumorigenic growth. Glutamine is frequently used by cancer cells for active bioenergetic and biosynthetic needs. This study aims to investigate whether targeting glutamine metabolism is a promising therapeutic strategy for thyroid cancer. METHODS: The expression of glutaminase (GLS) and glutamate dehydrogenase (GDH) in thyroid cancer tissues was evaluated by immunohistochemistry, and glutamine metabolism-related genes were assessed using real time-qPCR and western blotting. The effects of glutamine metabolism inhibitor 6-diazo-5-oxo-l-norleucine (DON) on thyroid cancer cells were determined by CCK-8, clone formation assay, Edu incorporation assay, flow cytometry, and Transwell assay. The mechanistic study was performed by real time-qPCR, western blotting, Seahorse assay, and gas chromatography-mass spectrometer assay. The effect of DON prodrug (JHU-083) on thyroid cancer in vivo was assessed using xenograft tumor models in BALB/c nude mice. RESULTS: GLS and GDH were over-expressed in thyroid cancer tissues, and GLS expression was positively associated with lymph-node metastasis and TNM stage. The growth of thyroid cancer cells was significantly inhibited when cultured in glutamine-free medium. Targeting glutamine metabolism with DON inhibited the proliferation of thyroid cancer cells. DON treatment did not promote apoptosis, but increased the proportion of cells in the S phase, accompanied by the decreased expression of cyclin-dependent kinase 2 and cyclin A. DON treatment also significantly inhibited the migration and invasion of thyroid cancer cells by reducing the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Non-essential amino acids, including proline, alanine, aspartate, asparagine, and glycine, were reduced in thyroid cancer cells treated with DON, which could explain the decrease of proteins involved in migration, invasion, and cell cycle. The efficacy and safety of DON prodrug (JHU-083) for thyroid cancer treatment were verified in a mouse model. In addition to suppressing the proliferation and metastasis potential of thyroid cancer in vivo, enhanced innate immune response was also observed in JHU-083-treated xenograft tumors as a result of decreased expression of cluster of differentiation 47 and programmed cell death ligand 1. CONCLUSIONS: Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.

Diversity of Botryosphaeriaceae Species Associated with Chinese Hickory Tree (Carya cathayensis) Trunk Cankers.

Tree trunk cankers represent serious fungal diseases that pose significant threats to Chinese hickory trees (Carya cathayensis). To characterize the pathogen diversity associated with this disease, tissues were collected between 2016 and 2018 from the primary Chinese hickory plantation regions. A total of 97 cultures were isolated from trees in six towns (Longgang, Qingliangfeng, Changhua, Tuankou, Taiyang Town, and Lin'an urban area) within the Linan district, where 60% of Chinese hickory tree yields originate. The isolated cultures caused cankers on Chinese hickory tree branches, but infections did not occur on fruits or leaves under tested conditions. Combined morphological observations and phylogenetic analysis of multiple genes (ITS, ß-tubulin, and EF) indicated that five Botryosphaeriaceae species were recovered, including 89 isolates of Botryosphaeria dothidea, 4 isolates of Botryosphaeriaceae fabicerciana, 1 isolate of Botryosphaeriaceae qingyuanensis, 1 isolate of Botryosphaeriaceae corticis, and two isolates of Lasiodiplodia theobromae. B. dothidea was the most prevalent, and this is the first report of B. corticis, B. qingyuanensis, and L. theobromae infections in Chinese hickory trees. We investigated the mycelial growth, spore germination, and pathogenicity of these species at different temperatures. L. theobromae grew the fastest and B. cortices grew the slowest on potato dextrose agar. The optimum temperature of spore germination for all species was 30°C. L. theobromae was the most virulent species, followed by B. dothidea and B. qingyuanensis, then B. fabicerciana, and finally B. cortices. These new insights into fungal pathogen diversity provide critical new information to understand and manage tree trunk cankers of Chinese hickory.

Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development.

Autism is a prevailing neurodevelopmental disorder with a large genetic/genomic component. Recently, the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) gene was implicated as a risk factor for autism spectrum disorder (ASD). We identified five DYRK1A variants in ASD patients and found that the dose of DYRK1A protein has a crucial role in various aspects of postnatal neural development. Dyrk1a loss of function and gain of function led to defects in dendritic growth, dendritic spine development and radial migration during cortical development. Importantly, two autism-associated truncations, R205X and E239X, were shown to be Dyrk1a loss-of-function mutants. Studies of the truncated Dyrk1a mutants may provide new insights into the role of Dyrk1a in brain development, as well as the role of Dyrk1a loss of function in the pathophysiology of autism.

Effect analysis of nasotracheal suction mechanical ventilation treatment of cerebral ischemic stroke induced by sleep apnea.

OBJECTIVE: To investigate the difference between the clinical effects of nasotracheal suction (NTS) mechanical ventilation and noninvasive positive pressure ventilation (CPAP) treatment of cerebral ischemic stroke (IS) induced by sleep apnea. PATIENTS AND METHODS: Fifty-three patients diagnosed with cerebral IS caused by sleep apnea from February 2013 to February 2014 were selected for this study from our hospital. After the approval of the hospital's Ethics Committee and patients' signed consent, the patients were randomly divided into a test group (n=29 cases) and a control group (n=24 cases). All patients were given conventional treatment for stroke. The control group received the noninvasive ventilator application with CPAP model. The test group was treated with nasal endotracheal suction of mechanical ventilation treatment. Using the NIHSS scale and Barthel index, we compared the status of the nervous system on admission and after seven days stroke recovery treatment of the two groups. Through the comparison of apnea-hypopnea index (AHI), oxygen desaturation index (ODI), LSaO2 and MSaO2 of the two groups on the seventh day, we compared the efficacy of the obstructive sleep apnea-hypopnea syndrome (OSAHS). RESULTS: The NIHSS score and Barthel index score of mild, moderate and severe were compared on the OSAHS patients at admission, and the difference was not statistically significant (p > 0.05). After treatment, all patients showed lower NIHSS score and increased Barthel scores, and the difference had statistical significance (p < 0.05). For the mild OSAHS patients, we compared the NIHSS score and Barthel index score of the test and control group, and the difference was not statistically significant (p > 0.05). For the moderate and severe OSAHS patients, the NIHSS score of the test group decreased significantly. However, the Barthel index scores increased significantly, and the difference had statistical significance (p > 0.05). The AHI, LSaO2, MSaO2, and ODI index of the two groups of patients were compared with the treatment, and the differences were not statistically significant (p > 0.05). After treatment, the AHI and the ODI index of the two groups decreased, LSaO2 and MSaO2 index increased, and AHI and ODI index of the test group decreased more than that of the control group. However, the LSaO2 and the MSaO2 index increased, and the difference had statistical significance (p > 0.05). The total effective rate of patients of the test group was higher than that of the control group, but no effectiveness and overall mortality was lower than the control group. The difference was statistically significant (p > 0.05). CONCLUSIONS: Compared with noninvasive ventilator therapy, nasotracheal suction mechanical ventilation and noninvasive positive pressure ventilation treatment of cerebral IS induced by sleep apnea can naturally improve the prognosis of nervous system recovery, and improve the respiratory ventilation function. This may be a better treatment option for moderate and severe sleep apnea patients that is worthy of clinical application.

Plasma levels of TNF-α and MMP-9 in patients with silicosis.

OBJECTIVE: Silicosis is usually recognized at later stages of the disease, and early biomarkers for silicosis will be useful for timely diagnosis. We aimed at examining plasma levels of TNF-α and MMP-9, and correlation between these, in patients with different stages of silicosis in order to test suitability of these inflammatory factors as early biomarkers for silicosis. PATIENTS AND METHODS: TNF-α and MMP-9 were quantified by ELISA in plasma specimens from 30 healthy individuals (control group), 28 individuals exposed to silica dust but without clinical disease, and 30 patients with silicosis. RESULTS: Plasma levels of TNF-α and MMP-9 were increased in individuals exposed to silica dust (p < 0.05 vs. control individuals) and were further elevated in patients with silicosis (p < 0.05 vs. control individuals and individuals exposed to silica dust). There was a significant correlation between plasma levels of TNF-α and MMP-9 both in individuals exposed to silica dust (r = 0.696, p < 0.01) and patients with silicosis (r = 0.768, p < 0.01). CONCLUSIONS: Plasma levels of TNF-α and MMP-9 are increased prior to development of clinically recognized silicosis, suggesting that these biomarkers are involved in the onset and development of silicosis. Combined detection of TNF-α and MMP-9 may be useful for early diagnosis of silicosis.