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Head and neck squamous cell carcinoma (HNSCC) is a particularly aggressive cancer with poor prognosis, largely due to lymph node metastasis and local recurrence. Emerging evidence suggests that epithelial-to-mesenchymal transition (EMT) is important for cancer metastasis, and correlated with increased cancer stem cells (CSCs) characteristics. However, the mechanisms underlying metastasis to lymph nodes in HNSCC is poorly defined. In this study, we show that E-cadherin repression correlates with cancer metastasis and poor prognosis in HNSCC. We found that G9a, a histone methyltransferase, interacts with Snail and mediates Snail-induced transcriptional repression of E-cadherin and EMT, through methylation of histone H3 lysine-9 (H3K9). Moreover, G9a is required for both lymph node-related metastasis and TGF-β-induced EMT in HNSCC cells since knockdown of G9a reversed EMT, inhibited cell migration and tumorsphere formation, and suppressed the expression of CSC markers. Our study demonstrates that the G9a protein is essential for the induction of EMT and CSC-like properties in HNSCC. Thus, targeting the G9a-Snail axis may represent a novel strategy for treatment of metastatic HNSCC.

GPRC5A is a G-protein-coupled receptor expressed in lung tissue but repressed in most human lung cancers.

On December 31, 2019, several cases of pneumonia of unknown etiology have been reported in Wuhan, Hubei province, China [1][2][3]. On January 7, 2020, Chinese health authorities confirmed that these cases were associated with a novel coronavirus, which was subsequently named 2019 nCoV by WHO [4]. Previous study [5] reported that virus infection can cause several neurological complications, including polyneuritis, Guillain-Barre syndrome (GBS), meningitis, encephalomyelitis, and encephalopathy. We describe a rare case of 2019CoV infection and acute uni lateral isolated oculomotor nerve palsy. In this case, the diagnosis was made based on the chest computed CT mani festations and throat swab sample test.A 62yearold man was admitted to our department with a 5day history of persistent diplopia and a droopy left eyelid. During initial hospital assessment, he endorsed limb weak ness and poor spirit. He denied any fever, neck stiffness, headache, cough, shortness of breath, chest pain, or photo phobia. He had a history of alcohol and tobacco use, type II diabetes mellitus and hypertension (both well controlled by drugs), and lacunar infarction (without sequela).On examination, it revealed body temperature of 36.5 °C (97.7 °F), blood pressure of 142/72 mmHg, respiratory rate of 22 breaths per minute, pulse rate of 70 beats per minute and oxygen saturation of 95% while the patient was breath ing ambient air. There were coarse rales in the both lung field. The patient was alert and oriented to person, place, and time. His speech was fluent. Pupils were 3 mm and equally reactive to light. He had complete ptosis of the left eyelid, and his left eye was down and out at rest. The left eye was unable to adduct and look up. Left eyelid closure was weak. Both eyes were without orbital pain. Hearing was intact. No palate or tongue weakness/asymmetry was noted. Strength in upper and lower limbs was 5/5 throughout. Deep tendon reflexes were 2 + and symmetric throughout. Toes were downgoing bilaterally. Sensation to light touch, pinprick, and temperature was intact on the two sides. No pathologi cal reflection of Babinski's sign is induced. Romberg test was negative when eyes were open or close. The sign of meningeal irritation was negative. The laboratory results showed white blood cell count: 9.45 × 10 9 /L and neutrophil percentage: 69.6% were normal. Random blood glucose was 9.2 mmol/L (normal range 0-11.1 mmol/L) and hemoglobin A1C was 6.1% (normal range 0-6.2%). Respiratory patho gens test showed influenza A and B virus antigen, myco plasma pneumonia antigen, adenovirus antigen, and syncy tial virus were all negative. However, inflammatory markers were significantly elevated Creactive protein (142.21 mg/L; normal range 0-10 mg/L) and Serum amyloid A protein (300.00 mg/L; normal range 0-10 mg/L). Erythrocyte sedimentation rate was elevated (91.6 mm/h; normal range 0-15 mm/h). Magnetic resonance imaging (MRI) was not found new infarction, bleeding of brainstem or pituitary apo plexy, tumor, and multiple sclerosis (Figs. 1, 2). Ma...

The interplay between p53 and RAS signaling regulates cancer chemoresistance, but the detailed mechanism is unclear. In this study, we investigated the interactive effects of p53 and RAS on ovarian cancer cisplatin resistance to explore the potential therapeutic targets. Methods : An inducible p53 and RAS mutants active in either MAPK/ERK (S35 and E38) or PI3K/AKT (C40) or both (V12) were sequentially introduced into a p53-null ovarian cancer cell line-SKOV3. Comparative microarray analysis was performed using Gene Chip Prime View Human Gene Expression arrays (Affymetrix). In vitro assays of autophagy and apoptosis and in vivo animal experiments were performed by p53 induction and/or cisplatin treatment using the established cell lines. The correlation between HDAC4 and HIF-1α or CREBZF and the association of HDAC4, HIF-1α, CREBZF, ERK, AKT, and p53 mRNA levels with patient survival in 523 serous ovarian cancer cases from TCGA was assessed. Results : We show that p53 and RAS mutants differentially control cellular apoptosis and autophagy to inhibit or to promote chemoresistance through dysregulation of Bax, Bcl2, ATG3, and ATG12. ERK and AKT active RAS mutants are mutually suppressive to confer or to deprive cisplatin resistance. Further studies demonstrate that p53 induces HIF-1α degradation and HDAC4 cytoplasmic translocation and phosphorylation. S35, E38, and V12 but not C40 promote HDAC4 phosphorylation and its cytoplasmic translocation along with HIF-1α. Wild-type p53 expression in RAS mutant cells enhances HIF-1α turnover in ovarian and lung cancer cells. Autophagy and anti-apoptotic processes can be promoted by the overexpression and cytoplasmic translocation of HDAC4 and HIF1-α. Moreover, the phosphorylation and cytoplasmic translocation of HDAC4 activate the transcription factor CREBZF to promote ATG3 transcription. High HDAC4 or CREBZF expression predicted poor overall survival (OS) and/or progression-free survival (PFS) in ovarian cancer patients, whereas high HIF-1α expression was statistically correlated with poor or good OS depending on p53 status. Conclusion : HIF-1α and HDAC4 may mediate the interaction between p53 and RAS signaling to actively control ovarian cancer cisplatin resistance through dysregulation of apoptosis and autophagy. Targeting HDAC4, HIF-1α and CREBZF may be considered in treatment of ovarian cancer with p53 and RAS mutations.

Constipation is a common affliction which causes discomfort and affects the quality of life of affected individuals. Naringenin (NAR), a natural flavonoid widely found in citrus fruits and tomatoes, has been reported to exhibit various pharmacological effects, such as anti-inflammatory, anti-atherogenic, anti-mutagenic, hepatoprotective and anticancer effects. Increasing evidence has indicated that NAR has potential for use in the treatment of constipation. Thus, the aim of this study was to evaluate the laxative effects of NAR in mice with loperamide-induced (Lop-induced) constipation. The data indicated that NAR relieved Lop-induced constipation in mice based on the changes of fecal parameters (numbers, weight and water content), the intestinal charcoal transit ratio and the histological alteration. ELISA revealed that NAR regulated the production levels of gastrointestinal metabolic components, such as motilin (MTL), gastrin (Gas), endothelin (ET), substance P (SP), acetylcholinesterase (AChE) and vasoactive intestinal peptide (VIP) in serum. The expression levels of enteric nerve-related factors, glial cell line-derived neurotrophic factor (GDNF), transient receptor potential vanilloid 1 (TRPV1), nitric oxide synthase (NOS), c-Kit, stem cell factor (SCF) and aquaporin 3 (AQP3) were examined by western blot analysis and RT-PCR analysis. The results of this study suggest that NAR relieves Lop-induced constipation by increasing the levels of interstitial cells of Cajal markers (c-Kit and SCF), as well as AQP3. Thus, NAR may be effective as a candidate in patients suffering from lifestyle-induced constipation.

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