Data mining on identifying diagnosis and prognosis biomarkers in head and neck squamous carcinoma.

Head and neck squamous carcinoma (HNSC) induces high cancer-related death worldwide. The biomarker screening on diagnosis and prognosis is of great importance. This research is aimed to explore the specific diagnostic and prognostic biomarkers for HNSC through bioinformatics analysis. The mutation and dysregulation data were acquired from UCSC Xena and TCGA databases. The top ten genes with mutation frequency in HNSC were TP53 (66%), TTN (35%), FAT1 (21%), CDKN2A (20%), MUC16 (17%), CSMD3 (16%), PIK3CA (16%), NOTCH1 (16%), SYNE1 (15%), LRP1B (14%). A total of 1,060 DEGs were identified, with 396 up-regulated and 665 downregulated in HNSC patients. Patients with lower expression of ACTN2 (P = 0.039, HR = 1.3), MYH1 (P = 0.005, HR = 1.5), MYH2 (P = 0.035, HR = 1.3), MYH7 (P = 0.053, HR = 1.3), and NEB (P = 0.0043, HR = 1.5) exhibit longer overall survival time in HNSC patients. The main DEGs were further analyzed by pan-cancer expression and immune cell infiltration analyses. MYH1, MYH2, and MYH7 were dysregulated in the cancers. Compared with HNSC, their expression levels are lower in the other types of cancers. MYH1, MYH2, and MYH7 were expected to be the specific diagnostic and prognostic molecular biomarkers of HNSC. All five DEGs have a significant positive correlation with CD4+T cells and macrophages.

Transcription factor p8 regulates autophagy in response to disulfiram via PI3K/mTOR/p70S6K signaling pathway in pancreatic cancer cells.

Disulfiram (DSF), which is an inhibitor of aldehyde dehydrogenase (ALDH) and approved by the FDA for the treatment of alcoholism previously, has been repurposed for use as a cancer treatment because of its potent effect in preclinical studies. In this study, we found that disulfiram forms potent complexes with copper (DSF/Cu) inhibited cell proliferation, induced apoptosis in human pancreatic cancer cells, which was detected by flow cytometry and western blotting. Meanwhile, autophagy and autophagic flux also clearly observed by transmission electron microscopy, confocal microscopy and flow cytometry. Our results also showed that DSF/Cu induced transcription factor p8 upregulation and PI3K/mTOR signaling pathway activation detected by real-time PCR and western blotting. Additionally, suppression of p8 inactivated the mTOR signaling pathway and autophagic flux maintained. Furthermore, mechanism study indicated that autophagy induced by DSF/Cu was regulated by p8 and was related to PI3K/mTOR/p70S6K signaling pathway in pancreatic cancer cells. Our findings provide insights into the role of p8 in regulating autophagy induced by DSF/Cu effects in pancreatic cancer cells.

The protective effect of a combination of human intracellular and extracellular antibodies against the highly pathogenic avian influenza H5N1 virus.

BACKGROUND: The highly pathogenic avian influenza H5N1 virus poses a serious threat to humans. Due to its antiviral activity, antibody-based therapy is one of the possible effective countermeasures. Here, a combination of intracellular and extracellular human antibodies was investigated and showed an improved protective effect. METHODS: The scFv4F5-based intracellular antibody vectors and IgG1 extracellular antibody were constructed and expressed, respectively, and the sensitivity, specificity, and affinity of these antibodies were determined in vitro. In vivo, the protective effect of IgG1 and the combination of antibodies were tested respectively. Furthermore, the dynamics of viral replication, the related cytokines and apoptosis-related proteins were detected. RESULTS: In vitro, the expressed intracellular antibody inhibited H5N1 virus propagation and the IgG1 exhibited high specificity, sensitivity, and affinity against the H5N1 virus. In vivo, the extracellular antibody could inhibit viral propagation in a dose-dependent manner. The protective effect of IgG1 was good in a mouse model, and the survival was 100% at a dose of 15 mg/kg under infection with 100 TCID50 virus. When the intracellular antibody was pre-transfected in combination with IgG1, it had a better protective effect. The survival was 16.67% under treatment with IgG1 alone and up to 83.33% under treatment with the combination of antibodies when challenge of 500 TCID 50 virus. Furthermore, the levels of cytokines IFN-γ, IL-6, IL-10 and some apoptosis-related proteins increased. CONCLUSIONS: This antibody combination technique could be used as an appropriate and powerful alternative to antiviral therapy.

Hydrogel adhesive formed via multiple chemical interactions: from persistent wet adhesion to rapid hemostasis.

To date, the robust and durable adhesion capability of hydrogel adhesives in wet environments remains a huge challenge. Herein, a physicochemically double-network crosslinked hydrogel matrix was prepared by mixing acrylic acid (AAc), chitosan (CS) and tannic acid (TA) as the main components and the subsequent in situ polymerization of AAc. The abundant reactive sites on the surface of the hydrogel matrix facilitate rapid, strong and repeatable adhesion to different surfaces of engineering solids and biological tissues in an aquatic environment. The formation of amide covalent bonds resulting from the addition of the bridging agent further expands the long-term application of the hydrogel in tissue repair, and the constructed hydrogel-tissue adhesive interface still has robust adhesion energy after soaking in a physiological environment for up to one month. Moreover, the hydrogel showed fantastic hemostatic performance due to its characteristics of platelet adhesion and high burst pressure. Overall, the persistent adhesion and excellent cytocompatibility of the hydrogel adhesive make it potentially applicable in medical adhesives.

Long Non-coding RNA RUNDC3A-AS1 Promotes Lung Metastasis of Thyroid Cancer via Targeting the miR-182-5p/ADAM9.

Long non-coding RNAs (lncRNAs) have been identified as influential indicators in variety of malignancies. Among which, LncRNA RUNDC3A-AS1 is reported to upregulate in thyroid cancer. However, the expression pattern and the pathological function of lncRNA RUNDC3A-AS1 in thyroid cancer is unclear. In this study, we examined the expression levels of lncRNA RUNDC3A-AS1 in the thyroid cancer tissues and cell lines via RT-qPCR analysis. The effects of RUNDC3A-AS1 on thyroid cancer cell metastasis were detected by transwell chamber assay, scratch assay in vitro and lung metastasis model in vivo. The results indicated that RUNDC3A-AS1 was highly expressed in the thyroid cancer tissues and cell lines. Functionally, knockdown of RUNDC3A-AS1 could repress the migration and invasion of thyroid cancer cells in vitro, and inhibit thyroid cancer metastasis to lung in vivo. Mechanistically, RUNDC3A-AS1 served as an inhibitor of miR-182-5p in tumor tissues and cell lines. RUNDC3A-AS1 inhibited the expression of miR-182-5p to increase the expression level of ADAM9, thus further aggravating the malignancy of thyroid cancer. Therefore, the RUNDC3A-AS1/miR-182-5p/ADAM9 axis may be a potential therapeutic target for the treatment of thyroid cancer metastasis.

Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors.

Tetrabenazine (TBZ) ((±)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (±)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (Ki=4.47 nM) was 8000-fold more potent than (-)-1 (Ki=36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: Ki=3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington's disease and other hyperkinetic disorders.

Synthesis of ranolazine metabolites and their anti-myocardial ischemia activities.

The anti-anginal drug Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, is thought to modulate the metabolism during myocardial ischemia by activating pyruvate dehydrogenase activity to promote glucose oxidation. Ranolazine and its five principal metabolites: CVT-2512, CVT-2513, CVT-2514, CVT-2738 and CVT-4786, were synthesized. The effect of Ranolazine and its metabolites on the ECG (electrocardiogram) of mice with myocardial ischemia induced by isoprenaline and their effect on alleviating the symptom of myocardial ischemia were tested and compared. The results showed that CVT-2738 and CVT-2513 could be protective against mice myocardial ischemia induced by isoprenaline. Within all the metabolites tested in this study, CVT-2738 exhibited the best potency, however, it was still less potent than Ranolazine.