PTEN-mediated FOXO signaling affects autophagy, migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease. Among them, abnormal proliferation, migration and vascularization of fibroblast-like synoviocytes (FLS) are the main pathological basis of persistent synovitis and bone destruction in RA. In the current study, we attempted to find effective molecular mechanisms for the treatment of RA by investigating RA-FLS. Firstly, the study was conducted to identify the potential target gene PTEN and its related signaling pathway through bioinformatics analysis. Subsequently, the target gene PTEN overexpression was regulated by cell transfection. The expression of FOXO signaling factors and autophagy-related proteins were detected by western blotting assay. Cell proliferation was measured by CCK-8 and EdU assays. Inflammation level was detected by ELISA. Cell migration and invasion were detected using wound healing assay and transwell chamber assay, respectively. Cell apoptosis was detected using flow cytometry. The results showed that overexpression of PTEN activated FOXO1 signaling in RA-FLS, and regulated autophagy, proliferation, invasion, migration, and the levels of pro-inflammatory factors in the disease. In conclusion, PTEN might provide an effective therapeutic strategy for rheumatoid arthritis by mediating the FOXO1 signaling pathway.

Extracellular Vesicles as Biomarkers in Head and Neck Squamous Cell Carcinoma: From Diagnosis to Disease-Free Survival.

Head and neck squamous cell carcinomas (HNSCCs) arising from different anatomical sites present with different incidences and characteristics, which requires a personalized treatment strategy. Despite the extensive research that has conducted on this malignancy, HNSCC still has a poor overall survival rate. Many attempts have been made to improve the outcomes, but one of the bottlenecks is thought to be the lack of an effective biomarker with high sensitivity and specificity. Extracellular vesicles (EVs) are secreted by various cells and participate in a great number of intercellular communications. Based on liquid biopsy, EV detection in several biofluids, such as blood, saliva, and urine, has been applied to identify the existence and progression of a variety of cancers. In HNSCC, tumor-derived EVs exhibit many functionalities by transporting diverse cargoes, which highlights their importance in tumor screening, the determination of multidisciplinary therapy, prediction of prognosis, and evaluation of therapeutic effects. This review illustrates the classification and formation of EV subtypes, the cargoes conveyed by these vesicles, and their respective functions in HNSCC cancer biology, and discloses their potential as biomarkers during the whole process of tumor diagnosis, treatment, and follow-up.

Mitochondrial Respiration Inhibition Suppresses Papillary Thyroid Carcinoma Via PI3K/Akt/FoxO1/Cyclin D1 Pathway.

Background: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, but little is known regarding PTC metabolic phenotypes and the effects of mitochondrial activity on PTC progression. The great potential of mitochondria-targeting therapy in cancer treatment promoted us to use tool compounds from a family of Mito-Fu derivatives to investigate how the regulation of mitochondrial respiration affected tumor progression characteristics and molecular changes in PTC. Methods: Mito-Fu L20, a representative of 12 synthetic derivatives, was chosen for mitochondrial inhibition experiments. Sample sections from PTC patients were collected and processed to explore potential molecular alterations in tumor lymph node metastasis (LNM). In vitro analyses were performed using human PTC cell lines (K1 and TPC-1), with the human normal thyroid follicular cell line (Nthy) as a control. K1 cells were injected into nude mice to generate an animal model. The mice were injected with normal saline or Mito-Fu L20 at 20 or 50 mg/kg every other day; their body weights and tumor volumes were also measured over time. To elucidate the resulting metabolic phenotype, we measured oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), cellular adenosine triphosphate (ATP) levels and reactive oxygen species (ROS) production, and mitochondrial membrane potential. Wound healing and Transwell assays, cell cycle assays, real-time fluorescence quantitative PCR, Western blotting, and immunohistochemical staining were performed to explore glycolysis-dominant metabolism in PTC. Results: Cyclin D1 and mitochondrial complex IV were detected in tumor samples from PTC patients with LNM. Mito-Fu L20 showed dose-independent and reversible modulation of mitochondrial respiration in PTC. In addition to mitochondrial dysfunction and early apoptosis, G1/S phase arrest. Notably, reversible mitochondrial inhibition yielded durable suppression of tumor proliferation, migration, and invasion via the PI3K/Akt/FoxO1/Cyclin D1 pathway. In vivo experiments demonstrated that Mito-Fu L20 has a good safety profile and specific restorative effect on mitochondrial activity in the liver. In addition, Mito-Fu L20 showed antitumor effects, alleviated tumor angiogenesis, and improved thyroid function. Conclusion: Reversible inhibition of ATP production and durable suppression of PTC growth indicates that the downregulation of mitochondrial function has a negative impact on tumor progression and LNM via the PI3K/Akt/FoxO1/Cyclin D1 pathway. The results provide new insights into the antitumor potential and clinical translation of mitochondrial inhibitors.

D3 Versus D2 Lymphadenectomy in Right Hemicolectomy: A Systematic Review and Meta-analysis.

PURPOSE: D3 lymphadenectomy for right colon cancer improves oncological outcomes. This meta-analysis aimed to compare operation data, histopathological characteristics, perioperative conditions, and long-term survival after D3 and D2 lymphadenectomy in right hemicolectomy. METHODS: We searched PubMed, Embase, and the Cochrane Library for relevant articles (up to March 31, 2020). Random-effects and fixed-effects meta-analysis models were used. Review Manager (RevMan) version 5.3 and Stata version 15.1 were used for pooled estimates. RESULTS: After screening 714 articles, 7 articles with a total of 1368 patients were eligible for inclusion. Compared with D2, D3 lymphadenectomy improves results in terms of blood loss (weighted mean difference [WMD] = -20.63, 95% confidence interval [CI] -28.19 to -13.16, P < .01), harvested lymph nodes (WMD = 8.86, 95% CI 7.74 to 9.98, P < .01), 3-year overall survival (OS) (hazard ratio [HR] = 2.03, 95% CI 1.20 to 3.43, P < .01), 5-year OS (HR = 2.22, 95% CI 1.15 to 4.30, P = .02), and 5-year disease-free survival (DFS) (HR = 2.16, 95% CI 1.19 to 3.90, P = .01). There was no significant difference regarding operation time, anastomosis leakage, wound infection, overall morbidity, postoperative hospital stay, mortality, length of dissected colon, and 3-year DFS (P >= .05). CONCLUSIONS: It is suggested in this review that D3 lymphadenectomy is superior to D2 lymphadenectomy in terms of blood loss, harvested lymph nodes, 3-year OS, 5-year OS, and 5-year DFS. The conclusion must be drawn with caution due to the limited number of included studies. Further RCTs are needed for stronger evidence.

Development of Green Banana Fruit Wines: Chemical Compositions and In Vitro Antioxidative Activities.

This study aimed to develop functional fruit wines using whole fruit, pulp, and peels from green bananas. The boiled banana homogenates were mixed with cane sugar before wine fermentation. Quality parameters, phenolic compounds, flavor components, and antioxidative properties of the green banana peel wine (GBPW), green banana pulp wine (GBMW), and whole banana wine (GBW) were determined. High-performance liquid chromatography was used to determine the phytochemical compounds in three wines, and the flavor components were further analyzed using headspace solid-phase microextraction combined with gas chromatography-mass spectrometry. The flavor components and in vitro antioxidant activities were, respectively, determined using the relative odor activity value and the orthogonal projections on latent structure discrimination analysis (OPLS-DA). In vitro antioxidative capacities for these wines were evaluated using antioxidant chemical assays and cell culture methods. The total phenolic and total tannin content of the GBPW, GBMW, and GBW showed reducing trends with increasing fermentation days, whereas the total flavonoid content of the wine samples exhibited downward trends. The antioxidant capacities of the three wine samples were higher than those of the raw fruit samples, except for the metal chelation rate (%). Additionally, the main flavor component in the wine samples was 3-methyl-1-butanol. Its percentages in the GBPW, GBMW, and GBW were 72.02%, 54.04%, and 76.49%, respectively. The OPLS-DA results indicated that the three wines presented significantly different antioxidant activities. The cell-culture-based antioxidant analysis showed that these wine samples had protective effects against the oxidative stress of the 3T3-L1 preadipocytes induced by hydrogen peroxide. This study provided a theoretical basis for defining the antioxidant characteristics of banana wines and expanding novel channels for using banana peels to develop nutraceuticals.

DUSP4 alleviates LPS-induced chondrocyte injury in knee osteoarthritis via the MAPK signaling pathway.

Knee osteoarthritis (KOA) is characterized by cartilage damage, and the associated pathogenesis is complex. The expression of dual specificity protein phosphatase 4 (DUSP4) is significantly decreased in osteoarthritis (OA); however, the specific role and mechanism underlying DUSP4 in OA are yet to be elucidated. ATDC5 cells were treated with lipopolysaccharide (LPS) to establish the cell injury model. The expression levels of DUSP4 were decreased in OA chondrocytes, demonstrated by reverse transcription-quantitative PCR and western blot analysis. Following overexpression of DUSP4 by cell transfection, Cell Counting Kit-8, ELISA, TUNEL and western blotting assays were used to detect the cell viability, oxidative stress, inflammation and apoptosis levels of LPS-induced ATDC5 cells. Overexpression of DUSP4 inhibited the activation of the MAPK signaling pathway, thereby reducing oxidative stress levels, inflammatory response and apoptosis in the OA cell model. The mechanisms underlying DUSP4 in OA were further explored following the addition of MAPK signaling pathway agonist, phorbol 12-myristate 13-acetate (PMA). The addition of PMA reversed the inhibitory effects of DUSP4 overexpression on oxidative stress, inflammatory response and apoptosis in cells. In summary, DUSP4 alleviated LPS-induced chondrocyte injury in KOA via the MAPK signaling pathway.

Preparation of FA-targeted magnetic nanocomposites co-loading TFPI-2 plasmid and cis-platinum and its targeted therapy effects on nasopharyngeal carcinoma.

The majority of patients diagnosed with nasopharyngeal carcinoma (NPC) present with advanced-stage disease. The main treatment for these patients is concurrent chemoradiotherapy, which has various side effects. To improve the therapeutic effects and reduce the side effects of NPC chemoradiotherapy, we constructed a multifunctional folic acid (FA)-targeted magnetic nanocomposite codelivering tissue factor pathway inhibitor-2 (TFPI-2) and cisplatin (CDDP). This novel nanocomposite (FA-MNP/CDDP/TFPI-2) was obtained by amidation and electrostatic adsorption between FA-methoxypolyethylene glycol-polyethyleneimine (FA-MPEG-PEI) containing the TFPI-2 plasmid and magnetic nanoparticles modified by aldehyde sodium alginate loaded with CDDP. Transmission electron microscopy (TEM) images showed that the size of the individual magnetite particle core was approximately 11.5 nm. The structure and composition of the nanocomposites were identified and examined by 1H nuclear magnetic resonance (NMR) spectroscopy and ultraviolet (UV) spectrophotometry. The fluorescence analysis, Prussian blue iron staining, magnetic resonance (MR) imaging and whole-body fluorescence imaging results demonstrated that FA-MNP/CDDP/TFPI-2 showed high gene transfection efficiency and could target tumor cells via folate receptor (FR)-mediated delivery. The codelivery analysis showed that the obtained FA-MNP/CDDP/TFPI-2 composite could cause significantly more apoptosis than treatment with CDDP or TFPI-2 alone. The results showed that the FA-MNP/CDDP/TFPI-2 composites were successfully synthesized and indicated to be a specific molecular target for the FR with significant inhibitory effects on the growth of HNE-1 cells.

The predictive value of coexisting BRAFV600E and TERT promoter mutations on poor outcomes and high tumour aggressiveness in papillary thyroid carcinoma: A systematic review and meta-analysis.

BRAFV600E mutation is highly prevalent in patients with papillary thyroid carcinoma (PTC), and TERT promoter (TERTp) mutation is strongly associated with cancer-related mortality. However, predictive power of the two mutations remains inconclusive. We aimed to verify the prognostic effects of both mutations to assess the value of mutation detection for risk stratification in terms of PTC prognosis and tumour invasion, to guide PTC diagnosis and treatment. We conducted a literature search in the MEDLINE (PubMed), EMBASE, Web of Science and CENTRAL (Cochrane library) databases, from inception to February 2020. Basic characteristics, prognoses and clinicopathological features were collected from the included studies for further analysis. Twelve studies involving 4184 PTC patients were enrolled in our analysis. In total, 2412 (57.6%) of the patients carried either BRAFV600E or TERTp mutation, and 290 (6.9%) patients had both mutations. TERTp mutation was more common in patients with BRAFV600E mutation (RR = 1.75 [95% CI 1.44-2.13]). Patients with both mutations had a worse prognosis compared with those with a single mutation (vs BRAFV600E only: RR = 5.34 [4.20-6.78] vs TERTp only: RR = 2.12 [1.41-3.19]). TERTp mutation alone independently increased the risk of a poor prognosis (RR = 2.90 [1.93-4.35]) in terms of mortality (RR = 15.09 [7.75-29.37]), disease persistence (RR = 4.00 [2.03-7.90]), recurrence (RR = 4.34 [4.20-6.78]), lymph node metastasis (RR = 1.57 [1.24-1.99]) and distant metastasis (RR = 2.94 [1.13-7.65]). We found that PTC patients with BRAFV600E mutation were more likely to have TERTp mutation. TERTp mutation was an independent predictive factor for poor prognosis of PTC patients, but the predictive value of BRAFV600E mutation remains inconclusive. Patients with both mutations have remarkably higher risks of adverse outcomes compared with those with a single mutation. PTC patients could benefit from mutation detection for aiding risk stratification (BRAF + TERT+ > BRAF - TERT+ > BRAF + TERT-).

Disseminated peritoneal leiomyomatosis after uterine artery embolization, laparoscopic surgery, and high intensity focused ultrasound for uterine fibroids：a case report.

BACKGROUND: Disseminated peritoneal leiomyomatosis (DPL) is a rare, generally benign disorder. With the advent of laparoscopic surgery for uterine fibroids, the reported number of cases of DPL has significantly increased since the introduction of unconfined power morcellation. Morcellation and other procedures may be associated with DPL. METHODS: We present the case of a 48-year-old patient with DPL who underwent uterine artery embolization (UAE), laparoscopic myomectomy and high intensity focused ultrasound (HIFU) 11 years, 6 years, and 2 years before the final diagnosis of DPL was made. A subtotal hysterectomy with bilateral salpingo-oopherectomy was performed to remove the uterus, the fallopian tube and the ovaries. We carefully excised as many visible lesions as possible. RESULTS: After the surgical treatment performed in our center the patient became free of symptoms. CONCLUSION: In our case, the occurrence of DPL is most likely associated with laparoscopic myomectomy using power morcellation. In addition, it should be noted whether some other factors played a role in stimulating the growth of the multiple nodules.

Willingness to Self-Pay for Pre-exposure Prophylaxis in Men Who Have Sex With Men: A National Online Survey in Taiwan.

High cost of pre-exposure prophylaxis (PrEP) is a major concern for acceptability. This study determined the willingness of men who have sex with men to self-pay for PrEP and factors associated with the likelihood of condom use if taking PrEP. The Taiwan 2014 MSM Online Sex Survey was conducted and data such as demographics, attitudes toward PrEP, and sexual behaviors in the previous 3 months were collected. Of the 1,151 MSM who participated, 56% were willing to take PrEP, but only 23% were willing to self-pay $340 for PrEP. Willingness to self-pay for PrEP was significantly associated with the previous receipt of nonoccupational post-exposure prophylaxis (adjusted odds ratio [AOR], 3.02, 95%CI [1.49, 6.12]), and positive attitudes toward PrEP (AOR, 3.02, 95%CI [2.19, 4.17]). Of MSM who are willing to use PrEP, 73.6% would maintain condom use if taking PrEP. If PrEP is made available in Taiwan, more efforts should be focused on increasing awareness of MSM who are practicing risky behaviors.

Trends of HIV and sexually transmitted infections, estimated HIV incidence, and risky sexual behaviors among gay bathhouse attendees in Taiwan: 2004-2008.

Five serial cross-sectional surveys were done at eight gay bathhouses in Taiwan to investigate the trends of HIV and sexually transmitted infections (STIs) and estimated HIV incidence between 2004 and 2008. Bathhouse attendees completed a questionnaire and tests for HIV, syphilis, hepatitis C virus, and amoebiasis. Twenty-nine (38.6%) were identified as having recent HIV-1 infections. There was a significant increase in HIV incidence, from 7.8% in 2004 to 15% in 2007 (χ(2) = 17.59, P-trend <0.001). Recreational drug use is the primary risk behavior. Comprehensive screening programs in gay bathhouses for early detection of HIV and STIs are important.

[Clinical study of maternal serum leptin levels as a predictor of gestational diabetes mellitus and gestational impaired glucose tolerance].

OBJECTIVE: To investigate whether maternal serum leptin level can be used as a predictor of gestational diabetes mellitus (GDM) and gestational impaired glucose tolerance (GIGT). METHODS: Five hundred and eighty-three pregnant women were screened for GDM by the 50g oral glucose challenge test. At the same time, serum leptin levels were determined by radioimmunoassay, then the relationship between maternal serum leptin level and the incidence of GIGT and GDM was analyzed. According to the screening result, all the pregnant women were divided into three groups, the normal glucose group (NGT group), the gestational impaired glucose tolerance group (GIGT group), and gestational diabetes mellitus group (GDM group). GIGT group and GDM group were named as glucose intolerant group as a whole. RESULTS: (1) The serum leptin concentration of normal pregnant women ascended gradually from (7.0 +/- 1.8) microg/L in 24 gestational week to (9.4 +/- 2.1) microg/L during 34 - 36 gestational week, and then declined slightly but still maintained high level till delivery. (2) The serum leptin concentration of the glucose intolerant pregnant women ranged from (11.3 +/- 3.1) microg/L to(14.5 +/- 4.3) microg/L, and showed no difference among different gestational weeks (P > 0.05). (3) Serum leptin level of glucose intolerant women was (12.5 +/- 3.5) microg/L on average, much higher than that of NGT group, (8.5 +/- 2.6) microg/L (P < 0.05), and this difference remained in any gestational week (P < 0.05). (4) Most of the GDM clustered in the higher leptin level groups and 66.7% GDM had a serum leptin level higher than 14.0 microg/L. Moreover, 64.7% of women whose serum leptin level was above 17.0 microg/L had different degree of glucose intolerance. Serum leptin level positively correlated with the incidence of GIGT and GDM. CONCLUSION: Serum leptin level is correlated with glucose tolerance during pregnancy. Its abnormal increase during pregnancy might have a predictive value for GDM and GIGT.