FoxM1 knockdown enhanced radiosensitivity of esophageal cancer by inducing apoptosis.

Radioresistance is a main reason for local recurrence of esophageal squamous cell carcinoma (ESCC). Forkhead box M1 (FoxM1) is implicated in cancer progression and chemoresistance. This study aims to determine the role of FoxM1 in ESCC radioresistance. We found that FoxM1 protein was upregulated in ESCC tissues compared with adjacent normal tissues. In vitro assays revealed that following irradiation, Eca-109, TE-13, and KYSE-150 cells had increased levels of FoxM1 protein. FoxM1 knockdown resulted in significantly reduced colony formation and increased cell apoptosis following irradiation. Moreover, FoxM1 knockdown induced ESCC cells to accumulate in the radiosensitive G2 /M phase and impeded the repair of radiation-induced DNA damage. Mechanistic studies indicated that radiosensitization of ESCC enhanced by FoxM1 knockdown was associated with increased BAX/BCL2 ratio as well as downregulated Survivin and XIAP, followed by the activation of both extrinsic and intrinsic apoptosis pathways. In xenograft mouse model, the combination of radiation and FoxM1-shRNA led to a synergistic anti-tumor effect. In conclusion, FoxM1 is a promising target to enhance radiosensitivity of ESCC.

Long non-coding RNA ZNFX1 antisense 1 (ZFAS1) suppresses anti-oxidative stress in chondrocytes during osteoarthritis by sponging microRNA-1323.

LncRNAs play a regulatory role in osteoarthritis (OA); however, the detailed mechanism remains to be elucidated. This study aimed to investigate the role of lncRNA zinc finger NFX1-type containing 1 (ZNFX1) antisense 1 (ZFAS1) in OA progression and explore its possible mechanismsagainst oxidative stress. Human cartilage specimens were obtained from 10 patients without OA who underwent traumatic amputation and 25 patients with OA who underwent total knee replacement surgery. Chondrocytes were prepared from harvested articular cartilage. ZFAS1, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) expression levels were analyzed using quantitative reverse transcription PCR and WB. The chondrocyte growth was indicated by MTT and colony formation assays. Chondrocyte apoptosis, reactive oxygen species generation, and anti-oxidative enzymes activities were also measured. ZFAS1 expression was reduced in OA samples and lipopolysaccharide (LPS)-treated chondrocytes used as an OA cell model mimic. ZFAS1 overexpression facilitated proliferation and repressed oxidative stress, inflammation, and apoptosis in LPS-induced chondrocytes. ZFAS1 also activated the anti-oxidative Nrf2-HO-1 pathway. ZFAS1 directly targeted miR-1323, which partially reversed the effects of ZFAS1 on chondrocyte proliferation, oxidative stress, inflammation, and apoptosis. Furthermore, Nrf2 was negatively regulated by miR-1323. The effect of miR-1323 inhibition was partly abrogated by the administration of brusatol, an Nrf2 inhibitor. Collectively, the results showed that ZFAS1 promoted chondrocyte proliferation and repressed oxidative stress, possibly by regulating the novel miR-1323-Nrf2 axis of the inflammation and apoptosis triggered by LPS, indicating that ZFAS1 is a promising therapeutic target for OA.

Does timing of esophagectomy following neoadjuvant chemoradiation affect outcomes? A meta-analysis.

BACKGROUND: The optimal timing of esophagectomy after neoadjuvant chemoradiation treatment (nCRT) remains unclear. Here, a meta-analysis was conducted to determine whether prolonged interval between nCRT and surgery can affect the outcomes in esophageal cancer. MATERIALS AND METHODS: The databases PubMed, Embase, Web of Science, and Cochrane were systematically searched for studies reporting the outcomes in esophageal cancer according to the length of interval between nCRT and surgery. The primary outcome was rate of pathologic complete response (pCR), and the secondary outcomes included R0 resection rate, incidence of anastomotic leak, postoperative mortality, and two or five-year overall survival (OS). The intervals were classified into dichotomous (≤7-8 weeks and >7-8 weeks) for the pooled analysis, and a combined relative risk (RR) was calculated. RESULTS: A total of 13 studies involving 15,086 patients were analyzed. The overall results indicated that an interval longer than 7-8 weeks between the end of nCRT and the surgery was significantly associated with an improved pCR rate (RR, 1.13; 95% confidence interval [CI], 1.05-1.21; P = 0.001). However, it was related to a higher 30-day surgical mortality (RR, 1.51; 95% CI, 1.19-1.92; P = 0.0006). The subgroup analyses only detected a significant association of the extended interval with pCR and the surgical mortality rate in adenocarcinoma patients. Moreover, an increased time interval resulted in a lower 2-year (RR, 0.94; 95% CI, 0.90-0.98; P = 0.002) and 5-year OS (RR, 0.88; 95% CI, 0.82-0.95; P = 0.0009). No association with R0 resection rate or anastomotic complication resulting from delayed resection was detected. CONCLUSIONS: Although increasing the time interval from nCRT to esophagectomy was associated with significantly higher pathologic complete response rates in esophageal cancer, delaying the surgery might be disadvantageous for the long-term survival.

Effects of Tanshinone IIA on osteogenic differentiation of mouse bone marrow mesenchymal stem cells.

Tanshinone IIA (TSA) is a lipophilic diterpene purified from the Chinese herb Danshen, which exhibits potent antioxidant and anti-inflammatory properties. Effect of TSA remains largely uninvestigated on the osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs), which are widely used in cell-based therapy of bone diseases. In the present study, both ALP activity at day 7 and calcium content at day 24 were upregulated during the osteogenesis of mouse BM-MSCs treated with TSA (1 and 5 µM), demonstrating that it promoted the osteogenesis at both early and late stages. We found that TSA promoted osteogenesis and inhibited osteoclastogenesis, evident by RT-PCR analysis of osteogenic marker gene expressions. However, osteogenesis was inhibited by TSA at 20 µM. We further revealed that TSA (1 and 5 µM) upregulated BMP and Wnt signaling. Co-treatment with Wnt inhibitor DKK-1 or BMP inhibitor noggin significantly decreased the TSA-promoted osteogenesis, indicating that upregulation of BMP and Wnt signaling plays a significant role and contributes to the TSA-promoted osteogenesis. Of clinical interest, our study suggests TSA as a promising therapeutic strategy during implantation of BM-MSCs for a more effective treatment of bone diseases.

Reduced efficiency of functional brain network underlying intellectual decline in patients with low-grade glioma.

Low-grade glioma (LGG) patients are typically accompanied by varying degrees of intellectual impairments. However, the neural mechanisms underlying intellectual decline have not yet been well understood. The aim of this study is to investigate the relationship between possibly altered functional brain network properties and intellectual decline in LGG patients. Chinese revised Wechsler adult intelligence scale (WAIS-RC) was used to assess the intelligence of 21 LGG patients and 20 healthy controls, matched in age, gender and education. Resting-state functional magnetic resonance imaging (fMRI) was performed for all the subjects to analyze functional network characteristics with graph theory. The LGG patients showed significantly poor performance on intelligence test than controls (P<0.05). Compared with controls, the patients displayed disturbed small-world manner (increased characteristic path length L and normalized characteristic path length λ) and decreased global efficiency Eglob. Specially, we found that Eglob was positively correlated with intelligence quotient (IQ) test scores in LGG group. Furthermore, network hubs, which could significantly affect the network efficiency, were in the right insula and right posterior cingulate cortex in controls, while in the right thalamus and right posterior cingulate cortex in the patients. From the perspective of brain network, our results provided evidence of reduced global efficiency for poorer intellectual performance in LGG patients, which contributed to understanding the basis of intellectual impairments.

Resting-state magnetoencephalography study of "small world" characteristics and cognitive dysfunction in patients with glioma.

BACKGROUND: The purpose of this study was to analyze "small world" characteristics in glioma patients in order to understand the relationship between cognitive dysfunction and brain functional connectivity network in the resting state. METHODS: Resting-state magnetoencephalography was performed in 20 patients with glioma and 20 healthy subjects. The clustering coefficient of the resting functional connectivity network in the brain, average path length, and "small world" index (SWI) were calculated. Cognitive function was estimated by testing of attention, verbal fluency, memory, athletic ability, visual-spatial ability, and intelligence. RESULTS: Compared with healthy controls, patients with glioma showed decreased cognitive function, and diminished low and high gamma band "small world" characteristics in the resting functional connectivity network. CONCLUSION: The SWI is associated with cognitive function and is diminished in patients with glioma, and is therefore correlated with cognition dysfunction.