Inflammatory factors mediated the effect of air pollution on ischemic stroke: a two-step, mediation Mendelian randomization study.

OBJECTIVE: Numerous investigations have indicated a correlation between air pollution (AP) and an elevated ischemic stroke (IS) likelihood. The existing literature does not provide a consensus about the possible link between AP and IS. A two-sample Mendelian randomization (MR) analysis was utilized to systematically measure the causal link between AP and ischemic stroke. Furthermore, the mediating impact of inflammatory factors was also performed by a two-step MR. MATERIALS AND METHODS: A two-sample MR analysis was utilized to examine the AP impact on the incidence of IS. Additionally, a two-step MR approach was carried out to account for possible mediating variables. The indirect impact was determined by employing the product approach, which included multiplying the AP impact on inflammatory factors by the inflammatory factors' impacts on IS. The MR effect was identified through inverse variance-weighted (IVW) meta-analysis of each Wald Ratio. Additionally, complementary studies were conducted using the weighted median and MR-egger approaches. RESULTS: The IVW method with random effects showed that the per unit increase in genetically predicted PM2.5 was linked to the 0.362-fold elevated ischemic stroke risk (OR: 1.362, 95% CI: 1.032-1.796, p=0.029). Furthermore, the IVM technique, incorporating random effects, demonstrated that the per unit increase in genetically predicted PM2.5 was related to an elevated Interleukin (IL)-1ß risk (OR: 1.529, 95% CI: 1.191-1.963, p=0.001), IL-6 (OR: 1.498, 95% CI: 1.094-2.052, p=0.012) and IL-17 (OR: 1.478, 95% CI: 1.021-2.139, p=0.038). IL-1ß, IL-6, and IL-17 modulated the PM2.5 impact on ischemic stroke, while the proportion mediated by them was 59.5%. CONCLUSIONS: A positive correlation between genetically predicted PM2.5 levels and elevated ischemic stroke risk is mediated by IL-1ß, IL-6, and IL-17.

Metformin promotes differentiation of human bone marrow derived mesenchymal stem cells into osteoblast via GSK3ß inhibition.

OBJECTIVE: Metformin, a common and first-line drug for diabetes mellitus, is widely used in the world. Recently, many studies have documented that osteogenesis could be mediated by metformin. However, the specific mechanism by which metformin affects osteogenesis has not been clearly identified. Therefore, the aim of this study is to evaluate the role of GSK3ß in metformin-induced osteogenic differentiation of mesenchymal stem cells (MSCs). MATERIALS AND METHODS: Osteoblast-marker genes, including Col-1, OCN, and RUNX2, were measured by RT-PCR in differentiated MSCs treated with Metformin. Osteogenic differentiation viability was measured by Alkaline phosphatase (ALP) assays and Alizarin Red Staining. The expression of GSK3ß, ß-catenin and AMPK were measured by Western blotting in MSCs treated with metformin. RESULTS: We found that metformin at 100 µM significantly promoted osteogenic differentiation of human mesenchymal stem cells (hBMSCs). Next, we showed that GSK3ß and Wnt signaling pathway are involved in metformin-induced osteogenic differentiation of hBMSCs. Furthermore, osteogenic differentiation of hBMSCs induced by metformin could be eliminated by inhibiting phosphorylation of GSK3ß. CONCLUSIONS: The data suggested that metformin promoted the osteoblast differentiation of MSCs by, at least partly, inhibiting GSK3ß activity. Additionally, we also found that AMPK plays an essential role in the inhibition of GSK3ß by metformin.

URG4-silencing suppresses cell proliferation in nasopharyngeal carcinoma through induction of apoptosis.

OBJECTIVE: To investigate the expression and function of up-regulator of gene-4 (URG4) in nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Fresh NPC tumor tissue samples with paired adjacent normal nasopharyngeal tissues samples of 9 NPC patients were collected from NPC curative resection surgery. NPC cell lines (CNE1, CNE2 and HONE1) were cultured. Lentivirus-mediated URG4-specific short hairpin RNA (shRNA) stable transfection was done. The effect of URG4 on CNE4 and HONE1 cells viability was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). The plate-colony-formation assay was performed. Apoptosis analysis was done by flow cytometry. The expression levels of protein and RNA were detected by Western blotting and quantitative polymerase chain reaction (qPCR). RESULTS: We determined the expression of URG4/URGCP in NPC tissues and cell lines using qPCR analysis and found it was significantly upregulated in NPC. After that, stable URG4-silencing NPC cells were constructed by transfection with lentivirus-mediated shRNA. Functionally analyses indicated that knockdown of URG4 significantly impaired cell viability and colony formation ability, as confirmed by MTT and colony formation assays. Furthermore, URG4-silencing NPC cells showed more cells in the stage of early and late apoptosis compared with controls by flow cytometry assay. Western blot analysis further confirmed that knockdown of URG4 enhanced the expression of cleaved caspase-3, cleaved PARP and Bax, while decreased the expression of Bcl-2 and survivin. CONCLUSIONS: URG4/URGCP might play an essential role in NPC cell growth and proliferation and its silencing might be as a potential therapeutic target for NPC.

MRI-guided radiotherapy for head and neck cancer: initial clinical experience

Purpose. To report a single-institutional experience with the use of magnetic resonance imaging (MRI)-guided radiotherapy for cancers of the head and neck. Materials and methods. Between October 2014 and October 2016, 18 patients with newly diagnosed cancers of the head and neck were prospectively enrolled on an institutional registry trial investigating the feasibility and efficacy of external-beam radiotherapy delivered using on-board MRI. All patients had biopsy-proven evidence of malignancy, measurable disease, and the ability to provide consent. None had previously received any treatment. Median dose was 70 Gy (range 54-70 Gy). MRI scans were obtained as part of an image-guided registration protocol for alignment prior to and during each treatment. Concurrent chemotherapy was administered to 14 patients (78%). Patient-reported outcomes were assessed using the University of Washington quality of life instrument. Results. Seventeen of 18 patients completed the planned intensity-modulated radiotherapy (IMRT) treatment of which 15 (83%) had a complete response and 2 (11%) had a partial response based on initial post-therapy positron emission tomography (PET) at 3 months. The 1-year estimates of progression-free survival, overall survival, and local-regional control were 95, 96, and 95%, respectively. There were no treatment-related fatalities. The incidence of grade 3+ acute toxicity was 44%. The proportion of patients rating their health-related quality of life as "very good" or "outstanding" at 6 months and 1 year after completion of radiation therapy was 60 and 70%, respectively. Conclusions. MRI-guided radiotherapy achieves clinical outcomes comparable to contemporary series reporting on IMRT for head and neck cancer (AU)

No disponible

Optimal timing of operation for repairing atonic bladder after medullary cone injury: an experimental study in rats.

OBJECTIVE: To determine optimal timing of operation for repairing atonic bladder after medullary cone injury in rats. MATERIALS AND METHODS: I n all, 56 adult female Sprague-Dawley rats were equally randomized into seven groups: normal control group, and 4w, 6w, 8w, 10w, 12w and 16w groups after medullary cone injury, assigned as groups A-G. The model was established by sharp transaction of spinal cord at the level of L(4/5) vertebral body. Bladder weight, cross-sectional area and ultrastructure of the detrusor muscle and its neuromuscular junction (NMJ), fibrotic change, and alpha-smooth muscle antibody (alpha-SMA) expression in the detrusor muscle were examined individually. RESULTS: Bladder weight in groups E-G was significantly increased than that in group A (P<0.05). And cross-sectional area of detrusor muscle fiber in groups E-G was significantly smaller than that in group A (P<0.05). Transmission electronic microscopy showed that the number of synaptic vesicles, mitochondria and other organelles in NMJ decreased markedly in group E. In groups F and G, NMJ further degenerated with synaptic vesicles and organelles decreased or even disappeared. Masson's stain showed that the proportion of connective tissue in the detrusor muscle of groups E-G was significantly different from that of group A (P<0.05). alpha-SMA expression in the detrusor muscle decreased with the lapse of time. CONCLUSIONS: The 10th week after rat medullary cone injury can be regarded as the time node when the detrusor muscle and NMJ undergo changes, and therefore surgical nerve repair should be performed before this.