BackgroundThe study aims to present the effect of PIK3CA E542K and E545K mutations on glucose metabolism and proliferation and identify their underlying mechanisms in cervical cancer.MethodsThe maximum standard uptake value (SUVmax) of tumors was detected by18F-FDG PET/CT scan. In vitro, glycolysis analysis, extracellular acidification rate analysis, and ATP production were used to evaluate the impact of PIK3CA E542K and E545K mutations on glucose metabolism. The expression level of key glycolytic enzymes was evaluated by western blotting and immunohistochemical staining in cervical cancer cells and tumor tissues, respectively. Immunofluorescence analysis was used to observe the nuclear translocation of β-catenin. The target gene of β-catenin was analyzed by using luciferase reporter system. The glucose metabolic ability of the xenograft models was assessed by SUVmax from microPET/CT scanning.ResultsCervical cancer patients with mutant PIK3CA (E542K and E545K) exhibited a higher SUVmax value than those with wild-type PIK3CA (P = 0.037), which was confirmed in xenograft models. In vitro, enhanced glucose metabolism and proliferation was observed in SiHa and MS751 cells with mutant PIK3CA. The mRNA and protein expression of key glycolytic enzymes was increased. AKT/GSK3β/β-catenin signaling was highly activated in SiHa and MS751 cells with mutant PIK3CA. Knocking down β-catenin expression decreased glucose uptake and lactate production. In addition, the nuclear accumulation of β-catenin was found in SiHa cells and tumors with mutant PIK3CA. Furthermore, β-catenin downregulated the expression of SIRT3 via suppressing the activity of the SIRT3 promotor, and the reduced glucose uptake and lactate production due to the downregulation of β-catenin can be reversed by the transfection of SIRT3 siRNA in SiHa cells with mutant PIK3CA. The negative correlation between β-catenin and SIRT3 was further confirmed in cervical cancer tissues.ConclusionsThese findings provide evidence that the PI3K E542K and E545K/β-catenin/SIRT3 signaling axis regulates glucose metabolism and proliferation in cervical cancers with PIK3CA mutations, suggesting therapeutic targets in the treatment of cervical cancers.Trial registrationFUSCC 050432–4-1212B. Registered 24 December 2012 (retrospectively registered).Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0674-5) contains supplementary material, which is available to authorized users.

Serum zonulin, a biomarker for gut permeability, is increased in PCOS women and correlates with insulin resistance and severity of menstrual disorders. It suggests that alterations in gut permeability may play a role in the pathophysiology of PCOS, and serum zonulin might be used as a biomarker for both risk stratification and therapeutic outcomes in PCOS women.

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In recent decades, hybrid imaging techniques that exploit the advantages of multiple imaging technologies have aroused extensive attention due to the deficiencies of single imaging modes. Along with the development of single photon emission computed tomography-magnetic resonance imaging (SPECT-MRI), it is currently necessary to develop a series of dual probes that can combine the outstanding sensitivity of SPECT with the high spatial resolution of MRI. Herein, the commonly used technetium-99 (Tc) was labelled on the surface of manganese oxide-based mesoporous silica nanoparticles (MnO-MSNs) for use in SPECT-MRI dual-modal imaging. The radiolabelling yield was as high as 99.1 ± 0.6%, and the r value of the nanoprobes was able to reach 6.60 mM s due to the pH-responsive properties of the MnO-MSNs. The high-performance SPECT-MRI dual-modal imaging was confirmed in vivo in tumour-bearing mice, which could also provide semi-quantitative information for tumour detection. Importantly, these nanoprobes can deliver anti-cancer drugs in cancer therapy due to their unique mesoporous structures. Thus, nanotheranostics combining dual-modal imaging with anti-cancer therapeutic properties were achieved.

Background Catheter ablation is increasingly employed in the management of atrial fibrillation (AF). Data regarding safety of ablation of AF is largely derived from controlled clinical trials. Objectives The aim of this study was to analyze safety and complications of AF ablation performed in a “real world” setting outside of clinical trials, and obtain insights on predictors of complications. Methods We utilized the National Inpatient Sample database, to identify all patients who underwent AF ablations between 2015 and 2017 using International Classification of Disease—Tenth revision codes. Complications were defined as per the Agency for Health Care Research and Quality Guidelines. Statistical tests including multivariate logistic regression were performed to determine predictors of complications. Results Among 14,875 cases of AF ablation between 2015 and 2017, a total of 1884 complications were identified among 1080 (7.2%) patients. Patients with complications were likely to be older and female with a higher burden of comorbidities. A 27% increase in complications was observed from 2015 to 2017, driven by an increase in pericardial complications. Multivariate regression analysis revealed that pulmonary hypertension (adjusted odds ratio [aOR]: 1.99, p = .041) and chronic kidney disease (CKD; aOR: 1.67, p = .024), were independent predictors of complications. Centers with higher procedural volumes were associated with lower complication rates. Conclusions Complication rates related to AF ablations remain substantially high. Presence of pulmonary hypertension and CKD are predictive of higher procedural complications. Furthermore, hospital procedure volume is an important factor that correlates with complication rates.

ObjectiveThe present study focused on the development of a poloxamer 407 thermosensitive hydrogel loaded with keratinocyte growth factor-2 (KGF-2) and fibroblast growth factor-21 (FGF-21) as a therapeutic biomaterial in a scald-wound model of type-2 diabetes in Goto-Kakizaki (GK) rats.Research design and methodsIn this study, a poloxamer 407 thermosensitive hydrogel loaded with KGF-2 and/or FGF-21 was prepared and its physical and biological properties were characterized. The repairing effects of this hydrogel were investigated in a scald-wound model of type-2 diabetes in GK rats. The wound healing rate, epithelialization, and formation of granulation tissue were examined, and biomarkers reflecting regulation of proliferation and inflammation were quantified by immunostaining and Western blotting. T tests and analyses of variance were used for statistical analysis via Graphpad Prism V.6.0.ResultsA 17.0% (w/w) poloxamer 407 combined with 1.0% (w/w) glycerol exhibited controlled release characteristics and a three-dimensional structure. A KGF-2/FGF-21 poloxamer hydrogel promoted cellular migration without apoptosis. This KGF-2/FGF-21 poloxamer hydrogel also accelerated wound healing of scalded skin in GK rats better than that of a KGF-2 or FGF-21 hydrogel alone due to accelerated epithelialization, formation of granulation tissue, collagen synthesis, and angiogenesis via inhibition of inflammatory responses and increased expression of alpha-smooth muscle actin (α-SMA), collagen III, pan-keratin, transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), and CD31.ConclusionsA KGF-2/FGF-21 poloxamer hydrogel accelerated wound healing of scalded skin in GK rats, which was attributed to a synergistic effect of KGF-2-mediated cellular proliferation and FGF-21-mediated inhibition of inflammatory responses. Taken together, our findings provide a novel and potentially important insight into improving wound healing in patients with diabetic ulcers.