Dose-response analysis between hemoglobin A1c and risk of atrial fibrillation in patients with and without known diabetes.

BACKGROUND:The relationship between serum hemoglobin A1c (HbA1c) and atrial fibrillation (AF) or postoperative AF (POAF) in coronary artery bypass (CABG) patients is still under debate. It is also unclear whether there is a dose-response relationship between circulating HbA1c and the risk of AF or POAF. METHODS AND RESULTS:The Cochrane Library, PubMed, and EMBASE databases were searched. A robust-error meta-regression method was used to summarize the shape of the dose-response relationship. The RR and 95%CI were using a random-effects model. In total, 14 studies were included, totaling 17,914 AF cases among 352,325 participants. The summary RR per 1% increase in HbA1c was 1.16 (95% CI: 1.07-1.27). In the subgroup analysis, the summary RR was 1.13 (95% CI: 1.08-1.19) or 1.12 (95% CI: 1.05-1.20) for patients with diabetes or without known diabetes, respectively. The nonlinear analysis showed a nonlinear (Pnonlinear = 0.04) relationship between HbA1c and AF, with a significantly increased risk of AF if HbA1c was over 6.3%. However, HbA1c (per 1% increase) was not associated with POAF in patients with diabetes (RR: 1.13, P = 0.34) or without known diabetes (RR: 0.91, P = 0.37) among patients undergoing CABG. CONCLUSION:Our results suggest that higher HbA1c was associated with an increased risk of AF, both in diabetes and in without diabetes or with unknown diabetes. However, no association was found between HbA1c and POAF in patients undergoing CABG. Further prospective studies with larger population sizes are needed to explore the association between serum HbA1c level and the risk of POAF

Association between weight loss and outcomes in patients undergoing atrial fibrillation ablation: a systematic review and dose–response meta-analysis

Abstract Background Obesity is an strong risk factor for atrial fibrillation (AF), and obesity can affect the prognosis of AF. However, the role of weight loss on outcomes after ablation remains unclear. Objectives This study aims to determine the relationship between weight loss and outcomes in patients with AF ablation, as well as the potential dose–response relationship. Methods The Cochrane Library, PubMed, and Embase databases were searched to identify studies that reported a relationship between weight loss and ablation up to August 17, 2021. Relative risks (RRs) were pooled using random-effects models. Results One randomized, open-labeled clinical trial and seven cohort studies involving 1283 patients were included. The mean body mass index of all included studies was over 30 kg/m2. The clinical trial showed a non-significant benefit of weight loss intervention on AF recurrence (Odd risk [OR] = 1.02, 95% confidence interval [CI] 0.70–1.47). Meta-analysis based on observational studies showed that the recurrence rate of AF after ablation was significantly reduced (RR = 0.43, 95% CI 0.22–0.81, I2 = 97%) in relatively obese patients with weight loss compared with the control group. Each 10% reduction in weight was associated with a decreased risk of AF recurrence after ablation (RR = 0.54, 95% CI 0.33–0.88) with high statistical heterogeneity (I2 = 76%). An inverse linear association (Pnon-linearity = 0.27) between AF relapse and increasing weight loss was found. Conclusions Our results first suggest an inverse dose–response association between weight loss and risk of recurrent AF after ablation, with moderate certainty. Graphical Abstrac

AEG-1 Contributes to Metastasis in Hypoxia-Related Ovarian Cancer by Modulating the HIF-1alpha/NF-kappaB/VEGF Pathway

Objective. Ovarian carcinoma represents one of the deadliest malignancies among female cancer patients. Astrocyte-elevated gene-1 (AEG-1) participates in the ontogenesis of multiple human malignant diseases. Here we evaluated AEG-1, hypoxia-inducible factor- (HIF-) 1α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and vascular endothelial growth factor (VEGF) amounts in hypoxia induced ovarian carcinoma cells. This study aimed to explore the mechanism by which AEG-1 regulates metastasis in hypoxia induced ovarian carcinoma. Patients and Methods. AEG-1, HIF-1α, and VEGF protein amounts were evaluated by immunohistochemistry in 40 and 170 normal ovary and ovarian cancer tissue specimens, respectively. In addition, AEG-1, HIF-1α, NF-κB, and VEGF mRNA and protein levels were determined by reverse quantified RT-PCR and WB, respectively, at different time periods (0–24 h) in epithelial ovarian cancer (EOC) SKOV3 cells treated in a hypoxia incubator. Furthermore, NF-κB and VEGF gene and protein expression levels in AEG-1 knockdown EOC cells were quantitated by RT-PCR and WB, respectively. Results. AEG-1, HIF-1α, and VEGF amounts were significantly elevated in EOC tissue samples compared with normal ovary specimens (p<0.001). Positive expression of HIF-1α and AEG-1 was associated with higher metastatic rate (p<0.01), lower FIGO stage (p<0.001), and degree of differentiation (p<0.001). Meanwhile, EOC SKOV3 cells grew upon exposure to hypoxia for 8 h (p<0.001); at this time point, AEG-1, HIF-1α, NF-κB, and VEGF amounts peaked (p<0.001), at both the gene and the protein levels. After AEG-1 knockdown, HIF-1α, NF-κB, and VEGF amounts were significantly decreased in EOC SKOV3 cells, also under hypoxic conditions (p<0.01). Conclusions. As an independent prognostic factor, AEG-1 was found to be significantly associated with hypoxia in ovarian cancer by regulating the HIF-1alpha/NF-kappaB/VEGF pathway. Therefore, AEG-1 may be useful in determining disease stage and prognosis in ovarian cancer

3D Printing of Microenvironment‐Specific Bioinspired and Exosome‐Reinforced Hydrogel Scaffolds for Efficient Cartilage and Subchondral Bone Regeneration

Abstract In clinical practice, repairing osteochondral defects presents a challenge due to the varying biological properties of articular cartilages and subchondral bones. Thus, elucidating how spatial microenvironment‐specific biomimetic scaffolds can be used to simultaneously regenerate osteochondral tissue is an important research topic. Herein, a novel bioinspired double‐network hydrogel scaffold produced via 3D printing with tissue‐specific decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)‐derived exosomes is described. The bionic hydrogel scaffolds promote rat bone marrow MSC attachment, spread, migration, proliferation, and chondrogenic and osteogenic differentiation in vitro, as determined based on the sustained release of bioactive exosomes. Furthermore, the 3D‐printed microenvironment‐specific heterogeneous bilayer scaffolds efficiently accelerate the simultaneous regeneration of cartilage and subchondral bone tissues in a rat preclinical model. In conclusion, 3D dECM‐based microenvironment‐specific biomimetics encapsulated with bioactive exosomes can serve as a novel cell‐free recipe for stem cell therapy when treating injured or degenerative joints. This strategy provides a promising platform for complex zonal tissue regeneration whilst holding attractive clinical translation potential

Regulation of Intrinsic and Extrinsic Apoptotic Pathways in Osteosarcoma Cells Following Oleandrin Treatment

Our previous study has reported the anti-tumor effect of oleandrin on osteosarcoma (OS) cells. In the current study, we mainly explored its potential regulation on intrinsic and extrinsic apoptotic pathway in OS cells. Cells apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected using fluorescence staining and flow cytometry. Caspase-3 activity was detected using a commercial kit. The levels of cytoplasmic cytochrome c, mitochondrial cytochrome c, bcl-2, bax, caspase-9, Fas, FasL, caspase-8 and caspase-3 were detected by Western blotting. z-VAD-fmk was applied to block both intrinsic and extrinsic apoptosis pathways, and cells apoptosis was also tested. Furthermore, we used z-LEHD-fmk and Fas blocking antibody to inhibit intrinsic and extrinsic pathways, separately, and the selectivity of oleandrin on these pathways was explored. Results showed that oleandrin induced the apoptosis of OS cells, which was accompanied by an increase in ROS and a decrease in MMP. Furthermore, cytochrome c level was reduced in mitochondria but elevated in the cytoplasm. Caspase-3 activity was enhanced by oleandrin in a concentration- and time-dependent manner. Oleandrin also down-regulated the expression of bcl-2, but up-regulated bax, caspase-9, Fas, FasL, caspase-8 and caspase-3. In addition, the suppression of both apoptotic pathways by z-VAD-fmk greatly reverted the oleandrin-induced apoptosis. Moreover, the suppression of one pathway by a corresponding inhibitor did not affect the regulation of oleandrin on another pathway. Taken together, we concluded that oleandrin induced apoptosis of OS cells via activating both intrinsic and extrinsic apoptotic pathways

Metabolic Engineering of Pseudomonas putida KT2440 for Complete Mineralization of Methyl Parathion and γ‑Hexachlorocyclohexane

Agricultural soils are often cocontaminated with multiple pesticides. Unfortunately, microorganisms isolated from natural environments do not possess the ability to simultaneously degrade different classes of pesticides. Currently, we can use the approaches of synthetic biology to create a strain endowed with various catabolic pathways that do not exist in a natural microorganism. Here, we describe the metabolic engineering of a biosafety Pseudomonas putida strain KT2440 for complete mineralization of methyl parathion (MP) and γ-hexachlorocyclohexane (γ-HCH) by functional assembly of the MP and γ-HCH mineralization pathways. The engineered strain was genetically stable, and no growth inhibition was observed. Such a strain not only would reduce the toxicity of MP and γ-HCH but also would prevent the accumulation of potentially toxic intermediates in the environment. Furthermore, expression of <i>Vitreoscilla</i> hemoglobin improved the ability of the engineered strain to sequester O₂. The inoculation of the engineered strain to soils treated with MP and γ-HCH resulted in a higher degradation rate than in noninoculated soils. Moreover, introduced GFP may be used to monitor the activity of the engineered strain during bioremediation. The engineered strain may be a promising candidate for <i>in situ</i> bioremediation of soil cocontaminated with MP and γ-HCH

Targeting rare tumors: new focus for clinical research in China

Rare tumor has a huge unmet medical need without standard regimens, calling for novel therapeutic interventions. The National Cancer Center of China identified a threshold of incidence for rare tumor as 2.5/100,000, based on the characteristics of Chinese population. Molecular profiles for rare tumor patients in China further provided prospects for precise and individualized targeted treatment. An ongoing phase II clinical trial, the PLATFORM study, is the first trial tailored for rare solid tumors in China, featured by molecule‐guided therapeutics. With the promulgation of supportive policies to encourage the development of innovative drugs for rare tumors in China, opportunities will be provided for these patients and the gap will be filled in the treatment of rare tumors