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Background Chronic inflammatory disorders in atrial fibrillation (AF) contribute to the onset of ischemic stroke. Systemic immune inflammation index (SIII) and system inflammation response index (SIRI) are the two novel and convenient measurements that are positively associated with body inflammation. However, little is known regarding the association between SIII/SIRI with the presence of AF among the patients with ischemic stroke. Methods A total of 526 ischemic stroke patients (173 with AF and 353 without AF) were consecutively enrolled in our study from January 2017 to June 2019. SIII and SIRI were measured in both groups. Logistic regression analysis was used to analyse the potential association between SIII/SIRI and the presence of AF. Finally, the correlation between hospitalization expenses, changes in the National Institutes of Health Stroke Scale (NIHSS) scores and SIII/SIRI values were measured. Results In patients with ischemic stroke, SIII and SIRI values were significantly higher in AF patients than in non-AF patients (all p  < 0.001). Moreover, with increasing quartiles of SIII and SIRI in all patients, the proportion of patients with AF was higher than that of non-AF patients gradually. Logistic regression analyses demonstrated that log-transformed SIII and log-transformed SIRI were independently associated with the presence of AF in patients with ischemic stroke (log-transformed SIII: odds ratio [OR]: 1.047, 95% confidence interval CI = 0.322–1.105, p  = 0.047; log-transformed SIRI: OR: 6.197, 95% CI = 2.196–17.484, p  = 0.001). Finally, a positive correlation between hospitalization expenses, changes in the NIHSS scores and SIII/SIRI were found, which were more significant in patients with AF (all p  < 0.05). Conclusions Our study suggests SIII and SIRI are convenient and effective measurements for predicting the presence of AF in patients with ischemic stroke. Moreover, they were correlated with increased financial burden and poor short-term prognosis in AF patients presenting with ischemic stroke.

Aim： Tetrandrine, an alkaloid with a remarkable pharmacological profile, induces oxidative stress and mitochondrial dysfunction in hepatocytes; however, mitochondria are not the direct target of tetrandrine, which prompts us to elucidate the role of oxidative stress in tetrandrine-induced mitochondrial dysfunction and the sources of oxidative stress. Methods： Rat primary hepatocytes were isolated by two-step collagenase perfusion. Mitochondrial function was evaluated by analyzing ATP content, mitochondrial membrane potential （MMP） and the mitochondrial permeability transition. The oxidative stress was evaluated by examining changes in the levels of reactive oxygen species （ROS） and glutathione （GSH）. Results： ROS scavengers largely attenuated the cytotoxicity induced by tetrandrine in rat hepatocytes, indicating the important role of ROS in the hepatotoxicity of tetrandrine. Of the multiple ROS inhibitors that were tested, only inhibitors of CYP450 （SKF-525A and others） reduced the ROS levels and ameliorated the depletion of GSH. Mitochondrial function assays showed that the mitochondrial permeability transition （MPT） induced by tetrandrine was inhibited by SKF-525A and vitamin C （VC）, both of which also rescued the depletion of ATP levels and the mitochondrial membrane potential. Upon inhibiting specific CYP450 isoforms, we observed that the inhibitors of CYP2D, CYP2C, and CYP2E1 attenuated the ATP depletion that occurred following tetrandrine exposure, whereas the inhibitors of CYP2D and CYP2E1 reduced the ROS induced by tetrandrine. Overexpression of CYP2E1 enhanced the tetrandrine-induced cytotoxicity. Conclusion： We demonstrated that CYP450 plays an important role in the mitochondrial dysfunction induced by the administration of tetrandrine. ROS generated by CYP450, especially CYP2E1, may contribute to the mitochondrial dysfunction induced by tetrandrine.

Long-distance entanglement distribution is essential for both foundational tests of quantum physics and scalable quantum networks. Owing to channel loss, however, the previously achieved distance was limited to ~100 kilometers. Here we demonstrate satellite-based distribution of entangled photon pairs to two locations separated by 1203 kilometers on Earth, through two satellite-to-ground downlinks with a summed length varying from 1600 to 2400 kilometers. We observed a survival of two-photon entanglement and a violation of Bell inequality by 2.37 ± 0.09 under strict Einstein locality conditions. The obtained effective link efficiency is orders of magnitude higher than that of the direct bidirectional transmission of the two photons through telecommunication fibers.

Aim： Angiotensin Ⅱ is believed to play an important role in tissue repair and remodeling in lungs by the angiotensin type Ⅰ （AT1） receptor via a number of potential mechanisms. However, the role of the AT1 receptor in early lung injury has not been characterized. Methods： Bleomycin-induced pulmonary fibrosis （PF） in rats was utilized to value the treatment with valsartan, an AT1 receptor antagonist, by measurement of body weight, wet weight of the left lung, hydroxyproline content, mRNA expression of collagen Ⅰ/Ⅲ, and the degree of fibrosis in lung tissues on d 21. Tissue injury in the early phase was assessed on d 1, 3 and 7 by apoptosis, malondialdehyde content, myeloperoxidase activity, inflammatory cell count and protein content. Angiotensin converting enzyme （ACE） activity and the AT1 receptor in lung tissues were analyzed by biochemistry method and Western blotting, respectively. Results： Valsartan ameliorated PF induced by bleomycin in the rats on d 21. After bleomycin was injected intratracheally, increases in the lung AT1 receptor and ACE activity were observed by d 1, 3 and 7. Lung injury deteriorated in the early phase. Valsartan reduced the increase of the AT1 receptor, ACE activity and lung injury induced by bleomycin in the early phatse. Conclusion： These observations suggest that angiotensin Ⅱ may play a potent role in early lung injury via the AT1 receptor. AT1 receptor antagonists should be assessed as potential new therapies for fibrotic lung disease.

Background Unintentional weight loss (cachexia) has been associated with poor outcomes in chronic heart failure (CHF). Meteorin‐like (Metrnl) is a novel myokine with protective effects on cardiovascular diseases. However, the change of Metrnl concentrations and its role in elderly patients with CHF remains unclear. The aim of this study was to evaluate the association of serum Metrnl with weight loss and outcomes in elderly patients with CHF. Methods A total of 931 consecutive elderly patients (aged 60 years and older) with CHF and 135 age‐matched and sex‐matched control subjects were enrolled. Serum Metrnl concentration was measured by enzyme‐linked immunosorbent assay. Body weight was measured at baseline and 12 months. Results Median of serum Metrnl levels was lower in CHF patients when compared with controls [201.31 (184.95–261.16) pg/mL vs. 168.68 (103.15–197.54) pg/mL, P < 0.001]. Patients with the lowest levels of Metrnl had higher N‐terminal pro brain natriuretic peptide (NT‐proBNP) levels but lower left ventricular eject fraction (LVEF) and estimated glomerular filtration rate (P < 0.001). Lower serum Metrnl was associated with a higher risk of >5% weight loss from baseline to 12 months [odds ratio = 6.13, 95% confidence interval (CI) = 2.57–14.62 per log decrease; P < 0.001]. Serum Metrnl levels were decreased as LVEF decreased (P < 0.001) and were positively correlated with LVEF (r = 0.267, P < 0.001) but negatively correlated with NT‐proBNP levels (r = −0.257, P < 0.001). Cox regression analysis suggested that lower serum Metrnl was associated with higher cardiovascular mortality [hazard ratio (HR) = 6.71, 95% CI = 3.41–13.18 per log decrease; P < 0.001], CHF rehospitalization (HR = 3.07, 95% CI = 1.82–5.17 per log decrease; P < 0.001), and the combined major adverse cardiac event(s) (MACEs) (HR = 5.38, 95% CI = 3.51–8.25 per log decrease; P < 0.001). The Kaplan–Meier survival curves showed that low concentration of Metrnl was a prognostic indicator of MACEs in patients with CHF. Conclusions Our study suggests that lower serum Metrnl level is correlated with weight loss and the severity of cardiac dysfunction in elderly patients with CHF.

Reprogramming tumor‐associated macrophages (TAMs) to an inflammatory phenotype effectively increases the potential of immune checkpoint blockade (ICB) therapy. Artificial mitochondrial transplantation, an emerging and safe strategy, has made brilliant achievements in regulating the function of recipient cells in preclinic and clinic, but its performance in reprogramming the immunophenotype of TAMs has not been reported. Here, the metabolism of M2 TAMs is proposed resetting from oxidative phosphorylation (OXPHOS) to glycolysis for polarizing M1 TAMs through targeted transplantation of mannosylated mitochondria (mPEI/M1mt). Mitochondria isolated from M1 macrophages are coated with mannosylated polyethyleneimine (mPEI) through electrostatic interaction to form mPEI/M1mt, which can be targeted uptake by M2 macrophages expressed a high level of mannose receptors. Mechanistically, mPEI/M1mt accelerates phosphorylation of NF‐κB p65, MAPK p38 and JNK by glycolysis‐mediated elevation of intracellular ROS, thus prompting M1 macrophage polarization. In vivo, the transplantation of mPEI/M1mt excellently potentiates therapeutic effects of anti‐PD‐L1 by resetting an antitumor proinflammatory tumor microenvironment and stimulating CD8 and CD4 T cells dependent immune response. Altogether, this work provides a novel platform for improving cancer immunotherapy, meanwhile, broadens the scope of mitochondrial transplantation technology in clinics in the future. M1 mitochondria, extracted from inflammatory M1 macrophages, are engineered with mannosylated polyethyleneimine (mPEI/M1mt) to metabolically repolarize the immunophenotype of M2 tumor‐associated macrophages, acquiring an immune‐supportive tumor microenvironment (TME) and enhancing tumor anti‐PD‐L1 therapy. This approach not only expands the range of mitochondrial transplantation technology but also offers a new and promising clinical strategy for treating various types of tumors.

Ten previously undescribed pyrrolidine alkaloids, namely penicipyrrolidines O–X (1–10), were isolated from the mangrove-derived fungus Penicillium sp. DM27, along with five known compounds (11–15). Their structures were determined by comprehensive analysis of HRESIMS and NMR spectroscopic data, and the absolute configurations were established based on biosynthetic considerations and TDDFT-ECD calculations. All isolates were evaluated for their glucose uptake capacity. Notably, penicipyrrolidine P (2) significantly enhanced cellular glucose uptake in L6 myotubes by 3.83-fold, demonstrating activity comparable to that of metformin, whereas penicipyrrolidines Q and R (3 and 4) showed relatively weaker effects.

Objective. Tyrosine kinase inhibitors are exciting new anticancer strategies. As one of the most promising oral tyrosine kinase inhibitors, cediranib has been proven effective in treating various solid malignant tumors. This study aimed to evaluate the efficacy and safety of cediranib in cancer patients. Methods. A comprehensive literature review was conducted for phase II and phase III randomized controlled trials (RCTs) up to June 31, 2021, using databases from PubMed, Cochrane Library, Embase, and Web of Science. Relevant clinical trials reporting the efficacy and toxicity characteristics of cediranib in cancer patients were analyzed using Stata 15.1. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system was used to assess the strength of the evidence. Results. The systematic review yielded 14 eligible trials, comprising 4,387 patients with solid malignant tumors. The analysis results of RCTs showed that the cediranib-containing group had a significantly better PFS than the control group (HR: 0.75; 95% CI 0.69–0.82; P < 0.001), and the pooled OS of the cediranib-containing group was significantly higher than that of the control group (HR: 0.91; 95% CI 0.84–1.00; P = 0.041). The sensitivity analysis revealed that the pooled HR was stable and excluding a single study had no effect on the significance of the pooled HR. In addition, the meta-analysis passed Begg’s and Egger’s tests, indicating no publication bias. Regarding safety, the most common adverse events were diarrhea, nausea, hypertension, fatigue, sensory neuropathy, dyspnea, vomiting, headache, neutropenia, thrombocytopenia, and leukopenia. Conclusion. Cediranib treatment responds better than noncediranib therapy but can increase the risk of specific treatment-related toxicities.

Sequencing depth is a crucial parameter for variant calling accuracy and sensitivity. The trade‐off between sequencing breadth and depth is a well‐known limitation in capture‐based targeted next‐generation sequencing (NGS). Herein, we propose a differential depth sequencing method, SPRE‐Seq, to acquire different sequencing depths for different targeted regions in an NGS panel. The SPRE‐Seq performance was evaluated using a panel of reference standards and clinical samples based on our custom‐designed homologous recombination deficiency (HRD) assay. By applying SPRE‐Seq, the effective sequencing depths of the homologous recombination repair (HRR) and HRD regions of all seven HRD reference standards met the required thresholds with only half the sequencing data volume (reduced from 12 to 6 GB). The results for the HRR genes and HRD showed 100% consistency with the expected results. In clinical samples, the effective sequencing depth of the HRR regions was significantly higher, with a sequencing data volume of 6 GB using the SPRE‐Seq approach compared with 6 GB using a regular capture approach. However, there was no significant difference between a data volume of 6 GB using SPRE‐Seq and 12 GB using a regular capture method. The SPRE‐Seq approach was feasible and reliable for determining the HRD status and HRR somatic variants in reference standards and clinical samples at a low sequencing volume. SPRE‐Seq is a reliable, feasible, and cost‐effective method that can acquire an adequate sequencing depth of an NGS panel at a low sequencing data volume.

Solasodine is a main active component isolated from Solanum incanum L. that performs a wide range of functions containing anti‐oxidant, anti‐infection, and neurogenesis promotion. In this study, we explored the influence of solasodine on three types of human colorectal cancer (CRC) cell lines. The results show that solasodine prohibited CRC cell proliferation dose‐ and time‐dependently and impeded CRC cell motility by downregulating MMPs. Solasodine was also found to fuel caspase‐cascade reaction and increase the ratio between Bax and Bcl‐2 so as to induce CRC cell apoptosis. When cells were pretreated with AKT activator (insulin‐like growth factor‐1) followed by solasodine, the solasodine‐induced apoptosis was partially abrogated by insulin‐like growth factor‐1. Moreover, solasodine hindered tumor development and stimulated similar mechanisms in vivo. In general, our study provides the first evidence that solasodine has a suppressive effect on CRC cells and that this agent may be a novel therapeutic drug for CRC treatment. Solasodine inhibits CRC growth in vitro and in vivo. The mechanism involves suppression of AKT/GSK‐3β/β‐catenin signaling. Solasodine could be a potential antitumor agent for CRC.