Aneuploid serves as a prognostic marker and favors immunosuppressive microenvironment in ovarian cancer.

Ovarian cancer is the most lethal gynecologic neoplasm, and most patients experience recurrence and chemoresistance. Even the promising immunotherapy showed limited efficacy in ovarian cancer, probably due to the immunosuppressive microenvironment. However, the behind mechanisms of the immune exclusion or cold phenotype in ovarian cancer still remain to be explored. As a cancer dominated by copy number variations instead of mutations, ovarian cancer contains a high fraction of aneuploid, which might correlate with immune inhibition. Nevertheless, whether or how aneuploid affects ovarian cancer is still unclear. For exploring the role of aneuploid cancer cells and the potential ploidy-immune relationship, herein, the ploidy information was first comprehensively analyzed combining the karyotype data and copy number variation data obtained from Mitelman and cBioPortal databases, respectively. Ovarian cancer showed strong ploidy heterogeneity, with high fraction of aneuploid and recurrent arm-level and whole chromosome changes. Furthermore, clinical parameters were compared between the highly-aneuploid and the near-diploid ovarian cancers. Aneuploid indicated high grade, poor overall survival and poor disease-free survival in ovarian cancer. To understand the biofunction affected by aneuploid, the differentially expressed genes between the highly-aneuploid and the near-diploid groups were analyzed. Transcription data suggested that aneuploid cancer correlated with deregulated MHC expression, abnormal antigen presentation, and less infiltration of macrophages and activated T cells and higher level of T cell exclusion. Furthermore, the ploidy-MHC association was verified using the Human Protein Atlas database. All these data supported that aneuploid might be promising for cancer management and immune surveillance in ovarian cancer.

A follicle-stimulating hormone receptor-targeted near-infrared fluorescent probe for tumor-selective imaging and photothermal therapy.

Late detection, peritoneal dissemination, chemoresistance and weak response to targeted therapeutics lead to high mortality in ovarian cancer. More efficient and specific tumor imaging and therapeutic agents are needed to improve the resection rate of surgery and to eliminate residual disease. The expression patterns of follicle-stimulating hormone (FSH) receptor make it a suitable target for ovarian cancer. Here, we report a strategy to develop an organic near-infrared probe for FSH receptor-targeted tumor imaging and photothermal therapy. The FSH-Rh760 probe was conjugated from the Rh760 fluorophore with the FSH ß subunit 33-53 peptide. FSH-Rh760 specifically distinguished peritoneal metastatic ovarian cancerous foci from surrounding normal tissues with a high tumor-to-background ratio. The fluorescence signals in tumors peaked at 2 h and were cleared at 120 h postinjection. FSH-Rh760 treatment rapidly increased the abdomen temperature of mice up to ∼43 °C upon exposure to a near-infrared laser and effectively suppressed peritoneal tumor growth with tumor specificity. No significant systemic toxicities were observed. This study demonstrates the targeting ability and biocompatibility of FSH receptor-targeted theranostics and highlights its potential for clinical application in imaging-guided precision tumor resection and photothermal therapy to eliminate cancer lesions intraoperatively and postoperatively.

Generation of a PPP1CA knockout human pluripotent stem cell line via CRISPR/Cas9.

The Protein phosphatase 1 catalytic subunit alpha (PPP1CA) is a alpha subunit of the PP1 complex, which known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Increased PP1 activity has been observed in the end stage of heart failure. Here, a PPP1CA knockout human embryonic stem cell line, WAe009-A-B, was generated using the CRISPR/Cas9 system to further study the function of PPP1CA. The cell line confirmed with pluripotency, normal karyotype and differentiation potential.

An Analysis of the Effect of Noninvasive Positive Pressure Ventilation on Patients with Respiratory Failure Complicated by Diabetes Mellitus.

Objective: To observe the clinical effectiveness of noninvasive positive pressure ventilation in patients with respiratory failure complicated by diabetes. Methods: From May 2021 to May 2022, 90 patients with respiratory failure complicated by diabetes treated in our hospital were recruited and randomly assigned to receive either medication (control group) or noninvasive positive pressure ventilation (study group), with 45 patients in each group. The clinical endpoint was therapeutic outcomes. Results: Noninvasive positive pressure ventilation resulted in significantly lower Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) scores versus medications (P < 0.05). Patients with noninvasive positive pressure ventilation showed better pulmonary function indices versus those with medications (P > 0.05). There was no significant difference in arterial oxygen (PaO2), carbon dioxide partial pressure (PaCO2), and arterial oxygen pressure/inspired fraction of O2 (PaO2/FiO2) between the two groups prior to the intervention (P > 0.05). However, patients in the study group had significantly elevated PaO2 and PaO2/FiO2 and lower PaCO2 levels than those in the control group (P < 0.05). Following the intervention, noninvasive positive pressure ventilation resulted in significantly lower inflammatory factor levels versus medications (P > 0.05). After the intervention, markedly better glucose control was observed in the study group versus the control group (P < 0.05). The incidence of complications in the control group was 2.38%, which was significantly lower than that of the control group (16.67) (P < 0.05). Conclusion: Noninvasive positive pressure ventilation effectively suppresses the inflammatory response, improves the blood gas analysis index, and eliminates the negative emotions of patients, thereby maintaining hemodynamic stability and improving clinical efficacy with a better safety profile. Further studies are recommended prior to clinical promotion.

Mechanism of chlorogenic acid reducing lipopolysaccharide-induced acute lung injury in mice by regulating miR-223/NLRP3 axis. / ç»¿åŽŸé ¸é€šè¿‡è°ƒæŽ§miR-223/NLRP3è½´å‡è½»è„‚å¤šç³–è¯±å¯¼çš„å°é¼ æ€¥æ€§è‚ºæŸä¼¤çš„æœºåˆ¶.

OBJECTIVES: Chlorogenic acid has various physiological activities such as antibacterial, anti-inflammatory, and antiviral activities. Studies have shown that chlorogenic acid can alleviate the inflammatory response of mice with acute lung injury (ALI), but the specific mechanism is still unclear. This study aims to investigate whether chlorogenic acid attenuates lipopolysaccharide (LPS)-induced ALI in mice by regulating the microRNA-223 (miR-223)/nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) axis. METHODS: SPF grade BALBc male mice were randomly divided into a control group, a model group, a chlorogenic acid group, a chlorogenic acid+miR-223 negative control (miR-223 NC) group, and a chlorogenic acid+miR-223 inhibitor (miR-223 antagomir) group, 10 mice in each group. Except the control group, the other groups were instilled with 4 mg/kg LPS through the airway to establish the ALI mouse model. After the modeling, the mice in the chlorogenic acid group were continuously given chlorogenic acid (100 mg/kg) by gavage for 7 d. The chlorogenic acid+miR-223 NC group and the chlorogenic acid+miR-223 antagomir group were given 100 mg/kg chlorogenic acid by gavage every day, and then were injected with 10 µL of miR-223 NC (0.5 nmol/µL) and miR-223 antagomir (0.5 nmol/µL) respectively for 7 consecutive days.The control group and the model group were replaced with normal saline. The lung tissues of mice were taken to measure the ratios of lung wet to dry weight (W/D). The bronchoalveolar lavage fluid of mice was collected to measure the levels of TNF-α, IL-6, and IL-1ß by ELISA kit and to count the number of eosinophils (EOS), lymphocytes, neutrophils under light microscope. After HE staining, the pathological changes of lung tissues were observed and lung injury was scored. qRT-PCR method were used to determine the expression levels of miR-223 in lung tissues. Western blotting was used to determine the expression levels of NLRP3 protein in mouse lung tissues. Luciferase reporter assay was used to analyze the targeting relationship of miR-223 to NLRP3. RESULTS: Compared with the control group, the lung W/D value, the lung injury score and the level of inflammatory factors in the bronchoalveolar lavage fluid were significantly increased in the model group (all P<0.05); the infiltration of inflammatory cells in the lung tissue was severe; the alveolar space was significantly increased; the alveolar wall was significantly thickened; the number of EOS, lymphocytes, and neutrophils in the bronchoalveolar lavage fluid was significantly increased (all P<0.05); the expression levels of miR-223 in lung tissue were significantly decreased (P<0.05); and the protein expression levels of NLRP3 were significantly increased (P<0.05). Compared with the model group, the W/D value of lungs, lung injury score, and levels of inflammatory factors in bronchoalveolar lavage fluid were significantly decreased in the chlorogenic acid group, the chlorogenic acid+miR-223 NC group, and the chlorogenic acid+miR-223 antagomir group (all P<0.05); lung tissues damage was alleviated; the numbers of EOS, lymphocytes, and neutrophils in bronchoalveolar lavage fluid were significantly decreased (all P<0.05); the expression levels of miR-223 in lung tissues were significantly increased (P<0.05); and the expression levels of NLRP3 protein were significantly decreased (P<0.05). Compared with the chlorogenic acid group, the lung W/D value, lung injury score, and inflammatory factor levels in the bronchoalveolar lavage fluid were significantly increased in the chlorogenic acid+miR-223 antagomir group (all P<0.05); lung tissue damage was aggravated; the number of EOS, lymphocytes and neutrophils in bronchoalveolar lavage fluid significantly increased (all P<0.05); the expression levels of miR-223 in lung tissues were significantly decreased (P<0.05); and the expression levels of NLRP3 protein were significantly increased (P<0.05). The results of luciferase reporter assay showed that miR-223 had a targeting relationship with NLRP3. CONCLUSIONS: Chlorogenic acid may increase the level of miR-223, target the inhibition of NLRP3 expression, reduce LPS-induced inflammatory response in ALI mice, and alleviate pathological damage of lung tissues.

Significant association between rs28362491 polymorphism in NF-κB1 gene and coronary artery disease: a meta-analysis.

BACKGROUND: The association of rs28362491 polymorphism in NF-κB1 gene and coronary artery disease (CAD) risk was reported in several studies with inconsistent outcomes. This study aimed to comprehensively collect and synthesize the existing evidence to appraise whether rs28362491 was correlated to CAD susceptibility. METHODS: Databases of Web of Science, EMBASE, PubMed, Wanfang, and CNKI were retrieved from inception to August 1, 2019 without any restriction on language. The strengths of association between rs28362491 polymorphism and CAD were presented as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Thirteen case-control studies with 17 individual cohorts containing 9378 cases and 10,738 controls were incorporated into this meta-analysis. The findings indicated that rs28362491 polymorphism was significantly correlated to CAD risk in five genetic models: D vs. I, OR = 1.16, 95%CI 1.11-1.21, P<0.01; DD vs. II, OR = 1.37, 95%CI 1.25-1.49, P<0.01; DI vs. II, OR = 1.11, 95%CI 1.05-1.18, P<0.01; DD + DI vs. II, OR = 1.17, 95%CI 1.11-1.24, P<0.01; DD vs. DI + II, OR = 1.29, 95%CI 1.15-1.43, P<0.01. After stratification by ethnicity and gender, significant association still existed between rs28362491 and CAD, especially in the dominant model. CONCLUSIONS: The findings suggest that the mutant D allele in rs28362491 locus may increase the risk of CAD, and carriers of D allele appear to be more susceptible to CAD.

Preparation of Decellularized Triphasic Hierarchical Bone-Fibrocartilage-Tendon Composite Extracellular Matrix for Enthesis Regeneration.

Tendon to bone (enthesis) rupture, which may cause disability and persistent pain, shows high rate of re-rupture after surgical repair. Tendon or enthesis scaffolds have been widely studied, but few of these materials can recapitulate the tissue continuity. Thus, this study is conducted to prepare a triphasic decellularized bone-fibrocartilage-tendon (D-BFT) composite scaffold. The D-BFT scaffold is developed using a combination of physical, chemical, and enzymatic treatments using liquid nitrogen, Triton-X 100, sodium-dodecyl sulfate, and DNase I, which effectively removes the cell components while preserving the biological composite and microstructure. Moreover, the mechanical properties of D-BFT are highly preserved and similar to those of the human Achilles tendon. Additionally, in vitro, mesenchymal stem cells (MSCs) adhered, proliferated, and infiltrated into the D-BFT scaffold, and MSC differentiation is confirmed by up-regulation of osteogenic-related and tenogenic-related genes. The repair outcomes are explored by applying the D-BFT scaffold in the model of femur-tibia defects in vivo, which shows good repair results. Thus, the D-BFT scaffold developed in this study is a promising graft for enthesis regeneration.

Effect of intracoronary anisodamine and diltiazem administration during primary percutaneous coronary intervention in acute myocardial infarction.

OBJECTIVE: The aim of this study was to examine the role of intracoronary anisodamine and diltiazem administration performed before stenting on the immediate angiographic and clinical outcome in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: STEMI patients during primary PCI were randomized to two bolus injections of intracoronary anisodamine (1 mg/5 ml) and diltiazem (2 mg/5 ml) (COM group, n=54) or saline (5 ml) and diltiazem (2 mg/5 ml) (diltiazem group, n=54) before stenting. The primary endpoint was the incidence of no/slow reflow [thrombolysis in myocardial infarction (TIMI) flow grade≤2] immediately after stenting. TIMI myocardial perfusion grade and corrected TIMI frame count were assessed. The secondary endpoints were major adverse cardiac events including death, nonfatal myocardial infarction, and target vessel revascularization. RESULTS: The percent of TIMI flow grade 3 was found to be higher in the COM group than in the diltiazem group (92.6 vs. 75.9%, P=0.032). The percent of TIMI myocardial perfusion grade 3 was 46.3% in the diltiazem group and improved in the COM group (68.5%, P=0.032). Corrected TIMI frame count was significantly lower in the COM group than in the diltiazem group (P<0.0001). The COM group showed low incidences of bradyarrhythmia and rapid arrhythmia (7.4 vs. 24.1% and 3.7 vs. 18.5%, respectively, P=0.032, P=0.029). In addition, there were no significant differences in the secondary outcome measures. CONCLUSION: Intracoronary anisodamine and diltiazem administration before stenting improved the angiographic results and prevented reperfusion arrhythmia in patients with STEMI undergoing PCI.

Stereoselective binding of doxazosin enantiomers to plasma proteins from rats, dogs and humans in vitro.

AIM: (±)Doxazosin is a long-lasting inhibitor of α1-adrenoceptors that is widely used to treat benign prostatic hyperplasia and lower urinary tract symptoms. In this study we investigated the stereoselective binding of doxazosin enantiomers to the plasma proteins of rats, dogs and humans in vitro. METHODS: Human, dog and rat plasma were prepared. Equilibrium dialysis was used to determine the plasma protein binding of each enantiomer in vitro. Chiral HPLC with fluorescence detection was used to measure the drug concentrations on each side of the dialysis membrane bag. RESULTS: Both the enantiomers were highly bound to the plasma proteins of rats, dogs and humans [(-)doxazosin: 89.4%-94.3%; (+)doxazosin: 90.9%-95.4%]. (+)Doxazosin exhibited significantly higher protein binding capacities than (-)doxazosin in all the three species, and the difference in the bound concentration (Cb) between the two enantiomers was enhanced as their concentrations were increased. Although the percentage of the plasma protein binding in the dog plasma was significantly lower than that in the human plasma at 400 and 800 ng/mL, the corrected percentage of plasma protein binding was dog>human>rat. CONCLUSION: (-)Doxazosin and (+)doxazosin show stereoselective plasma protein binding with a significant species difference among rats, dogs and humans.