Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to ...increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients' clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464-0.9778), 0.9760 (0.9613-0.9906), and 0.9246 (0.8763-0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients.
The present study aimed to clarify whether eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have differential effects on blood pressure and inflammatory mediators. A systematic literature ...search was conducted in PubMed and Scopus updated to Apr. 2018. The mean changes in risk factors of chronic diseases were calculated as weighted mean difference (WMD) by using a random-effects model. Twenty randomized controlled trials (RCTs) were included. The summary estimate showed that EPA intervention significantly reduced systolic blood pressure (SBP) (-2.6 mmHg; 95%confident interval (CI): -4.6, -0.5 mmHg), especially in subjects with dyslipidemia (-3.8 mmHg; 95%CI: -6.7, -0.8 mmHg). The pooled effect indicated that supplemental DHA exerted a significant reduction in diastolic blood pressure (DBP) in subjects with dyslipidemia (-3.1 mmHg; 95%CI: -5.9, -0.2 mmHg). Both EPA (-0.56 mg/L; 95%CI: -1.13, 0.00) and DHA (-0.5 mg/L; 95%CI: -1.0, -0.03) significantly reduced the concentrations of C-reactive protein (CRP), respectively, especially in subjects with dyslipidemia and higher baseline CRP concentrations. Given that limited trials have focused on EPA or DHA intervention on concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α, further RCTs should be explored on these inflammatory factors. The present meta-analysis provides substantial evidence that EPA and DHA have independent (blood pressure) and shared (CRP concentration) effects on risk factors of chronic diseases, and high-quality RCTs with multi-center and large simple-size should be performed to confirm the present findings.
Understanding the mechanisms underlying abnormal egg production and pregnancy loss is significant for human fertility. SENP7, a SUMO poly-chain editing enzyme, has been regarded as a mitotic ...regulator of heterochromatin integrity and DNA repair. Herein, we report the roles of SENP7 in mammalian reproductive scenario. Mouse oocytes deficient in SENP7 experienced meiotic arrest at prophase I and metaphase I stages, causing a substantial decrease of mature eggs. Hyperaceylation and hypomethylation of histone H3 and up-regulation of Cdc14B/C accompanied by down-regulation of CyclinB1 and CyclinB2 were further recognized as contributors to defective M-phase entry and spindle assembly in oocytes. The spindle assembly checkpoint activated by defective spindle morphogenesis, which was also caused by mislocalization and ubiquitylation-mediated proteasomal degradation of γ-tubulin, blocked oocytes at meiosis I stage. SENP7-depleted embryos exhibited severely defective maternal-zygotic transition and progressive degeneration, resulting in nearly no blastocyst production. The disrupted epigenetic landscape on histone H3 restricted Rad51C loading onto DNA lesions due to elevated HP1α euchromatic deposition, and reduced DNA 5hmC challenged the permissive status for zygotic DNA repair, which induce embryo death. Our study pinpoints SENP7 as a novel determinant in epigenetic programming and major pathways that govern oocyte and embryo development programs in mammals.
•Nucleus-localized SENP7 dynamically shows spindle-associated profiles during oocyte and embryo development.•SENP7 depletion triggers prophase I arrest and spindle catastrophe in oocyte.•SENP7 programs zygotic DNA repair and spindle assembly to facilitate maternal-to-zygotic transition and embryo cleavage.•SENP7 intervenes epigenetic scenarios of histone H3 during oocyte and embryo development.
The aim of this study is to evaluate an AAV vector that can selectively target breast cancer cells and to investigate its specificity and anti-tumor effects on breast cancer cells both in vitro and ...in vivo, offering a new therapeutic approach for the treatment of EpCAM-positive breast cancer.
In this study, a modified AAV2 viral vector was used, in which EpCAM-specific DARPin EC1 was fused to the VP2 protein of AAV2, creating a viral vector that can target breast cancer cells. The targeting ability and anti-tumor effects of this viral vector were evaluated through in vitro and in vivo experiments.
The experimental results showed that the AAV2M
virus could specifically infect EpCAM-positive breast cancer cells and accurately deliver the suicide gene HSV-TK to tumor tissue in mice, significantly inhibiting tumor growth. Compared to the traditional AAV2 viral vector, the AAV2M
virus exhibited reduced accumulation in liver tissue and had no impact on tumor growth.
This study demonstrates that AAV2M
is a gene delivery vector capable of targeting breast cancer cells and achieving selective targeting in mice. The findings offer a potential gene delivery system and strategies for gene therapy targeting EpCAM-positive breast cancer and other tumor types.
Imatinib was the first BCR‐ABL inhibitor used in clinical practice to treat chronic myeloid leukaemia (CML) and significantly improve the life expectancy of CML patients in the chronic phase. ...However, a portion of CML patients are resistant to imatinib. This study aimed to determine whether menadione (Vitamin K3) can improve imatinib efficacy in CML and to thoroughly explore the combination regimen mechanism between imatinib and menadione. Menadione improved imatinib efficacy in K562 cells by downregulating ABCB1 expression and increased the intracellular concentration of imatinib, which confirmed that this combination regimen is more effective than imatinib monotherapy. The results demonstrate that menadione and imatinib combination therapy may be a promising approach to refractory CML.
Background and aims
4‐phenylbutyric acid (4‐PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a ...chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown.
Methods
4‐PBA was administered alone or in combination with diethylnitrosamine to investigate its long‐term effect on liver tumorigenesis. The role of 4‐PBA in oncogene‐induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co‐expressed with hMet and β‐catenin point mutation (S45Y) was also observed. RNA‐seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4‐PBA on liver and validate the underlying mechanism.
Results
4‐PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b‐Fzd5 mediating β‐catenin signaling. Peroxisome proliferator‐activated receptors (PPAR)‐α induced by 4‐PBA was responsible for the activation of β‐catenin signaling. Thus, intervention of PPAR‐α reversed 4‐PBA‐induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4‐PBA could not only upregulate the expression of PPAR‐α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR‐α expression predicted poor prognosis in HCC patients.
Conclusions
4‐PBA could upregulate PPAR‐α to initiate LCSCs by activating β‐catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor‐promoting effect of 4‐PBA under HCC‐inducing environment.
4‐PBA could promote HCC at early stage of tumor development in vivo.
4‐PBA initiated CSCs via activating Wnt5b‐Fzd5‐β‐catenin signaling pathway dependent of PPAR‐α activation.
4‐PBA could not only regulate the expression of PPAR‐α transcriptionally, but also stabilize it via direct binding.
The profound influence of environmental chemicals on human health including inducing life-threatening gene mutation has been publicly recognized. Being a substitute for the extensively used ...endocrine-disrupting chemical BPA, Bisphenol AF (BPAF) has been known as teratogen with developmental toxicities and therefore potentially putting human into the risk of biological hazards. Herein, we deciphered the detrimental effects of BPAF on spermatogenesis and spermiotiliosis in sexual maturity of mice exposing to BPAF (5, 20, 50 mg/kg/d) for consecutive 28 days. BPAF exposure significantly compromises blood-testis barrier integrity and sperm quantity and quality in a dose-dependent manner. Sperms from BPAF exposure mice are featured by severe DNA damage, altered SUMOylation and ubiquitination dynamics and interfered epigenetic inheritance with hypermethylation of H3K27me3 presumably due to the aggregation of cellular reactive oxygen species (ROS). Furthermore, BPAF treatment (50 μM for 24 h) compromises cytoskeleton architecture and tight junction permeability in primary cultured Sertoli cells evidenced by dysfunction of actin regulatory proteins (e.g. Arp3 and Palladin) via activation of ERK signaling, thereby perturbing the privilege microenvironment created by Sertoli cells for spermatogenesis. Overall, our study determines BPAF is deleterious for male fertility, leading to a better appreciation of its toxicological features in our life.
•BPAF exposure compromises sperm production and quality and disrupts the post-translational modifications of sperm.•BPAF exposure significantly compromises blood-testis barrier integrity both in vivo and in vitro.•BPAF perturbs the cytoskeleton architecture via activation of ERK1/2 signaling.
We report on the morphological selections and dynamical evolutions of buckling patterns in annealed SiAlNx films deposited on 6mm thick glass substrates. Various buckle modes, including ...straight-sided, bubble (or varicose) and telephone cord structures, are found to coexist in the same sample. The straight-sided mode appears only when the buckle width is less than a critical value (about 50μm in the experiment). When the buckle width increases, the straight-sided buckle destabilizes and evolves into the telephone cord structure gradually. If the buckling patterns form ridge cracks, the original straight-sided blisters and telephone cord buckles with smaller widths invariably evolve into the bubble mode, whereas the telephone cord buckles with larger widths can keep the antisymmetric mode. These buckle modes and their dynamical evolutions are discussed based on the stability diagram of unilateral buckling patterns.
The results of randomized controlled trials (RCTs) investigating resveratrol supplementation on risk factors of non-communicable diseases (NCDs) have been inconsistent. The present meta-analysis ...aimed to quantitatively evaluate the effects of resveratrol intervention on risk factors of NCDs. PubMed and Scopus databases were searched up to June 2017. Weighted mean differences were calculated for net changes in risk factors of NCDs by using a random-effects model. Pre-specified subgroup and univariate meta-regression analyses were carried out to explore the sources of heterogeneity. Twenty-nine studies (30 treatment arms) with 1069 participants were identified. Resveratrol supplementation significantly reduced the concentrations of fasting glucose (−4.77 mg/dL; 95% CI: −9.33 to −0.21 mg/dL; P = 0.040), total cholesterol (TC) (−9.75 mg/dL; 95% CI: −17.04 to −2.46 mg/dL; P = 0.009), and C-reactive protein (CRP) (−0.81 mg/L; 95% CI: −1.42 to −0.21 mg/L; P = 0.009). Resveratrol intervention exerted significant reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in subjects with type 2 diabetes mellitus (T2DM). Subgroup analysis also showed that the trials with resveratrol intervention ≥3 months significantly reduced the low-density lipoprotein cholesterol (LDL-C), DBP, and glycated hemoglobin (HbA1c) values. The results did not support that resveratrol intervention had favorable effects in altering high-density lipoprotein cholesterol (HDL-C), triglyceride (TAG), and homeostasis model assessment of insulin resistance (HOMA-IR). The present study provides substantial evidence that resveratrol supplementation has favorable effects on several risk factors of NCDs.
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