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Purpose Adequate pulmonary function is important for patients undergoing surgical resection of esophageal cancer, especially those that received neoadjuvant therapy. However, it is unknown if pre-operative radiation affects pulmonary function differently compared to chemotherapy. The purpose of this study was to compare changes in pulmonary function between patients undergoing minimally invasive esophagectomy (MIE) who received neoadjuvant chemotherapy or chemoradiotherapy. Methods Between March 2017 and March 2018, esophageal cancer patients requiring neoadjuvant therapy were prospectively enrolled and randomly assigned to receive chemotherapy (CT) or chemoradiotherapy (CRT) before MIE. All patients received pulmonary function testing before and after the neoadjuvant therapy. Changes in pulmonary function, operative data, and pulmonary complications were compared between the 2 groups. Results A total of 71 patients were randomized and underwent MIE after receiving CT (n = 34) or CRT (n = 37). Baseline clinical characteristics were comparable between the 2 groups. The CRT group experienced a greater decrease of forced expiratory volume at 1 s (FEV1) (2.66 to 2.18 L, p = 0.023) and diffusion capacity of the lung for carbon monoxide divided by the mean alveolar volume (DLCO/Va) (17.3%, p 1 2.53 to 2.41 L; DLCO/Va 4.8%). The incidence of pulmonary complications was higher in the CRT group (13.51 vs. 8.82%), but the difference was not significant (p = 0.532). Conclusions Preoperative CRT affects pulmonary function more than CT alone, but does not increase the risk of pulmonary complications in patients undergoing MIE.

There is controversy regarding the long-term prognosis and short-term postoperative complications of different surgical strategies for proximal gastric cancer (PGC).We searched for articles published in Embase (Ovid), Medline (Ovid), PubMed, Cochrane Library, and Web of Science between January 1, 1990, and February 1, 2021. We screened out the literature comparing different surgical strategies. We then evaluated the long-term and short-term outcome of different surgical strategies using a network meta-analysis, which summarizes the hazard ratio, odds ratio, mean difference, and 95% confidence interval.There were no significant differences between different surgical strategies for 5-year overall survival (OS), anastomotic leakage, or weight loss after 1 year. Compared with total gastrectomy with Roux-en-Y reconstruction (TG-RY) and proximal gastrectomy with double tract reconstruction (PG-DTR), the proximal gastrectomy with esophagogastrostomy (PG-EG) strategy significantly increased the incidence of reflux esophagitis; and the operation time and blood loss of the PG-EG strategy were significantly less than those of the other surgical strategies. The anastomotic stenosis rates of the PG-EG and proximal gastrectomy with jejunum interstitial (PG-JI) strategies were significantly higher than those of TG-RY and PG-DTR; the hemoglobin level after 1 year for the PG-DTR strategy was significantly higher than that of the TG-RY strategy.Our comprehensive literature research found that different surgical strategies had no significant difference in the long-term survival of PGC, but the incidence of reflux esophagitis and anastomotic stenosis after PG-DTR and TG-RY was significantly reduced.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a gland-forming malignancy arising in the pancreas. It is estimated that in developed countries the incidence of PDAC will continue to rise, and PDAC is now the fourth leading cause of cancer-related deaths in the USA. The mortality of PDAC patients closely parallels the incidence rate, as this malignancy generally remains asymptomatic until it reaches an advanced stage. Summary: The poor prognosis results from the aggressive nature of the tumor, late detection, and resistance to chemotherapy and radiotherapy. Retinoids, vitamin A (retinol) and its metabolites, such as retinoic acid (RA), play critical roles in important biological functions, including cell growth and differentiation, development, metabolism, and immunity. The actions of retinoids in maintaining normal pancreatic functions have generated considerable research interest from investigators interested in understanding and treating PDAC. Altered expression of retinoid receptors and other RA signaling pathway genes in human cancers offers opportunities for target discovery, drug design, and personalized medicine for distinct molecular retinoid subtypes. Key Messages: The goals of this review are to explore the potential activities of retinoids in the pancreas, to assess the evidence that retinoid functions become dysregulated in PDAC, and to describe the actions of retinoids in new therapies developed to increase patient survival.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a secretory serine protease that plays multiple biological functions in the regulation of physiological and pathological processes. PCSK9 inhibitors decrease the circulating LDL-cholesterol level with well-known preventive and therapeutic effects on atherosclerosis (AS). Still, increasing evidence shows that the direct impact of PCSK9 on the vascular wall also plays an important role in atherosclerotic progression. Compared with other vascular cells, a large proportion of PCSK9 is originated from vascular smooth muscle cells (VSMC). Therefore, defining the effect of VSMC-derived PCSK9 on response changes, such as phenotypic switch, apoptosis, autophagy, inflammation, foam cell formation, and calcification of VSMC, helps us better understand the “pleiotropic” effects of VSMC on the atherosclerotic process. In addition, our understanding of the mechanisms of PCSK9 controlling VSMC functions in vivo is far from enough. This review aims to holistically evaluate and analyze the current state of our knowledge regarding PCSK9 actions affecting VSMC functions and its mechanism in atherosclerotic lesion development. A mechanistic understanding of PCSK9 effects on VSMC will further underpin the success of a new therapeutic strategy targeting AS.

Oral squamous cell carcinoma (oral SCC) is an aggressive disease and despite intensive treatments, 5-year survival rates for patients have remained low in the last 20 years. Enhancer of zeste homolog 2 (EZH2), part of polycomb repressive complex 2 (PRC2), is highly expressed in human oral SCC samples and cell lines and has been associated with greater epithelia-to-mesenchymal transition (EMT), invasion and metastasis. Here, we developed a tamoxifen-regulated, transgenic mouse line (KcEZH2) in which EZH2 is selectively knocked out (KO) in some tongue epithelial basal stem cells (SCs) in adult mice. EZH2 KO SCs do not show the H3K27me3 mark, as assessed by double-label immunofluorescence. We used this mouse line to assess EZH2 actions during oral tumorigenesis with our immunocompetent 4-nitroquinoline 1-oxide model of oral SCC. We report that higher percentages of mice with invasive SCCs and high-grade neoplastic lesions are observed in mice containing EZH2 KO SCs (KcEZH2-2TΔ and KcEZH2-5TΔ mice). Moreover, EZH2 expression does not correlate with the expression of markers of invasive SCCs. Finally, EZH2 KO cells that are E-cadherin+ are present at invasion fronts infiltrating underlying muscle tissue. Our findings indicate that the knockout of EZH2 in basal SCs of tongue epithelia results in more aggressive carcinomas, and this should be considered when targeting EZH2 as a therapeutic strategy.

Vegetarian and prudent diets are associated with several health benefits but their role in stroke epidemiology is not as clear. This study aimed to evaluate stroke risk with vegetarian, low-animal, and high-animal diets.Studies reporting stroke risk with high versus low use of vegetarian or low/high-animal diets were identified by conducting literature search in Ebsco, Ovid, PubMed, Science Direct, and Web of Science databases. Relative risks (RRs) of stroke between high and low use of vegetarian, low-animal, and high-animal were pooled to achieve overall estimates. Relationship between stroke risk and increasing quantiles of dietary patterns was sought by performing metaregression analyses.17 studies (932545 individuals; follow-up 11.7 years [95% confidence interval (CI): 9.5, 13.9]) were included. Compared to low use, high use of vegetarian and low-animal diets was associated with lower risk of hemorrhagic stroke (RR: 0.71 [95% CI: 0.47, 0.96] and 0.82 [95% CI: 0.64, 0.99]), ischemic stroke (RR: 0.78 [95% CI: 0.66, 0.91] and 0.70 [95% CI: 0.45, 0.95]) and total stroke (RR: 0.84 [95% CI: 0.71, 0.96] and 0.72 [95% CI: 0.61, 0.83]) respectively. Dose-response analyses further supported these findings. High use of high-animal diet was associated with relatively higher risk of stroke [RR: 1.12 [95%CI: 0.94, 1.29]. In vegetarians, relative to high use of vegetables, high use of fruits posed lower risk of stroke.Stroke risk is lower with more use of a vegetarian or low-animal diet but relatively higher with more use of a high-animal diet.

Oxidative stress-induced damage to and dysfunction of retinal pigment epithelium (RPE) cells are important pathogenetic factors of age-related macular degeneration (AMD); however, the underlying molecular mechanism is not fully understood. Long noncoding RNAs (lncRNAs) have important roles in various biological processes. In this study, using an oxidative damage model in RPE cells, we identified a novel oxidation-related lncRNA named CYLD-AS1. We further revealed that the expression of CYLD-AS1 was increased in RPEs during oxidative stress. Depletion of CYLD-AS1 promoted cell proliferation and mitochondrial function and protected RPE cells against hydrogen peroxide (H

Apurinic endonuclease 1 (APE1) has been suggested as an oncogene of lung tumours and our bioinformatics analysis identified the association between Erlotinib resistance and interleukin-6 (IL-6). Thus, we performed this work to delineate the mechanistic actions of APE1/IL-6 signalling in Erlotinib resistance of non-small cell lung cancer (NSCLC).We selected human NSCLC cell lines HCC827 and PC9 to establish Erlotinib-resistant HCC827R and PC9R cells. Cancer stem cells (CSCs) were isolated from Erlotinib-sensitive HCC827P and PC9P cells (PCSCs) and from HCC827R and PC9R cells (RCSCs). Further, extracellular vesicles (EVs) were separated from PCSCs (PCSC-EVs) and RCSCs (RCSC-EVs) and co-cultured with RCSCs with or without short hairpin RNA (shRNA)-targeting APE1 (APE1 shRNA) transduction. In addition, functional assays were conducted to determine the effect of APE1 shRNA on malignant phenotypes of cancer cells in vitro and in vivo and the activation of IL-6/STAT3 signalling.It was found that NSCLC cells could internalize both RCSC-EVs and PCSC-EVs. RCSC-EVs augmented the resistance of NSCLC cells to Erlotinib. The overexpression of APE1 occurred in NSCLC tissues, and IL-6 was enriched in serum samples of patients with NSCLC. APE1 shRNA was demonstrated to restrict the Erlotinib resistance of NSCLC cells by inactivating the IL-6/STAT3 signalling. Additionally, shAPE1-loaded RCSC-EVs suppressed the Erlotinib resistance of NSCLC via the IL-6/STAT3 axis both in vitro and in vivo, as reflected by impeded malignant phenotypes and xenograft tumour formation.Collectively, these data indicate that APE1 confers Erlotinib resistance by activating the IL-6/STAT3 signalling, suggesting targeting APE1 as a possible therapeutic target in Erlotinib-resistant NSCLC.

Cardiac angiosarcomas are highly aggressive, extremely rare malignancies with a poor prognosis. We report the case of a 39-year-old woman presenting with a right atrial angiosarcoma with perforation of the right atrium. There is almost always a diagnostic lag for cardiac angiosarcoma, leading to a poor prognosis. Cardiovascular sarcoma is one of the most invasive malignant tumors. Radical resection surgery as the core of comprehensive treatment presently is the best treatment plan.

Osteoarthritis (OA) is the most prevalent type of degenerative joint disease, and its pathological progression is highly associated with oxidative stress. Natural antioxidants can attenuate oxidative stress and chondrocyte injury, suggesting that antioxidants have potential applications in the management of OA. Ellagic acid (EA), a natural polyphenol derived from fruits or nuts, exerts antioxidant and anti-inflammatory effects in diseases related to oxidative stress. Herein, we investigated the effects of EA on interleukin-1β (IL-1β)-induced oxidative stress and degeneration in C28/I2 human chondrocytes. EA efficiently suppressed IL-1β-induced oxidative stress and ameliorated oxidative stress-induced dysfunction of chondrocytes, as indicated by the promotion of cartilage matrix secretion. Moreover, EA remarkably suppressed cell apoptosis and senescence, and reduced the expression of proinflammatory factors and metalloproteinases, suggesting that EA could alleviate chondrocyte injury under oxidative stress. Mechanistically, EA upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as well as its downstream targets NADPH quinone oxidoreductase 1 and heme oxygenase-1. ML385, a specific Keap1/Nrf2 pathway inhibitor, blocked the antioxidant and chondroprotective effects of EA. Our findings demonstrated that EA could attenuate oxidative stress and exert protective effects on chondrocytes by upregulating the Keap1/Nrf2 signaling pathway.

Aim The aim of this study was to explore surgery decision conflict and its related factors among newly diagnosed early breast cancer patients in China. Design A cross‐sectional survey study was conducted. Methods A total of 262 patients confronted with surgery decision‐making were enrolled. The related factors were assessed with a demographic questionnaire, the Chinese version of the Decision Conflict Scale (DCS‐C‐16) and the Patient Participation Competence Scale (PPCS). Results Patients had a high level of decision conflict that was negatively correlated with the PPCS score. Age, marital status, living environment, education level, family income, cancer stage and the PPCS score were independent factors influencing decision conflict. Marital status, education level, cancer stage and participation competence were significant predictors of decision conflict. Patients who had higher participation competence were married, were well educated and had a lower cancer stage were likely to experience lower decision conflict.

Background The adverse reactions (ADRs) of targeted therapy were closely associated with treatment response, clinical outcome, quality of life (QoL) of patients with cancer. However, few studies presented the correlation between ADRs of targeted therapy and treatment effects among cancer patients. This study was to explore the characteristics of ADRs with targeted therapy and the prognosis of cancer patients based on the clinical data. Methods A retrospective secondary data analysis was conducted within an ADR data set including 2703 patients with targeted therapy from three Henan medical centers of China between January 2018 and December 2019. The significance was evaluated with chi-square test between groups with or without ADRs. Univariate and multivariate logistic regression with backward stepwise method were applied to assess the difference of pathological characteristics in patients with cancer. Using the univariate Cox regression method, the actuarial probability of overall survival was performed to compare the clinical outcomes between these two groups. Results A total of 485 patients were enrolled in this study. Of all patients, 61.0% (n = 296) occurred ADRs including skin damage, fatigue, mucosal damage, hypertension and gastrointestinal discomfort as the top 5 complications during the target therapy. And 62.1% of ADRs were mild to moderate, more than half of the ADRs occurred within one month, 68.6% ADRs lasted more than one month. Older patients (P = 0.022) and patients with lower education level (P = 0.036), more than 2 comorbidities (P = 0.021), longer medication time (P = 0.022), drug combination (P = 0.033) and intravenous administration (P = 0.019) were more likely to have ADRs. Those with ADRs were more likely to stop taking (P = 0.000), change (P = 0.000), adjust (P = 0.000), or not take the medicine on time (P = 0.000). The number of patients with recurrence (P = 0.000) and metastasis (P = 0.006) were statistically significant difference between ADRs and non-ADRs group. And the patients were significantly poor prognosis in ADRs groups compared with non-ADRs group. Conclusion The high incidence of ADRs would affect the treatment and prognosis of patients with cancer. We should pay more attention to these ADRs and develop effective management strategies.

Within a short period of time, COVID-19 grew into a world-wide pandemic. Transmission by pre-symptomatic and asymptomatic viral carriers rendered intervention and containment of the disease extremely challenging. Based on reported infection case studies, we construct an epidemiological model that focuses on transmission around the symptom onset. The model is calibrated against incubation period and pairwise transmission statistics during the initial outbreaks of the pandemic outside Wuhan with minimal non-pharmaceutical interventions. Mathematical treatment of the model yields explicit expressions for the size of latent and pre-symptomatic subpopulations during the exponential growth phase, with the local epidemic growth rate as input. We then explore reduction of the basic reproduction number R0 through specific transmission control measures such as contact tracing, testing, social distancing, wearing masks and sheltering in place. When these measures are implemented in combination, their effects on R0 multiply. We also compare our model behaviour to the first wave of the COVID-19 spreading in various affected regions and highlight generic and less generic features of the pandemic development., Transmission by pre-symptomatic and asymptomatic viral carriers makes intervention and containment of the COVID-19 extremely challenging. Here, the authors construct an epidemiological model that focuses on transmission around the symptom onset, exploring specific transmission control measures.

Coronary heart disease (CHD) is closely related to hypercholesterolemia, and lowering serum cholesterol is currently the most important strategy in reducing CHD. In humans, the serum cholesterol level is determined mainly by three metabolic pathways, namely, dietary cholesterol intake, cholesterol synthesis, and cholesterol degradation in vivo. An intervention that targets the key molecules in the three pathways is an important strategy in lowering serum lipids. Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) to reduce low-density lipoprotein (LDL) by about 20% to 45%. However, up to 15% of patients cannot tolerate the potential side effects of high statin dosages, and several patients also still do not reach their optimal LDL goals after being treated with statins. Ezetimibe inhibits cholesterol absorption by targeting the Niemann–Pick C1-like 1 protein (NPC1L1), which is related to cholesterol absorption in the intestines. Ezetimibe lowers LDL by about 18% when used alone and by an additional 25% when combined with statin therapy. The proprotein convertase subtilisin/kexin type 9 (PCSK9) increases hepatic LDLR degradation, thereby reducing the liver’s ability to remove LDL, which can lead to hypercholesterolemia. Evolocumab, which is a PCSK9 monoclonal antibody, can reduce LDL from baseline by 53% to 56%. The three drugs exert lipid-lowering effects by regulating the three key pathways in lipid metabolism. Combining any with the two other drugs on the basis of statin treatment has improved the lipid-lowering effect. Whether the combination of the three musketeers will reduce the side effects of monotherapy and achieve the lipid-lowering effect should be studied further in the future.

Atherosclerosis is a chronic inflammatory vascular disease. Atherosclerotic cardiovascular disease is the main cause of death in both developed and developing countries. Many pathophysiological factors, including abnormal cholesterol metabolism, vascular inflammatory response, endothelial dysfunction and vascular smooth muscle cell proliferation and apoptosis, contribute to the development of atherosclerosis and the molecular mechanisms underlying the development of atherosclerosis are not fully understood. Ubiquitination is a multistep post-translational protein modification that participates in many important cellular processes. Emerging evidence suggests that ubiquitination plays important roles in the pathogenesis of atherosclerosis in many ways, including regulation of vascular inflammation, endothelial cell and vascular smooth muscle cell function, lipid metabolism and atherosclerotic plaque stability. This review summarizes important contributions of various E3 ligases to the development of atherosclerosis. Targeting ubiquitin E3 ligases may provide a novel strategy for the prevention of the progression of atherosclerosis.

Background/purpose Antimicrobial resistance in Taiwan has been on the rise for two decades. The implementation of pneumococcal conjugate vaccination (PCV13) and enhanced antimicrobial control (2013–2015) by the government may have changed the antibiotic resistance. Methods Four respiratory pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, and Moraxella catarrhalis) isolated in a single medical center during 2008–2017 were studied. We defined three temporal stages: (a) the first era (2008–2012), prior to implementation of the national immunization program (PCV13 vaccination), (b) the second era (2013–2015), during which an enhanced antibiotic control strategy was implemented, and (c) the third era (2016–2017), after implementation. Antimicrobial drug sensitivities were collected from two other hospitals: one from east Taiwan, one from west-central Taiwan. Results S. pneumoniae was frequently isolated during the first era. It declined progressively during the second era of PCV13 vaccination. S. pyogenes and M. catarrhalis were not frequently isolated. The drug susceptibility of S. pneumoniae to ceftriaxone and vancomycin remained high. The antimicrobial susceptibility of H. influenzae to amoxillin/clavulante declined over the three temporal stages, from 91.9%-79.5%–58.5% (all p Conclusion Antimicrobial resistance of H. influenzae increased during the latter part of the study period. The PCV13 vaccination program reduced the invasive pneumococcal disease and reduced the stress on the emergent drug resistance. This enhanced antibiotic control strategy was effective in terms of nosocomial drug resistance but not for community-associated pathogens.

The regeneration of bone defects in patients with diabetes mellitus (DM) is remarkably impaired by hyperglycemia and over-expressed proinflammatory cytokines, proteinases (such as matrix metalloproteinases, MMPs), etc. In view of the fact that exosomes represent a promising nanomaterial, herein, we reported the excellent capacity of stem cells from apical papilla-derived exosomes (SCAP-Exo) to facilitate angiogenesis and osteogenesis whether in normal or diabetic conditions

We aimed to establish a long noncoding RNA (lncRNA)-based signature for accurately predicting prognosis and guiding the personalized clinical management of oral squamous cell carcinoma (OSCC).OSCC RNA sequencing profiles were acquired from The Cancer Genome Atlas and Gene Expression Omnibus. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were performed to construct a lncRNA-based prognostic signature. Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves and calibration curves were used to assess the effectiveness and accuracy of the signature. Additionally, we conducted single-sample gene-set enrichment analysis to infer the different degrees of immunocyte infiltration. Weighted correlation network analysis, enrichment analysis and Spearman's correlation analysis were implemented to screen immune-related genes that interact with the lncRNA signature.In total, 14 lncRNAs were defined as potential prognostic biomarkers. Based on these lncRNAs, patients were divided into low- and high-risk subgroups with different survival times (p 0.001). In addition, the reliability of the prognostic signature was verified by Kaplan-Meier analysis, ROC analysis and calibration curves. Patients in the low-risk group exhibited more significant immune cell infiltration. Simultaneously, a potential regulatory network consisting of eight lncRNAs and 159 protein-coding genes in the top 10 immune-related biological process terms was constructed.Our findings suggested that the 14-lncRNA signature has satisfactory performance in predicting the prognosis of OSCC, thereby providing new insights to the pathogenesis, clinical patient management and therapeutic intervention. The different immune cell infiltration statuses of OSCC patients may encourage immunotherapy.

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a member of the proprotein convertase family, is an important drug target because of its crucial role in lipid metabolism. Emerging evidence suggests a direct role of localized PCSK9 in the pathogenesis of vascular diseases. With this in our consideration, we reviewed PCSK9 physiology with respect to recent development and major studies (clinical and experimental) on PCSK9 functionality in vascular disease. PCSK9 upregulates low-density lipoprotein (LDL)-cholesterol levels by binding to the LDL-receptor (LDLR) and facilitating its lysosomal degradation. PCSK9 gain-of-function mutations have been confirmed as a novel genetic mechanism for familial hypercholesterolemia. Elevated serum PCSK9 levels in patients with vascular diseases may contribute to coronary artery disease, atherosclerosis, cerebrovascular diseases, vasculitis, aortic diseases, and arterial aging pathogenesis. Experimental models of atherosclerosis, arterial aneurysm, and coronary or carotid artery ligation also support PCSK9 contribution to inflammatory response and disease progression, through LDLR-dependent or -independent mechanisms. More recently, several clinical trials have confirmed that anti-PCSK9 monoclonal antibodies can reduce systemic LDL levels, total nonfatal cardiovascular events, and all-cause mortality. Interaction of PCSK9 with other receptor proteins (LDLR-related proteins, cluster of differentiation family members, epithelial Na+ channels, and sortilin) may underlie its roles in vascular disease. Improved understanding of PCSK9 roles and molecular mechanisms in various vascular diseases will facilitate advances in lipid-lowering therapy and disease prevention.

Oral infections are common among individuals of all ages and can activate local and systemic inflammation. The inflammatory response plays an important role in atherosclerosis. An increasing number of studies have reported an association between oral pathogen infection and atherosclerotic coronary heart disease. For instance, epidemiological studies support the positive correlation between oral infections and atherosclerosis. The presence of oral pathogens in human atherosclerotic plaques has been detected by multiple methods, and oral infections promote atherosclerosis in animal experiments. Various mechanisms are involved in oral infections, thereby promoting atherosclerosis. First, oral infections can trigger the local and systemic inflammatory response, causing vascular endothelial damage. Oral-derived pathogens that enter atherosclerotic plaque can activate macrophages and cause an intra-plaque inflammatory response. Second, oral infections can promote intra-plaque macrophage cholesterol accumulation and foam cell formation. Third, oral infections can regulate plasma lipid levels, thereby increasing atherogenic lipid low-density lipoprotein and triglyceride levels. Although atherosclerosis caused by oral infections is currently studied, the precise mechanism remains to be further explored. The rise of gut microbiota research also makes the relationship between oral microbiota and disease, especially the relationship with coronary heart disease, worthy of attention and in-depth research.

Background. Posterior capsule opacification (PCO), a complication of extracapsular lens extraction surgery that causes visual impairment, is characterized by aberrant proliferation and epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs). Curcumin, exerting inhibitive effects on cell proliferation and EMT in cancer, serves as a possible antidote towards PCO. Methods. Cellular proliferation of LECs after treatment of curcumin was measured with MTT assay and flow cytometry. The transcriptional and expressional levels of proteins related to proliferation and EMT of LECs were quantified by western blotting and real-time PCR. Results. Curcumin was found to suppress the proliferation of LECs by inducing G2/M arrest via possible inhibition of cell cycle-related proteins including CDK1, cyclin B1, and CDC25C. It had also inactivated proliferation pathways involving ERK1/2 and Akt pathways in LECs. On the other hand, curcumin downregulated the EMT of LECs through blocking the TGF-β/Smad pathway and interfering Notch pathway which play important roles in PCO. Conclusions. This study shows that curcumin could suppress the proliferation and EMT in LECs, and it might be a potential therapeutic protection against visual loss induced by PCO.

Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.

Biodegradable aliphatic polyesters, especially polylactide (PLA), polyglycolide (PGA), and their copolymer poly(lactide-co-glycolide) (PLGA), are the most representative and widely used synthetic polymers in the field of tissue engineering and regenerative medicine. However, these polyesters often give rise to aseptic inflammation because of their acidic degradation products after implantation. Here, unidirectional shell-core structured fibers of chitosan/poly(lactide-co-glycolide) (i.e., CTS/PLGA) with acid-neutralizing capability were developed for addressing the noted issue by coating the PLGA fiber surfaces with a layer of the alkaline chitosan by coaxial electrospinning. Our results showed that during a period of 8-week degradation, the shell-layer of chitosan with its unique alkaline nature for acid-neutralization obviously hindered the pH decrease as a result of the degradation of PLGA-core. In a mocked acidic environment testing of the human dermal fibroblasts, chitosan-enabled acidity neutralization could significantly reduce in vitro the secretion of inflammatory factors and downregulate the expression of related inflammatory genes. Thereafter, biocompatibility assessment in vitro showed that the CTS/PLGA fibers had poorer cell adhesion capacity than the PLGA fibers but were cytocompatible and promoted cell migration and secretion of collagen. Moreover, subcutaneous embedding for two and four weeks in vivo revealed that the CTS/PLGA fibers significantly reduced the recruitment of inflammatory cells and the formation of foreign body giant cells (FBGCs). This study thereby demonstrated the evident acid-neutralizing effect of the chitosan-coating layer on alleviating the inflammatory responses caused by the acidic degradation products of the PLGA-core. Our highly aligned CTS/PLGA fibers, as a kind of quasi "pH-neutral fibers" with the acid-neutralizing capability, could be potentially applied for engineering those architecturally anisotropic tissues (e.g., tendon/ligament) toward improved efficacy of regeneration. STATEMENT OF SIGNIFICANCE: It is well known that acidic degradation products from representative aliphatic polyesters (e.g., PLA, PGA, and PLGA) give rise to the problem of aseptic inflammation. Various alkaline components acting as neutralizing agents have been used to address the noted issue. However, rather less attention has been paid to engineer these polyesters into a fibrous form with acid-neutralizing functionality. The present study proposes the concept of "pH-neutral fibers" and develops shell-core structured unidirectional fibers of chitosan/poly(lactide-co-glycolide) with acid-neutralizing capability for ameliorating inflammatory responses caused by the acidic degradation products of PLGA. It provides a comprehensive study encompassing fiber characterization and in vitro and in vivo evaluation, which would pave the way for developing sophisticated pH-neutral fibers for functional tissue regeneration.

Coronary angiography is an important diagnostic tool for coronary heart disease. While it can identify anatomical coronary stenosis, its ability to identify hemodynamic changes is limited. The Fractional Flow Reserve (FFR) technique, combined with coronary angiography, facilitates both the functional and anatomical assessment of heart disease. New studies have shown that FFR has unique advantages in guiding percutaneous coronary intervention (PCI), and it is currently being used in coronary artery bypass graft (CABG) as well as for assessing the prognosis of patients after surgery. It may also play a significant role in assessing the patency of a graft. However, some studies have shown that in considering the cardioprotective benefits of CABG, applying FFR guidelines to CABG may reduce or impair its "surgical collateralization" effect and increase the rate of incomplete revascularization. We compared the advantages and disadvantages of FFR to guide PCI and CABG, which will provide health practitioners with useful resources to determine the best diagnosis and treatment for patients.

The regeneration of diabetic bone defects remains challenging as the innate healing process is impaired by glucose fluctuation, reactive oxygen species (ROS), and overexpression of proteinases (such as matrix metalloproteinases, MMPs). A "diagnostic" and therapeutic dual-logic-based hydrogel for diabetic bone regeneration is therefore developed through the design of a double-network hydrogel consisting of phenylboronic-acid-crosslinked poly(vinyl alcohol) and gelatin colloids. It exhibits a "diagnostic" logic to interpret pathological cues (glucose fluctuation, ROS, MMPs) and determines when to release drug in a diabetic microenvironment and a therapeutic logic to program different cargo release to match immune-osteo cascade for better tissue regeneration. The hydrogel is also shown to be mechanically adaptable to the local complexity at the bone defect. Furthermore, the underlying therapeutic mechanism is elucidated, whereby the logic-based cargo release enables the regulation of macrophage polarization by remodeling the mitochondria-related antioxidative system, resulting in enhanced osteogenesis in diabetic bone defects. This study provides critical insight into the design and biological mechanism of dual-logic-based tissue-engineering strategies for diabetic bone regeneration.

Oxidative stress-induced degeneration and dysfunction of chondrocytes play a key role in the pathological progression of osteoarthritis (OA), a common degenerative joint disease in the elderly. Epigallocatechin-3-O-gallate (EGCG) increases Nrf2-mediated antioxidase expression levels. We aimed to determine the effects of EGCG on C28/I2 human chondrocytes subjected to interleukin-1β (IL-1β)-induced oxidative stress. EGCG suppressed IL-1β-induced oxidative stress, as indicated by decreased malondialdehyde (MDA) and reactive oxygen species (ROS) generation. Additionally, EGCG attenuated the IL-1β-induced reduction in cartilage matrix generated by chondrocytes by upregulating collagen II, aggrecan, sulfated proteoglycans, and SRY-box transcription factor 9 (SOX9). EGCG reversed the IL-1β-induced increased cyclooxygenase 2 (COX2), inducible nitric oxide synthase (iNOS), collagen X, and matrix metalloproteinases (MMPs). Furthermore, EGCG inhibited apoptosis and senescence of IL-1β-treated chondrocytes, as indicated by the decrease in mitochondrial membrane potential and senescence-associated β-galactosidase-positive cells, respectively. Mechanically, EGCG upregulated nuclear factor erythroid 2-related factor 2 (Nrf2), oxygenase-1 (HO-1), and NADPH quinone oxidoreductase1 (NQO1). The antioxidant and chondroprotective effects of EGCG were blocked by ML385, a Keap1/Nrf2/ARE signaling pathway inhibitor. Thus, EGCG ameliorated oxidative stress-induced chondrocyte dysfunction and exerted chondroprotective effects via Keap1/Nrf2/ARE signaling. This provides a novel perspective on the molecular mechanisms underlying the therapeutic effects of EGCG on OA.

Purpose. Leukocyte telomere length (LTL) is an important biomarker of aging. The oxidative balance score (OBS) is used to assess the oxidative stress-related exposures of diet and lifestyle. This study is aimed at exploring if the OBS was associated with LTL. Methods. 3220 adults were included in this study from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. LTL was assayed from leukocyte DNA. Twenty dietary and lifestyle factors were selected to score the OBS. Survey-based multivariable linear regression was conducted to assess the association between the OBS and log-transformed LTL. Results. The association between the OBS and log-transformed LTL was positive in females but not males. For females, compared with the lowest OBS category as a reference, the multivariable-adjusted beta estimate (95% confidence interval, CI) for the highest OBS category was 0.0701 (0.0205–0.1197) ( p for trend < 0.01 ), and the multivariable-adjusted beta estimate (95% CI) of the continuous OBS was 0.0039 (0.0014–0.0065). There was also the gender difference in the correlations of the dietary OBS and the lifestyle OBS with log-transformed LTL. Conclusion. There was a positive association between the OBS and LTL in females. This result suggested that diet and lifestyle might affect LTL by regulating oxidative balance.

Significance: Artificial skin (AS) is widely used in dermatology, pharmacology, and toxicology, and has great potential in transplant medicine, burn wound care, and chronic wound treatment. There is a great demand for high-quality AS product and a non-invasive detection method is highly desirable. Aim: To quantify the constructure parameters (i.e., thickness and surface roughness) of AS samples in the culture cycle and explore the growth regularities using optical coherent tomography (OCT). Approach: An adaptive interface detection algorithm is developed to recognize surface points in each A-scan, offering a rapid method to calculate parameters without constructing OCT B-scan pictures and further achieving realizing real-time quantification of AS thickness and surface roughness. Experiments on standard roughness plates and H&E-staining microscopy were performed as a verification. Results: As applied on the whole cycle of AS culture, our method’s results show that during the air–liquid culture, the surface roughness of the skin first decreases and then exhibits an increase, which implies coincidence with the degree of keratinization under a microscope. And normal and typical abnormal samples can be differentiated by thickness and roughness parameters during the culture cycle. Conclusions: The adaptive interface detection algorithm is suitable for high-sensitivity, fast detection, and quantification of the interface with layered characteristic tissues, and can be used for non-destructive detection of the growth regularity of AS sample thickness and roughness during the culture cycle.

In this paper,metabolomics and network pharmacology were used to investigate the bioactive components of Harrisonia perforata and their possible mechanisms of action. Metabolites in the flowers,fruits,branches,leaves and stalks of H. perforata were analyzed by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. Meanwhile,multiple statistical analysis methods including principal component analysis( PCA) and orthogonal partial least squares discriminant analysis( OPLS-DA)were applied to screen and identify differential compounds. With metabolomics method,9 differential compounds were preliminarily identified from leaves and other non-traditional medicinal parts. Subsequently,these compounds were explored by using network pharmacology. With gastrointestinal absorption and drug-likeness as limiting conditions,they were imported into the Swiss ADME,from which 7 compounds with potential medicinal activity were obtained. Then,their targets were predicted by PharmMapper,with Human Protein Targets Only and Normalized Fit Scoregt;0. 9 set as limiting conditions,and 60 standardized potential targets were identified with Uniprot. KEGG( Kyoto encyclopedia of genes and genomes) pathway data was obtained using metascape and thequot; potential active ingredients-target-pathwayquot; network was constructed with Cytoscape 3. 7. 2. The enrichment analysis of KEGG demonstrated that the 60 targets were enriched in 78 signaling pathways( min overlap: 3,P value cutoff: 0. 01,min enrichment: 1. 5),many of which are related to anti-bacteria,anti-inflammation and anti-virus,such as IL-17 signaling pathway,RIG-I-like receptor signaling pathway and NOD-like receptor signaling pathway. Finally,depending on the clinical activity of H. perforata,the relevant signaling pathways were analyzed through experimental data and literature. Dehydroconiferyl alcohol was reported to have the anti-inflammatory effect and perforamone D to possess the antimycobacterial activity. The KEGG pathway enrichment analysis showed that dehydroconiferyl alcohol could act on the Alzheimerapos;s disease( AD) signaling pathway by targeting CDK5 R1 and BACE1. ACh E inhibitor is the most promising drug to treat AD,while dehydroconiferyl alcohol has been proved to inhibit ACh E according to literature. The experimental results revealed that the extract of leaves of H. perforata can effectively inhibit the growth of Staphylococcus aureus. These are consistent with the enrichment analysis results of KEGG. This study explored the bioactive components and pharmacodynamics of the leaves of the H. perforata,laying a theoretical foundation for its in-depth development and rational application.

Heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) is a new promising target for the treatment of ovarian cancer. Our previous study showed that cross‐reacting material 197 (CRM197), a specific HB‐EGF inhibitor, significantly reverses resistance against paclitaxel in paclitaxel‐resistant ovarian cancer cells. However, the mechanism of the effect of CRM197 on the reversion of paclitaxel resistance was unclear. In this study, in vitro and in vivo data suggested that CRM197 treatment sensitized paclitaxel‐resistant ovarian cancer cells to paclitaxel, at least in part, via nucleus accumbens‐1 (NAC‐1) and its downstream pathway, DNA damage‐inducible 45‐γ interacting protein (Gadd45gip1)/growth arrest and DNA damage‐inducible 45 (Gadd45), in A2780/Taxol and SKOV3/Taxol cells. The results also showed that CRM197 activated the proapoptotic JNK/p38MAPK pathway to enhance caspase‐3 activity and apoptosis by downregulation of the NAC‐1/Gadd45gip1/Gadd45 pathway, leading to reversion of paclitaxel resistance in A2780/Taxol and SKOV3/Taxol cells. This study provides the first mechanism through which CRM197 significantly reverses resistance against paclitaxel by modulating the NAC‐1/Gadd45gip1/Gadd45 pathway in paclitaxel‐resistant ovarian cancer cells, and the mechanism of HB‐EGF inhibition as a novel therapeutic strategy for patients with paclitaxel‐resistant ovarian cancer., CRM197 treatment sensitized the paclitaxel‐resistant ovarian cancer to paclitaxel, at least in part, via NAC‐1 and its downstream Gadd45gip1/ Gadd45 pathway in A2780/Taxol and SKOV3/Taxol cells. The data also shown that CRM197 activates the proapoptotic JNK/p38MAPK pathway to enhance caspase‐3 activity and cell apoptosis by the downregulation of NAC‐1/Gadd45gip1/Gadd45 pathway, resulting in the reversion of paclitaxel resistance in A2780/Taxol and SKOV3/Taxol cells. This study provides the first mechanism through which CRM197 significantly reverses resistance against paclitaxel by modulating the NAC‐1/Gadd45gip1/Gadd45 pathway in paclitaxel‐resistant ovarian cancer cells, and the mechanism of HB‐EGF inhibition as a novel therapeutic strategy for patients with paclitaxel‐resistant ovarian cancer.

It is known that ypN0 status after induction treatment can be divided into “natural” N0 (cN0/ypN0) and “downstaged” N0 (cN+/ypN0). Whether natural N0 patients and downstaged N0 patients with esophageal squamous cell carcinoma (ESCC) after neoadjvant chemoradiotherapy (nCRT) have similar prognosis is unknown. An institutional database was reviewed to identify ESCC patients after nCRT, whose CT scans were retrieved and reviewed to reclassify nodal status. The patients were divided into 3 groups based on node status: natural N0, downstaged N0, and ypN+. Impact of nodal status on survival and associations with survival were analyzed. We identified 110 patients, and 25 had natural N0 disease, 52 had downstaged N0 disease, and 33 had ypN+ disease. The 3-year OS was 76.7%, 79.5%, and 49% in natural N0, downstaged N0 and ypN+ group, respectively, and, correspondingly, the 3-year DFS was 77%, 73.9%, and 36.3%. In multivariable analysis, OS (P = 0.794) and DFS (P = 0.957) did not differ between natural N0 and downstaged N0 groups, but it was significantly shorter in ypN+ group (OS, P = 0.032; DFS, P = 0.021). In subgroups with “poor response” of primary tumor, the prognosis of natural N0 and downstaged N0 paitents was poor almost identical to ypN+ in both OS (P = 0.721; P = 0.252) and DFS (P = 0.694; P = 0.114). The ypN0 status is an important hallmark demonstrating the effectiveness of nCRT for ESCC, regardless of cN status. Additionally, the survival of natural N0 and downstaged N0 patients with bad response at primary site may be poor, similar to ypN+ patients.

For trochanteric fractures, helical blade placement is crucial to the prognosis of operations. Existing measurement methods used for blade placement include the Cleveland zone, the tip-apex distance (TAD), the calcar-referenced tip-apex distance (CalTAD), and the Parker's ratio. These methods all lack a direct view on blade direction. The current study proposed the axis-blade angle (ABA) to solve direction problem and investigated its clinical applicability.A retrospective study collected 156 patients between May 2014 and February 2018. The occurrence of mechanical complications was analyzed in relation to age, gender, fracture side, American Society of Anesthesiologists classification, fracture classification, reduction quality, bone quality, the Cleveland zone, the Parker's ratio, the TAD, the CalTAD, and the ABA.119 patients, including 25 with mechanical complications, were suitable for full analysis. In the univariate analysis, the Cleveland zone, reduction quality, the TAD, the CalTAD and the ABA were statistically associated with mechanical complications. In the multivariate analysis, reduction quality (p = 0.008) and the ABA (p 0.001; adjusted OR 0.86;95% CI 0.77 to 0.96) showed significant results, which indicated that reduction quality and the ABA were two independent influencing factors for mechanical complications. Calculation of the receiver operating characteristic (ROC) curve indicated that the ABA was a reliable predictor of mechanical complications at the cut-off of -10°.The ABA provides instruction for the intraoperative adjustment of guide wire direction. Placing the helical blade with an ABA -10° can effectively reduce the risk of mechanical complications.

Tissue factor pathway inhibitor (TFPI) reduces the development of atherosclerosis by regulating tissue factor (TF) mediated coagulation pathway. In this review, we focus on recent findings on the inhibitory effects of TFPI on endothelial cell activation, vascular smooth muscle cell (VSMC) proliferation and migration, inflammatory cell recruitment and extracellular matrix which are associated with the development of atherosclerosis. Meanwhile, we are also concerned about the impact of TFPI levels and genetic polymorphisms on clinical atherogenesis. This article aims to explain the mechanism in inhibiting the development of atherosclerosis and clinical effects of TFPI, and provide new ideas for the clinical researches and mechanism studies of atherothrombosis.

Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule that plays important roles in the cardiovascular system. In our previous studies, we demonstrated that H2S regulates lipid metabolism. In the present study, we aimed to explore the mechanisms through which H2S regulates lipid metabolism in HepG2 cells in vitro. Treatment of the HepG2 cells with H2S inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and increased the level of low‑density lipoprotein receptor (LDLR) in a time‑ and dose‑dependent manner. The knockdown of PCSK9 by siRNA effectively increased the levels of LDLR and 1,1'‑dioctadecyl‑3,3,3',3'‑tetramethyl‑indocarbocyanine perchlorate‑labeled LDL (DiI‑LDL) uptake in the H2S‑treated HepG2 cells. Furthermore, the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt)‑sterol regulatory element binding proteins 2 (SREBP‑2) signaling pathway was confirmed to be involved in H2S‑regulated PCSK9 expression. Notably, the HepG2 cells were incubated with 30% serum and DiI‑LDL for 24 h, and the results revealed that H2S increased lipid uptake, but caused no increase in lipid accumulation. On the whole, the findings of this study demonstrate that H2S is involved in the regulation of lipid metabolism in HepG2 cells through the regulation of the expression of PCSK9 via the PI3K/Akt‑SREBP‑2 signaling pathway. To the very best of our knowledge, this study is the first to report that H2S can regulate the expression of PCSK9.

ObjectivesWe determined if the time interval between two ovulation induction intrauterine artificial insemination (IUI) treatment cycles should be extended by one or more natural menstrual cycles in patients undergoing successive cycles of ovulation stimulation, and whether this affects clinical pregnancy rate (CPR).DesignThis study was conducted on infertility patients treated under the ovulation induction programme IUI in a large reproductive centre in China. Study participants were assigned into continuous and discontinuous groups. Differences in baseline clinical pregnancy and abortion rates were compared between the groups. A multivariate logistic model was used to evaluate the effects of time interval on clinical pregnancy outcomes.SettingReproductive Centre of Maternal and Child Health Hospital of Lianyungang city.InterventionsNone.Primary and secondary outcome measuresThe primary outcome measure was CPR, the secondary outcome measure was the abortion rate.ResultsA total of 550 IUI treatment cycles involving 275 couples were included in this study. Differences in CPR and abortion rate between the groups were not significant (20.5% vs 21.9% and 27.8% vs 22.0%, p≥0.05). Stratified analyses based on infertility factors did not reveal any significant differences in pregnancy and abortion rates between the groups (p≥0.05). Multivariate analysis showed that increased endometrial thickness correlates with CPR (OR 1.205, 95% CI 1.05 to 1.384, p=0.008). Compared with primary infertility, secondary infertility significantly correlated with improved CPR (OR 2.637, 95% CI 1.313 to 5.298, p=0.006). The effects of time interval between the first two ovulation induction IUI treatment cycles on clinical pregnancy were not significant (OR 1.007, 95% CI 0.513 to 1.974, p=0.985).ConclusionsLonger time intervals between the first two ovulation induction IUI treatment cycles did not significantly improve CPR. Therefore, in the absence of clear clinical indications, it may not be necessary to deliberately prolong the interval between two ovulation induction IUI treatment cycles.

Autophagy exists widely in various physiological and pathological conditions. Lots of investigations have verified that the autophagic activity is always related to the occurrence and the development of cancer. Endometriosis (EMs) is a disease that endometrium-like tissues abnormally grow outside the uterus and also considered to possess the characters of tumor because of its malignant biological behavior.Recently, several studies have already revealed that autophagy may play a potential role in proliferative-phase EMs. However, the function of autophagic activity in secretory-phase EMs is still unclear.In our work, we explored autophagic activity between normal endometrium and EMs lesion endometrium during different menstrual phases and EMs stages. The clinical endometrium samples from 73 women were selected in this study, including 30 healthy individuals and 43 patients with EMs (endometrium samples include eutopic and its matched ectopic endometrium). All the participants were divided into two groups according to the menstrual cycle, namely proliferative-phase and secretive- phase group. Among the patients with EMs, 22 individuals in proliferative phase and the other 21 individuals in secretory phase were further classified into the groups of Stage I-II and Stage III-IV according to revised-American Fertility Society (r-AFS). Two autophagy-related proteins microtubuleassociated protein 1 light chain 3 beta-II (LC3B-II) and sequestosome protein (P62), which are believed to be the indicators of autophagy activity, were chosen in the study. Immunohistochemical (IHC) staining, Western blot assay and Real-Time quantitative Polymerase Chain Reaction (RTqPCR) were used to examine the expression of LC3B-II and P62 in protein and mRNA level accordingly.It showed that the expression of LC3B-II both in protein and mRNA level decreased and that of P62 increased in secretory phase of the healthy group (P0.05), but showed no significant difference in ectopic and its eutopic endometrium group during proliferative and secretory phase (P0.05). In addition, the expression of LC3B-II in ectopic endometrium group was significantly lower than that of its eutopic endometrium group (P0.05), and the expression of P62 was significantly higher accordingly (P0.05). At the same time, both LC3B-II and P62 levels remained same between eutopic endometrium group and control group (P0.05). Furthermore, compared to Stage I-II EMs group, the expression of LC3B-II was significantly lower (P0.05) and P62 was significantly higher (P0.05) in Stage III-IV EMs during secretory phase.Taken together, the periodicity-losing in EMs and the decreased autophagic activity in ectopic endometrium may exert a potential role in the pathogenesis of EMs. Down-regulated autophagy of ectopic endometrium in secretory phase may be related to the progression of EMs.

Hydrogen sulfide (H2S) exerts an anti-atherosclerotic effect and decreases foam cell formation. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a key factor involved in foam cell formation. However, the association between H2S and Lp-PLA2 expression levels with respect to foam cell formation has not yet been elucidated. The present study investigated whether H2S can affect foam cell formation and potential signalling pathways via regulation of the expression and activity of Lp-PLA2. Using human monocytic THP-1 cells as a model system, it was observed that oxidized low-density lipoprotein (ox-LDL) not only upregulates the expression level and activity of Lp-PLA2, it also downregulates the expression level and activity of Cystathionine γ lyase. Exogenous supplementation of H2S decreased the expression and activity of Lp-PLA2 induced by ox-LDL. Moreover, ox-LDL induced the expression level and activity of Lp-PLA2 via activation of the p38MAPK signalling pathway. H2S blocked the expression levels and activity of Lp-PLA2 induced by ox-LDL via inhibition of the p38MAPK signalling pathway. Furthermore, H2S inhibited Lp-PLA2 activity by blocking the p38MAPK signaling pathway and significantly decreased lipid accumulation in ox-LDL-induced macrophages, as detected by Oil Red O staining. The results of the present study indicated that H2S inhibited ox-LDL-induced Lp-PLA2 expression levels and activity by blocking the p38MAPK signalling pathway, thereby improving foam cell formation. These findings may provide novel insights into the role of H2S intervention in the progression of atherosclerosis.

There is a growing evidence that Fyn kinase is upregulated in glioblastoma multiforme (GBM), where it plays a key role in tumor proliferation and invasion. In the present study, the antitumor effects of rosmarinic acid (RA), a Fyn inhibitor, were explored in human‑derived U251 and U343 glioma cell lines. These cells were treated with various concentrations of RA to determine its effects on proliferation, migration, invasion, apoptosis, and gene and protein expression levels. The CCK‑8 assay revealed that RA significantly suppressed cell viability of U251 and U343 cells. Furthermore, RA significantly reduced proliferation rates, inhibited migration and invasion, and decreased the expression levels of invasion‑related factors, such as matrix metalloproteinase (MMP)‑2 and MMP‑9. TUNEL staining revealed that RA resulted in a dose‑dependent increase of U251 and U343 cell apoptosis. In line with this finding, the expression of apoptosis suppressor protein Bcl‑2 was downregulated and that of the pro‑apoptotic proteins Bax and cleaved caspase‑3 was increased. In addition, it was revealed that the phosphatidylinositol 3‑kinase (PI3K)/Akt/nuclear factor‑κB (NF‑κB) signaling pathway was involved in RA‑induced cytotoxicity in U251 and U343 cells. Collectively, the present study suggested RA as a drug candidate for the treatment of GBM.

Background: Lutembacher’s syndrome (LS) is a rare cardiovascular anomaly that is defined as any combination of congenital or iatrogenic atrial septal defect (ASD) with congenital or acquired mitral stenosis (MS). The clinical features and hemodynamic effects of LS depend on the balance between ASD and MS. Case Report: In this case report, we describe a rare case of LS with a huge right atrium in a 39-year-old male patient who was admitted to the hospital with worsening fatigue and breathlessness on exertion. Clinical examination revealed central cyanosis, raised jugular venous pressure bilaterally, clear breath sounds bilaterally with no dry and wet rales, hyperdynamic apex beat, and dull heart sounds. His vital signs on admission included blood pressure of 90/60 mmHg, irregular pulse of 76 beats/min, and oxygen saturation of 90.4%. Echocardiography revealed moderate to severe MS with ASD (ostium secundum). The patient’s condition deteriorated after initial medical management, and he underwent open heart surgery for mitral valve replacement, ASD repair, tricuspid annuloplasty, and right atrial volume reduction. Conclusions: This case report describes the successful surgical management of this rare condition.

Objective: To investigate the role of the application of role-play in endodontic study in improving the communication skills of Chinese dental undergraduates prior to their direct interactions with patients at the Fourth Military Medical University’s School of Stomatology, China. Methods: Students were recruited from the 5-year bachelor’s programme (n = 36) and randomly divided into six groups, and from the 8-year DDS programme (n = 10) and randomly divided into two groups to participate in the role-play training. Cases selected randomly from the case pool were distributed to the groups. The teacher gave an outline of the roles in the simulation. Each member of each group randomly selected their own role for the role-play. Four types of surveys were distributed to students and faculty members at different points after the role-plays had taken place, to evaluate their attitude towards the use of role-plays in endodontic study. Frequency analysis and a one sample t test were used to describe and analyse students’ acceptance of role-play as a teaching technique. The level of statistical significance was set at P0.05. Results: Students’ performance and satisfaction as well as the supporting faculty responses were very favourable towards role-playing. In total, 93.5% of students responded favourably to the role-play, answering ‘strongly agree’ or ‘agree’ to the positive statements about their role-play performance. A total of 95.1% of students stated that they had benefited psychologically and technically from the role-play (‘strongly agree’ or ‘agree’) after their 1-year rotating internship. Conclusion: The application of role-play in endodontic study is an effective way of educating Chinese dental undergraduates and can be beneficial for their transition from students to dentists.

The science around the use of masks by the public to impede COVID-19 transmission is advancing rapidly. In this narrative review, we develop an analytical framework to examine mask usage, synthesizing the relevant literature to inform multiple areas: population impact, transmission characteristics, source control, wearer protection, sociological considerations, and implementation considerations. A primary route of transmission of COVID-19 is via respiratory particles, and it is known to be transmissible from presymptomatic, paucisymptomatic, and asymptomatic individuals. Reducing disease spread requires two things: limiting contacts of infected individuals via physical distancing and other measures and reducing the transmission probability per contact. The preponderance of evidence indicates that mask wearing reduces transmissibility per contact by reducing transmission of infected respiratory particles in both laboratory and clinical contexts. Public mask wearing is most effective at reducing spread of the virus when compliance is high. Given the current shortages of medical masks, we recommend the adoption of public cloth mask wearing, as an effective form of source control, in conjunction with existing hygiene, distancing, and contact tracing strategies. Because many respiratory particles become smaller due to evaporation, we recommend increasing focus on a previously overlooked aspect of mask usage: mask wearing by infectious people (“source control”) with benefits at the population level, rather than only mask wearing by susceptible people, such as health care workers, with focus on individual outcomes. We recommend that public officials and governments strongly encourage the use of widespread face masks in public, including the use of appropriate regulation.

Harpertrioate A (

Background There is controversy regarding the efficacy of different treatment strategies for acute left malignant colonic obstruction. This study investigated the 5-year overall survival (OS) and disease-free survival (DFS) of several treatment strategies for acute left malignant colonic obstruction. Methods We searched for articles published in PubMed, Embase (Ovid), MEDLINE (Ovid), Web of Science, and Cochrane Library between January 1, 2000, and July 1, 2020. We screened out the literature comparing different treatment strategies. Evaluate the primary and secondary outcomes of different treatment strategies. The network meta-analysis summarizes the hazard ratio, odds ratio, mean difference, and its 95% confidence interval. Results The network meta-analysis involved 48 articles, including 8 (randomized controlled trials) RCTs and 40 non-RCTs. Primary outcomes: the 5-year overall survival (OS) and disease-free survival (DFS) of the CS-BTS strategy and the DS-BTS strategy were significantly better than those of the ES strategy, and the 5-year OS of the DS-BTS strategy was significantly better than that of CS-BTS. The long-term survival of TCT-BTS was not significantly different from those of CS-BTS and ES. Secondary outcomes: compared with emergency resection (ER) strategies, colonic stent-bridge to surgery (CS-BTS) and transanal colorectal tube-bridge to surgery (TCT-BTS) strategies can significantly increase the primary anastomosis rate, CS-BTS and decompressing stoma-bridge to surgery (DS-BTS) strategies can significantly reduce mortality, and CS-BTS strategies can significantly reduce the permanent stoma rate. The hospital stay of DS-BTS is significantly longer than that of other strategies. There was no significant difference in the anastomotic leakage levels of several treatment strategies. Conclusion Comprehensive literature research, we find that CS-BTS and DS-BTS strategies can bring better 5-year OS and DFS than ER. DS-BTS strategies have a better 5-year OS than CS-BTS strategies. Without considering the hospital stays, DS-BTS strategy is the best choice.

Vitamin A (VA), all-trans-retinol (ROL), and its analogs are collectively called retinoids. Acting through the retinoic acid receptors RARα, RARβ, and RARγ, all-trans-retinoic acid, an active metabolite of VA, is a potent regulator of numerous biological pathways, including embryonic and somatic cellular differentiation, immune functions, and energy metabolism. The liver is the primary organ for retinoid storage and metabolism in humans. For reasons that remain incompletely understood, a body of evidence shows that reductions in liver retinoids, aberrant retinoid metabolism, and reductions in RAR signaling are implicated in numerous diseases of the liver, including hepatocellular carcinoma, non-alcohol-associated fatty liver diseases, and alcohol-associated liver diseases. Conversely, restoration of retinoid signaling, pharmacological treatments with natural and synthetic retinoids, and newer agonists for specific RARs show promising benefits for treatment of a number of these liver diseases. Here we provide a comprehensive review of the literature demonstrating a role for retinoids in limiting the pathogenesis of these diseases and in the treatment of liver diseases.

Background Early mobilisation reduces postoperative complications such as pneumonia, deep vein thrombosis and hospital length of stay. Many authors have reported poor compliance with early mobilisation within Enhanced Recovery After Surgery initiatives. Objectives The primary objective was to increase postoperative day (POD) 2 mobilisation rate from 23% to 75% in patients undergoing elective major hepatopancreatobiliary (HPB) surgery within 6 months. Methods We report a multidisciplinary team clinical practice improvement project (CPIP) to improve postoperative mobilisation of patients undergoing elective major HPB surgery. We identified the common barriers to mobilisation and analysed using the fishbone or cause-and-effect diagram and Pareto chart. A series of Plan–Do–Study–Act cycles followed this. We tracked the rate of early mobilisation and mean distance walked. In the post hoc analysis, we examined the potential cost savings based on reduced hospital length of stay. Results Mobilisation rate on POD 2 following elective major HPB surgery improved from 23% to 78.9%, and this sustained at 6 months after the CPIP. Wound pain was the most common reason for failure to ambulate on POD 2. Hospital length of stay reduced from a median of 8 days to 6 days with an estimated cost saving of S$2228 per hospital stay. Conclusion Multidisciplinary quality improvement intervention effort resulted in an improved POD 2 mobilisation rate for patients who underwent elective major HPB surgery. This observed outcome was sustained at 6 months after completion of the CPIP with potential cost savings.

Three new diterpenoids (

Fibers produced from electrospinning are well-known to be extremely fine with diameters ranging from tens of nanometers to a few microns. Such ultrafine fibers not only allow for engineering scaffolds resembling the ultrastructure of the native extracellular matrix, but also offer possibility to explore the remodeling behavior of cells in vitro, due to their mechanically ‘adequate’ softness endowed by their ultrafine fineness. However, the remodeling effect of cells on the biomimicking fibrous substrates remains to be understood, because the crisscrossing and entangling among nanofibers in those tightly packed fibrous mats ultimately lead to merely a topological phenomenon, similar to that of the nanofiber-like topography embossed on the surface of a solid matter. In this study, the effect of nanofiber density on cellular response behavior was investigated by reducing the density of electrospun fiber networks. Using polycaprolactone (PCL) as a model polymer, randomly oriented fiber networks with various densities, namely, 37.7 ± 16.3 μg/cm2 (D1), 103.8 ± 16.3 μg/cm2 (D2), 198.2 ± 40.0 μg/cm2 (D3), and 471.8 ± 32.7 μg/cm2 (D4), were prepared by electrospinning for varied collection durations (10 s, 50 s, 100 s, and 10 min, respectively). By examining the responsive behavior of the human induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSCs) cultured on these nanofibrous networks, we showed that the fiber network with a moderate density (D2) is beneficial to the cell attachment, spreading, actin polymerization, contractility and migration. There also showed an increased tendency in nuclear localization of the Yes-associated protein (YAP) and subsequent activation of YAP responsive gene transcription, and cell proliferation and collagen synthesis were also enhanced on the D2. However, further increasing the fiber density (D3, D4) gave rise to weakened induction effect of fibers on the cellular responses. These results enrich our understanding on the effect of fiber density on cell behavior, and disclose the dependence of cellular responses on fiber density. This study paves the way to precisely design biomimetic fibrous scaffolds for achieving enhanced cell-scaffold interactions and tissue regeneration.

The study was to investigate the characteristics of residual tumors of esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy.The resection specimens of 187 patients undergoing surgery after neoadjuvant chemoradiotherapy in Zhongshan Hospital of Fudan University were reevaluated. Tumor regression grade determined by residual tumor ratios was scored for each specific layer of the esophageal wall and all removed lymph nodes for 4 grades as tumor regression grade 1, 0% residual tumors, tumor regression grade 2, less than 10%; tumor regression grade 3, 10% to 50%; tumor regression grade 4, greater than 50%. The pretreatment pathologic tumor stage and pretreatment pathologic lymph node stage before neoadjuvant chemoradiotherapy were recorded reflecting the original depth of primary tumor and number of originally involved lymph nodes, respectively. According to regression directionality, regression pattern was classified into 4 categories as type I: regression toward the lumen, type II: regression toward the invasive front, type III: concentric regression, and type IV: scattered regression. Statistical analyses were performed using Mann-Whitney, chi-square, Cochran Q tests, and Kendall τ-b coefficient, appropriately.A total of 138 patients have residual tumors, and 97 patients (70.3%), 100 patients (72.5%), 89 patients (64.5%), 63 patients (45.7%), and 68 patients (49.3%) have malignant cells in mucosa, submucosa, muscularis propria, adventitia/surrounding stroma, and lymph nodes, respectively. A total of 115 patients (83.3%) had residual tumors in the mucosa or submucosa, but 63 (54.8%) were graded as tumor regression grade 2 with small amounts of tumors in these 2 layers, 9 patients (6.5%) had residual tumors only in the deep 2 layers, and 14 patients (10.1%) had residual tumors only in lymph nodes. Overall, 86 patients (62.7%) with residual tumors are difficult to identify via present techniques. In patients with tumors that involved all esophageal layers before neoadjuvant chemoradiotherapy, only muscularis propria contained residual tumors significantly more frequently than the adventitia/surrounding stroma (P .001). The random type IV and nonrandom regression patterns of type I to III were comparable with 48.9% and 51.1%, respectively. In patients with positive lymph node before neoadjuvant chemoradiotherapy, only a small portion of patients (29.2%, 28/96) achieved ypN0 status (nodes pathological complete response), even worse than the primary lesions (33.6%, 63/187) in esophageal squamous cell carcinoma.The small amount of viable tumor cells in the superficial layers, low pathological complete response rate of lymph nodes, and diverse regression patterns lead to difficulty of detecting residual tumors in esophageal squamous cell carcinoma.

Salusin-β is abundantly expressed in many organs and tissues including heart, blood vessels, brain and kidneys. Recent studies have identified salusin-β as a bioactive peptide that contributes to various diseases, such as atherosclerosis, hypertension, diabetes and metabolic syndrome. However, the role of salusin-β in the pathogenesis of acute kidney injury (AKI) is largely unclear. In the present study, we investigated the roles of salusin-β in cisplatin or lipopolysaccharide (LPS)-induced renal injury. Herein, we found that salusin-β expression was upregulated in both renal tubular cells and kidney tissues induced by both cisplatin and LPS. In vitro, silencing of salusin-β diminished, whereas overexpression of salusin-β exaggerated the increased PKC phosphorylation, oxidative stress, histone γH2AX expression, p53 activation and apoptosis in either cisplatin or LPS-challenged renal tubular cells. More importantly, salusin-β overexpression-induced tubular cell apoptosis were abolished by using the PKC inhibitor Go 6976, reactive oxygen species (ROS) scavenger NAC, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (Apo) or p53 inhibitor Pifithrin-α. In animals, blockade of salusin-β alleviated PKC phosphorylation, ROS accumulation, DNA damage, and p53 activation as well as renal dysfunction in mice after administration of cisplatin or LPS. Taken together, these results suggest that overexpressed salusin-β is deleterious in AKI by activation of the PKC/ROS signaling pathway, thereby priming renal tubular cells for apoptosis and death., Graphical abstract Image 1, Highlights • Both cisplatin and LPS elevated the renal levels of endogenous salusin-β in mice. • Treatment with neutralizing the salusin-β antibody ameliorated renal dysfunction and tubular cell DNA damage and apoptosis. • Deletion of salusin-β alleviated, while overexpression of salusin-β aggravated tubular epithelial cell DNA damage and apoptosis. • Salusin-β contributed to tubular cell DNA damage and apoptosis through the PKC/ROS signaling pathway.