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Purpose This study aimed to compare the effects of ground and treadmill running on energy metabolism and muscle contractile properties, providing a basis for the general public to choose running venues. Methods Ten male college students (age, 20.10 ± 1.53 years; height, 176.20 ± 5.49 cm; weight, 72.14 ± 8.25 kg; body fat percent, 12.41% ± 4.65%) were recruited in this study. Energy expenditure (EE) was measured using the accelerometer (GT9X) combined with specific estimation equations. Average heart rate (HR) was measured using a heart rate band (Polar). Muscle contractile properties were assessed by measuring muscle displacement (Dm) and contraction velocity (Vc) using tensiomyography (TMG-S1). Blood glucose (Glu) and lactate (Lac) were measured by portable devices (eB-G and Lactate Scout). The running speed was 9 km/h and the duration was 25 min. Two-way ANOVA (protocol × time) was used to analyze the effect of running protocols on energy metabolism and muscle contractile properties. Results EE of treadmill running was significantly higher than EE of ground running (protocol main effect, P < 0.001), and HR of treadmill running was significantly higher than that of ground running in the first testing time (protocol simple effect, P = 0.026; protocol × time interaction P = 0.043). The decrease in Dm of the rectus femoris after treadmill running was significantly higher than that of ground running (protocol main effect, P = 0.009). The interaction of different running protocols and testing times on Lac was significant (P = 0.025), but all results of the simple effects analysis were not statistically significant (P > 0.05). Conclusion Our study found a difference in energy expenditure between treadmill and ground running at 9 km/h with duration of 25 min. In addition, treadmills are more likely to cause a decrease in muscle displacement distance of the rectus femoris measured after exercise than ground running. Future studies are needed to further investigate whether the differences are induced by internal metabolism or the environmental conditions of running.

Blood-brain barrier (BBB) dysfunction is associated with an accumulation of neurotoxic molecules and increased infiltration of peripheral cells within the brain parenchyma. Accruing evidence suggests that microglia and astrocytes play a crucial role in the recovery of BBB integrity and the corralling of infiltrating cells into clusters after brain damage, but the mechanisms involved remain unclear. Intriguingly, the results of flow cytometry and immunofluorescence analyses have shown that BBB permeability to peripheral cells is substantially enhanced during normal aging at 12 months in mice. Thus, we used the SMART-seq2 method to perform RNA sequencing of microglia and astrocytes at five time points before and immediately after the BBB permeability change. Our comprehensive analyses revealed that microglia are characterized by marked alterations in the negative regulation of protein phosphorylation and phagocytic vesicles, whereas astrocytes show elevated enzyme or peptidase-inhibitor activity in the recovery of BBB function. Moreover, we identified a cassette of key genes that might ameliorate the insults of pathophysiological events in aging and neurodegenerative disease., Graphical abstract, Microglia are characterized by marked alterations in the negative regulation of protein phosphorylation and phagocytic vesicles in the recovery of BBB function. Astrocytes show elevated enzyme or peptidase-inhibitor activity in the recovery of BBB function. Microglia and astrocytes play an active role in ameliorating BBB dysfunction and corralling infiltrating cells.

Lung cancer is a most common cancer worldwide. Tumor-associated macrophage (TAM) is known a key effector cell in tumor microenvironment. Meanwhile, STAT6 is crucial to cancer development. We aimed to determine the interaction between STAT6 and TAMs in lung cancer. In this work, firstly, we established mouse model of lung cancer. Then, immunofluorescence was performed to determine STAT6 and CD206 level in lung cancer tissue and adjacent normal tissues as well as model mice. RT-qPCR was applied to detect differentiation of macrophage and determine related gene expression. After treatment of siRNA of STAT6 or STAT6 inhibitor (AS1517499), Transwell assay and MTT were used to determine cell proliferation and migration. STAT6 was upregulated in lung cancer tissues while arginase was more active in M2 macrophage rather than M1 macrophage. Transfection of si-STAT6 not only decreased differentiation in M2 macrophage but also inhibited proliferative, migratory and invasive ability of cancer cells while AS1517499 led to reduced tumor growth. STAT6 inhibition caused decreased expression of M2 macrophages. Similarly, intratumoral T cell markers showed that CD8+T cell gene expression and CD4-mediated T cell marker FoxP3 was increased slightly. Taken altogether, macrophage-STAT6 promotes cell migration and proliferation in lung cancer.

This study aimed to construct an atlas of the cell landscape and comprehensively characterize the cellular repertoire of the pulmonary endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Five pulmonary endarterectomized tissues were collected. 10× Genomics single-cell RNA sequencing was performed, followed by the identification of cluster marker genes and cell types. Gene Ontology (GO) enrichment analysis was conducted. Seventeen cell clusters were characterized, corresponding to 10,518 marker genes, and then classified into eight cell types, including fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, cysteine rich secretory protein LCCL domain containing 2 (CRISPLD2)+ cell, cancer stem cell, and undefined. The specific marker genes of fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, and cancer stem cell were significantly enriched for multiple functions associated with muscle cell migration, endothelial cell migration, T cell activation, neutrophil activation, erythrocyte homeostasis, and tissue remodeling, respectively. No functions were significantly enriched for the marker gene of CRISPLD2+ cell. Our study, for the first time, provides an atlas of the cell landscape of the pulmonary endarterectomized tissues of CTEPH patients at single-cell resolution, which may serve as a valuable resource for further elucidation of disease pathophysiology.

Background After the low quality of Chinese clinical practice guidelines (CPGs) for respiratory diseases published from 1979 to 2013 was reported, some handbooks were published to standardize guidelines' development recently. There was a great increase in the production and dissemination of CPGs annually in China, whose quality and potential impact were unknown. Methods A systematic search of four literature databases was performed for the period January 2013 to December 2018 to identify Chinese CPGs for respiratory diseases. Eligible CPGs were evaluated using the appraisal of guidelines for research and evaluation II (AGREE II) instrument. Results A total of 197 CPGs were identified for review. Compared with the result of previous study, the increased scores of the six AGREE II domains were screened: Scope and purpose (57.3% vs. 57.8%), Stakeholder involvement (17.6% vs. 25.0%), Rigor of development (10.2% vs. 13.2%), Clarity and presentation (55.2% vs. 58.4%), Applicability (9.3% vs. 25.9%), and Editorial independence (1.1% vs. 6.3%). The improved overall assessment for included CPGs were: Recommended (4, 2.0% vs. 0, 0%) and Recommended with modifications (26, 13.2% vs. 3, 2.8%). The improved level of evidence used to make recommendations were 59, 11.9% versus 168, 22.4% and 88, 17.7% versus 195, 26.0%, A and B, respectively. Conclusions The overall quality of CPGs for respiratory diseases published from 2013 to 2018 in China was slightly improved, but had a big gap with the optimum level, especially in Rigor of development and Editorial independence. Increased efforts are required to enable the development of high-quality evidence-based CPGs for respiratory diseases.

Clinical use of various forms of immunotherapeutic drugs in glioblastoma (GBM), has highlighted severe T cell dysfunction such as exhaustion in GBM patients. However, reversing T cell exhaustion using immune checkpoint inhibitors in GBM clinical trials has not shown significant overall survival benefit. Phenotypically, CD8+ T cells with downregulated CD28 coreceptors, low CD27 expression, increased CD57 expression, and telomere shortening are classified as senescent T cells. These senescent T cells are normally seen as part of aging and also in many forms of solid cancers. Absence of CD28 on T cells leads to several functional irregularities including reduced TCR diversity, incomplete activation of T cells, and defects in Ag-induced proliferation. In the context of GBM, presence and/or function of these CD8+CD28– T cells is unknown. In this clinical correlative study, we investigated the effect of aging as well as tumor microenvironment on CD8+ T cell phenotype as an indicator of its function in GBM patients. We systematically analyzed and describe a large population of CD8+CD28– T cells in both the blood and tumor-infiltrating lymphocytes of GBM patients. We found that phenotypically these CD8+CD28– T cells represent a distinct population compared with exhausted T cells. Comparative transcriptomic and pathway analysis of CD8+CD28– T cell populations in GBM patients revealed that tumor microenvironment might be influencing several immune related pathways and thus further exaggerating the age associated immune dysfunction in this patient population.

Aims Glioma is a highly invasive brain tumor, which makes prognosis challenging and renders patients resistant to various treatments. Induction of cell death is promising in cancer therapy. Ferroptosis, a recently discovered regulated cell death, can be induced for killing glioma cells. However, the prognostic prediction of ferroptosis‐related genes (FRGs) in glioma remains elusive. Methods The mRNA expression profiles and gene variation and corresponding clinical data of glioma patients and NON‐TUMOR control were downloaded from public databases. Risk score based on a FRGs signature was constructed in REMBRANDT cohort and validated in other datasets including CGGA‐693, CGGA‐325, and TCGA. Results Our results demonstrated that the majority of FRGs was differentially expressed among GBM, LGG, and NON‐TUMOR groups (96.6%). Furthermore, the glioma patients with low‐risk score exhibited a more satisfactory clinical outcome. The better prognosis was also validated in the glioma patients with low‐risk score no matter to which grade they were affiliated. Functional analysis revealed that the high‐risk score group was positively correlated with the enrichment scores for immune checkpoint blockade‐related positive signatures, indicating the critical role of glioma immunotherapy via risk score. Conclusion A novel FRGs‐related risk score can predict prognosis and immunotherapy in glioma patients., A random survival forest model was constructed to obtain the risk score based on 59 ferroptosis genes in glioma patients in REMBRANDT cohort and it was validated in other datasets including CGGA‐325, CGGA‐693, and TCGA cohorts. Finally, a novel ferroptosis‐related risk score can predict prognosis and immunotherapy in glioma patients.

Cancer has become one of the most common diseases with high mortality in humans. Early and accurate diagnosis of cancer is of great significance to enhance the survival rate of patients. Therefore, effective molecular ligands capable of selectively recognizing cancer are urgently needed. In this work, we identified a new DNA aptamer named SW1 by tissue-based systematic evolution of ligands by exponential enrichment (tissue-SELEX), in which cancerous liver tissue sections were used as the positive control and adjacent normal liver tissue sections were used as the negative control. Taking immobilized liver cancer SMMC-7721 cells as the research object, aptamer SW1 exhibited excellent affinity with a Kd value of 123.62 ± 17.53 nM, and its binding target was preliminarily determined as a non-nucleic acid substance in the nucleus. Moreover, tissue imaging results showed that SW1 explicitly recognized cancerous liver tissues with a high detection rate of 72.7% but displayed a low detection rate to adjacent normal tissues. In addition to liver cancer cells and tissues, aptamer SW1 has been demonstrated to recognize various other types of cancer cells and tissues. Furthermore, SW1-A, an optimized aptamer of SW1, maintained its excellent affinity toward liver cancer cells and tissues. Collectively, these results indicate that SW1 possesses great potential for use as an effective molecular probe for clinical diagnosis of cancer.

Osteosarcoma (OS) is the most prevalent form of bone cancer. It has a high metastatic potential and progresses rapidly. The molecular mechanisms of OS remain unclear and this study aims to examine the functional role of circPVT1 and miR‐423‐5p in OS. Quantitative RT‐PCR (qRT‐PCR) and western blotting were used to examine levels of miR‐423‐5p, circPVT1, Wnt5a, Ror2, and glycolysis‐related proteins, including HK2, PKM2, GLUT1, and LDHA. Colony formation and transwell assays were used to test the roles of miR‐423‐5p, circPVT1, and Wnt5a/Ror2 in OS cell proliferation, migration, and invasion. Dual luciferase assay and Ago2‐RIP were used to validate the interactions of miR‐423‐5p/Wnt5a, miR‐423‐5p/Ror2, and circPVT1/miR‐423‐5p. Glucose uptake assay and measurement of lactate production were performed to assess the glycolysis process. A nude mouse xenograft model was used to evaluate the effects of sh‐circPVT1 and miR‐423‐5p mimics on tumor growth and metastasis in vivo. miR‐423‐5p was reduced in both OS tissues and OS cell lines, while Wnt5a/Ror2 and circPVT1 were elevated. miR‐423‐5p bound to 3′‐UTR of Wnt5a and Ror2 mRNA, and inhibited glycolysis and OS cell proliferation, migration, and invasion by targeting Wnt5a and Ror2. circPVT1 interacted with miR‐423‐5p and activated Wnt5a/Ror2 signaling by sponging miR‐423‐5p. Knockdown of circPVT1 or overexpression of miR‐423‐5p suppressed OS tumor growth and metastasis in vivo. miR‐423‐5p inhibited OS glycolysis, proliferation, migration, and metastasis by targeting and suppressing Wnt5a/Ror2 signaling pathway, while circPVT1 promoted those processes by acting as a sponge of miR‐423‐5p., miR‐423‐5p was diminished while circPVT1 and Wnt5a/Ror2 were increased in OS. miR‐423‐5p restrained glycolysis, OS cell proliferation, and migration by targeting Wnt5a/Ror2 signaling. circPVT1 bound to miR‐423‐5p and acted as a sponge. circPVT1 promoted glycolysis, OS cell proliferation, and metastasis by binding to miR‐423‐5p. Knockdown of circPVT1 or overexpression of miR‐423‐5p inhibited OS tumor growth and metastasis in vivo.

The majority of non-melanoma skin cancer (NMSC) is cutaneous basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), which are also called keratinocyte carcinomas, as both of them originate from keratinocytes. The incidence of keratinocyte carcinomas is over 5 million per year in the US, three-fold higher than the total incidence of all other types of cancer combined. While there are several reports on gene expression profiling of BCC and SCC, there are significant variations in the reported gene expression changes in different studies. One reason is that tumor-adjacent normal skin specimens were not included in many studies as matched controls. Furthermore, while numerous studies of skin stem cells in mouse models have been reported, their relevance to human skin cancer remains unknown. In this report, we analyzed gene expression profiles of paired specimens of keratinocyte carcinomas with their matched normal skin tissues as the control. Among several novel findings, we discovered a significant number of zinc finger encoding genes up-regulated in human BCC. In BCC, a novel link was found between hedgehog signaling, Wnt signaling, and the cilium. While the SCC cancer-stem-cell gene signature is shared between human and mouse SCCs, the hair follicle stem-cell signature of mice was not highly represented in human SCC. Differential gene expression (DEG) in human BCC shares gene signature with both bulge and epidermal stem cells. We have also determined that human BCCs and SCCs have distinct gene expression patterns, and some of them are not fully reflected in current mouse models.

The Capsule Endoscopy Group of the Chinese Society of Digestive Endoscopy has issued recommendations for capsule endoscopy (CE) practice during the COVID-19 pandemic to standardize workflow, preventive strategies, and management of a CE unit and in so doing, ensure the safety of both medical staff and patients.

We report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene. Areg expression is upregulated ~ 10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis, Areg is up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice with Areg knockout, and found that Areg deficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in the Areg null mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.

Aim: In other respiratory infectious diseases, obesity may be associated with a poor outcome. For coronavirus disease 2019 (COVID-19), the association between obesity and severity or prognosis requires further analysis. Methods: This was a retrospective, single-center study. Hospitalized patients were recruited in Renmin Hospital of Wuhan University from January 2, 2020 to February 20, 2020. The data of body mass index (BMI) was obtained from follow-up of surviving patients. According to BMI, normal weight was defined as 18.5-23.9 kg/m2, overweight as 24.0-27.9 kg/m2 and obesity as > 28.0 kg/m2. Results: A total of 463 patients were enrolled, of which 242 (52.3%) patients were in the normal weight group; 179 (38.7%) were in the overweight group; and 42 (9.1%) were in the obesity group. Compared to the normal group, obese patients were more likely to have a higher heart rate; lower finger oxygen saturation; higher levels of white blood cells, neutrophil counts, basophil counts, intravenous glucose, triacylglycerol, uric acid, alanine aminotransferase, creatine kinase-MB, CD19+ cell counts and percentage; and lower levels of monocyte percentage, high density lipoprotein and CD3+ cell percentage. In addition, the proportions of hypertension (21.5% vs. 42.6%) and severe+critical illness (47.8 vs. 81.0 %) were significantly higher in the obesity group than those in normal group. However, no significant differences were observed between the normal and obesity groups in critical illness, organ damage and defined endpoint (mechanical ventilation or intensive care unit). Multiple logistic regression showed that obesity increased the risk of developing severe+critical illness (Odd ratio 3.586, 95% CI 1.550-8.298, P=0.003) in patients with COVID-19, and did not affect the risk of critical illness, organ damage and endpoints. Overweight did not affect the risk of severity, organ damage or endpoint in patients with COVID-19. Conclusion: Obesity may be a risk factor for developing severity in patients with COVID-19.

Osimertinib (OSI) resistance commonly occurs during the treatment of non-small-cell lung cancer (NSCLC). This study aims to investigate whether the thermal effects of radiofrequency ablation (RFA) can increase the sensitivity of OSI-resistant NSCLC to OSI treatment and whether OSI effectively inhibits the recurrence of OSI-resistant NSCLC following RFA treatment and improve survival of NSCLC patients. In vitro, OSI-resistant NCI-H1975 (NCI-H1975/OSIR) cells and thermotolerant NCI-H1975/OSIR (NCI-H1975/OSIR-a-h) cells were established using human NSCLC cell line NCI-H1975. Cell viability, apoptosis, sensitivity to OSI, threonine-methionine amino acid substitution at position 790 (T790M) mutation levels, and protein expression of epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), hypoxia-inducible factor-1 alpha (HIF-1a) were detected using different methods. In vivo, a nude mouse model of metastatic human lung cancer was developed and subjected to RFA treatment. The tumor growth, apoptosis, sensitivity to OSI, expression of EGFR/PI3K/AKT/HIF-1a, and CD34 levels were detected in the micrometastases of the transition zone (TZ) around the central ablation zone, and the reference zone (RZ) far from central ablation zone. NCI-H1975/OSIR and thermotolerant NCI-H1975/OSIR cell models were successfully established. Thermotolerant NCI-H1975/OSIR cells show higher sensitivity to OSI than NCI-H1975/OSIR cells and NCI-H1975 cells. OSI treatment can inhibit the EGFR/PI3K/AKT pathway and induce apoptosis in both NCI-H1975 cells and thermotolerant NCI-H1975/OSIR cells, but not in NCI-H1975/OSIR cells. In vivo, RFA treatment increases sensitivity to OSI in NCI-H1975/OSIR cell micrometastases in the TZ but not in the RZ. OSI intervention effectively inhibits the over-proliferation of micrometastases and activation of the EGFR/PI3K/AKT pathway, and induces apoptosis of micrometastases in the TZ, but shows little effects on the micrometastases in the RZ. The thermal effects can increase the sensitivity of OSI-resistant NSCLC cells to OSI through the EGFR/PI3K/AKT/HIF-1a signaling pathway, indicating that RFA combined with OSI might be a clinically effective and comprehensive therapy for the treatment of OSI-resistant NSCLC.

Circular RNAs (circRNAs) are a kind of non-coding RNA molecule with highly stable circular structures. CircRNAs are primarily composed of exons and/or introns. Recently, a lot of exciting studies showed that circRNA played an essential role in the development of nervous system diseases. Here, classification, characteristics, biogenesis, and the association of circRNA dysregulation with nervous system diseases, such as Alzheimer’s disease, are summarized. The review not only contributes to a better understanding of circRNAs, but also provides new research directions toward the diagnosis, treatment, and prevention of nervous system diseases.

Pax3 and Pax7 are closely related transcription factors that are widely expressed in the developing nervous system and somites. During the normal development in the central nervous system (CNS), Pax3 and Pax7 are mainly expressed in the dorsal part of the neural tube. Further analysis revealed that Pax3 and Pax7 shared redundant functions in the spinal cord development. However, it is still unknown whether Pax3 and Pax7 play a role in neuronal differentiation. In this study, Pax3 and Pax7 genes were overexpressed in Neuro‐2a, the mouse neuroblastoma cell line. CCK‐8 and EdU assay results showed that overexpression of Pax3 inhibited cell viability and proliferation of Neuro‐2a cells, whereas the overexpression of Pax7 had no significant difference on their cell viability and proliferation. Overexpression of Pax3 not only increased the percentage of cells in the S phase and G0/G1 phase, but also decreased that in the G2 phase. Moreover, the total neurite lengths of Neuro‐2a cells were significantly shorter in Pax3 overexpressed group than those in negative control group and showed no significant difference between Pax7 overexpressed group and negative control group. These results suggested that Pax3 not only inhibited the cell viability and proliferation but also affected the cell cycle and the neurite outgrowth of Neuro‐2a cells. RNA sequencing analysis showed up‐regulated genes in Pax3 overexpressed group were involved in cell cycle machinery, which may reveal the potential mechanism of Neuro‐2a cells proliferation.

Limited data exist on changes in the extracellular matrix (ECM) collagen biomarkers levels during chronic thromboembolic pulmonary hypertension (CTEPH) development. This study aimed to investigate ECM collagen biomarkers levels in stable patients with CTEPH. Patients with CTEPH and healthy persons were enrolled. Serum levels of procollagen III N-terminal peptide (PIIINP), carboxyterminal propeptide of type I procollagen (PICP), matrix metalloproteinases (MMP2), MMP9, and tissue inhibitor of metalloproteinases 1(TIMP1) were measured by ELISA. Clinical data coincident with samples were collected. The pulmonary endarterectomy (PEA) and control pulmonary artery tissue samples were analyzed for genetic and immunohistochemical differences. The serum concentrations of PIIINP, PICP, MMP2, and MMP9 decreased significantly in CTEPH patients compared to healthy controls (P < 0.001 for each). CTEPH patients had higher serum concentrations of TIMP1 (median, 111.97 [interquartile range, 84.35–139.93]) compared to healthy controls (74.97 [44.03–108.45] ng/mL, P < 0.001). The MMP2 to TIMP1 ratio was lower in patients than in the controls (P < 0.001). After adjusting for the body mass index (BMI), the MMP2 to TIMP1 ratio correlated negatively with pulmonary vascular resistance (PVR) (r = − 0.327, P = 0.025). Increased TIMP1 (P = 0.04) gene expression was identified in tissues of CTEPH patients. Immunohistochemistry results of vascular walls substantiated qRT-PCR results. This study indicates that ECM collagen biomarkers levels were significantly different in stable patients with CTEPH and healthy controls with significantly increased TIMP1 and decreased MMP2 and MMP9. Differences in TIMP1 expression should be expected not only among healthy controls and patients serum, but also across pathological tissue regions. These findings suggest that the state of vascular remodeling in pulmonary vascular bed in stable patients may be represented by ECM collagen biomarkers levels. We conclude that TIMP1 may play an important role in pulmonary vascular reconstruction in stable CTEPH patients.

The outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread worldwide. This study sought to share our experiences with in-hospital management and outcomes of acute myocardial infarction (AMI) during the COVID-19 pandemic. We retrospectively analyzed consecutive AMI patients, including those with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI), from February 1, 2020, to April 15, 2020 (during the COVID-19 pandemic), and from January 1, 2019, to December 31, 2019 (before the COVID-19 pandemic), respectively. Fifty-three AMI patients (31 STEMI, 22 NSTEMI) during the COVID-19 pandemic were matched to 53 AMI patients before the pandemic. Baseline characteristics were comparable between the matched patients. STEMI patients during the COVID-19 pandemic had a longer delay time, less primary or remedial PCI and more emergency thrombolysis than those before the pandemic. Less coronary angiography and stenting were performed in AMI patients during the COVID-19 pandemic than before the pandemic. There were no statistically significant differences in the clinical outcomes between the matched patients. However, STEMI patients during the COVID-19 pandemic had a 4-fold (12.9% vs. 3.2%) increase in all-cause mortality rate compared with those before the pandemic. AMI combined with COVID-19 infection was associated with higher rates of mortality than AMI alone. This study demonstrates that the COVID-19 pandemic results in significant reperfusion delays in STEMI patients and has a marked impact on the treatment options selection in AMI patients. The mortality rate of STEMI patients exhibits an increasing trend during the pandemic of COVID-19.

Objective Acute aortic dissection (AAD) is the most devasting cardiovascular disease associated with high mortality. The occurrence and progression of AAD can be regulated by inflammatory processes, and further understanding of this inflammatory pathogenesis may improve the treatment of AAD. Interleukin 20 (IL-20), as an inflammatory mediator, has been demonstrated to be associated with several inflammatory diseases. However, the association between IL and 20 and AAD is still unknown. Methods Five aortic dissection tissue samples and five control aortic tissue samples were evaluated in our study. The expression of IL-20 and its receptor subunits (IL-20Rα and IL-20Rβ) was detected by immunofluorescence staining. From January 2018 to March 2018, 70 consecutive AAD patients and 25 non-AAD (NAD) patients were enrolled in this study. Diagnosis was based on computed tomography angiography (CTA) results. Blood samples were obtained from the patients on the first day of hospitalization. Plasma IL-20, TNF-α and IL-6 concentrations were evaluated with enzyme-linked immunosorbent assay (ELISA) kits. Results The expression levels of IL-20 and its receptor subunits (IL-20Rα and IL-20Rβ) were increased in the sites of arterial wall dissection in the AAD patients. In a separate group, the plasma IL-20, TNF-α and IL-6 concentrations were significantly higher in the AAD patients than in the non-AAD patients. Spearman’s correlation analysis showed that plasma IL-20 was positively correlated with plasma TNF-α and IL-6, D-dimer, C-reaction protein (CRP), creatinine, fasting blood glucose, systolic blood pressure (SBP), and diastolic blood pressure (DBP). Multiple linear regression revealed that IL-20, in addition to IL-6, glucose, CRP and D-dimer, was independently associated with the presence of AAD. Conclusion IL-20 was closely associated with the presence of AAD. IL-20 may contribute to the inflammatory pathogenesis of AAD.

Tumour drug resistance is one of the most urgent issues faced by anti‐tumour therapies. P‐glycoprotein (P‐gp) has been reported to be correlated with drug resistance. In this study, we aimed to study the synergistic effect of fluorouracil (5FU) and Ubenimex (UBE) on drug resistance in lung cancer. In this study, the tumour inhibitory role of 5FU and UBE was assessed in nude mice bearing A549 or A549/ADR. Real‐time polymerase chain reaction, Western blot and immunohistochemical were performed to analyse the mRNA and protein expression of P‐gp. TUNEL assay was used to evaluate the apoptosis of A549/ADR cells under 5FU and UBE treatment. MTT assay was performed to calculate the IC50 value of 5FU and UBE in A549 or A549/ADR. Combined administration of 5FU and UBE significantly inhibited the tumour growth of multidrug‐resistant cell lines A549/ADR in nude mice by down‐regulating the mRNA and protein expression of P‐gp. The apoptosis of A549/ADR was remarkably elevated in nude mice treated with 5FU and UBE. The IC50 value of 5FU and UBE was dramatically declined in A549/ADR cells compared with that of 5FU or UBE alone. Combined treatment of 5FU and UBE remarkably enhanced the apoptosis of A549/ADR cells by enhancing the intracellular accumulation of the drugs. The results of this study demonstrated that UBE combined with fluorouracil attenuated multiple drug resistance and inhibited the expression of P‐gp in lung cancer.

Radiofrequency ablation produces a heat-tolerance effect and increases HIF-1αp, and HSP70 expression is distributed in the lesion, but whether HSP70 mediates HIF-1α SUMOylation in lung cancer cells remains unclear. Mouse lung cancer LLC cells were cultured under hypoxia and randomly assigned into control group, heat tolerance group and HSP70 siRNA group followed by analysis of HSP70 and HIF-1α level by real time PCR and Western blot, association of HIF-1α with SUMO-1 and SUMO-2/3 by immunoprecipitation, SENP-1, Ubc9 and E3 ligase expression. CD4 + T cells were isolated and divided into control group, hyperbaric oxygen group, normal temperature hypoxia group, and high temperature hypoxia group followed by measurement of T17 and Treg cell by flow cytometry, and HIF-1α level. HSP70 and HIF-1α level was increased in heat tolerance group and reduced by HSP70 siRNA. Meanwhile, HSP70 siRNA decreased HSP70 binding to SENP-1, Ubc9, and E3 ligase. Heat tolerance group showed decreased SENP-1 expression, increased Ubc9 and E3 ligase expression. HIF-1 bound to SUMO-1, but not SUMO-2/3. HIF-1α expression was increased in CD4+ T cells in treatment group, with significantly increased CD4+ T cells apoptosis and changes of Treg and Th17 compared to control (P < 0 05). HSP70 can promote the heat tolerance effect of lung cancer cells by promoting SUMO-1 expression of HIF-1α; the heat tolerance effect leads to abnormal cellular immune response, which may affect the therapeutic effect.

Increased inflammation is the key mechanism that mediates sepsis induced cardiac injury. Resolvin D1 (RvD1), a bioactive lipid mediator synthesized from docosahexaenoic acid, can attenuate the severity of many inflammation-related diseases through anti-inflammatory and pro-resolving properties. However, the protective role of RvD1 in sepsis induced cardiac injury remains unclear. Mice were randomly divided into three groups: the control group, LPS group and RvD1 + LPS group. LPS (10 mg/kg, i.p.) was used to establish a sepsis-induced cardiac injury model. RvD1 (5 ug/kg, i.p.) was injected 30 min before LPS injection. RvD1 treatment significantly attenuated the deteriorated cardiac function and cardiac injury induced by LPS, as evidenced by the improved left ventricular ejection fraction, serum levels of cardiac injury markers and severity of cardiomyocyte apoptosis. In addition, RvD1 treatment significantly attenuated the infiltration of pro-inflammatory M1 macrophages and expression of inflammatory cytokines in the heart. Mechanistically, the attenuated activation of NK-κB and MAPK signaling mediated the anti-inflammatory and antiapoptotic effects of RvD1. In addition, LPS-induced infiltration of neutrophils and M1 macrophages in the spleen was significantly attenuated by the RvD1 treatment. Results of the present study suggest that RvD1 protects the heart against LPS-induced injuries by attenuating the local and systemic inflammatory response, highlighting the therapeutic effects of RvD1 in sepsis-induced cardiac injury.

Genetic risk factors are important for the occurrence and prognosis of venous thromboembolism (VTE). The studies of thrombophilia families are important for dissecting the genetic background of the thrombotic disease. We conducted the systematic review of all published family-based studies on VTE genetics across all racial groups through PubMed and Embase prior to 13th April 2020. This systematic review of 287 families (including 225 Caucasian families, 52 East Asian families, and families of other ethnicities) revealed a total of 21 different genes; the five most reported mutated genes were F5 (88/287, 30.7%), SERPINC1 (67/287, 23.3%), PROC (65/287, 22.6%), F2 (40/287, 13.9%) and PROS1 (48/287, 16.7%). For Caucasian families, F5 mutations were most frequently reported at 37.8% (85/225), while PROS1 mutations were most frequently reported, at 40.4% (21/52), for East Asian families (Chinese, Japanese and Korean). Factor V Leiden was reported more frequently in Caucasians than in East Asians. Missense mutations were reported frequently in the SERPINC1, PROC and PROS1 genes. In conclusion, our study found the most likely mutated genes associated with VTE among different ethnic groups and provided indications for VTE genetic testing and research in the future.

Background Fluorogenic thrombin generation (TG) assays are commonly used to determine global coagulation phenotype in plasma. Whole blood (WB)-TG assays reach one step closer to physiology by involving the intrinsic blood cells, but erythrocytes cause variable quenching of the fluorescence signals, hampering its routine application.Objective To develop a new assay for continuous WB-TG measurement.Methods In the new WB-TG assay, the erythrocyte-caused distortion of signal was solved by continuously mixing the sample during the measurement. The assay was validated by evaluating the reproducibility and comparing with the paper-based WB-TG assay. Reconstituted human blood and WB from 119 healthy donors was tested to explore the influences of hematocrit and platelet count on TG.Results This novel WB-TG assay showed good reproducibility while being less affected by contact activation compared with the previous paper-based assay. Reconstitution experiments showed that the lag time of TG was shortened by the addition of platelets but not erythrocytes. Increasing hematocrit strongly augmented the peak thrombin, even in the presence of high platelet counts. The lag time and peak of WB-TG of 119 healthy donors were positively related to erythrocyte count after adjusting for age, sex, and oral contraceptive use with multiple linear regression analyses. The reference range and interindividual variation of WB-TG were determined in the healthy cohort.Conclusions A novel WB-TG assay was developed, which is a straightforward tool to measure the involvement of platelets and erythrocytes in TG and may assist the research of blood cell-associated coagulation disorders.

Resumen Introduccion y objetivos La interleucina 5 (IL-5) es una citocina antiinflamatoria que se ha involucrado en las enfermedades cardiovasculares, incluidos los aneurismas aorticos y la insuficiencia cardiaca. El objetivo de este estudio es investigar el papel de la IL-5 en la enfermedad coronaria (EC) y sus posibles mecanismos. Metodos Se analizo la expresion de la IL-5 en muestras de arterias coronarias humanas de 17 pacientes con EC y donantes fallecidos. Ademas, se determinaron las concentraciones plasmaticas de IL-5, IL-17 e interferon gamma en pacientes con EC usando kits ELISA con muestras de pacientes con dolor toracico (sin EC) como controles. Se separaron las celulas murinas CD4+T helper (Th), y el efecto de la IL-5 en la diferenciacion de Th1, celula T reguladora y Th17 y la cantidad de ARNm de sus citocinas caracteristicas se determinaron mediante citometria de flujo y reaccion en cadena de la polimerasa tras transcripcion inversa respectivamente. Resultados La IL-5 disminuyo significativamente en las placas coronarias de los pacientes con EC comparados con el grupo de donantes fallecidos, y la IL-5 derivo fundamentalmente de los macrofagos de las placas de las arterias coronarias. Ademas, comparados con el grupo sin EC, las concentraciones plasmaticas de IL-5 en el grupo de EC fueron significativamente menores, y la secuencia de mayor a menor fue angina estable, angina inestable e infarto de miocardio. El analisis de regresion linear binaria mostro que la IL-5 se correlaciono independientemente con la aparicion de la EC. Ademas, el tratamiento con IL-5 recombinante de raton disminuyo los valores de Th1 y Th17 y la expresion del ARNm de sus citocinas caracteristicas en lipoproteinas oxidadas de baja densidad tratadas con CD4+Th. Conclusiones Los valores de IL-5 disminuyeron en los pacientes con EC e inhiben la diferenciacion in vitro de Th1 y Th17 inducida por lipoproteinas oxidadas de baja densidad.

Introduction and objectives Interleukin (IL)-5 is an anti-inflammatory cytokine that has been demonstrated to be involved in cardiovascular diseases, including aortic aneurysm and heart failure. This study aimed to investigate the involvement of IL-5 in coronary artery disease (CAD) and the possible mechanisms. Methods We analyzed IL-5 expression in human coronary artery specimens collected from CAD patients and deceased donors. Plasma IL-5, IL-17, and interferon-γ levels in CAD patients were detected using ELISA kits, with samples from chest pain patients (non-CAD) as controls. Mouse CD4+T helper (Th) cells were separated, and the effect of IL-5 on Th1, regulatory T cell and Th17 differentiation and mRNA levels of their characteristic cytokines were detected using flow cytometry and reverse transcription-quantitative polymerase chain reaction, respectively. Results IL-5 was significantly decreased in the coronary plaque of CAD patients compared with the deceased donors group, and IL-5 was mainly derived from macrophages in the coronary artery plaque. Compared with the non-CAD group, plasma IL-5 levels in the CAD groups were significantly lower, and the sequence from high to low was stable angina pectoris, unstable angina pectoris, and acute myocardial infarction. Binary linear regression analysis showed that IL-5 was independently correlated with the occurrence of CAD. Recombinant mouse IL-5 treatment decreased Th1 and Th17 levels and mRNA expression of their characteristic cytokines in oxidized low-density lipoprotein-treated CD4+Th cells. Conclusion IL-5 levels were decreased in CAD patients and inhibited oxidized low-density lipoprotein Th1 and Th17 differentiation in vitro.

Cancer cells have been reported to exhibit high resistance against immune system recognition through various cell intrinsic and extrinsic mechanisms. Considerable challenges have been encountered in monotherapy with chemotherapeutics to attain the desired antitumor efficacy. In this study, a nanodelivery system was designed to incorporate doxorubicin (DOX) and programmed death-ligand 1 (PD-L1) small interfering RNA (siRNA), that is, siPD-L1. DOX and siPD-L1 were formed from a stimuli-responsive polymer with a poly-L-lysine-lipoic acid reduction-sensitive core and a tumor extracellular pH-stimulated shedding polyethylene glycol layer. The codelivery system was stable under physiological pH conditions and demonstrated enhanced cellular uptake at the tumor site. Moreover, the combined treatment of DOX and siPD-L1 exhibited improved antitumor effect in vitro and in vivo compared with either modality alone. The combination of chemotherapy and immunotherapy presented in this work through the codelivery of a chemotherapeutic agent and a gene-silencing agent (siRNA) may provide a new strategy for cancer treatment.

Coronavirus disease 2019 (COVID-19) has caused a global pandemic in just a few months, causing millions infected. Nearly 20% of COVID-19 patients present severe coagulation abnormalities, which may occur in almost all of the severe and critical ill COVID-19 cases. Concomitant venous thromboembolism (VTE), a potential cause of unexplained deaths, has been frequently reported in COVID-19 cases, but its management is still challenging due to the complexity between antithrombotic therapy and coagulation disorders. Based on frontline practical experience and comprehensive literature review, here a panel of experts and physicians from China and Europe developed an evidence and opinion-based consensus on the prophylaxis and management of VTE associated with COVID-19. This statement aims for clinicians treating COVID-19 and provides practical recommendations in detailed situations, for example, how to choose thromboprophylactic measures for patients with diverse severity of disease and bleeding risk, or which kind of anticoagulant should be prescribed. With limited experience on COVID19-associated VTE, this expert consensus statement should be helpful for clinicians worldwide with specific suggestions.

Like most solid tumors, glioblastoma multiforme (GBM) harbors multiple overexpressed and mutated genes that affect several signaling pathways. Suppressing tumor growth of solid tumors like GBM without toxicity may be achieved by small molecules that selectively modulate a collection of targets across different signaling pathways, also known as selective polypharmacology. Phenotypic screening can be an effective method to uncover such compounds, but the lack of approaches to create focused libraries tailored to tumor targets has limited its impact. Here, we create rational libraries for phenotypic screening by structure-based molecular docking chemical libraries to GBM-specific targets identified using the tumor’s RNA sequence and mutation data along with cellular protein–protein interaction data. Screening this enriched library of 47 candidates led to several active compounds, including 1 (IPR-2025), which (i) inhibited cell viability of low-passage patient-derived GBM spheroids with single-digit micromolar IC(50) values that are substantially better than standard-of-care temozolomide, (ii) blocked tube-formation of endothelial cells in Matrigel with submicromolar IC(50) values, and (iii) had no effect on primary hematopoietic CD34(+) progenitor spheroids or astrocyte cell viability. RNA sequencing provided the potential mechanism of action for 1, and mass spectrometry-based thermal proteome profiling confirmed that the compound engages multiple targets. The ability of 1 to inhibit GBM phenotypes without affecting normal cell viability suggests that our screening approach may hold promise for generating lead compounds with selective polypharmacology for the development of treatments of incurable diseases like GBM.

Background and Aims Patients with cirrhosis have a rebalanced hemostasis, often with normal or elevated thrombin-generating (TG) capacity in plasma. Whole blood (WB) TG allows faster determination and, importantly, includes the influence of all circulating blood cells. We aimed to study the TG profile of patients with cirrhosis in WB and in platelet poor plasma.Methods Thrombin-generating capacity in WB and plasma were assessed with a near-patient WB-TG assay and the calibrated automated thrombinography assay, respectively. TG assays were tested in presence and absence of thrombomodulin. Conventional coagulation tests were also performed.Results Thirty-four patients with cirrhosis and twenty-two controls were analyzed. Compared with controls, patients had substantially deranged results in conventional coagulation tests. Comparable WB-TG capacity (endogenous thrombin potential until peak, ETPp) but significantly lower peak thrombin were found in patients, and these results persisted when thrombomodulin was present. TG of the patients was more resistant to thrombomodulin than controls in both WB and plasma, although the inhibitory effect of thrombomodulin was drastically weaker in WB than in plasma. The peak of WB-TG in patients correlated moderately with their hematocrit and platelet count. Significant correlations were found between TG results in WB and plasma.Conclusions The WB-TG assay shows a normal to hypocoagulable state in patients with cirrhosis with a decreased anticoagulant activity of TM compared to plasma-TG. The clinical value of this assay needs further validation.

OBJECTIVES Right ventricular (RV) function is identified as a key determinant of the outcome in patients with pulmonary hypertension (PH). Several studies have assessed the role of peak global longitudinal RV strain in PH patients; however, less emphasis was given to the RV regional longitudinal strain. The aim of this study was to evaluate the regional RV systolic strain in PH patients and investigate the relationship of these parameters with the severity of PH. METHODS RV regional longitudinal peak systolic strain (LPSS) and strain rate (LPSSR) were measured using speckle tracking echocardiography on 100 patients with PH who underwent right heart catheterization, and 29 control subjects. Severe PH was identified by a decreased cardiac index (CI) (

Osteosarcoma (OS) is one of the most common malignant tumors in young adults and has a high distant metastasis rate. The p53 protein, a potent prognostic biomarker for patients with OS, is altered in ~50% of OS cases. p53 was reported to exert its effects through regulating the transcription of microRNAs (miRNAs/miRs) and other genes. In the present study, the expression of miR‑181b, a critical OS oncomiR, was shown to be significantly upregulated whereas p53 expression was downregulated within OS tissues and cells; in tissue samples, miR‑181b and p53 were negatively correlated. p53 inhibited the transcription of miR‑181b via targeting its promoter region, whereas miR‑181b bound the TP53 3'‑untranslated region (UTR) to inhibit p53 expression. miR‑181b silencing considerably increased p53, p21, and epithelial‑Cadherin protein levels but decreased Cyclin D1 protein levels in OS cells. In addition, miR‑181b inhibition reduced OS cell proliferation and invasion. In contrast, p53 knockdown had the opposite effects on these proteins and OS cell proliferation and invasion. Above all, p53 knockdown significantly attenuated the effects of miR‑181b inhibition. Moreover, OS cell xenograft assays further confirmed the roles of the miR‑181b/p53 axis in OS growth. In conclusion, miR‑181b and p53 are negatively regulated by one another and therefore form a negative feedback axis that regulates the proliferation and invasion abilities of OS cells. Targeting miR‑181b to inhibit its abnormal upregulation might be a potent strategy for OS treatment.