Exosomal HMGA2 protein from EBV-positive NPC cells destroys vascular endothelial barriers and induces endothelial-to-mesenchymal transition to promote metastasis.

Increased vascular permeability facilitates metastasis. Cancer-secreted exosomes are emerging mediators of cancer-host crosstalk. Epstein-Barr virus (EBV), identified as the first human tumor-associated virus, plays a crucial role in metastatic tumors, especially in nasopharyngeal carcinoma (NPC). To date, whether and how exosomes from EBV-infected NPC cells affect vascular permeability remains unclear. Here, we show that exosomes from EBV-positive NPC cells, but not exosomes from EBV-negative NPC cells, destroy endothelial cell tight junction (TJ) proteins, which are natural barriers against metastasis, and promote endothelial-to-mesenchymal transition (EndMT) in endothelial cells. Proteomic analysis revealed that the level of HMGA2 protein was higher in exosomes derived from EBV-positive NPC cells compared with that in exosomes derived from EBV-negative NPC cells. Depletion of HMGA2 in exosomes derived from EBV-positive NPC cells attenuates endothelial cell dysfunction and tumor cell metastasis. In contrast, exosomes from HMGA2 overexpressing EBV-negative NPC cells promoted these processes. Furthermore, we showed that HMGA2 upregulates the expression of Snail, which contributes to TJ proteins reduction and EndMT in endothelial cells. Moreover, the level of HMGA2 in circulating exosomes is significantly higher in NPC patients with metastasis than in those without metastasis and healthy negative controls, and the level of HMGA2 in tumor cells is associated with TJ and EndMT protein expression in endothelial cells. Collectively, our findings suggest exosomal HMGA2 from EBV-positive NPC cells promotes tumor metastasis by targeting multiple endothelial TJ and promoting EndMT, which highlights secreted HMGA2 as a potential therapeutic target and a predictive marker for NPC metastasis.

Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma.

Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis. IMPLICATIONS: This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.

3- to 24-month Follow-up on COVID-19 with Pulmonary Tuberculosis Survivors after Discharge: Results from a Prospective, Multicenter Study.

Objective: Coronavirus disease 2019 (COVID-19) and tuberculosis (TB) are major public health and social issues worldwide. The long-term follow-up of COVID-19 with pulmonary TB (PTB) survivors after discharge is unclear. This study aimed to comprehensively describe clinical outcomes, including sequela and recurrence at 3, 12, and 24 months after discharge, among COVID-19 with PTB survivors. Methods: From January 22, 2020 to May 6, 2022, with a follow-up by August 26, 2022, a prospective, multicenter follow-up study was conducted on COVID-19 with PTB survivors after discharge in 13 hospitals from four provinces in China. Clinical outcomes, including sequela, recurrence of COVID-19, and PTB survivors, were collected via telephone and face-to-face interviews at 3, 12, and 24 months after discharge. Results: Thirty-two COVID-19 with PTB survivors were included. The median age was 52 (45, 59) years, and 23 (71.9%) were men. Among them, nearly two-thirds (62.5%) of the survivors were moderate, three (9.4%) were severe, and more than half (59.4%) had at least one comorbidity (PTB excluded). The proportion of COVID-19 survivors with at least one sequela symptom decreased from 40.6% at 3 months to 15.8% at 24 months, with anxiety having a higher proportion over a follow-up. Cough and amnesia recovered at the 12-month follow-up, while anxiety, fatigue, and trouble sleeping remained after 24 months. Additionally, one (3.1%) case presented two recurrences of PTB and no re-positive COVID-19 during the follow-up period. Conclusion: The proportion of long symptoms in COVID-19 with PTB survivors decreased over time, while nearly one in six still experience persistent symptoms with a higher proportion of anxiety. The recurrence of PTB and the psychological support of COVID-19 with PTB after discharge require more attention.

Clinical characteristics and treatment outcome of COVID-19 patients with stroke in China: A multicenter retrospective study.

OBJECTIVE: Previous studies mainly reported the clinical characteristics of novel coronavirus 2019 (COVID-19) infections, but the research on clinical characteristics and treatment outcomes of COVID-19 patients with stroke is still rare. METHODS: A multi-center retrospective study was conducted at 11 hospitals in 4 provinces of China, and COVID-19 patients with stroke were enrolled from February 24 to May 4, 2020. We analyzed epidemiological, demographic, and clinical characteristics of cases as well as the laboratory test results, treatment regimens and outcomes, and the clinical characteristics and therapeutic outcomes were compared between severe and nonsevere patients, and by age group, respectively. RESULTS: A total of 27 patients [mean age: 66.41 (SD 12.1) years] were enrolled. Among them, 9 (33.3%) were severe patients and 18 (66.7%) were nonsevere patients; 17 (63.0%) were female; 19 (70.4%) were aged 60 years and above. The most common symptoms were fever [19 (70.4%)], fatigue [12 (44.4%)] and cough [11 (40.7%)], respectively. Abnormal laboratory findings of COVID-19 patients with stroke included high levels of C-reactive protein [19 (73.1%)], D-dimer [14 (58.3%)], blood glucose [14 (53.8%)], fibrinogen [13 (50.0%)], and decreased lymphocytes [12 (44.4%)]. Comparing to nonsevere cases with stroke, severe patients with stroke were likely to be older, susceptible to receiving oxygen inhalation, and had more complications (p < 0.05). In addition, there were significant differences in lymphocytes, neutrophils, lactate dehydrogenase, C-reactive protein, creatine kinase between the severe cases and nonsevere cases (p < 0.05). The older patients had a decreased platelet count and elevated fibrinogen, compared with the younger (p < 0.05). All patients (100%) received antiviral treatment, 12 (44.4%) received antibiotics treatment, 26 (96.3%) received Traditional Chinese Medicine (Lung cleansing & detoxifying decoction), and oxygen inhalation was in 18 (66.7%). The median duration of hospitalization was 16 days. By May 4, 2020, a total of 26 (96.3%) patients were cured and discharged, and 1 (3.7%) patients died. CONCLUSION: COVID-19 patients with stroke had poor indicators of coagulation system, and severe and older patients might have a higher risk of complications and unfavorable coagulation system. However, the overall treatment outcome is favorable.

Mammalian Metallothionein-2A and Oxidative Stress.

Mammalian metallothionein-2A (MT2A) has received considerable attention in recent years due to its crucial pathophysiological role in anti-oxidant, anti-apoptosis, detoxification and anti-inflammation. For many years, most studies evaluating the effects of MT2A have focused on reactive oxygen species (ROS), as second messengers that lead to oxidative stress injury of cells and tissues. Recent studies have highlighted that oxidative stress could activate mitogen-activated protein kinases (MAPKs), and MT2A, as a mediator of MAPKs, to regulate the pathogenesis of various diseases. However, the molecule mechanism of MT2A remains elusive. A deeper understanding of the functional, biochemical and molecular characteristics of MT2A would be identified, in order to bring new opportunities for oxidative stress therapy.

Interposed abdominal compression-cardiopulmonary resuscitation after cardiac surgery.

OBJECTIVES: The management of cardiac arrest after cardiac surgery differs from the management of cardiac arrest under other circumstances. In other studies, interposed abdominal compression-cardiopulmonary resuscitation (IAC-CPR) resulted in a better outcome compared with conventional CPR. The aim of the present study was to determine the feasibility, safety and efficacy of IAC-CPR compared with conventional CPR in patients with cardiac arrest after cardiac surgery. METHODS: Data on all cardiac surgical patients who suffered a sudden cardiac arrest during the first 24 h after surgery were collected prospectively. Cardiac arrest was defined as the cessation of cardiac mechanical activity with the absence of a palpable central pulse, apnoea and unresponsiveness, including ventricular fibrillation, asystole and pulseless electrical activity. Forty patients were randomized to either conventional CPR (n = 21) or IAC-CPR (n = 19). IAC-CPR was initially performed by compressing the abdomen midway between the xiphoid and the umbilicus during the relaxation phase of chest compression. If spontaneous circulation was not restored after 10-15 min, the surgical team would immediately proceed to resternotomy. The endpoints of the study were safety, return of spontaneous circulation (ROSC) >5 min, survival to hospital discharge and survival for 6 months. RESULTS: With IAC-CPR, there were more patients in terms of ROSC, survival to hospital discharge, survival for 6 months and fewer CPR-related injuries compared with patients who underwent conventional CPR. CONCLUSIONS: IAC-CPR is feasible and safe and may be advantageous in cases of cardiac arrest after cardiac surgery.

Pigment epithelium-derived factor promotes Fas-induced cardiomyocyte apoptosis via its receptor phospholipase A2.

AIMS: Cardiovascular diseases cause significant morbidity and mortality worldwide. Recently, our research team demonstrated that a multifunctional cytokine, pigment epithelium-derived factor (PEDF), plays a critical role in regulating myocardial infarction. However, few researchers have studied the molecular mechanisms by which PEDF and its receptors influence the pathophysiology of cardiovascular disease. We tested the hypothesis that PEDF affects cardiomyocyte apoptosis under hypoxic conditions and determined the role that its receptors phospholipase A2 (PLA2) and laminin receptor play in this process. MAIN METHODS: Cardiomyocytes were isolated from neonatal mice and treated with PEDF under normoxic and hypoxic conditions; then, apoptosis was assessed using Annexin V/PI staining and flow cytometry. Western blotting and immunofluorescence staining were used to detect PEDF receptor expression, and siRNA knockdown of PEDF receptors was performed to determine which receptor was involved in mediating cardiomyocyte apoptosis. KEY FINDINGS: Our results demonstrated that PEDF increased cardiomyocyte apoptosis during hypoxia via Fas and that PEDF receptors were expressed on cardiomyocyte cell membranes. Furthermore, siRNA experiments indicated that the PEDF receptor PLA2 was responsible for inducing cardiomyocyte apoptosis via the Fas pathway. SIGNIFICANCE: PEDF promoted Fas-induced cardiomyocyte apoptosis via its receptor PLA2.

Expression of ADAM-15 in rat myocardial infarction.

A disintegrin and metalloprotease-15 (ADAM-15) is a potential novel regulator of inflammatory response and tissue remodelling, which is thought to have the ability to attenuate the cardiac function resulting from myocardial infarction (MI). Therefore, the aim of our study was to investigate the expression of ADAM-15 in rat MI. Wistar rats were subjected to MI by ligation of the left anterior descending coronary artery. Euthanasia was performed at 1, 3, 7 and 14 days following MI. The mRNA and protein expression levels of ADAM-15 were detected respectively by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. The localization of ADAM-15 protein was observed by immunohistochemistry. Compared with sham-MI, the expression of ADAM-15 in MI increased at day 1, reached to maximum at day 3, decreased at day 7 and day 14 gradually. In addition, we also found that the localization of ADAM-15 was mainly at cardiac myocytes in the border area of MI and some macrophages in the border and infarcted areas. This study revealed a significant difference of ADAM-15 expression in rat MI and indicated that ADAM-15 maybe one of the important factors involved in inflammatory response and cardiac remodelling of rat MI.