The coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was identified in December 2019 and has subsequently spread worldwide. Currently, there is no effective method to cure COVID‐19. Mesenchymal stromal cells (MSCs) may be able to effectively treat COVID‐19, especially for severe and critical patients. Menstrual blood‐derived MSCs have recently received much attention due to their superior proliferation ability and their lack of ethical problems. Forty‐four patients were enrolled from January to April 2020 in a multicenter, open‐label, nonrandomized, parallel‐controlled exploratory trial. Twenty‐six patients received allogeneic, menstrual blood‐derived MSC therapy, and concomitant medications (experimental group), and 18 patients received only concomitant medications (control group). The experimental group was treated with three infusions totaling 9 × 10 7 MSCs, one infusion every other day. Primary and secondary endpoints related to safety and efficacy were assessed at various time points during the 1‐month period following MSC infusion. Safety was measured using the frequency of treatment‐related adverse events (AEs). Patients in the MSC group showed significantly lower mortality (7.69% died in the experimental group vs 33.33% in the control group; P = .048). There was a significant improvement in dyspnea while undergoing MSC infusion on days 1, 3, and 5. Additionally, SpO 2 was significantly improved following MSC infusion, and chest imaging results were improved in the experimental group in the first month after MSC infusion. The incidence of most AEs did not differ between the groups. MSC‐based therapy may serve as a promising alternative method for treating severe and critical COVID‐19.

ObjectiveTo determine whether gross tumor volume (GTV) and the maximum diameter of resectable cervical cancer at magnetic resonance imaging (MRI) could predict lymph node metastasis (LNM) and lymphovascular space invasion (LVSI).Materials and MethodsA total of 315 consecutive patients with cervical cancer were retrospectively identified. Gross tumor volume and the maximum diameter of tumor were evaluated on MRI. Univariate and multivariate logistic regression analyses were performed to determine whether tumor size could predict LNM and LVSI. Cutoffs of GTV, maximum diameter, and the International Federation of Gynecology and Obstetrics (FIGO) classification of tumor were first investigated in 255 patients (group A) and then validated in an independent cohort of 60 patients (group B) using area under the receiver operating characteristic curve (AUC) analysis for predicting the presence of LNM and LVSI.ResultsUnivariate analysis showed that GTV and the maximum diameter of tumor could predict LNM and LVSI (all P < 0.0001). Multivariate analyses indicated GTV as an independent risk factor of LNM and LVSI (all P < 0.0001). In group A, GTV, the maximum diameter, and the FIGO stage could identify LNM (AUC, 0.813, 0.741, and 0.69, respectively) and LVSI (AUC, 0.806, 0.751, and 0.684, respectively). In group B, GTV, the maximum diameter, and the FIGO stage could help identify LNM (AUC, 0.902, 0.825, and 0.759, respectively) and LVSI (AUC, 0.771, 0.748, and 0.700, respectively).ConclusionsGross tumor volume and the maximum diameter of resectable cervical cancer at MRI demonstrated capability in predicting LNM and LVSI, which were more accurate than FIGO stage.

Abnormal cardiac fibrosis indicates cardiac dysfunction and poor prognosis in myocardial infarction (MI) patients. Many studies have demonstrated that the ubiquitin proteasome system (UPS) plays a significant role in the pathogenesis of fibrosis. Ubiquitin C-terminal hydrolase L1 (UCHL1), a member of the UPS, is related to fibrosis in several heart diseases. However, whether UCHL1 regulates cardiac fibrosis following MI has yet to be determined. In the present study, we found that UCHL1 was dramatically increased in infarct hearts and TGF-β1-stimulated cardiac fibroblasts (CFs). Inhibition of UCHL1 with LDN57444 (LDN) reversed the myocardial fibrosis in post-MI heart and improved cardiac function. Treatment of LDN or UCHL1 siRNA abolished the TGF-β1-induced fibrotic response of CFs. We further identified GRP78 as an interactor of UCHL1 through screening using immunoprecipitationmass spectrometer. We determined that UCHL1 interacted with glucose-regulated protein of 78 kDa (GRP78) and prompted GRP78 degradation via ubiquitination. Furthermore, we found that GRP78 was upregulated after UCHL1 knockdown and that the GRP78 inhibitor HA15 diminished the antifibrotic function exerted by UCHL1 knockdown in CFs stimulated with TGF-β1. This suggests that UCHL1 regulates cardiac fibrosis post MI through interactions with GRP78. This work identifies that the UCHL1-GRP78 axis is involved in cardiac fibrosis after MI. Myocardial infarction (MI) has been the main cause of cardiovascular diseases for centuries and remains a major issue. Although improved survival from acute MI has been observed due to the effectiveness of revascularisation and other therapies, the incidence of heart failure has increased as a consequence of adverse ventricular remodelling 1,2. Among the factors involved in ventricular remodelling, cardiac fibrosis, which results from the disequilibrium of synthesis and deregulation of extracellular matrix, is a pivotal 3,4. In the acute stage, cardiac fibrosis, is a repairing process that protects the infarct heart from rupture; at the subacute and chronic stage, in cases where cardiac fibrosis abnormally persists, it inevitably leads to cardiac dysfunction and ventricular wall stiffness increasing the risk of heart failure 4,5. Thus, it is essential to control levels of cardiac fibrosis. Cardiac fibroblasts (CFs) are central mediators of the cardiac fibrotic response 6. CFs are mainly stimulated by TGFβ-1 following MI and differentiate into activated myofibroblasts which express α-smooth muscle actin (α-SMA). This results in the secretion of a large amount of extracellular matrix, including fibronectin and collagen I (Col1), which is, in part, regulated by the activation of Smad2/3 4,7,8. To date, no studies have fully elucidated how this process is regulated. The ubiquitin proteasome system (UPS), which consists of E1 ubiquitin-activating enzymes, E2 conjugating enzymes and E3 ubiquitin ligases and deubiquitinating enzymes, is responsible for the degradation and stability of the majority of proteins 9,10. Rece...

Both Epac and PKA are effectors of the second messenger cAMP. Utilizing an exchange protein directly activated by cAMP (Epac) pathway-specific cAMP analog (ESCA), we previously reported that Epac signaling regulates proglucagon gene (gcg) expression in the glucagon-like peptide-1 (GLP-1)-producing intestinal endocrine L-cell lines GLUTag and STC-1. We now show that Epac-2 is also expressed in glucagon-producing pancreatic alpha-cell lines, including PKA-deficient InR1-G9 cells, and that ESCA stimulates gcg promoter and mRNA expression in the InR1-G9 cells. Using a dominant-negative Epac-2 expression plasmid (Epac-2DN), we found that Epac inhibition attenuated forskolin-stimulated gcg promoter expression in the PKA-active STC-1 cell line and blocked forskolin-stimulated gcg promoter expression in the InR1-G9 cells. Consistently, ESCA was shown to stimulate glucagon and GLP-1 production in the InR1-G9 and GLUTag cell lines, respectively. Surprisingly, ESCA treatment did not show a notable stimulation of glucagon or GLP-1 secretion from these two cell lines. This is in contrast to its ability to stimulate insulin secretion from the pancreatic INS-1 beta-cell line. Our findings suggest that Epac is selectively involved in peptide hormone secretion in pancreatic and intestinal endocrine cells and that distinct signaling cascades are involved in stimulating production vs. secretion of glucagon and GLP-1 in response to cAMP elevation.

The aim of the study was to determine whether extrapancreatic inflammation on computed tomography (EPIC) is helpful in predicting organ failure in the early phase of acute pancreatitis (AP) as defined by the 2012 revised Atlanta classification.Patients (n = 208) who underwent abdominal computed tomography (CT) within 24 hours after AP onset and admission were retrospectively identified. Each patient's EPIC score, Balthazar score, bedside index of severity in acute pancreatitis (BISAP), and systemic inflammatory response syndrome (SIRS) score were obtained. Primary endpoints were organ failure occurrence and death. Scores were evaluated by receiver operator characteristic (ROC) curve and area under the curve (AUC) analysis.Median age was 45 years (range: 18–83 years). Forty-seven patients (22.6%) developed organ failure, and 5 patients (2.4%) developed infection and underwent surgery. Two patients died. The median EPIC score was 2 (range: 0–7). EPIC score accuracy (AUC = 0.724) in predicting organ failure was similar to that of BISAP (0.773) and SIRS (0.801) scores, whereas Balthazar scoring was not significant (P = .293). An EPIC score of 3 or greater had a sensitivity and specificity of 80.65% and 63.16%, respectively. EPIC scores correlated moderately with organ failure severity (Spearman r = 0.321) and number of failed organs (r = 0.343).The EPIC scoring system can be useful in predicting the occurrence of organ failure, but it does not differentiate severity and number of failed organs in early phase AP.

Objective To investigate the computed tomography (CT) characteristics and diagnostic value of novel coronavirus pneumonia (NCP or COVID-19) in pregnancy. Methods This study included ten pregnant women infected with COVID-19, treated in the Zhongnan Hospital of Wuhan University from January 20, 2020 to February 6, 2020. Clinical and chest CT data were collected and clinical symptoms, laboratory indicators, and CT images were analyzed to explore CT characteristics and diagnostic value for COVID-19 during pregnancy. Results Laboratory examination showed that white blood cell count was normal in nine patients, and slightly higher in one patient (10.23 × 109). The lymphocyte ratio decreased in two patients by 12% and 14%, respectively. The levels of C-reactive protein was elevated in seven patients (range, 21.16-60.3 mg/L) and the levels of D-dimer was increased in eight patients (range, 507-2141 ng/mL). Six patients had low levels of total protein (range, 35.3-56.5 mg/ L). Two patients showed small patchy ground glass opacity (GGO) involving single lung, while eight patients showed multilobe GGO in both the lungs, with partial consolidation. Peripheral and non-peripheral lesion distributions were seen in ten (100%) and four (40%) patients, respectively. There were four patients who had signs of intra-bronchial air-bronchogram, six patients had small bilateral pleural effusions, while none had lymphadenopathy. Dynamic observations were performed in four patients after COVID-19 treatment. Among these four patients, one patient showed normal on the initial examination, and new lesions were observed after 3 days; 1 patient showed progression after 7 days of treatment, with expansion of the lesion area; and the other 2 patients showed improvement after 14 days of

Purpose: To determine whether dynamic contrastenhanced magnetic resonance imaging (DCE-MRI) could monitor progression of liver fibrosis in a piglet model, and which DCE-MRI parameter is most accurate for staging this disease. Materials and Methods:Sixteen piglets were prospectively used to model liver fibrosis and underwent liver DCE-MRI followed by biopsy on the 0, 5th, 9th, 16th, and 21st weekends after modeling of fibrosis. Time of peak (TOP), time to peak (TTP), positive enhancement integral (PEI), maximum slope of increase (MSI), and maximum slope of decrease (MSD) were measured and statistically analyzed for the monitoring and staging.Results: As fibrosis progresses, TOP and TTP tended to increase, whereas MSI, MSD, and PEI tended to decrease (all P < 0.05). TOP, TTP, and MSI could discriminate fibrosis stage 0 from 1-4, 0-1 from 2-4, 0-2 from 3-4, and 0-3 from 4; PEI could distinguish the above-mentioned stages except 0-3 from 4; and MSD could distinguish stage 0-3 from 4, and 0 from 1-4 (all P < 0.05). For predicting stage !1, !2, and !3, the area under receiver operating characteristic curve (AUC) of MSI was largest among all parameters; for stage 4 AUC of TTP was largest.Conclusion: DCE-MRI has the potential to dynamically stage progression of liver fibrosis.

• Radiation dose is a key concern with the increased using cerebral CT perfusion. Cerebral CT perfusion of 70 kV reduces radiation dose without compromising image quality. • A 70-kV protocol could be used for cerebral CT perfusion.