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Abstract Background The outbreak of COVID-19 has resulted in serious concerns in China and abroad. To investigate clinical features of confirmed and suspected patients with COVID-19 in west China, and to examine differences between severe versus non-severe patients. Methods Patients admitted for COVID-19 between January 21 and February 11 from fifteen hospitals in Sichuan Province, China were included. Experienced clinicians trained with methods abstracted data from medical records using pre-defined, pilot-tested forms. Clinical characteristics between severe and non-severe patients were compared. Results Of the 169 patients included, 147 were laboratory-confirmed, 22 were suspected. For confirmed cases, the most common symptoms from onset to admission were cough (70·7%), fever (70·5%) and sputum (33·3%), and the most common chest CT patterns were patchy or stripes shadowing (78·0%); throughout the course of disease, 19·0% had no fever, and 12·4% had no radiologic abnormality; twelve (8·2%) received mechanical ventilation, four (2·7%) were transferred to ICU, and no death occurred. Compared to non-severe cases, severe ones were more likely to have underlying comorbidities (62·5% vs 26·2%, P = 0·001), to present with cough (92·0% vs 66·4%, P = 0·02), sputum (60·0% vs 27·9%, P = 0·004) and shortness of breath (40·0% vs 8·2%, P

Abstract Background Although microvascular dysfunction is a widespread phenomenon in type 2 diabetes (T2D) and is recognized as a main cause of T2D-aggravated ischemic stroke injury, the underlying mechanisms by which T2D-mediated exacerbation of cerebral damage after ischemic stroke is still largely uncharacterized. Here, we found that methylglyoxal-mediated miR-148a-3p decline can trigger blood-brain barrier dysfunction, thereby exacerbating cerebrovascular injury in diabetic stroke. Methods Using T2D models generated with streptozotocin plus a high-fat diet or db/db mice, and then inducing focal ischemic stroke through middle cerebral artery occlusion and reperfusion (MCAO/R), we established a diabetic stroke mouse model. RNA-sequencing was applied to identify the differentially expressed miRNAs in peri-cerebral infarction of diabetic stroke mice. RT-qPCR confirmed the potential miRNA in the plasma of ischemic stroke patients with or without T2D. Fluorescence in situ hybridization was used to image the localization of the miRNA. Brain pathology was analyzed using magnetic resonance imaging, laser-Doppler flowmetry, and transmission electron microscope in diabetic stroke mice. Immunofluorescence and immunoblotting were performed to elucidate the molecular mechanisms. Results miR-148a-3p level was downregulated in the peri-infarct cortex of stroke mice and this downregulation was even more enhanced in diabetic stroke mice. A similar decrease in miR-148a-3p expression was also confirmed in the plasma of ischemic stroke patients with T2D compared to patients with ischemic stroke only. This miR-148a-3p downregulation intensified the severity of BBB damage, infarct size, and neurological function impairment caused by stroke. Notably, the reduction in miR-148a-3p levels was primarily triggered by methylglyoxal, a toxic byproduct of glucose metabolism commonly associated with T2D. Furthermore, methylglyoxal somewhat replicated the influence of T2D in exacerbating BBB damage and increasing infarct size caused by ischemia. Mechanistically, we found that downregulation of miR-148a-3p de-repressed SMAD2 and activated matrix metalloproteinase 9 signaling pathway, promoting blood-brain barrier impairment, and exacerbating the cerebral ischemic injury. Conclusions Blood-brain barrier damage caused by methylglyoxal-mediated miR-148a-3p downregulation may provide a novel target for the therapeutic intervention for the treatment of stroke patients with diabetes.

Abstract Acute lung injury (ALI) is one of the life-threatening complications of sepsis, and macrophage polarization plays a crucial role in the sepsis-associated ALI. However, the regulatory mechanisms of macrophage polarization in ALI and in the development of inflammation are largely unknown. In this study, we demonstrated that macrophage polarization occurs in sepsis-associated ALI and is accompanied by mitochondrial dysfunction and inflammation, and a decrease of PRDX3 promotes the initiation of macrophage polarization and mitochondrial dysfunction. Mechanistically, PRDX3 overexpression promotes M1 macrophages to differentiate into M2 macrophages, and enhances mitochondrial functional recovery after injury by reducing the level of glycolysis and increasing TCA cycle activity. In conclusion, we identified PRDX3 as a critical hub integrating oxidative stress, inflammation, and metabolic reprogramming in macrophage polarization. The findings illustrate an adaptive mechanism underlying the link between macrophage polarization and sepsis-associated ALI.

Abstract Background Optimal medical therapy (OMT) for uncomplicated type B aortic dissection (uTBAD) provides excellent short-term outcomes during follow up; however, its long-term therapeutic effectiveness is unsatisfactory. This study evaluated the predictive value of systemic immune-inflammation index (SII) for adverse events among patients with acute uTBAD undergoing OMT. Methods We performed a retrospective analysis of a prospectively maintained database between 2013 and 2020. The primary end point in this study was composite outcomes including aortic intervention, all-cause mortality, retrograde type A aortic dissection (rTAAD) and aortic diameter growth > 5 mm. The patients were divided into high and low SII groups according to the optimal cut-off value of SII as determined using the receiver operating characteristic curve. Cox proportional hazards models were constructed to estimate the hazards ratios and identify the predictors of composite outcomes. Results A total of 124 patients with acute uTBAD who underwent OMT were enrolled. One patient died during hospitalisation. At the end of a mean follow-up duration of 51 ± 23 months, 53 (43.1%) patients experienced composite outcomes, 15 patients (12.2%) died, 31 (25.2%) underwent aortic intervention, 21 (17.1%) exhibited diameter growth of > 5 mm, and 2 developed rTAAD. The patients were divided into low SII group (n = 78, 62.9%) and high SII group (n = 46, 37.1%) as per the optimal cut-off SII value of 1449. The incidence of composite outcomes in high SII group was significantly higher than that in low SII (28 [60.9%] vs. 26[33.3%], p 1449 at the time of diagnosis is an independent predictor of OMT failure.

Abstract Background Abdominal aortic aneurysms (AAAs) can result in high mortality upon rupture but are usually undiagnosed because of the absence of symptoms in the early stage. Ultrasound screening is regarded as an impactful way to prevent the AAA-related death but cannot be performed efficiently; therefore, a target population, especially in Asia, for this procedure is lacking. Additionally, although dyslipidaemia and atherosclerosis are associated with AAA. However, it remains undetermined whether the non-high-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol ratio (NHHR) is associated with AAA. Therefore, this study was aimed at examining whether NHHR is associated with AAA. Method A total of 9559 participants who underwent AAA screening at Guangdong Provincial People’s Hospital and through screening in two communities in Dongguan, from June 2019 to June 2021 joined in this screening program. The diagnosis of AAA was confirmed by the ultrasound examination of the abdominal aorta rather than any known or suspected AAA. Clinical and laboratory data of participants were collected. The participants were separated into a normal group and an AAA group according to the abdominal aortic status. To eliminate confounding factors, a propensity score matching (PSM) approach was utilized. The independent relationship between NHHR and AAA was assessed through the utilization of multivariable logistic regression analysis. In addition, internal consistency was evaluated through subgroup analysis, which controlled for significant risk factors. Results Of all the participants, 219 (2.29%) participants were diagnosed with AAA. A significant elevation in NHHR was identified in the AAA group when contrasted with that in the normal group (P

Abstract Background Patients with omphalocele, a midline abdominal wall defect at the umbilical cord base, have a low survival rate. However, the long-term outcomes of fetuses with prenatally diagnosed omphalocele have scarcely been studied. Therefore, we investigated the ultrasonographic features, genetic characteristics, and maternal and fetal outcomes of fetuses with omphalocele and provided a reference for the perinatal management of such cases. Methods A total of 120 pregnant females with fetal omphalocele were diagnosed using prenatal ultrasonography at the Fujian Provincial Maternity and Child Health Hospital from January 2015 to March 2022. Amniotic fluid or cord blood samples were drawn at different gestational weeks for routine karyotype analysis, chromosomal microarray analysis (CMA) detection, and whole exome sequencing (WES). The maternal and fetal outcomes were followed up. Results Among the 120 fetuses, 27 were diagnosed with isolated omphalocele and 93 with nonisolated omphalocele using prenatal ultrasonography. Cardiac anomalies were the most observed cause in 17 fetuses. Routine karyotyping and CMA were performed on 35 patients, and chromosomal abnormalities were observed in five patients, trisomy 18 in three, trisomy 13 in one, and chromosome 8–11 translocation in one patient; all were non-isolated omphalocele cases. Six nonisolated cases had normal CMA results and conventional karyotype tests, and further WES examination revealed one pathogenic variant and two suspected pathogenic variants. Of the 120 fetuses, 112 were successfully followed up. Eighty of the 112 patients requested pregnancy termination. Seven of the cases died in utero. A 72% 1-year survival rate was observed from the successful 25 live births. Conclusion The prognosis of fetuses with nonisolated omphalocele varies greatly, and individualized analysis should be performed to determine fetal retention carefully. Routine karyotyping with CMA testing should be provided for fetuses with omphalocele. WES is an option if karyotype and CMA tests are normal. If the fetal karyotype is normal and no associated abnormalities are observed, fetuses with omphalocele could have a high survival rate, and most will have a good prognosis.

Abstract Background Although the pressure of pulmonary vein increases before pulmonary artery in pulmonary hypertension due to left heart disease (PH-LHD), only a few studies have assessed pulmonary vein smooth muscle cells (PVSMCs) because of the lack of a simple and feasible isolation method. Methods In this study, we introduced a simple method to obtain PVSMCs. Primary pulmonary veins were removed by puncture needle cannula guidance. Then, PVSMCs were cultured by the tissue explant method and purified by the differential adhesion method. The cells were characterized by hematoxylin-eosin (HE) staining, immunohistochemistry, western blotting, and immunofluorescence to observe the morphology and verify the expression of alpha-smooth muscle actin (α-SMA). Results The HE staining results showed that the pulmonary vein media was thinner than the pulmonary artery, the intima and adventitia of the pulmonary vein were removed by this method, and the obtained cells with good activity exhibited morphological characteristics of smooth muscle cells. In addition, higher α-SMA expression was observed in the cells obtained by our isolation method than in the traditional method. Conclusion This study established a simple and feasible method to isolate and culture PVSMCs that might facilitate the cytological experiments for PH-LHD.

Abstract Background Idiopathic pulmonary fibrosis is a chronic progressive, lethal disease in which ectopic lung fibroblast (LF) activation plays a vital part. We have previously shown that alamandine (ALA) exerts anti-fibrosis effects via the MAS-related G-protein coupled receptor D (MrgD). Here, we further investigate how it moderates transforming growth factor β1 (TGF-β1)-induced LF activation by regulating glucose metabolism and mitochondria autophagy (mitophagy). Methods In vitro, we examined glycolysis-related protein hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and lactic acid in cells treated with TGF-β1. The oxygen consumption rate and the extracellular acidification rate were detected using Seahorse assays. Then, mitophagy was evaluated using transmission electron microscopy, mt-Keima, and the co-localization of Parkin and COX IV with LC3 and LAMP1, respectively. The autophagic degradation of HK2 and PFKFB3 was detected by 3MA and bafilomycin A1 and assessed by their co-localization with LC3 and LAMP1, respectively. The effects of ALA on LF activation markers collagen I and α-SMA were detected. The effects of ALA on glucose metabolism, mitophagy, and the activation of LF were also investigated in vivo. Results We found that the ALA/MrgD axis improved TGF-β1-mediated LF activation by repressing glycolysis by downregulating HK2 and PFKFB3 expression. Lactic acid sustained positive feedback between glycolysis and LF activation by maintaining the expression of HK2 and PFKFB3. We also showed that glycolysis enhancement resulted from blocking the autophagic degradation of HK2 and PFKFB3 while upregulated mRNA levels by TGF-β1, while all of those improved by ALA adding. Importantly, we determined that moderation of Parkin/LC3-mediated mitophagy by TGF-β1 also promotes glycolysis but is reversed by ALA. Furthermore, we proved that ALA counteracts the effects of bleomycin on HK2, PFKFB3, LC3, Parkin, and LF activation in vivo. Conclusion In this study, we show that the ALA/MrgD axis prevents TGF-β1-mediated fibroblast activation via regulation of aerobic glycolysis and mitophagy.

Abstract Background Fibronectin glomerulopathy is a rare, familial glomerular disease characterized by mesangial fibronectin deposition in the glomeruli. It is caused by the genetic defect in fibronectin and does not involve the activation of the immune system. Therefore, glomerular immunoglobulin and complement staining is generally absent or weak. Monoclonal gammopathy (MG) is an increasing cause of renal lesion, featured by light chain (κ or λ) and/or heavy chain restriction in glomeruli. Herein, we report a case of fibronectin glomerulopathy presenting as strong IgA and C3 immunostaining in renal biopsy, concomitant with monoclonal gammopathy (monoclonal IgA κ). Case presentation A 44-year-old female was admitted to our hospital for one-month pedal edema. The serum albumin of 19.6 g/l, and the 24-h urine protein was 15.092 g. Immunofixation electrophoresis displayed monoclonal IgA. The renal biopsy showed the mesangial deposits positive for IgA (3+) and C3 (3+) and also for IgG (2+), IgM (2+), and C1q (2+) IF microscopy. In addition, the staining intensity of light chain κ was slight greater than that of light chain λ. The glomerular deposits were strongly positive by FN by immuohistochemistry. The patient was treated with bortezomib, dexamethasone in combination with cyclophosphamide and gained partial remission. Conclusion We present the first FNG patient with strong IgA and C3 immunostaining in the context of monoclonal IgA κ in the circulation. Perhaps FNG, monoclonal IgA κ and immune activation are potentially interplayed and eventually induce renal injuries.

Abstract Background Cigarette smoking (CS) is a strong risk factor for idiopathic pulmonary fibrosis (IPF). It can activate lung fibroblasts (LF) by inducing redox imbalance. We previously showed that clearing mitochondrial reactive oxygen species (mtROS) protects against CS-induced pulmonary fibrosis. However, the precise mechanisms of mtROS in LF need further investigation. Here we focused on mtROS to elucidate how it was regulated by CS in LF and how it contributed to LF activation. Methods We treated cells with 1% cigarette smoking extract (CSE) and examined mtROS level by MitoSOX™ indicator. And the effect of CSE on expression of SIRT1, SOD2, mitochondrial NOX4 (mtNOX4), fatty acid oxidation (FAO)-related protein PPARα and CPT1a and LF activation marker Collagen I and α-SMA were detected. Nile Red staining was performed to show cellular lipid content. Then, lipid droplets, autophagosome and lysosome were marked by Bodipy 493/503, LC3 and LAMP1, respectively. And lipophagy was evaluated by the colocalization of lipid droplets with LC3 and LAMP1. The role of autophagy on lipid metabolism and LF activation were explored. Additionally, the effect of mitochondria-targeted ROS scavenger mitoquinone and SIRT1 activator SRT1720 on mitochondrial oxidative stress, autophagy flux, lipid metabolism and LF activation were investigated in vitro and in vivo. Results We found that CS promoted mtROS production by increasing mtNOX4 and decreasing SOD2. Next, we proved mtROS inhibited the expression of PPARα and CPT1a. It also reduced lipophagy and upregulated cellular lipid content, suggesting lipid metabolism was disturbed by CS. In addition, we showed both insufficient FAO and lipophagy resulted from blocked autophagy flux caused by mtROS. Moreover, we uncovered decreased SIRT1 was responsible for mitochondrial redox imbalance. Furthermore, we proved that both SRT1720 and mitoquinone counteracted the effect of CS on NOX4, SOD2, PPARα and CPT1a in vivo. Conclusions We demonstrated that CS decreased SIRT1 to activate LF through dysregulating lipid metabolism, which was due to increased mtROS and impaired autophagy flux. These events may serve as therapeutic targets for IPF patients.

Abstract Background The high degree of heterogeneity brought great challenges to the diagnosis and treatment of acute myeloid leukemia (AML). Although several different AML prognostic scoring models have been proposed to assess the prognosis of patients, the accuracy still needs to be improved. As important components of the tumor microenvironment, immune cells played important roles in the physiological functions of tumors and had certain research value. Therefore, whether the tumor immune microenvironment (TIME) can be used to assess the prognosis of AML aroused our great interest. Methods The patients’ gene expression profile from 7 GEO databases was normalized after removing the batch effect. TIME cell components were explored through Xcell tools and then hierarchically clustered to establish TIME classification. Subsequently, a prognostic model was established by Lasso-Cox. Multiple GEO databases and the Cancer Genome Atlas dataset were employed to validate the prognostic performance of the model. Receiver operating characteristic (ROC) and the concordance index (C-index) were utilized to assess the prognostic efficacy. Results After analyzing the composition of TIME cells in AML, we found infiltration of ten types of cells with prognostic significance. Then using hierarchical clustering methods, we established a TIME classification system, which clustered all patients into three groups with distinct prognostic characteristics. Using the differential genes between the first and third groups in the TIME classification, we constructed a 121-gene prognostic model. The model successfully divided 1229 patients into the low and high groups which had obvious differences in prognosis. The high group with shorter overall survival had more patients older than 60 years and more poor-risk patients (both P

Abstract Background This study aimed to explore whether the mechanical stretching-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in pulmonary veins occurred through the stretch-activated channel (SAC)/ mitogen-activated protein kinases (MAPKs) pathway. Methods Sixty male Sprague-Dawley rats were divided into three sham groups and seven model groups. A metal clip was placed on the ascending aorta in the model group to establish PH-LHD rat model. The sham group received a similar operation without ascending aorta clamped. On day 25, pulmonary vein was given mechanical stretching with 0 g, 2.0 g tension in two model groups and two sham groups. Another four model groups were given 2.0 g tension after MAPKs pathway inhibitors soaked. The last sham group and model group rats’ pulmonary veins, pulmonary artery and lung tissues were obtained on day 35. Pulmonary vein, pulmonary artery and lung tissue were evaluated by echocardiography, HE staining, immunohistochemistry and western blotting respectively. Results On day 25, left heart weight, right ventricular pressure (35.339 cmH2O) and left atrial pressure (13.657 cmH2O) were increased in model group than those in sham group. Echocardiography showed left heart failure in the PH-LHD group (Interventrieular septum dimension 1.716 mm, left ventricular internal end diastolic dimension 4.888 mm, left ventricular posterior wall thickness in diastole 1.749 mm, ejection fraction 76.917%). But there was no difference in lung tissue between the sham group and PH-LHD group as showed by HE staining. Our results showed that the expression of IL-6 and TNF-α was highly expressed in PH-LHD rats’ serum and pulmonary vein, which were further increased after 2.0 g tension was given and were decreased after SAC/MAPKs inhibitors treatment. Meanwhile, on day 25, immunohistochemistry analysis showed the expression of IL-6 and TNF-α was higher in the PH-LHD rats’ pulmonary vein than that in pulmonary artery and lung tissue, and these expressions in pulmonary vein of PH-LHD group were also higher than that in sham group. However, on day 35, IL-6 and TNF-α were all increased in the pulmonary veins, arteries and lung tissues. Besides, our results uncovered that SAC/MAPKs pathway were upregulating in PH-LHD rats’ pulmonary vein. Conclusion In conclusion, pulmonary vein mechanical stretching exacerbated PH-LHD possibly through the SAC/MAPKs pathway and upregulating expression of IL-6 and TNF-α.

Abstract NG2 is a type I transmembrane glycoprotein known as chondroitin sulfate proteoglycan 4 (CSPG4). In the healthy central nervous system, NG2 is exclusively expressed by oligodendrocyte progenitor cells and by vasculature pericytes. A large body of immunohistochemical studies showed that under pathological conditions such as acute brain injuries and experimental autoimmune encephalomyelitis (EAE), a number of activated microglia were NG2 immuno-positive, suggesting NG2 expression in these cells. Alternative explanations for the microglial NG2 labeling consider the biochemical properties of NG2 or the phagocytic activity of activated microglia. Reportedly, the transmembrane NG2 proteoglycan can be cleaved by a variety of proteases to deposit the NG2 ectodomain into the extracellular matrix. The ectodomain, however, could also stick to the microglial surface. Since microglia are phagocytic cells engulfing debris of dying cells, it is difficult to identify a genuine expression of NG2. Recent studies showing (1) pericytes giving rise to microglial after stroke, and (2) immune cells of NG2-EYFP knock-in mice lacking NG2 expression in an EAE model generated doubts for the de novo expression of NG2 in microglia after acute brain injuries. In the current study, we took advantage of three knock-in mouse lines (NG2-CreERT2, CX3CR1-EGFP and NG2-EYFP) to study NG2 expression indicated by transgenic fluorescent proteins in microglia after tMCAO (transient middle cerebral artery occlusion) or cortical stab wound injury (SWI). We provide strong evidence that NG2-expressing cells, including OPCs and pericytes, did not differentiate into microglia after acute brain injuries, whereas activated microglia did express NG2 in a disease-dependent manner. A subset of microglia continuously activated the NG2 gene at least within the first week after tMCAO, whereas within 3 days after SWI a limited number of microglia at the lesion site transiently expressed NG2. Immunohistochemical studies demonstrated that these microglia with NG2 gene activity also synthesized the NG2 protein, suggesting activated microglia as an additional source of the NG2 proteoglycan after acute brain injuries.

Abstract Background Early radiation-induced temporal lobe injury (RTLI) diagnosis in nasopharyngeal carcinoma (NPC) is clinically challenging, and prediction models of RTLI are lacking. Hence, we aimed to develop radiomic models for early detection of RTLI. Methods We retrospectively included a total of 242 NPC patients who underwent regular follow-up magnetic resonance imaging (MRI) examinations, including contrast-enhanced T1-weighted and T2-weighted imaging. For each MRI sequence, four non-texture and 10,320 texture features were extracted from medial temporal lobe, gray matter, and white matter, respectively. The relief and 0.632 + bootstrap algorithms were applied for initial and subsequent feature selection, respectively. Random forest method was used to construct the prediction model. Three models, 1, 2 and 3, were developed for predicting the results of the last three follow-up MRI scans at different times before RTLI onset, respectively. The area under the curve (AUC) was used to evaluate the performance of models. Results Of the 242 patients, 171 (70.7%) were men, and the mean age of all the patients was 48.5 ± 10.4 years. The median follow-up and latency from radiotherapy until RTLI were 46 and 41 months, respectively. In the testing cohort, models 1, 2, and 3, with 20 texture features derived from the medial temporal lobe, yielded mean AUCs of 0.830 (95% CI: 0.823–0.837), 0.773 (95% CI: 0.763–0.782), and 0.716 (95% CI: 0.699–0.733), respectively. Conclusion The three developed radiomic models can dynamically predict RTLI in advance, enabling early detection and allowing clinicians to take preventive measures to stop or slow down the deterioration of RTLI.

Abstract Background Intravenous chemotherapy (IVC) and intra-arterial chemotherapy (IAC) have become the primary treatments for retinoblastoma; however, some controversy remains over which method is more effective. We conducted a meta-analysis to compare the clinical efficacy of IVC and IAC. Methods We systematically searched literature published on PubMed, Embase, and Cochrane Library up to May 2017. Studies containing either IAC or IVC that reported on efficacy were included. The effects estimate was expressed as a pooled rate with 95% confidence interval (CI), using a fixed-effects or random-effects model. Results Twenty-six studies were identified which included 1541 eyes (IAC: 11 trials, 445 eyes; IVC: 16 trials, 1096 eyes). The mean follow-up times were 49.4 months (range, 13.0–105.3 months) for IVC and 21.7 months (range, 8.8–38.7 months) for IAC. For the International Classification of Intraocular Retinoblastoma (ICRB) grading, the overall success rate was higher with IAC than with IVC (75.7% [95%CI: 65.7%–83.6%] vs. 69.5% [95%CI: 51.9%–82.8%], P