TAK-242 protects against oxygen-glucose deprivation and reoxygenation-induced injury in brain microvascular endothelial cells and alters the expression pattern of lncRNAs.

Background: Deep hypothermic circulatory arrest (DHCA) is a technique used during the surgical treatment of aneurysms of the thoracic aorta in adult patients, and complex congenital heart disease in neonates. And brain microvascular endothelial cells (BMECs) are essential components of the cerebrovascular network and participate in maintaining the blood-brain barrier (BBB) and brain function. In our previous study, we found that oxygen-glucose deprivation and reoxygenation (OGD/R) activated Toll-like receptor 4 (TLR4) signaling in BMECs, and induced pyroptosis and inflammation. In this study, we further investigated the potential mechanism of ethyl(6R)-6-[N-(2-Chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate (TAK-242) on BMECs under OGD/R, as in patients with sepsis, the TAK-242 was tested in clinical trials. Methods: To confirm the function of TAK-242 on BMECs under OGD/R, cell viability, inflammatory factors, inflammation-associated pyroptosis, and nuclear factor-κB (NF-κB) signaling were determined using Cell Counting Kit-8 (CCK-8) assay, enzyme-linked immunosorbent assay (ELISA), and western blotting, respectively. To investigate the lncRNAs associated with TLR4 during OGD/R, long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) expression patterns were profiled with RNA deep sequencing. Moreover, to confirm whether lncRNA-encoded short peptides, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used. Results: Relative control group, OGD/R inhibited the cell viability, increased the section of inflammatory factors secretion, including IL-1ß, IL-6, and TNF-α, and promoted the pathways of TLR4/NLRP3/Caspase-1 and TLR4/NF-κB. However, TAK-242 + OGD/R group promoted OGD/R cell viability, decreased OGD/R-induced inflammatory factors secretion, and inhibited the pathways of TLR4/NLRP3/Caspase-1 and TLR4/NF-κB. In addition, AABR07000411.1, AABR070006957.1, and AABR070008256.1 were decreased in OGD/R cells compared with controls, but TAK-242 restored their expression under OGD/R condition. AABR07000473.1, AC130862.4, and LOC10254972.6 were induced by OGD/R, but were suppressed in TAK-242 + OGD/R cells compared with OGD/R. Moreover, AABR07049961.1, AC127076.2, AABR07066020.1, and AABR07025303.1-encoded short peptides were dysregulated in OGD/R cells, and TAK-242 attenuated the dysregulation of AABR07049961.1, AC127076.2, and AABR07066020.1-encoded short peptides. Conclusions: TAK-242 alters the expression pattern of lncRNAs in OGD/R cells, and differently expressed lncRNAs may exert a protective effect against OGD/R injury through a mechanism of competing endogenous RNA (ceRNA) and encoding short peptides. These findings maybe provide a new theory basis for the treatment of DHCA.

Role of exosomal noncoding RNA in esophageal carcinoma.

Esophageal cancer is a common malignant tumor with a high degree of malignancy. Understanding its pathogenesis and identifying early diagnostic biomarkers can significantly improve the prognosis of esophageal cancer patients. Exosomes are small double-membrane vesicles found in various body fluids containing various components (DNA, RNA, and proteins) that mediate intercellular signal communication. Non-coding RNAs are a class of gene transcription products that encode polypeptide functions and are widely detected in exosomes. There is growing evidence that exosomal non-coding RNAs are involved in cancer growth, metastasis and angiogenesis, and can also be used as diagnostic and prognostic markers. This article reviews the recent progress in exosomal non-coding RNAs in esophageal cancer, including research progress, diagnostic value, proliferation, migration, invasion, and drug resistance, provide new ideas for the precise treatment of esophageal cancer.

CircFBXW7 Inhibits Proliferation, Migration, and Invasion of Nonsmall Cell Lung Cancer Cells by Regulating miR-492.

Background: CircFBXW7 has been determined to be involved in various cancers; however, its role in nonsmall cell lung cancer (NSCLC) remains unclear. This study examined the function and potential mechanism of circFBXW7 in NSCLC. Methods: The structure of circFBXW7 was verified via RT-PCR and Sanger sequencing. The expression of circFBXW7 in NSCLC was determined by qRT-PCR. The effect of circFBXW7 overexpression on the proliferation, migration, and invasion of NSCLC cells was examined by CCK-8 and Transwell assays. Furthermore, a circFBXW7-miRNA network was established to explore their interaction. Predicted miRNA was determined by qRT-PCR. Moreover, the miRNA mimics were synthesized, wherein its effect on proliferation, migration, and invasion of NSCLC cells overexpressed circFBXW7 was assessed. Results: The circularity of circFBXW7 was verified. The expression of circFBXW7 was found to be downregulated in NSCLC cells compared with that in normal human lung epithelial BEAS-2B cells. Overexpression of circFBXW7 reduced cell proliferation, migration, and invasion. Furthermore, according to the circFBXW7-miRNA network prediction and qRT-PCR validation, miR-492 was identified to be the target of circFBXW7. The inhibitory effect of circFBXW7 overexpression on cell proliferation, migration, and invasion was reversed by miR-492 mimics. Conclusion: CircFBXW7 is downregulated in NSCLC. CircFBXW7 inhibits NSCLC cells proliferation, migration, and invasion by regulating miR-492.

miR-666-3p Mediates the Protective Effects of Mesenchymal Stem Cell-derived Exosomes Against Oxygen-glucose Deprivation and Reoxygenation- induced Cell Injury in Brain Microvascular Endothelial Cells via Mitogen-activated Protein Kinase Pathway.

BACKGROUND: Previous studies have reported that mesenchymal stem cell (MSC)- derived exosomes can protect primary rat brain microvascular endothelial cells (BMECs) against oxygen-glucose deprivation and reoxygenation (OGD/R)-induced injury. OBJECTIVE: The aim was to identify the key factors mediating the protective effects of MSC-derived exosomes. METHODS: Primary rat BMECs were either pretreated or not pretreated with MSC-derived exosomes before exposure to OGD/R. Naïve cells were used as a control. After performing small RNA deep sequencing, quantitative reverse transcription polymerase chain reaction was performed to validate microRNA (miRNA) expression. The effects of rno-miR-666-3p on cell viability, apoptosis, and inflammation in OGD/R-exposed cells were assessed by performing the Cell Counting Kit 8 assay, flow cytometry, and enzyme-linked immunosorbent assay, respectively. Moreover, the role of rno-miR-666-3p in regulating gene expression in OGD/R-exposed cells was studied using mRNA deep sequencing. Lastly, to evaluate whether mitogen-activated protein kinase 1 (MAPK1) was the target of rno-miR-666-3p, western blotting and the dual-luciferase assay were performed. RESULTS: MSC-derived exosomes altered the miRNA expression patterns in OGD/R-exposed BMECs. In particular, the expression levels of rno-miR-666-3p, rno-miR-92a-2-5p, and rnomiR- 219a-2-3p decreased in OGD/R-exposed cells compared with those in the control; however, MSC-derived exosomes restored the expression levels of these miRNAs under OGD/R conditions. rno-miR-666-3p overexpression enhanced cell viability and alleviated the apoptosis of OGD/R-exposed cells. Moreover, rno-miR-666-3p suppressed OGD/R-induced inflammation. mRNA deep sequencing revealed that rno-miR-666-3p is closely associated with the MAPK signaling pathway. Western blotting and the dual-luciferase assay confirmed that MAPK1 is the target of rnomiR- 666-3p. CONCLUSION: MSC-derived exosomes restore rno-miR-666-3p expression in OGD/R-exposed BMECs. Moreover, this specific miRNA exerts protective effects against OGD/R by suppressing the MAPK signaling pathway.

Peripheral blood inflammation indices are effective predictors of anastomotic leakage in elective esophageal surgery.

BACKGROUND: This study investigated the predictive value of peripheral inflammatory indices, including neutrophil count, lymphocyte count, platelet count, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), in anastomotic leakage during elective esophageal surgery. METHODS: This retrospective study included all patients who underwent esophagectomy for esophageal squamous cell carcinoma from 2016 to 2020 in our institution. The peripheral blood inflammatory indices were obtained on preoperative days 1-7 (PRD 1-7), and postoperative days 1-3 (POD 1-3) and 4-7 (POD 4-7). Univariate, multivariate logistic, and receiver operating characteristic curve analyses were conducted to evaluate the diagnostic value of these peripheral blood inflammatory indices. RESULTS: A total of 198 patients were included in the study, and 25 (13%) patients experienced anastomotic leakage. Multivariate analyses identified diet, neutrophil count, and PLR on POD 1-3, and NLR on POD 4-7 as independent factors associated with anastomotic leakage. Using the receiver operating characteristic curve, the variable with the best area under curve was a neutrophil cutoff count of 4.1 [0.737; 95% CI: 0.639-0.835], with a sensitivity and specificity of 60.0% and 66.5%, respectively. This was followed by an NLR cutoff value of 9.5 on POD 4-7 (0.628; 95% CI: 0.505-0.752) and a cutoff PLR value of 220.1 on POD 1-3 (0.643; 95% CI: 0.536-0.750). Diet showed a poor result on the receiver operating characteristic curve analysis. CONCLUSIONS: Neutrophil count and PLR on POD 1-3 and NLR on POD 4-7 were shown to have predictive value for anastomotic leakage in elective esophageal surgery.

Clinical value of 2019 European League Against Rheumatism/American College of Rheumatology classification criteria in childhood-onset systemic lupus erythematosus / 中华实用儿科临床杂志

Objective:To compare the performance among the American College of Rheumatology (ACR) 1997, the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and the 2019 European League Against Rheumatism (EULAR)/ACR criteria, in a childhood-onset systemic lupus erythematosus(CSLE) cohort.Methods:A medical chart review study was conducted of 182 cases of SLE patients and 163 controls with defined rheumatic diseases in pediatrics department of Renji Hospital, Shanghai Jiaotong University School Medicine, from January 2013 to May 2017, to establish each ACR1997, SLICC2012 and 2019EULAR/ACR criterion.The performance of the three criteria was statistically analyzed.Results:(1) Comparing the patients with SLE and controls, the difference in fever(21.4% vs.8.0%), skin lesions(54.9% vs.31.9%), nonscarring alopecia(3.8% vs.0), renal disorder(41.2% vs.5.5%), neurologic disorder(7.7% vs.1.8%), hematologic disorder [leukopenia(32.4% vs.1.8%), thrombocytopenia(31.9% vs.0)], low complement(83.5% vs.12.9%), anti-nuclear antibody(98.4% vs.23.3%), anti-dsDNA antibody(94.0% vs.8.6%), anti-Sm antibody(19.2% vs.0%), and antiphospholipid antibodies(16.5% vs.3.7%)had statistical significance (all P<0.05). But the difference in oral ulcers, synovitis, serositis and positive Coombs test had no statistical significance (all P>0.05). (2) Sensitivities of ACR1997, SLICC2012 and 2019EULAR/ACR criteria were 67.0%(122/182 cases), 95.6% (174/182 cases)and 97.8% (178/182 cases)( P<0.001), with specificities 99.4%(162/163 cases), 98.2% (160/163 cases)and 94.5%(154/163 cases) ( P=0.016), respectively.In terms of accuracy, the three classifications were 82.3%(284/345 cases), 96.8% (334/345 cases)and 96.2%(332/345 cases), respectively, the difference was statistically significant ( P<0.001). (3) Only 120 cases (65.9%) of patients with SLE met all 3 criteria.Eight cases of SLE patients who only met the 2019EULAR/ACR criteria exhibit high rate of single organ involvement (7 cases). Four cases of SLE patients were missed by the 2019EULAR/ACR, 3 cases of which were antinuclear antibody negative.(4) The SLICC2012 and 2019EULAR/ACR criteria had increased sensitivity for major organ damage than ACR1997.The total score of 2019 EULAR/ACR criteria correlated positively with SLE disease activity ( R2= 0.451, P<0.001). Conclusions:In this SLE population, the 2019EULAR/ACR criteria is more sensitive than ACR1997 and SLICC2012 criteria, allowing earlier classification and recognition of patients with single or major organ damage.Although the specificity is slightly lower than the previous two criteria, it is still worthy of clinical promotion.

Clinical features and factors associated with osteonecrosis in childhood-onset systemic lupus erythematosus / 中华实用儿科临床杂志

Objective@#To analyze the clinical features and factors associated with osteonecrosis in children with systemic lupus erythematosus (SLE).@*Methods@#A retrospective analysis of 15 SLE patients with osteonecrosis in Department of Pediatrics, Renji Hospital Affiliated to School of Medicine of Shanghai Jiaotong University from January 2013 to May 2017 was carried out.Forty-two SLE patients without osteonecrosis were selected as control group.The clinical, laboratory variables and the treatment were compared among SLE patients who were with and without osteonecrosis.@*Results@#(1) Fifteen patients developed osteonecrosis that constituted 8.6% of all the 175 hospitalized SLE patients during the same period.(2) Of 15 patients, 2 patients were male, 13 patients were female, who developed osteonecrosis with an average age of (13.9±2.7) years (range: 10-18 years old). The duration of SLE before the diagnosis of osteonecrosis ranged from 6 days to 141 months, the median was 10 months, and 80.0% (12/15 cases) was diagnosed with osteonecrosis within 2 years of SLE diagnosis.There were 36 joints involved in 15 patients, all of which were detected by magnetic resonance imaging(MRI). The knees were the most commonly involved joints(14/15 cases, 93.3%), followed by hip and ankle joints.(3) Univariate analysis revealed that the level of Triglyceride [(2.080±1.500) mmol/L vs.(1.350±0.945) mmol/L], maximum daily dose of glucocorticoid[(1.25±0.33) mg/kg vs.(1.07±0.22) mg/kg], positive rate of gene associated with glucocorticoid-induced osteonecrosis of femoral head(100.0% vs.54.8%)were significantly higher in SLE with osteonecrosis than those in controls(all P<0.05). While the level of 25(OH)D3[(21.37±11.29) μg/L vs.(31.45±17.73) μg/L] was significantly lower than that of controls(P<0.05). Multiple factor Logistic regression analysis showed that hypertriglyceridemia and daily maximum dose of glucocorticoid were the risk factors for osteonecrosis.@*Conclusions@#Osteonecrosis mostly occurred in children over 10 years old, knee joint involvement is the most common.The high-risk time of osteonecrosis is within 2 years of SLE diagnosis.Hypertriglyceridemia and daily ma-ximum dose of glucocorticoid are risk factors associated with osteonecrosis in children with SLE.

Clinical features and factors associated with osteonecrosis in childhood-onset systemic lupus erythematosus / 中华实用儿科临床杂志

Objective To analyze the clinical features and factors associated with osteonecrosis in children with systemic lupus erythematosus (SLE).Methods A retrospective analysis of 15 SLE patients with osteonecrosis in Department of Pediatrics,Renji Hospital Affiliated to School of Medicine of Shanghai Jiaotong University from January 2013 to May 2017 was carried out.Forty-two SLE patients without osteonecrosis were selected as control group.The clinical,laboratory variables and the treatment were compared among SLE patients who were with and without osteonecrosis.Results (1) Fifteen patients developed osteonecrosis that constituted 8.6％ of all the 175 hospitalized SLE patients during the same period.(2) Of 15 patients,2 patients were male,13 patients were female,who developed osteonecrosis with an average age of (13.9 ± 2.7) years (range:10-18 years old).The duration of SLE before the diagnosis of osteonecrosis ranged from 6 days to 141 months,the median was 10 months,and 80.0％ (12/15 cases) was diagnosed with osteonecrosis within 2 years of SLE diagnosis.There were 36 joints involved in 15 patients,all of which were detected by magnetic resonance imaging(MRI).The knees were the most commonly involved joints(14/15 cases,93.3％),followed by hip and ankle joints.(3) Univariate analysis revealed that the level of Triglyceride [(2.080 ± 1.500) mmol/L vs.(1.350 ± 0.945) mmol/L],maximum daily dose of glucocorticoid [(1.25 ± 0.33) mg/kg vs.(1.07 ± 0.22) mg/kg],positive rate of gene associated with glucocorticoid-induced osteonecrosis of femoral head (100.0％ vs.54.8％) were significantly higher in SLE with osteonecrosis than those in controls (all P ＜ 0.05).While the level of 25 (OH) D3 [(21.37 ± 11.29) μg/L vs.(31.45 ± 17.73) μg/L] was significantly lower than that of controls(P ＜ 0.05).Multiple factor Logistic regression analysis showed that hypertriglyceridemia and daily maximum dose of glucocorticoid were the risk factors for osteonecrosis.Conclusions Osteonecrosis mostly occurred in children over 10 years old,knee joint involvement is the most common.The high-risk time of osteonecrosis is within 2 years of SLE diagnosis.Hypertriglyceridemia and daily ma-ximum dose of glucocorticoid are risk factors associated with osteonecrosis in children with SLE.

Progress of osteonecrosis in children with systemic lupus erythematosus / 国际儿科学杂志

Systemic lupus erythematosus (SLE)isa chronic multisystem autoimmune disease.Osteonecrosis is a common complication of SLE and the main cause of disability.The clinical manifestations of osteonecrosis could be joint pain,difficulty in walking,or asymptomatic.The development of osteonecrosis is related to various factors.In addition to the long-term use of corticosteroids,the typical features of SLE,the administration of immunosuppressives and gene polymorphisms are also the main factors for the development of osteonecrosis in SLE.In order to improve the understanding of osteonecrosis in children with SLE,this article reviews the clinical manifestations,the risk factors and treatment of osteonecrosis in SLE.

Progress of extrapulmonary manifestations of Mycoplasma pneumoniae infection in children / 国际儿科学杂志

Mycoplasma pneumoniae (MP),a type of prokaryotes without cell wall between bacteria and viruses,is one of the most common agents of respiratory tract infection in children.However,it can also cause a wide range of extrapulmonary manifestations in the absence of any pulmonary symptoms.MP infection may present a variety of clinical manifestations,involving cardiovascular,neurological,digestive,hematological,mucocutaneous and other symptoms.This article reviews the progress of extrapulmonary manifestations of MP infection to improve the comprehension for diagnosis.

Efficacy of High-Intensity Atorvastatin for Asian Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Statins have proven cardioprotective effects, but higher doses are accompanied by various concerns and may not lead to superior clinical outcomes in Chinese/Asian populations. OBJECTIVE: We designed a trial to test the efficacy of high-intensity statin therapy for the reduction of periprocedural myocardial infarction (MI) and 1-year major adverse cardiovascular events (MACEs, including cardiovascular death, spontaneous MI, unplanned revascularization) in an Asian population. METHODS: A total of 798 Chinese patients with stable angina or acute coronary syndrome (ACS) were randomized to high-intensity atorvastatin (80 mg/d before percutaneous coronary intervention [PCI] and 40 mg/d thereafter for 1 year, n = 400) or moderate-intensity atorvastatin (20 mg/d for 1 year, n = 398). The primary end point was 1-year incidence of MACEs. RESULT: In patients with stable angina, 1-year MACE rates were not significantly different between moderate- and high-intensity groups (7.6% vs 5.7%, P = 0.53). In contrast, in patients with ACS, the 1-year MACE rate was significantly higher in the moderate- than in the high-intensity atorvastatin group (16.8% vs 10.1%, P = 0.021; adjusted hazard ratio = 1.71, 95% CI = 1.08 to 2.77, P = 0.021). CONCLUSIONS: Whereas stable angina patients derive similar benefit from moderate- and high-intensity atorvastatin therapy over the duration of 1 year after PCI, high-intensity statin therapy is superior in ACS patients.

Application of a fasciocutaneous free flap for treatment of a severe soft tissue injury of the foot and ankle: a case report.

UNLABELLED: The authors report an unusual case wherein a fasciocutaneous free flap from an amputated upper limb was used to repair a severe soft tissue injury of the ipsilateral forefoot and ankle. After amputating the nonviable portions of the forefoot, a residual limb flap from the patient's forearm, pedicled with the brachial artery, was used to cover the lower extremity defect. Three years after the injury, the patient was able to maintain balance and ambulate without assistance on the reconstructed lower extremity. LEVEL OF CLINICAL EVIDENCE: 4.