Proton pump inhibitors stabilize the expression of PD-L1 on cell membrane depending on the phosphorylation of GSK3ß.

BACKGROUND: Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD-L1 translocation in various tumor cells. METHODS: C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD-L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD-L1-related pathways after being treated with PPIs. The related gene expression is performed by qRT-PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD-L1 in the tissue samples by immunohistochemistry. RESULTS: We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD-L1 on cell membrane at clinically relevant concentrations. Furthermore, pre-treatment with PPIs appeared to synergize the efficiency of anti-PD-L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD-L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3ß, then leading to PD-L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD-L1 was negated following GSK3ß knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD-L1 expression in esophageal cancer patients. CONCLUSION: We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD-L1 by inducing GSK3ß phosphorylation and facilitate primary tumor progression and metastasis.

Risk factor analysis and nomogram construction in patients with distant metastatic prostate cancer at different PSA levels: a study based on the SEER database.

OBJECTIVE: Prostate cancer (PCa) is the most common malignant tumor in the male genitourinary system. Once PCa has metastasized, it is very difficult to cure. The purpose of this study was to investigate the prognostic risk factor analysis of patients with different prostate-specific antigen (PSA) levels in distant metastatic PCa. At the same time, we construct effective models for predicting the survival rate of prostate cancer patients. PATIENTS AND METHODS: Data on prostate cancer patients with the presence of distant metastases were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. PCa patients with distant metastases were categorized into two groups based on PSA levels, one with PSA <20 ng/mL and the other with PSA ≥20 ng/mL. Univariate and multivariate COX regression analyses were used to identify independent factors affecting the prognosis of the patients. A nomogram was constructed using the independent prognostic factors, and the results were evaluated using calibration curves, timeROC curves, and Kaplan-Meier curves. RESULTS: In the PSA <20 ng/mL group, there were a total of 1,832 patients. COX regression analysis showed that age, marital status, N stage, grade, Gleason score, and medical household income inflation were independent prognostic factors for overall survival (OS) in patients. In addition, we found that age, marital status, N stage, bone metastasis, grade, and Gleason score were independent prognostic factors for cancer-specific survival (CSS) in patients. In the PSA ≥20 ng/mL group, there were a total of 5,314 patients. It was found that age, ethnicity, marital status, bone metastasis, first malignant primary indicator, grade, Gleason score, and medical household income inflation were patients' independent prognostic factors for OS. For CSS, we found that age, ethnicity, marital status, T stage, radiotherapy, bone metastasis, Gleason score, and Median household income inflation were independent prognostic factors. Constructing a nomogram can accurately predict the prognosis of this group of patients. CONCLUSIONS: We found different independent prognostic factors for different PSA levels in patients with distant metastatic PCa. A new nomogram was constructed to predict OS and CSS in patients, which helps in clinical-assisted decision-making.

Prognostic significance of serum cystatin C in acute brainstem infarctions patients.

OBJECTIVES: Some studies show that high circulating cystatin C (CysC) may predict cardiovascular events and death after ischemic stroke onset. However, the association between serum CysC and outcome in ischemic stroke patients remains contradictory. We sought to assess the association between a specific stroke subgroup, brainstem infarction (BSI) and serum CysC. MATERIALS AND METHODS: A total of 324 acute BSI patients were included in the study. Serum CysC was used to calculate estimated glomerular filtration rate (eGFRCysC) at baseline. Modified Rankin scale score ((mRS) ≥3) six months after acute BSI indicates poor functional outcome. Patients were categorized into two groups according to mRS and eGFRCysC. Logistic regression analyses were performed to determine independent risk factors. RESULTS: Lower eGFRCysC was associated with hemoglobin A1c (HbA1c). This risk remained statistically significant after controlling for age, hypertension, initial National Institutes of Health Stroke Scale (NIHSS) score, HbA1c, fibrinogen and homocysteine. The serum eGFRCysC levels were significantly lower in the poor functional outcome group than the good functional outcome group (P<0.001). Multivariate logistic regression analyses showed that eGFRCysC level was significantly lower in the poor outcome group after adjusting for age, previous infarctions, initial NIHSS score, and HbA1c. CONCLUSIONS: Lower eGFRCysC levels were strongly associated with poor functional outcome of acute BSI patients with a higher HbA1c level. Lower eGFRCysC may be a more helpful serologic biomarker for the prediction of prognosis in BSI.

A comprehensive analysis of essential meiotic endonuclease 1 to prognosis and immune infiltration in kidney renal clear cell carcinoma.

OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer, and its molecular pathogenesis is unclear. In this study, we investigated the prognostic value of essential meiotic endonuclease 1 (EME1) in kidney renal clear cell carcinoma (KIRC). MATERIALS AND METHODS: We downloaded the RNA-Seq expression of 526 KIRC tissues and 72 normal tissues from the TCGA database and the corresponding clinical data. The gene expression profiles associated with four clear cell renal cell carcinomas were downloaded from the GEO database for analysis. The expression of EME1 in clear renal cell carcinoma and its correlation with the clinical baseline data were analyzed. Kaplan-Meier survival curve analysis was performed to assess the relationship between EME1 and patient survival. Enrichment analysis was performed to elucidate the possible functions of EME1. We also analyzed the relationship between the EME1 expression and immune infiltration through TIMER2.0 and TISIDB online databases as well as the relationship between EME1 and common immune checkpoints. RESULTS: EME1 was identified as a risk factor for overall survival in clear cell renal cell carcinoma with a hazard ratio of 3.201 (95% confidence interval: 2.430-4.215; p < 0.001). EME1 was highly expressed in KIRC compared to that in normal tissues (p < 0.001) and in the worse TNM stages and late stages (stage 3/4) (p < 0.001). High EME1 expression was strongly associated with the advanced T stage (p = 0.003), advanced N stage (p = 0.002), and advanced M stage (p = 0.006). Research data on KIRC were simultaneously collected and analyzed from the GEO database, including GSE40435, GSE53000, GSE68417, and GSE53757. EME1 predicted the survival status in KIRC patients (AUC = 0.62). We further established a nomogram including the correlation between the high and low EME1 expression, and EME1 was found to contribute to the prediction of the probability of patient survival with a c-index = 0.796. Kaplan-Meier analysis revealed a lower likelihood of survival with a high EME1 expression (p < 0.001). In addition, further bioinformatics analysis suggested that EME1 may be associated with the extent of immune infiltration in KIRC. CONCLUSIONS: An increased expression of EME1 in KIRC is thus associated with advanced clinicopathological features, possibly acting as a potential biomarker of poor prognosis in KIRC.

[Clinical effect of the giant deep inferior epigastric artery paraumbilical perforator flap in repairing the circular high-voltage electric burn wounds on the wrist].

Objective: To investigate the clinical effect of the giant deep inferior epigastric artery paraumbilical perforator flap in repairing the circular high-voltage electric burn wounds on the wrist. Methods: A retrospective observational study method was used. From September 2016 to October 2021, thirteen male patients (aged 20-43 years) with annular high voltage (10-100 kV) electrical burns on the wrist were admitted to the Beijing Jishuitan Hospital. At the early stage after injury, the patient's wrist was subjected to incision, tension reduction and debridement, with the wound area after debridement being 27 cm×16 cm-32 cm×19 cm; in 12 patients with vascular injury, the radial or ulnar artery was reconstructed by great saphenous vein transplantation, with the length of 15-25 cm; the wrist wound was repaired by free transplantation of the deep inferior epigastric artery paraumbilical perforator flap (if the wound was giant, the lower abdominal flap carrying other perforators was used), with the area of 30 cm×19 cm-35 cm×20 cm. The donor site was repaired by direct suture+skin grafting or relay flap transplantation. After surgery, the survival of flap in recipient area, as well as survival of the skin or flap in donor site were observed. During follow-up, the appearances of the flap in recipient area and the recovery of hand function, as well as the healing of donor site, occurrence of abdominal wall hernia, and scar in skin graft area were observed. Results: After surgery, all the 13 patients' paraumbilical perforator flaps survived. Among them, 3 patients had subcutaneous fat necrosis at the distal end of the wrist flap, and the wound had mild infection, which healed after re-expansion and dressing change. All the skin grafts in the donor site of 10 patients survived, and the flaps in the donor site of 3 patients survived well. The patients were followed up for 6 months to 3 years. The flaps in recipient area were in good shape, 8 cases had partial recovery of hand function, and 5 cases had loss of finger flexion function; the donor site of abdominal flap healed well with no abdominal hernia occurred, and the skin graft site had no obvious scar hyperplasia and was soft in texture. Conclusions: Early vascular reconstruction after injury, together with free transplantation of the giant deep inferior epigastric artery paraumbilical perforator flap are effective in repairing circular high-voltage electrical burn wounds on the wrist.

Evolving roles of CD38 metabolism in solid tumour microenvironment.

Given that plenty of clinical findings and reviews have already explained in detail on the progression of CD38 in multiple myeloma and haematological system tumours, here we no longer give unnecessary discussion on the above progression. Though therapeutic antibodies have been regarded as a greatest breakthrough in multiple myeloma immunotherapies due to the durable anti-tumour responses in the clinic, but the role of CD38 in the immunologic regulation and evasion of non-hematopoietic solid tumours are just initiated and controversial. Therefore, we will focus on the bio-function of CD38 enzymatic substrates or metabolites in the variety of non-hematopoietic malignancies and the potential therapeutic value of targeting the CD38-NAD+ or CD38-cADPR/ADPR signal axis. Though limited, we review some ongoing researches and clinical trials on therapeutic approaches in solid tumour as well.

Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion.

Exhausted CD8+ T cells with limited effector functions and high expression of multiple co-inhibitory receptors are one of the main barriers hindering antitumor immunity. The NADase CD38 has received considerable attention as a biomarker of CD8+ T cell exhaustion, but it remains unclear whether the increased CD38 directly promotes T cell dysfunctionality. Here, we surprisingly found that although Cd38 deficiency partially reverses NAD+ degradation and T cell dysfunction in vitro, the terminal exhausted differentiation of adoptively transferred CD8+ T cells in tumor is not impacted by either deficiency or overexpression of CD38. Monitoring the dynamic NAD+ levels shows that NAD+ levels are comparable between tumor infiltrated WT and Cd38 -/- OT-1 cells. Therefore, our results suggest that decreased NAD+ are correlated with T cell dysfunction, but deficiency of CD38 is not enough for rescuing NAD+ in tumor infiltrated CD8+ T cells and fails to increase the efficacy of antitumor T cell therapy.

Multiple SARS-CoV-2 Variants Exhibit Variable Target Cell Infectivity and Ability to Evade Antibody Neutralization.

The continuous emergence of SARS-coronavirus 2 (SARS-CoV-2) variants, especially the variants of concern (VOC), exacerbated the impact of the coronavirus disease 2019 (COVID-19) pandemic. As the key of viral entry into host cells, the spike (S) protein is the major target of therapeutic monoclonal antibodies (mAbs) and polyclonal antibodies elicited by infection or vaccination. However, the mutations of S protein in variants may change the infectivity and antigenicity of SARS-CoV-2, leading to the immune escape from those neutralizing antibodies. To characterize the mutations of S protein in newly emerging variants, the proteolytic property and binding affinity with receptor were assessed, and the vesicular stomatitis virus (VSV)-based pseudovirus system was used to assess the infectivity and immune escape. We found that some SARS-CoV-2 variants have changed significantly in viral infectivity; especially, B.1.617.2 is more likely to infect less susceptible cells than D614G, and the virus infection process can be completed in a shorter time. In addition, neutralizing mAbs and vaccinated sera partially or completely failed to inhibit host cell entry mediated by the S protein of certain SARS-CoV-2 variants. However, SARS-CoV-2 variant S protein-mediated viral infection can still be blocked by protease inhibitors and endocytosis inhibitors. This work provides a deeper understanding of the rise and evolution of SARS-CoV-2 variants and their immune evasion.

Unidirectional single-mode lasing realization and temperature-induced mode switching in asymmetric GaN coupled cavities.

Effective lasing mode control and unidirectional coupling of semiconductor microlasers are vital to boost their applications in optical interconnects, on-chip communication, and bio-sensors. In this study, symmetric and asymmetric GaN floating microdisks and coupled cavities are designed based on the Vernier effect and then fabricated via electron beam lithography, dry-etching of GaN, and isotropic wet-etching of silicon (Si) support. The lasing properties, including model number, threshold, radiation direction, and mode switching method, are studied. Compared to its symmetrical structure, both experimental and simulated optical field distributions indicate that the lasing outgoing direction can be controlled with a vertebral angle on the disk. The whispering gallery mode (WGM) lasing of the structures, with a quasi-single-mode lasing at 374.36 nm, a dual-mode lasing at 372.36 nm, and 373.64 nm at coupled cavities, are obtained statically. More interestingly, a switching between dual-mode and single-mode can be achieved dynamically via a thermal-induced mode shifting.

Corrigendum: Characterization of SARS-CoV-2 Variants N501Y.V1 and N501Y.V2 Spike on Viral Infectivity.

[This corrects the article DOI: 10.3389/fcimb.2021.720357.].

Characterization of SARS-CoV-2 Variants N501Y.V1 and N501Y.V2 Spike on Viral Infectivity.

SARS-coronavirus 2 (SARS-CoV-2), pathogen of coronavirus disease 2019 (COVID-19), is constantly evolving to adapt to the host and evade antiviral immunity. The newly emerging variants N501Y.V1 (B.1.1.7) and N501Y.V2 (B.1.351), first reported in the United Kingdom and South Africa respectively, raised concerns due to the unusually rapid global spread. The mutations in spike (S) protein may contribute to the rapid spread of these variants. Here, with a vesicular stomatitis virus (VSV)-based pseudotype system, we demonstrated that the pseudovirus bearing N501Y.V2 S protein has higher infection efficiency than pseudovirus with wildtype (WT) and D614G S protein. Moreover, pseudovirus with N501Y.V1 or N501Y.V2 S protein has better thermal stability than WT and D614G, suggesting these mutations of variants may increase the stability of SARS-CoV-2 S protein and virion. However, the pseudovirus bearing N501Y.V1 or N501Y.V2 S protein has similar sensitivity to inhibitors of protease and endocytosis with WT and D614G. These findings could be of value in preventing the spread of virus and developing drugs for emerging SARS-CoV-2 variants.

[Application strategy and clinical effects of paraumbilical perforator flap with inferior epigastric vessels in repairing destructive wounds].

Objective: To explore the application strategy and clinical effects of paraumbilical perforator flap with inferior epigastric vessels in repairing various destructive wounds. Methods: The retrospective observational study method was applied. From January 2015 to December 2020, 28 patients (21 males and 7 females, aged 25 to 66 years) with destructive wounds in various body parts were admitted to Beijing Jishuitan Hospital. The wound areas of patients ranged from 17 cm×8 cm to 35 cm×22 cm after debridement. Pedicled or free paraumbilical perforator flaps with inferior epigastric vessels were used to repair the wounds respectively. The areas of flaps were from 18 cm×10 cm to 37 cm×24 cm, and the lengths of vascular pedicles were 13.0-17.0 (15.1±2.3) cm. For type Ⅲ high-voltage electric burn wounds of wrist, two methods were used to reconstruct the blood flow of hand, one is to bridge the radial artery with saphenous vein grafting and the other one is to design blood flow-through flap. The strength of abdominal wall in the donor site was strengthened by polypropylene patch, and then the wounds were directly sutured. If the wounds could not be sutured directly, then allogenic acellular dermal matrix (ADM) was applied to strengthen the abdominal wall first, and then autologous medium-thickness skin graft was taken from the thigh to cover the wounds. The flap transplantation, hand blood flow reconstruction, the repair of donor site, the flap survival, the wound and donor site healing after operation, the appearance of flaps, and the wound and donor site recovery during follow-up were observed. Results: Among the patients in this group, 13 patients were treated with pedicled flap grafting, while 15 patients were treated with free flap grafting. The hand blood flow of 7 patients with type Ⅲ high-voltage electric burn wounds of wrist was reconstructed by bridging radial artery with saphenous vein grafting. The hand blood flow of 3 patients with type Ⅲ high-voltage electric burn wounds of wrist was reconstructed with blood flow-through flap. In 16 patients, the strength of abdominal wall was strengthened using patch in the donor site,and then the donor sites were sutured directly. In 12 patients, the strength of abdominal wall was strengthened using allogenic ADM, and then the donor sites were covered by skin grafting. All the transplanted flaps survived completely. The wounds of 24 patients were healed, while the wounds of 3 patients with type Ⅲ high-voltage electric burn wounds of wrist and 1 patient with chronic radiation ulcer of ilium failed to heal because of there were still some necrotic tissue and purulent secretion under the flaps. The wounds were healed eventually after debridement and dressing changes. During the follow-up of 6 months to 3 years, the flap survived well with good appearance in all patients, and there was no recurrence, or no abdominal wall hernia occurred in the donor site. Conclusions: Paraumbilical perforator flap with inferior epigastric vessels has flexible design, long vascular pedicle, large area for cut. It can be pedicled or freely transplanted, which is a good choice for repairing destructive wounds in various areas.

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression.

It has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.

IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor.

CD8+ T cell exhaustion dampens antitumor immunity. Although several transcription factors have been identified that regulate T cell exhaustion, the molecular mechanisms by which CD8+ T cells are triggered to enter an exhausted state remain unclear. Here, we show that interleukin-2 (IL-2) acts as an environmental cue to induce CD8+ T cell exhaustion within tumor microenvironments. We find that a continuously high level of IL-2 leads to the persistent activation of STAT5 in CD8+ T cells, which in turn induces strong expression of tryptophan hydroxylase 1, thus catalyzing the conversion to tryptophan to 5-hydroxytryptophan (5-HTP). 5-HTP subsequently activates AhR nuclear translocation, causing a coordinated upregulation of inhibitory receptors and downregulation of cytokine and effector-molecule production, thereby rendering T cells dysfunctional in the tumor microenvironment. This molecular pathway is not only present in mouse tumor models but is also observed in people with cancer, identifying IL-2 as a novel inducer of T cell exhaustion.

[Epidemiological characteristics of imported COVID-19 cases in Guangzhou].

Objective: To understand the epidemiological characteristics of imported COVID-19 cases in Guangzhou and provide scientific basis for the prevention and control of the disease. Methods: The data of imported COVID-19 in Guangzhou reported as of April 1, 2020 were collected from National Notifiable Disease Report System of China. The software Excel 2010 and SPSS 19.0 were applied for data cleaning and statistical analysis. Results: As of April 1, 2020, a total of 103 imported COVID-19 cases had been reported in Guangzhou, in which 92 were confirmed cases and 11 were asymptomatic infection cases. The number of the confirmed imported cases accounted for 11.4% (92/806) in of the total in China at the same time. The male to female ratio of the cases was 1.58∶1 (63∶40). The median age of the cases was 31 years (P(25)-P(75):22-40 years), range of age was 11-63 years. The main occupational distributions of the cases were business services (41/103, 39.8%) and students (36/103, 35.0%). The imported cases whose destinations were 19 provinces and municipalities rather than Guangdong after entering the country accounted for 43.7%. The main source countries of infections were the United Kingdom (27/103, 26.2%), the Philippines (13/103, 12.6%), the United States (13/103, 12.6%) and Nigeria (7/103, 6.8%). There were 34 inbound flights from which the imported COVID-19 cases were detected, in which 10 flights (10/34, 29.4%) were found to carry more than 3 cases, with an average voyage time of (11.14±0.53) hours. A total of 29 imported cases(28.2%) showed symptoms before entering the country, and 65 cases (63.1%) had been isolated before the onset of the disease. The mean free activity time of the isolated cases after the onset was (6.76±0.79) days. The average number of the imported cases' close contacts was 53. There were 13 clusters of COVID-19 caused by the imported cases, involving 36 cases (including 1 imported associated case). Conclusions: The sources of the imported COVID-19 cases in Guangzhou were widely distributed, and no cases had been found to be infected on the flights. In the early stage of the imported epidemic, there was high risk for the spread of the epidemic. Strengthened prevention and control of imported COVID-19 effectively reduced the of transmission risk of COVID-19 in communities.

[Progress in research of association of adverse childhood experiences with prevalence of common chronic diseases in adulthood].

The effects of adverse childhood experiences on adult health has aroused increasing concern in the world in recent years, but limited studies have been conducted in China. This study synthesized the measurement of adverse childhood experiences, the association between adverse childhood experiences and the prevalence common chronic diseases in adulthood and possible mechanisms. It was found that though measurement range of adverse childhood experiences might be different among studies, current used measurement scales basically met the requirement of disease prevention. Most categories of adverse childhood experiences were positively related to risk of common chronic diseases, and the relationship was influenced by social economic status, sex and age. However, people with exposure to famine in childhood had lower prevalence of hypertension compared with those without the exposure. The possible mechanisms might be that the occurrence of adverse childhood experiences might damage physiological functions or increase the adoption of poor healthy behaviors and lifestyles, and finally increased the risk of chronic diseases directly or indirectly. While premature death due to adverse childhood experiences might reverse the association because of nonrandom selection. It is necessary for us to select appropriate indexes of adverse childhood experiences and conduct more studies to prove the association between adverse childhood experiences and prevalence of common chronic diseases in adulthood and explore the related mechanism for the better prevention of chronic diseases in China.

Inhibition of microRNA-184 reduces H2O2-mediated cardiomyocyte injury via targeting FBXO28.

OBJECTIVE: Cardiovascular disease, especially coronary heart disease, is one of the diseases with the highest mortality. A large number of studies have found that microRNAs (miRNAs) are closely related to the occurrence and development of myocardial ischemia. This article mainly focused on the regulation of miR-184 on oxidative stress, inflammation, and apoptosis in myocardial infarction (MI). MATERIALS AND METHODS: MiR-184 inhibitor or negative control (NC) were transfected into H9c2 cells. Then, H9c2 cells were treated with H2O2 to construct a cardiomyocyte injury model. H9c2 cells were divided into 4 groups: control group, H22O2 treatment group, H2O2 + NC group, and H2O2 + miR-184 inhibitor group. The oxidative stress of H9c2 cells was observed by the expression levels of SOD, ROS, and MDA in each group. The inflammatory response of H9c2 cells was reflected by the expression of TNF-α, IL-6, and IL-1ß detected by ELISA kits. Western blot was used to detect the expression of cleaved Caspase-3, Bcl-2, Bax and F-box protein 28 (FBXO28). Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was utilized to detect miR-184 expression. TdT-mediated dUTP Nick-End Labeling (TUNEL) staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay were used to observe the apoptosis and cell viability. The Luciferase reporter experiment was used to prove whether miR-184 could target FBXO28. RESULTS: MiR-184 expression was significantly increased in H2O2-induced H9c2 cell injury model. After H9c2 cells were transfected with miR-184 inhibitor to silence miR-184, the levels of ROS and MDA were markedly reduced, while the expression of SOD was greatly increased. At the same time, the expression of inflammatory factors was greatly reduced. Silencing miR-184 also increased Bcl-2 expression, and reduced the expression of cleaved Caspase-3 and Bax. In addition, compared with the H2O2 + NC group, the number of TUNEL positive cells in the H2O2 + miR-184 inhibitor group was also significantly reduced, and the cell viability was remarkably increased. The Luciferase reporter experiment proved that FBXO28 is a target gene of miR-184. CONCLUSIONS: MiR-184 expression was increased in H2O2-treated H9c2 cells. Inhibition of miR-184 markedly inhibited oxidative stress and inflammation in cardiomyocytes, thereby inhibiting cardiomyocyte apoptosis, through the regulation of FBXO28.

[Exploration on the method of aesthetic repair of the donor sites of flaps].

Objective: To explore the excellent methods for aesthetic repair of the donor sites of flaps. Methods: From January 2013 to March 2018, 120 patients (94 males and 26 females, aged from 3 to 60 years) were admitted to the Department of Burns of Beijing Jishuitan Hospital. Wounds areas after debridement or removing scar were ranged from 8.0 cm×3.5 cm to 24.0 cm×18.0 cm. Twenty patients with facial and neck scar were repaired with expanded flaps, including 4 scalp flaps, 8 supraclavicular flaps, 4 deltoid flaps, and 4 trapezius myocutaneous flaps. The flaps in ideal donor sites were selected to repair the wounds in 40 patients, including 20 cases of hand wounds or scars repaired with inguinal flaps, 10 children of foot skin defects or scars repaired with cross inguinal skin flap, 10 cases of knee joint wounds repaired with medial or lateral thigh flaps. The optimal flap design was used to repair wounds in 50 patients. Among the patients, wounds of 36 patients were repaired with relaying flaps, including donor sites of free anterolateral thigh flaps of 8 patients repaired with anteromedial thigh perforator flaps and donor sites of free anterolateral thigh flaps of 8 patients repaired with ilioinguinal flaps or superficial abdominal artery flaps, and donor sites of flaps of 20 patients repaired with peroneal perforator relaying flaps. Besides, wounds of 9 patients were repaired with free lobulated anterolateral thigh flaps, and wounds of 5 patients were repaired with modified V-Y propelling latissimus dorsi myocutaneous flaps. The donor sites of flaps were repaired with allogenic acellular dermal matrix combined with autologous split-thickness skin grafts in 10 cases. The areas of the flaps or myocutaneous flaps were ranged from 6.0 cm×4.0 cm to 30.0 cm×20.0 cm. The survival of flap, myocutaneous flap, or skin graft and the repair of donor site after operation and during follow-up were observed. Results: Blood flow obstacle at 0.5 cm to the distal margin of the flap occurred in 1 patient repaired with expanded flap, which were healed after dressing change. Blood supply disorder occurred at the tip of the anteromedial thigh perforator flap of 1 patient repaired by optimal flap design, which were healed completely after second debridement and restitching. The other flaps or myocutaneous flaps survived well. The allogenic acellular dermal matrix and the autologous split-thickness skin graft survived with good color and texture. During follow-up of 3 months to 4 years, the donor sites of flaps had good appearance, only with linear scar and the function recovered well. The donor sites of skin grafts had no scar hyperplasia, only with scattered pigmentation. Conclusions: According to the characteristics of donor sites of flaps, individualized and reasonable design before the operation such as pre-expanding of the flaps, selecting the ideal donor sites, optimization of the flap design or allogenic acellular dermal matrix combined with autologous split-thickness skin graft to repair donor sites of flaps can minimize the damage for function and appearance of donor sites of flaps and achieve aesthetic effects of donor sites of flaps.