Regulatory T cells in inflammation and resolution of acute lung injury

IntroductionAcute respiratory distress syndrome (ARDS) is characterized by hypoxemia and increased lung permeability and would result in acute respiratory failure and with high mortality. In patients who survive from acute lung injury (ALI)/ARDS, it is an active process of the transition from injury to resolution depending on the coordinated immune system. The roles of regulatory CD4⁺T cells (Tregs) are now gradually being clarified during inflammation and resolution of ARDS. However, clear conclusions about roles of Tregs in ALI/ARDS are only a few.ObjectiveThis review provides an overview of phenotype, differentiation, and suppressive mechanisms of Tregs and focuses on keys of biology of Tregs in alveolar space during the inflammatory response and resolution of ALI/ARDS.Data SourceLiterature search of Web of Science, PubMed, and EMBASE was made to find relative articles about Tregs in ALI/ARDS. We used the following search terms: Tregs, ALI, ARDS, inflammation, and resolution.ConclusionMore and more studies have indicated Tregs involved in the processes of inflammation and resolution of ALI/ARDS. A deep understanding of the roles of Tregs may indicate new treatments for patients of ARDS. Therapies aimed at expansion or adaptive transfer of Tregs could be an effective therapy to ARDS patients.     

Crushing Characteristics of Coarse Aggregates for Asphalt Mixtures under Simulated Laboratory Compaction Loads and Repeated Traffic Loads

The crushing characteristics of coarse aggregates for asphalt concrete were investigated under static and dynamic aggregate crushing value tests (ACVTs). The effect of various compaction loads was also examined by using a Marshall hammer, gyratory compactor and steel roller. Six types of coarse aggregates were tested, including basalt aggregate, steel slag, limestone aggregate, marble aggregate, recycled concrete aggregate and slightly weathered limestone aggregate. Test results indicate that static ACVT failed to reflect the crushing behavior of coarse aggregates under traditional traffic and compaction loads. The type of aggregate strongly influenced the crushing resistance, independent of type of load. The compaction loads simulated by using a Marshall hammer, gyratory compactor and steel roller resulted in a high aggregate breakage ratio and can distinguish the coarse aggregates with high crushing susceptibility. The crushing resistance was evaluated by using various crushing parameters and the corresponding critical value of these parameters was established. Gyratory compactor compaction resulted in more serious aggregate crushing when compared to Marshall hammer and steel roller compaction. Finite element modelling results on roller compaction and Marshall hammer compaction are in agreement with the aggregate crushing results. The aggregate crushing mechanism was found to be controlled by the fracture mode; the contribution of the attrition and abrasion modes was relatively small. When coarse aggregates with low crushing resistance are considered for the use for asphalt mixture, proper compaction is proved to be vital to prevent excessive aggregate breakage during mixture preparation and construction.     

Clinical Outcomes of Arthroscopy‐Assisted Modified Triple Endobutton Plate Fixation in Rockwood Type III Acute Acromioclavicular Joint Dislocation: A Retrospective Study

ObjectiveThe common triple Endobutton plate (CTEP) fixation is a lengthy procedure that is associated with high failure rates. Therefore, we used arthroscopy to improve the Endobutton fixation method by shortening the duration of surgery and reducing operative complications. This study explored the safety and effectiveness of arthroscopy‐assisted modified triple Endobutton plate (MTEP) fixation in Rockwood type III managing acute acromioclavicular joint (ACJ) dislocation.MethodsThis was a retrospective single‐center study involving 73 patients with Rockwood type III acute ACJ dislocation treated between January 2016 and January 2021. The 73 patients were classified into three groups, the acromioclavicular hook plate (ACHP) group (22 cases), CTEP group (24 cases) and MTEP group (27 cases), based on the type of surgical treatment they received. Clinical outcome data from the patient records, including the Constant–Murley score (CMS), American Shoulder and Elbow Surgeons score (ASES) and University of California at Los Angeles shoulder rating scale score (UCLA), were retrospectively reviewed. The scores were assessed before surgery and at the third and twelfth month after surgery. The clavicle‐coracoid (CC) distance on the affected side was estimated from imaging scans taken before surgery, on the second day after surgery, and within the third and twelfth month after surgery. The student''s t‐test was used to compare normally distributed data for independent samples, while homogeneity of variance test was used to compare normally distributed data among multiple groups. Non‐normally distributed data were compared using Mann–Whitney rank‐sum tests.ResultsThere were no differences in age, gender, body mass index (BMI), dislocated side, trauma etiology, and duration of follow‐up among the three groups. There was also no significant difference in the duration of surgery between the ACHP and MTEP groups, although the duration in the two groups was shorter than in the CTEP group (P < 0.05). The duration of hospitalization for the MTEP group was significantly shorter than for the CTEP group which was in turn shorter than for the ACHP group (both P < 0.05). There was no significant difference in postoperative CMS, ASES, and UCLA scores between the CTEP and MTEP groups but the score for the two groups differed significantly from those of the ACHP group (all Ps < 0.05). In addition, there was no significant difference in CC distance among the three groups after surgery (P > 0.05).ConclusionArthroscopic reconstruction of the coracoclavicular ligament using MTEP fixation to manage acute Rockwood type III ACJ dislocation is minimally invasive, and is associated with rapid functional recovery, few complications and satisfactory early clinical results.     

Upregulation of matrix metalloproteinase 14 (MMP14) is associated with poor prognosis in renal clear cell carcinoma—a bioinformatics analysis

BackgroundMatrix metalloproteinase 14 (MMP14) has been reported to be upregulated in some types of cancer and to promote cancer cell invasion and metastasis. However, the expression profile and functional role of MMP14 in kidney renal clear cell carcinoma (KIRC) remains unknown. This study investigated the association between MMP14 expression level and prognosis in KIRC.MethodsThe messenger RNA (mRNA) expression profile and clinical data (including T stage, N stage, M stage, pathologic stage, gender, race, age, histologic grade, serum calcium, hemoglobin) were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. Protein expression was evaluated by immunohistochemistry in the Human Protein Atlas (HPA) database. Correlation analyses between MMP14 and all mRNAs in KIRC were batch calculated, and gene set enrichment analyses (GSEA) were then conducted of Disease Ontology (DO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using R packages. Multivariate logistic regression analysis was used to explore the prognostic factors of KIRC patients.ResultsThe gene expression of MMP14 was significantly upregulated in KIRC tissues when compared with the normal tissue (P<0.001). The predictive ability of MMP14 as a variable for predicting tumor and normal outcomes had certain accuracy based on the receiver operating characteristic (ROC) model [area under the curve (AUC) =0.881, confidence interval (CI): 0.844-0.917]. When compared with the normal kidney tissue, the protein expression of MMP14 in KIRC got an increased trend, but due to the limited sample size, the difference is not statistically significant (P>0.05). Survival analysis revealed that MMP14 was significantly associated with overall survival in KIRC (P=0.013). GSEA of DO terms indicated high expression of MMP14 was related to KIRC, and GSEA of KEGG pathways showed that MMP14 and its coexpressed genes were significantly positively correlated with pathways in cancer. Signaling pathway GSEA indicated the upregulation of MMP14 in KIRC may activate cancer pathways.ConclusionsMMP14 may be associated with poor prognosis in KIRC and may be a potential prognostic marker for KIRC.     

Clonal relationship and alcohol consumption-associated mutational signature in synchronous hypopharyngeal tumours and oesophageal squamous cell carcinoma

Background The patients with dual oesophageal squamous cell carcinoma (ESCC) and hypopharyngeal cancer (HPC) have poor prognosis; their underlying genetic pathogenesis is unclear. We hypothesise that development of synchronous ESCC/HPC depends on multicentricity or independent origin, rather than multifocality due to local or lateral spreading.Method Multiple region whole-exome sequencing (M-WES) and clonality analysis were used to assess clonal relationship and spatial inter- or intra-tumour heterogeneity (ITH) in 62 tumour regions from eight dual ESCC/HPC and ten ESCC patients.Results All synchronous ESCC/HPC patients had COSMIC 16 mutation signatures, compared to only 40% ESCC in the current study (p = 0.013) and public data set (n = 165, p = 0.003). This alcohol consumption-related mutation signature 16, commonly involved in multiple alcohol-related cancers, was significantly associated with drinking and alcohol metabolism-related ADH1B rs1229984. The mutational landscape and copy number profiles were completely distinct between the two primary tumours; clonality analysis further suggested the two primary tumours shared no or only one clone accompanying independent subclone evolution. M-WES strategy demonstrated higher sensitivity and accuracy for detection of mutational prevalence and the late branch mutations among different regions in the ESCC tumours, compared to traditional sequencing analysis based on single biopsy strategy. Patients with high ITH assessed by cancer cell fraction analysis after M-WES were significantly associated with both relapse and survival.Conclusions Our hypothesis-generating M-WES ITH assessment data have implications for prognostication. Collectively, our findings support multicentric independent clonal evolution, the field cancerisation theory, and suggest novel insights implicating an aetiologic role of alcohol metabolism in dual ESCC/HPC carcinogenesis.Subject terms: Oesophageal cancer, Cancer genomics     

Development and validation of a predictive model for endocervical curettage in patients referred for colposcopy: A multicenter retrospective diagnostic study in China

ObjectiveThis study aimed to develop a nomogram that can predict occult high-grade squamous intraepithelial lesions or worse (HSIL+) and determine the need for endocervical curettage (ECC) in patients referred for colposcopy.MethodsThis retrospective multicenter study included 4,149 patients who were referred to any one of six tertiary hospitals in China for colposcopy between January 2020 and November 2021 because of abnormal screening results. ECC data were extracted from the medical records. Univariate and multivariate logistic regression analyses were performed to identify factors that could predict HSIL+ on ECC. Patients were randomly assigned to a training set or to an internal validation set for performance and comparability testing. The model was externally validated and tested in patients from two additional hospitals. The nomogram was assessed in terms of discrimination and calibration and subjected to decision curve analysis.ResultsHSIL+ was found on ECC in 38.8% (n=388) of cases. Our predictive nomogram included age group, cytology, human papillomavirus (HPV) status, visibility of the cervix and colposcopic impression. The nomogram had good overall discrimination, which was internally validated [area under the receiver-operator characteristic (AUC), 0.839; 95% confidence interval (95% CI), 0.773−0.904]. In terms of external validation, the AUC was 0.843 (95% CI, 0.773−0.912) for the consecutive sample and 0.843 (95% CI, 0.783−0.902) for the comparative sample. Calibration analysis suggested good consistency between predicted and observed probabilities. Decision curve analysis suggested this nomogram would be clinically useful with almost the entire range of threshold probabilities.ConclusionsThis internally and externally validated nomogram can be easily applied and incorporates multiple clinically relevant variables that can be used to identify patients with occult HSIL+ who need ECC.     

Gastroblastoma Treated by Endoscopic Submucosal Excavation with a Novel PTCH1::GLI2 Fusion: A Rare Case Report and Literature Review

Gastroblastoma is an extremely rare stomach tumor that primarily presents in adolescent and early adulthood, with a biphasic cell morphology of epithelioid and spindle cells. In light of its similarity to other childhood blastomas, it has been named gastroblastoma. Few patients showed a potential of metastasis and recurrence, however, most of the reported cases were alive, with no evidence of the disease after surgical treatment. Commonly, MALAT1-GLI1 fusion has been considered to be the most relevant mutation. Herein, we present a case of an asymptomatic 58-year-old man who happened to find a submucosal gastric mass during a gastroscope and received endoscopic submucosal excavation (ESE). He turned out to have a gastroblastoma with a novel PTCH1::GLI2 fusion confirmed by Sanger sequencing. The patient was discharged two days after ESE without any complication and was recurrence-free during his one-year follow-up. According to the previous literature and our own experience, in cases with characteristic histopathology and immunohistochemistry patterns, a diagnosis of gastroblastoma should be considered even without a MALAT1-GLI1 fusion. Gastroblastoma pursues a favorable clinical outcome and endoscopic therapy could be an effective alternative treatment choice.     

Decreased APOC1 expression inhibited cancer progression and was associated with better prognosis and immune microenvironment in esophageal cancer

Several studies have demonstrated the involvement of apolipoprotein C1 (APOC1) in multiple cancers. However, the role of APOC1 in esophageal cancer (ESCA) has not been elucidated. Hence, we examined the expression of APOC1 in ESCA tissues acquired from The Cancer Genome Atlas (TCGA) database and clinical samples from our hospital. An investigation of the association of APOC1 with the clinicopathological characteristics, prognosis, and diagnosis of ESCA was carried out on the basis of survival, receiver operating characteristics, and correlation analyses. Gene ontology, KEGG analysis, and protein-protein interaction network showed that co-expressed APOC1 genes were involved in the functions, mechanisms, and action network. The effects of APOC1 expression on ESCA cells were explored using CCK-8, migration and invasion assays. The relationship between APOC1 expression and ESCA immune-infiltrating cells and cell markers were examined using correlation analysis. We found that APOC1 was overexpressed in TCGA ESCA tissues and the same was validated in clinical ESCA tissues, with the area under the curve for APOC1 being 0.887. Overexpression of APOC1 was associated with short overall survival, disease-specific survival, progression-free interval, T stage, pathological stage, body mass index, and histological grade. Inhibition of APOC1 expression significantly reduced the proliferation, migration, and invasion of ESCA cells. Furthermore, APOC1 expression positively correlated with the ESTIMATE, immune, and stromal scores in ESCA. Overexpression of APOC1 correlated with the tumor purity, B cells, T helper cells, natural killer cells, cytotoxic cells, and other immune cells. Moreover, APOC1 was involved in ESCA progression via T cell receptor, B cell receptor, and other immune signaling pathways. Thus, APOC1 overexpression is expected to be a biomarker for dismal prognosis and diagnosis of ESCA. Inhibition of APOC1 expression significantly reduced the proliferation, migration, and invasion of ESCA cells. Overexpression of APOC1 was associated with the immune microenvironment in ESCA. Thus, APOC1 may be an efficient biomarker for proper prognosis and diagnosis of ESCA.     

Construction and validation of NSMC-ASIL,a predictive model for risk assessment of malignant hepatic nodules

Most malignant hepatic nodules (MHNs) eventually progress to hepatocellular carcinoma (HCC). However, assessment of the risk of malignancy in high-risk groups of patients with hepatic nodules remains a challenge. This study aimed to develop and validate a simple scoring system to predict the risk of development of MHNs. 1144 patients with primary nodular lesions of hepatic were divided into training cohort and validation cohort. The nomogram model for predicting the risk of MHNs was established according to age, sex, nodule size, prothrombin time (PT), alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), γ-glutamine acyltransferase isoenzyme (γ-GT), alanine aminotransferase (ALT), total bile acid (TBA), and total bilirubin (TBIL) in training cohort by logistic regression and validated in validation cohort. The area under receiver operating characteristic curve (AUC) of the predictive model for diagnosing MHNs in training cohort was 0.969 (95% CI: 0.959-0.979), with sensitivity 93.38% and specificity 90.75%, and the AUC in the validation cohort was 0.986 (95% CI: 0.975-0.996), with sensitivity 90.81% and specificity 94.26%. The AUC, sensitivity, and specificity of this model for the diagnosis of early-stage HCC were 0.942, 88.64% and 87.35% in training cohort, and 0.956, 87.04% and 91.85% in validation cohort, respectively. We established a nomogram model that used intuitive data for reliably predicting the risk of MHNs, and this model also showed good diagnostic accuracy in predicting early-stage HCC.