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Background: Airway inflammation produced by neutrophils is a critical factor in the development of chronic obstructive pulmonary disease (COPD). Poor or excessive neutrophil polarization and chemotaxis may lead to pathogen accumulation and tissue damage. However, it is unclear how cigarette smoke extract (CSE) attracts neutrophils and to what extent COPD is affected by the improper polarization of these abnormal neutrophils. This study sought to assess the polarization and migration dynamics of neutrophils isolated from patients with different severities of COPD compared to healthy smoking and non-smoking control subjects, and to detect how CSE triggers the polarization of neutrophils., Methods: The neutrophils were freshly isolated using standard isolation protocol. The polarization of the neutrophils was observed using a Zigmond chamber when stimulated by a linear concentration gradient of CSE or N-formyl-methionine-leucine-phenylalanine (fMLP). Confocal laser-scanning microscopy was used to observe the intracellular calcium of the neutrophils. The experimental data are presented as the mean ± standard deviation. SPSS 20.0 software was used for the statistical analysis. A P value <0.05 was considered statistically significant., Results: The neutrophils from the COPD patients showed a higher frequency of spontaneous polarization and a lower prevalence of directionality polarization than those from the healthy control (HC) and smoker subjects. The abnormal polarization of the neutrophils from the COPD patients was altered by the influence of store-operated calcium entry (SOCE) component matrix interaction molecules 1 and 2 and calcium release-activated calcium channel protein 1 [stromal interaction molecule 1 (STIM1), Stromal interaction molecule 2 (STIM2), and calcium release-activated calcium modulator 1 (ORAI1)]., Conclusions: The COPD neutrophils exhibited unique polarization and migration patterns compared to those of the cells examined from other populations. The attraction of CSEs to neutrophils was mediated by the SOCE/Akt/Src pathway., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-1480/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Brain glioblastoma multiforme (GBM) is the most common primary malignant intracranial tumor. The prognosis of this disease is extremely poor. While the introduction of β-interferon (IFN-β) regimen in the treatment of gliomas has significantly improved the outcome of patients; The mechanism by which IFN-β induces increased TMZ sensitivity has not been described. Therefore, the main objective of the study was to elucidate the molecular mechanisms responsible for the beneficial effect of IFNβ in GBM., Methods: Messenger RNA expression profiles and clinicopathological data were downloaded from The Cancer Genome Atlas (TCGA) GBM and GSE83300 dataset from the Gene Expression Omnibus. Univariate Cox regression analysis and lasso Cox regression model established a novel 4-gene IFN-β signature (peroxiredoxin 1, Sec61 subunit beta, X-ray repair cross-complementing 5, and Bcl-2-like protein 2) for GBM prognosis prediction. Further, GBM samples (n=50) and normal brain tissues (n=50) were then used for real-time polymerase chain reaction experiments. Gene set enrichment analysis (GSEA) was performed to further understand the underlying molecular mechanisms. Pearson correlation was applied to calculate the correlation between the long non-coding RNAs (lncRNAs) and IFN-β-associated genes. An lncRNA with a correlation coefficient |R 2 |>0.3 and P<0.05 was considered to be an IFN-β-associated lncRNA., Results: Patients in the high-risk group had significantly poorer survival than patients in the low-risk group. The signature was found to be an independent prognostic factor for GBM survival. Furthermore, GSEA revealed several significantly enriched pathways, which might help explain the underlying mechanisms. Our study identified a novel robust 4-gene IFN-β signature for GBM prognosis prediction. The signature might contain potential biomarkers for metabolic therapy and treatment response prediction for GBM patients., Conclusions: In the present study, we established a novel IFN-β-associated gene signature to predict the overall survival of GBM patients, which may help in clinical decision making for individual treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-1986). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: PYD and CARD domain-containing ( PYCARD ) was upregulated in TMZ-resistant cell lines and glioma tissue and was correlated with poor prognosis, its role in glioma is unclear known. The aim of this study was to elucidate the relationship between PYCARD and glioma based on Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA) databases., Methods: Glioma-resistant cells were compared with parental cells based on the GSE53014 and GSE113510 data sets. The relationship between PYCARD , tumor microenvironment, and long noncoding RNAs (lncRNAs) was assessed using logistic regression. Moreover, Kaplan-Meier and Cox regression were used to analyze the relationship between PYCARD expression and survival rate. Gene set enrichment analysis (GSEA) was also used to determine the biological function of PYCARD and lncRNAs. Cell viability and cell migration assays were used to evaluate the ability of cells to migrate and proliferate. Finally, we analyzed the expression patterns of PYCARD genes in a wide range of cancers., Results: Elevated expression of PYCARD promoted glioma cell proliferation and migration. PYCARD expression was significantly positively associated with gamma delta T cells but negatively correlated with M2 macrophages in glioblastoma multiforme (GBM). Likewise, PYCARD expression was significantly positively associated with monocytes but negatively associated with activated mast cells in low grade glioma (LGG). We also found that 3 PYCARD -related lncRNAs in GBM and 4 PYCARD -related lncRNAs in LGG had a predictive value for glioma patients. The pan-cancer analysis showed that PYCARD expression was higher in most cancer groups., Conclusions: High expression of PYCARD is an independent predictor of unfavorable prognosis and chemotherapy resistance in glioma., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-2346). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: The aim of our study was to explore the prognostic significance of the preoperative controlling nutritional status (CONUT) score and establish a nomogram to predict overall survival (OS) and to achieve a more accurate prognostic risk stratification., Methods: Clinicopathological records of 371 patients who underwent surgical resection for biliary tract cancers (BTC) from December 2002 to December 2017 were reviewed retrospectively. The associations of the CONUT score with clinicopathological factors and OS were evaluated. Univariate and multivariable Cox regression analysis were used to screen out independent predictors. A nomogram was developed and validated to estimate OS., Results: The CONUT score was an independent predictor of OS [hazard ratio 1.478, 95% confidence interval (CI), 1.078-2.025, P=0.015]. And patients with a high CONUT score tended to have a poor prognosis with poor differentiation (P=0.011) of tumor cells and longer hospital stays (P=0.046). Besides the CONUT score, carbohydrate antigen 19-9, surgical method, and the American Joint Committee on Cancer (AJCC; 7th edition) TNM stage were contained in the final prognostic model. An OS nomogram was generated to visually predict 1-, 3-, and 5-year OS. The C-index was 0.714 (95% CI, 0.673-0.755) and 0.679 (95% CI, 0.616-0.742) in the development and validation cohort respectively. The nomogram provided superior discriminative power than the AJCC TNM staging system. The nomogram also demonstrated good risk stratification power in the entire cohort of BTC patients as well as for both BTC and surgical method subgroups., Conclusions: The nomogram based on the CONUT score can predict OS in patients with BTCs, and it performed better than the AJCC TNM staging system., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-6770). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Cognitive deficit is acknowledged as a core feature of clinical manifestations of bipolar disorder (BD). However, the underlying mechanism of cognitive impairment in bipolar II depression has remained uncertain. We aim to determine the association of cognitive impairments with biochemical metabolism using proton magnetic resonance spectroscopy ( 1 H-MRS) and a battery of neuropsychological testing., Methods: The current study was designed to assess four cognitive domains in a sample of 110 patients with bipolar II depression and 110 healthy controls, using a battery of 6 cognitive tests, including the Digit Symbol Substitution Test (DSST), Wisconsin Cart Sorting Test (WCST), Trail Making Test Part B (TMT-B), Digit Span Test (DST), TMT-part A (TMT-A) and Verbal Fluency Test (VFT). Metabolite levels were obtained in the following brain regions of interest: bilateral prefrontal white matter (PWM), bilateral anterior cingulate cortex (ACC), bilateral lenticular nucleus (LN), and bilateral thalamus. N-acetyl aspartate (NAA)/creatine (Cr) and choline-containing compounds (Cho)/Cr ratios are analyzed., Results: Patients with bipolar II depression performed significantly worse on DSST (score), TMT (completion time), DSB (score), and VFT (valid word number) when compared with healthy controls. In the bilateral PWM, NAA/Cr ratios in the PWM were significantly reduced (bilaterally) than those in healthy controls. Correlation analysis was conducted with data from patients with bipolar II depression, we found that the NAA/Cr ratio of the left PWM was positively correlated with the score of DS and DSB, and the NAA/Cr ratio of the right PWM was negatively correlated with the completion time of TMT-B., Conclusions: Our findings suggested that psychomotor speed, executive function, working memory, and verbal fluency are impaired in patients with BD II depression. Hypoactivity NAA/Cr in bilateral PWM may be associated with BD II depression's pathophysiology and results in cognitive dysfunction., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-7098). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: Contrast media (CM) is widely used in cardiac catheterization; however, it may cause contrast-induced acute kidney injury (CI-AKI) which severely increases mortality. MicroRNA (miRNA) has been found to participate in the process of acute kidney injury (AKI), and this discovery has great potential for diagnosis and treatment. However, the role of miRNA in CI-AKI is still unclear. This study aimed to investigate the regulatory effect miRNAs exert in CI-AKI., Methods: We established a novel, representative, isotonic CI-AKI model by using CM iodixanol, a CM which is commonly used in clinic. Next-generation sequencing and reverse transcription polymerase chain reaction (RT-qPCR) were performed to determine the expression of miRNA-188 in CI-AKI. Western blot analysis of the apoptosis regulator protein and TUNEL assay were ordered to evaluate apoptosis. Bioinformatics and double luciferin reporter gene assay were performed to predict and to confirm the interaction between microRNA-188 and SRSF7., Results: The novel isotonic CI-AKI rat model we established exhibited typical characteristics of CI-AKI in serum creatinine, cystatin C, HE staining, and under electron microscope observation. Sequencing and RT-qPCR demonstrated that miRNA-188 was significantly up-regulated both in CI-AKI rat and HK-2 cell models while overexpression of miRNA-188 significantly aggravated apoptosis in CI-AKI cell models. SRSF7 was identified as a direct target gene of miRNA-188, and dual luciferase reporter assay determined the direct interaction between SRSF7 and miRNA-188. In addition, SRSF7 silencing reduced the cell viability rate of the CI-AKI cell model., Conclusions: The present study's findings indicate that miRNA-188 aggravated contrast-induced apoptosis by regulating SRSF7, which may serve as a potential drug target for CI-AKI intervention., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Breast cancer susceptibility gene 1 (BRCA1) expression has been suggested as a predictor in anti-neoplastic treatment with anti-microtubule agents. However, the existing evidence is conflicting. Consulting the literature, we sought to examine the true impact of BRCA1 expression on the efficacy of anti-microtubule agents., Methods: Medline by PubMed and Embase databases were searched for eligible studies. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). Additional subgroup analyses stratified for detection methods, regimen, and patient origin were also performed., Results: A total of 13 relevant studies involving a total of 1,490 cases were enrolled. Involved agents included paclitaxel, docetaxel and vinorelbine; Malignancies included non-small cell lung cancer, gastric cancer, esophageal carcinoma, ovarian carcinoma, malignant pleural mesothelioma, breast cancer, and small cell lung cancer. Through meta-analyses, we observed a potentially greater ORR in the population with high BRCA1 expression vs. low BRCA1 expression (OR 1.63, 95% CI: 0.92 to 2.88, P=0.09) but the heterogeneity is severe (P=0.01; I(2)=61%). Similar results were observed in PFS (high vs. low expression, HR 0.93, 95% CI: 0.75 to 1.15, P=0.49; heterogeneity, P<0.01, I(2)=75%). After stratification by testing methods, a significantly higher ORR in the population with high BRCA1 expression was shown in the subgroup using mRNA as a quantitative method (OR 2.90, 95% CI: 1.92 to 4.39, P<0.01; I(2)=0) whereas the difference in the subgroup using immunohistochemistry (IHC) was not significant (OR 0.60, 95% CI: 0.33 to 1.10, P=0.10; I(2)=0). Stratification by regimen (platinum-based vs. non platinum-based) and patient origin (Asian vs. Caucasian) did not reduce the heterogeneity., Conclusions: Although the predictive value of BRCA1 expression on the anti-microtubule chemotherapy remained uncertain based on overall results, our exploratory analyses suggested that detection using mRNA might be a preferred technique, however, further validation is required to substantiate our findings.