Genomic profiling and immune landscape of olfactory neuroblastoma in China

BackgroundOlfactory neuroblastoma (ONB) is a rare malignant neoplasm of the olfactory mucosa. The paucity of genomic data has prevented the development of individualized ONB treatments. Here, we investigated the genomic and immune landscape of ONB in Chinese patients.MethodsWhole exome sequencing (WES) and multiplex immunofluorescence (MIF) analysis were performed on tissue samples from 19 Chinese ONB patients. Patients were divided into low- and high-grade groups.ResultsOverall, 929 nonsynonymous alterations were identified in 18 (94.74%) ONB cases. The most prevalent altered cancer-related genes were CTNNB1 (16%) and ZNRF3 (16%). The most mutated oncogenic pathways were the WNT and RAS pathways. The median tumor mutation burden (TMB) was 0.45, ranging from 0 to 3.25. Only one case expressed PD-L1 (> 1%) in the tumor region. The percentage of CD8+ tumor-infiltrating lymphocytes (TILs) in the tumor region ranged from 0.03% to 84.9%, with a median of 1.08%. No significant differences were observed between the low- and high-grade groups for clinicopathological features, mutant genes, mutant pathways, TMB, tumor neoantigen burden (TNB), mutant-allele tumor heterogeneity (MATH), PD-L1 expression levels, or CD8+ TIL percentage. However, the low-grade group showed significantly more CD68+ macrophages in both the tumor and total region than the high-grade group. Notably, CD68+CD163- macrophages accounted for an average of 80.5% of CD68+ macrophages.ConclusionThis study presents data on the genomic and immune landscape of ONB cases in China. CTNNB1 and ZNRF3 were the most prevalent altered cancer-related genes. The results of TMB, PD-L1, and CD8+ Tils suggest that ONB may be insensitive to immunotherapy. M1 macrophages may be positively associated with the prognosis of ONB.Implications for PracticeIn this study, the most prevalent altered cancer-related genes were CTNNB1 (16%) and ZNRF3 (16%). The most mutated oncogenic pathways were the WNT and RAS pathways. The median tumor mutation burden (TMB) was 0.45, ranging from 0 to 3.25. Only one (1/15) case expressed PD-L1 (> 1%) in the tumor region. However, the low-grade group showed significantly more CD68+ macrophages in both the tumor and total region than the high-grade group. The higher level of CD68-related macrophages indicates that M1 macrophages potentially play an important role in ONB development that is possibly associated with prognosis

Prognostic implications of ezrin and phosphorylated ezrin expression in non-small cell lung cancer

BACKGROUND: The cytoskeletal organizer ezrin is a member of the ezrin-radixin-moesin (ERM) family and plays important roles in not only cell motility, cell adhesion, and apoptosis, but also in various cell signaling pathways. Phosphorylation at Thr-567 and Tyr-353 are key regulatory events in the transition of the dormant to active form of ezrin. This study investigated the prognostic implications of ezrin and phosphorylated ezrin (p-ezrin) expression in non-small cell lung carcinoma (NSCLC). METHODS: Ezrin and p-ezrin protein expressions were examined by immunohistochemistry in 150 NSCLC and adjacent non-tumor tissues and 14 normal lung tissues. qRT-PCR was used to determine ezrin mRNA expression levels in fresh tissues. The correlations between overexpression of ezrin and p-ezrin and the clinicopathological features of NSCLC were analyzed. The survival rates were calculated by the Kaplan-Meier method for 108 NSCLC cases. RESULTS: Ezrin and ezrin(Thr-567) proteins showed cytosolic and membranous staining patterns; however, ezrin(Tyr-353) protein only showed cytosolic staining. Ezrin and p-ezrin were significantly upregulated in NSCLC compared with the normal counterparts. Increased ezrin, ezrin(Thr-567), and ezrin(Tyr-353) levels were correlated with the late stage and poor differentiation of NSCLC. However, only ezrin(Thr-567) was correlated with the presence of lymph node metastasis. In regard to survival, only ezrin(Thr-567) was related with the overall survival time of patients with NSCLC, and both ezrin and ezrin(Thr-567) were associated with shortened survival time for patients with early stage NSCLC. CONCLUSIONS: Ezrin and p-ezrin, especially ezrin(Thr-567), may prove to be useful as a novel prognostic biomarker of NSCLC

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

金沢大学医学部附属病院薬剤部We examined whether the oral bioavailability of cyclosporin A is controlled primarily by P-glycoprotein (P-gp) or CYP3A in the small intestine. In situ loop method was used to evaluate the uptake of cyclosporin A (40 nmol) at the upper and lower intestine of wild-type and mdr1a/1b knockout mice treated or not treated with dexamethasone (75 mg/kg/day, 7 days, i.p.). Expression of CYP3A mRNA in the control group was higher in the upper than the lower intestine, while that of the multidrug resistance-1a (mdr1a) mRNA was in the opposite order. Dexamethasone administration potently induced CYP3A and mdr1a mRNAs in the lower and upper intestine, respectively. At 45 min after cyclosporin A administration into an upper intestinal loop of the control group of wild-type mice, the ratio of residual cyclosporin A to dose did not differ significantly from that of mdr1a/1b knockout mice, whereas in dexamethasone-treated wild-type mice, the residual ratio was increased significantly. The ratio of the cyclosporin A metabolite M17 to cyclosporin A in portal venous blood at an upper intestinal loop of mdr1a/1b knockout mice was much higher than that a lower intestinal loop. The M17/cyclosporin A ratio of portal venous blood at a lower intestinal loop in mdr1a/1b knockout mice was increased significantly by dexamethasone treatment. These results suggest that, under physiological conditions, the oral bioavailability of cyclosporin A is mainly controlled by CYP3A in the upper intestine, rather than liver, but when P-gp is induced by steroid, the intestinal absorption of cyclosporin A may be inhibited. © 2006 Elsevier Inc. All rights reserved

Meta-analysis of etrolizumab placebo in ulcerative colitis: safety and efficacy outcomes

Background: The existing body of scientific literature offers inconclusive findings on the safety and therapeutic effectiveness of etrolizumab (ETR) for the treatment of ulcerative colitis (UC). Objectives: The goal of this meta-analysis is to furnish a comprehensive synthesis of evidence that evaluates the safety and therapeutic effects of ETR in the management of UC. Design: Meta-analysis. Data sources and methods: PubMed, Embase, and Web of science were searched to collect relevant English studies, and the reference lists of eligible studies were manually searched to avoid missing any eligible studies. Outcome measures encompassed clinical response, incidence of adverse events, histological remission, endoscopic remission, endoscopic improvement, and antidrug antibodies. Relevant data were extracted by two independent investigators. Results: The meta-analysis incorporated five eligible studies, involving a total of 1528 patients, with 1015 treated with ETR and 513 with placebo. The pooled analysis indicates that ETR is both effective and safe. The adverse event rates, endoscopic and histological response, as well as overall remission were comparable between the two groups. The monoclonal antibody group had a lower incidence rate of adverse reactions than the placebo group [odds ratio (OR): 0.81; 95% confidence interval (CI): 0.63–1.03; p  = 0.09)]. Clinical response was higher in the ETR group than in the placebo group (OR: 1.56; 95% CI: 1.20–2.02; p  = 0.0009), and endoscopic improvement was more favorable in the ETR group (OR: 1.88; 95% CI: 1.45–2,45; p  < 0.00001). A higher rate of endoscopic remission was found in the ETR group than in the placebo group (OR: 2.48; 95% CI: 1.75–3.50; p  < 0.00001); histological remission was significantly higher in the ETR group than in the placebo group (OR: 2.11; 95% CI: 1.55–2.86; p  < 0.00001). The placebo group had a lower rate of positive antidrug antibodies (OR: 1.31; 95% CI: 0.79–2.17; p  < 0.29), and the incidence of complications was significantly higher in the ETR group compared with the placebo group (OR: 2.05; 95% CI: 1.48–2.83; p  < 0.0001). Conclusion: Given the heterogeneity and potential biases in the included studies, gastroenterologists should cautiously tailor drug delivery strategies based on their clinical experience and the unique needs of individual patients. PROSPERO registration: CRD4202339610

DOK7 Inhibits Cell Proliferation, Migration, and Invasion of Breast Cancer via the PI3K/PTEN/AKT Pathway

Recently, increasing attention has been paid to the correlation between the expression of downstream of kinase 7 (DOK7) and the occurrence and development of various tumors. In this study, we clarified the effects of DOK7 in breast cancer. First, we showed that DOK7 expression was obviously reduced in the breast cancer tissues and lower levels of DOK7 linked to more aggressive behaviors and worse prognosis of patients. Furthermore, DOK7 expression of various breast cancer cell lines was lower than that of human noncancerous MCF-10A cells. Overexpression of DOK7 inhibited proliferation, migration, and invasion, while silencing DOK7 expression promoted the malignancy of breast cancer. In addition, overexpression of DOK7 suppressed tumor proliferation and lung metastasis in animal models. Finally, to investigate the possible signaling mechanism, we first found that the level of p-AKT protein was extremely downregulated and the level of PTEN protein was remarkably upregulated after overexpressing DOK7 in breast cancer cells. Repression of PTEN expression using PTEN siRNA or SF1670 (PTEN inhibitor) rescued the tumor-inhibiting effect induced by DOK7 overexpression, suggesting that DOK7 inhibits proliferation, migration, and invasion of breast cancer cells though the PI3K/PTEN/AKT pathway. These results suggest that the downregulation of DOK7 may become a novel breast cancer therapeutic target

Angiectatic nasal polyps with pleomorphism ‒ a diagnostic pitfall

Objective: To generalise the features of PANP in case of potential clinical and pathological pitfall of diagnosis. Methods: Thirteen patients diagnosed as PANP were retrospectively analyzed in the Pathology Department of Capital Medical University from August 2014 to December 2019. Immunohistochemical staining with CD34, CK, Vim, Calponin, Ki67, Bcl-2, and STAT-6 was performed with envision-two steps method. Results: PANP is a benign tumor presenting with gross variegated tan to gray soft fleshy tissue with foci of obvious hemorrhage and necrosis. The imaging shows internal heterogeneous hyperintensity with a peripheral hypointense rim while postcontrast images display a strong nodular and patchy enhancement. Vimentin (Vim) stain was consistently positive, while negative for CD34, STAT-6 and Bcl-2 (focal positive in two cases). Calponin and CK stain was positive in nine cases, respectively. Conclusion: PANP is a clinically rare tumor which may simulate malignancy lesion. Recognizing of characteristic features in these thirteen patients would be beneficial to avoid misdiagnosis and unnecessary aggressive treatment. Level of evidence: This work was Level 2 of evidence according to the Guide for Authors

Predictive significance of tissue eosinophilia for nasal polyp recurrence in the Chinese population

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) remains a challenging clinical entity with its propensity for recurrence. Tissue eosinophilia is a hallmark of CRSwNP, and its role in polyp recurrence is a subject of much investigation. Objective: The aim of this study was to evaluate the association between clinical parameters, especially tissue eosinophilia and polyp recurrence, and to identify the optimal cutoff value of tissue eosinophilia as a predictor for polyp recurrence in Chinese subjects. Methods: Overall, 387 patients with CRSwNP were enrolled in this retrospective analysis and postoperative follow-up for polyp recurrence was over a period that lasted > 24 months (mean [standard deviation], 34.03 +/- 4.95 months). The baseline demographic and clinical features and the preoperative computed tomography were compared, and mucosal specimens obtained at endoscopic sinus surgery were assessed for inflammatory cells by using histocytologic staining. Predictive factors associated with polyp recurrence were analyzed by logistic regression analysis, and optimal cutoff points of the predictors were determined by receiver operating characteristic curves and the Youden index. Results: A total of 55.3% patients (214/387) experienced recurrence. Tissue eosinophilia markedly outweighed other parameters and correlated with polyp recurrence. Receiver operating characteristic curves indicated that a cutoff value of 27% tissue eosinophils predicted recurrence with 96.7% sensitivity and 92.5% specificity (area under the curve = 0.969; p < 0.001); and an absolute count of 55 eosinophils per high power field predicted recurrence with 87.4% sensitivity and 97.1% specificity (area under the curve = 0.969; p < 0.001). Conclusion: A tissue eosinophil proportion of > 27% of total cells or a tissue eosinophil absolute count of > 55 eosinophils per high power field may act as a reliable prognostic indicator for nasal polyp recurrence within 2 years after surgery

Cellular phenotyping of chronic rhinosinusitis with nasal polyps

Background: Defining the phenotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) with prognosis may lead to delivery of personalized treatment. This study aimed to identify cellular phenotypes of CRSwNP using cluster analysis and define an algorithm for different clusters associated with polyp recurrence. Methods: Overall, 366 patients with CRSwNP were enrolled in this retrospective analysis. Eighteen variables, including clinical characteristics and tissue/peripheral inflammatory cells assessments, were selected for factor analysis. Unsupervised cluster analysis was performed after variables reduction and standardization and differences in polyp recurrence during follow-up for a minimum of 24 months were analysed among clusters. Discriminant analysis was further used to develop a clinically useful algorithm for predicting clustering. Results: Five phenotypic clusters were identified. Clusters 1 and 2 were plasma cell-dominant and lymphocyte-dominant phenotypes, respectively. Cluster 3 revealed a mixed inflammatory pattern. Cluster 4 was characterized by infiltration of predominantly neutrophils. Cluster 5 was characterized by a marked tissue eosinophilia and highest recurrence rate of 98.5%. The clinical algorithm predicted clustering with 93.7% accuracy. Conclusions: Chinese CRSwNP patients may be classified into five phenotypes with different polyp recurrence rates, based on the presence of predominantly plasma cells, lymphocytes, neutrophils, eosinophils or mixed inflammatory cells in polyps