Epithelium-derived kallistatin promotes CD4+ T-cell chemotaxis to TH2-type inflammation in chronic rhinosinusitis.

BACKGROUND: The function of kallistatin in airway inflammation, particularly chronic rhinosinusitis with nasal polyps (CRSwNP), has not been elucidated. OBJECTIVE: We sought to investigate the role of kallistatin in airway inflammation. METHODS: Kallistatin and proinflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin-overexpressing transgenic mice to elucidate the role of kallistatin in airway inflammation. Furthermore, the levels of plasma IgE and proinflammatory cytokines in the airways were evaluated in the kallistatin-/- rat in vivo model under a type 2 inflammatory background. Finally, the Notch signaling pathway was explored to understand the role of kallistatin in CRSwNP. RESULTS: We showed that the expression of kallistatin was significantly higher in nasal polyps than in the normal nasal mucosa and correlated with IL-4 expression. We also discovered that the nasal mucosa of kallistatin-overexpressing transgenic mice expressed higher levels of IL-4 expression, associating to TH2-type inflammation. Interestingly, we observed lower IL-4 levels in the nasal mucosa and lower total plasma IgE of the kallistatin-/- group treated with house dust mite allergen compared with the wild-type house dust mite group. Finally, we observed a significant increase in the expression of Jagged2 in the nasal epithelium cells transduced with adenovirus-kallistatin. This heightened expression correlated with increased secretion of IL-4, attributed to the augmented population of CD4+CD45+Notch1+ T cells. These findings collectively may contribute to the induction of TH2-type inflammation. CONCLUSIONS: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the TH2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4+ T cells.

A novel risk score for disease control prediction of chronic rhinosinusitis.

OBJECTIVES: To assess the impact of risk factors on the disease control among chronic rhinosinusitis (CRS) patients, following 1 year of functional endoscopic sinus surgery (FESS), and combining the risk factors to formulate a convenient, visualised prediction model. DESIGN: A retrospective and nonconcurrent cohort study. SETTING AND PARTICIPANTS: A total of 325 patients with CRS from June 2018 to July 2020 at the First Affiliated Hospital of Sun Yat-sen University, the Third Affliated Hospital of Sun Yat-sen University, the Seventh Affiliated Hospital of Sun Yat-sen University. MAIN OUTCOMES MEASURES: Outcomes were time to event measures: the disease control of CRS after surgery 1 year. The presence of nasal polyps, smoking habits, allergic rhinitis (AR), the ratio of tissue eosinophil (TER) and peripheral blood eosinophil count (PBEC) and asthma was assessed. The logistic regression models were used to conduct multivariate and univariate analyses. Asthma, TER, AR, PBEC were also included in the nomogram. The calibration curve and area under curve (AUC) were used to evaluate the forecast performance of the model. RESULTS: In univariate analyses, most of the covariates had significant associations with the endpoints, except for age, gender and smoking. The nomogram showed the highest accuracy with an AUC of 0.760 (95% CI, 0.688-0.830) in the training cohort. CONCLUSIONS: In this cohort study that included the asthma, AR, TER, PBEC, which had significantly affected the disease control of CRS after surgery. The model provided relatively accurate prediction in the disease control of CRS after FESS and served as a visualised reference for daily diagnosis and treatment.

Response to crizotinib in a patient with MET-amplified hepatocellular carcinoma.

AIMS: Molecular profiling of hepatocellular carcinoma (HCC) has helped identify actionable genomic alterations that could guide therapeutic decision-making and clinical trial enrollment. However, in clinical practice, next-generation sequencing (NGS) is not extensively used in routine clinical care to identify patients with HCC who are likely to benefit from genome-directed targeted therapies. METHODS: Here, we describe the case of a 66-year-old man with advanced HCC. After rapid progression on transarterial chemoembolization, the tissue sample obtained from biopsy was subjected to NGS to verify whether precision therapy was an option. RESULTS: Our analysis revealed high MET amplification. The patient received crizotinib (250 mg, bid) and showed a remarkable response. CONCLUSIONS: Our case report suggests NGS could help identify patients with high MET amplification in HCC who were likely to benefit from MET inhibitors; moreover, this requires further investigation in clinical trials.

A novel nomogram to predict the overall survival in esthesinoeroblastoma.

BACKGROUND: Increasing evidence indicates that the pathology and the modified Kadish system have some influence on the prognosis of esthesioneuroblastoma (ENB). However, an accurate system to combine pathology with a modified Kadish system has not been established. METHODS: This study aimed to set up and evaluate a model to predict overall survival (OS) accurately in ENB, including clinical characteristics, treatment and pathological variables. We screened the information of patients with ENB between January 1, 1976, and December 30, 2016 from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program as a training cohort. The validation cohort consisted of patients with ENB at Sun Yat-sen University Cancer Center and The First Affiliated Hospital of Sun Yat-sen University in the same period, and 87 patients were included. The Pearson's chi-squared test was used to assess significance of clinicopathological and demographic characteristics. We used the Cox proportional hazards model to examine univariate and multivariate analyses. The model coefficients were used to calculate the Hazard ratios (HR) with 95% confidence intervals (CI). Prognostic factors with a p-value < 0.05 in multivariate analysis were included in the nomogram. The concordance index (c-index) and calibration curve were used to evaluate the predictive power of the nomogram. RESULTS: The c-index of training cohort and validation cohort are 0.737 (95% CI, 0.709 to 0.765) and 0.791 (95% CI, 0.767 to 0.815) respectively. The calibration curves revealed a good agreement between the nomogram prediction and actual observation regarding the probability of 3-year and 5-year survival. We used a nomogram to calculate the 3-year and 5-year growth probability and stratified patients into three risk groups. CONCLUSIONS: The nomogram provided the risk group information and identified mortality risk and can serve as a reference for designing a reasonable follow-up plan.

RBFOX2 confers tumor growth by PI3K/AKT and MAPK signaling in gastric cancer.

RNA-binding Fox (RBFOX)2, a member of a family of RNA-binding proteins, is well known as a regulator of alternative pre-mRNA splicing. However, its possible role in gastric cancer is unknown. In this study, we investigated the biologic role and clinical significance of RBFOX2 in gastric cancer growth and elucidated its underlying molecular mechanisms. We found that RBFOX2 was highly expressed in gastric cancer cell lines and tumor tissue compared with the adjacent nontumor tissue. We also found that RBFOX2 overexpression was correlated with poor overall survival in patients with gastric cancers. Multivariate survival analyses revealed that higher RBFOX2 expression was an independent prognostic factor for the overall survival of patients with gastric cancers. Suppression of RBFOX2 by shRNA inhibited gastric cancer cell proliferation, colony formation and induced apoptosis. Mechanism studies revealed that these effects were achieved through the simultaneous modulation of multiple signaling pathways. Knockdown of RBFOX2 expression by shRNA markedly inhibited the phosphorylation of phosphatidylinositol 3-hydroxy kinase, threonine kinase and extracellular signal-regulated kinase and Jun N-terminal kinases proteins. In contrast, the ectopic expression of RBFOX2 had the opposite effects. Moreover, RBFOX2 knockdown also induced the cleavage of caspase-3 and caspase-9 proteins. Collectively, these results demonstrate that RBFOX2 plays a critical role in regulating gastric cancer cell proliferation and survival and may be a potential prognostic biomarker and therapeutic target for gastric cancer.

Effect of Fu's subcutaneous needling for cancer pain management: protocol for a pragmatic randomised controlled trial.

INTRODUCTION: Pain is a common symptom in patients with cancer, and pain management is crucial for these patients. Fu's subcutaneous needling (FSN) is a modern acupuncture therapy based on basic medicine commonly used in patients with pain. However, evidence of its effectiveness in treating cancer pain has not been systematically proven. Therefore, this pragmatic randomised controlled trial aims to evaluate the effectiveness and safety of FSN for cancer pain management. METHODS AND ANALYSIS: Overall, 120 eligible patients will be recruited and randomly assigned into two groups using block randomisation. Both groups will be administered analgesic drugs according to the National Comprehensive Cancer Network guidelines. The treatment group will receive FSN therapy one time a day for 6 days. Additionally, we will assess analgesic consumption as the primary outcome and the Numerical Rating Scale, outbreak pain, symptom assessment and adverse events as secondary outcomes to evaluate the effect and safety of FSN in treating cancer pain. The incidence of adverse events will be monitored to assess the safety of FSN. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (approval No: K(2021)096). The results will be published in a peer-reviewed journal, and trial participants will be informed via email and/or phone calls. TRIAL REGISTRATION NUMBER: ChiCTR2200056348.

Distinct Genomic Landscape of Colorectal Mucinous Carcinoma Determined via Comprehensive Genomic Profiling: Steps to a New Treatment Strategy.

Colorectal mucinous carcinoma (MC) is associated with inferior prognosis and response to treatment compared to adenocarcinoma (AC). The molecular landscapes of MC and adenocarcinoma with mucous composition (AMC) are not well-defined. We aimed to describe the genomic landscape of MC and AMC in a large colorectal cancer cohort. Tumor samples from patients with MC, AMC, or AC were analyzed using next-generation sequencing. MC had a molecular signature distinct from that of AC; genomic features were similar between AMC and MC but not between AMC and AC. HER2 amplification and TP53 and APC mutation rates were lower, whereas SMAD4, PIK3CA, ACVR2A, KMT2D, LRP1, TGFBR2, GRIN2A, BRAF V600E, PTEN, and BRCA2 mutation rates were higher in MC than in AC. The mutation frequencies in MAPK, PI3K, and TGF- pathways were higher, whereas those of cell cycle proteins and Wnt were lower in MC and AMC than in AC. The proportion of hypermutated tumors was significantly higher in MC and AMC than in AC. As MC has a distinct molecular signature from AC, immunotherapy can be potentially applied in treating MC. Similar molecular profiles of AMC and MC suggest that treatment strategies for MC, but not AC, can be used for AMC treatment.

Crizotinib inhibits activation of MET pathway caused by MET extracellular SEMA domain duplication.

OBJECTIVE: Aberrant MET activation, which promotes cell proliferation and tumor metastasis, occurs in many types of cancer and results from multiple mechanisms. A novel MET duplication mutation was found in a non-small cell lung cancer (NSCLC) patient. The clinical response to crizotinib was investigated and the functional relevance was characterized in cellular models. MATERIALS AND METHODS: Next-generation sequencing (NGS) was performed on the tumor tissue and circulating tumor DNA (ctDNA) of a patient with advanced NSCLC. In vitro studies including western blot, proliferation assays and colony formation assays were used to confirm the clinical observations. RESULTS: The patient was identified to harbor a duplication of the MET SEMA domain. After a month of treatment, the patient showed a marked response to crizotinib, a multikinase inhibitor with potent activity against MET. Functional in vitro studies demonstrated that expression of MET SEMA duplication in NIH-3T3 cells stimulated the activation of MET signaling. Crizotinib treatment obviously repressed cell proliferation, colony formation, and MET signaling pathway. CONCLUSION: Crizotinib treatment resulted in a clinical response in a patient with MET SEMA duplication. Results of cellular analyses together with the clinical data suggest that this novel alteration may represent an actionable target in NSCLC patients.