Chinese Expert Consensus on the Use of Biologics in Patients with Chronic Rhinosinusitis (2022, Zhuhai).

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disease in otolaryngology, mainly manifested as nasal congestion, nasal discharge, facial pain/pressure, and smell disorder. CRS with nasal polyps (CRSwNP), an important phenotype of CRS, has a high recurrence rate even after receiving corticosteroids and/or functional endoscopic sinus surgery. In recent years, clinicians have focused on the application of biological agents in CRSwNP. However, it has not reached a consensus on the timing and selection of biologics for the treatment of CRS so far. SUMMARY: We reviewed the previous studies of biologics in CRS and summarized the indications, contraindications, efficacy assessment, prognosis, and adverse effects of biologics. Also, we evaluated the treatment response and adverse reactions of dupilumab, omalizumab, and mepolizumab in the management of CRS and made recommendations. KEY MESSAGES: Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP by the US Food and Drug Administration. Type 2 and eosinophilic inflammation, need for systemic steroids or contraindication to systemic steroids, significantly impaired quality of life, anosmia, and comorbid asthma are required for the use of biologics. Based on current evidence, dupilumab has the prominent advantage in improving quality of life and reducing the risk of comorbid asthma in CRSwNP among the approved monoclonal antibodies. Most patients tolerate biological agents well in general with few major or severe adverse effects. Biologics have provided more options for severe uncontrolled CRSwNP patients or patients who refuse to have surgery. In the future, more novel biologics will be assessed in high-quality clinical trials and applied clinically.

A nationwide survey of otolaryngologists' compliance with Chinese guidelines for diagnosis and treatment of allergic rhinitis.

BACKGROUND: A higher compliance with clinical guidelines helps improve treatment outcomes. But the clinical practice of otolaryngologists is not always consistent with guidelines. OBJECTIVE: To describe otolaryngologists' compliance with guidelines about allergic rhinitis (AR) management and identify factors responsible for the discordance between clinical practice and guideline recommendations in China. METHODS: A cross-sectional nationwide survey was designed and conducted via an online platform. Recruitment was done by emailing otolaryngologists registered in the Chinese Society of Otorhinolaryngology-Head and Neck Surgery or by inviting otolaryngologists to scan a Quick Respond (QR) code that linked to the questionnaire at various academic meetings. RESULTS: A total of 2142 otolaryngologists were eligible and completed the survey. Of them, 64.7% had over 10 years work experience and 97.4% had a bachelor's degree or higher. About 18.3% of the participants strictly copied the guideline in clinical practice, while 73.7% used the guideline that had been adjusted according to their clinical experience. Otolaryngologists were most concerned about the efficacy, safety, and minimum age of AR medications, and least concerned about patient preferences. Regarding the use of intranasal steroids (INS), leukotriene receptor antagonists (LTRA), and H1-antihistamines, 86.8%, 55.7% and 51.2% of otolaryngologists complied with the guideline recommendations, respectively. Educational background was a factor affecting the compliance with guidelines and acceptance of INS. CONCLUSION: A vast majority of Chinese otolaryngologists complied with the current Chinese AR guidelines. A difference still existed between the otolaryngologists' real-world and guideline-recommended management. The otolaryngologists should pay more attention to patient preferences. A higher education could improve otolaryngologists' adherence to the guidelines.

Annealing effect on UV-illuminated recovery in gas response of graphene-based NO2 sensors.

The response and recovery of a graphene-based sensor for nitrogen dioxide (NO2) sensing is improved by a combination of two treatments including rapid thermal annealing (RTA) of graphene and UV illumination during the pump down period. A two-dimensional monolayer graphene grown by chemical vapor deposition was transferred to an arc-shape electrode and subsequently heated at temperatures from 200 to 400 °C for 1 min in N2 atmosphere by RTA to eliminate the chemical residues on the graphene generated in the transfer process. The effect of RTA and poly(methyl methacrylate) (PMMA) residues was investigated using Raman spectroscopy. The shift of the G and 2D bands could be due to graphene suffering from compressive strain and hole doping from the substrate enhanced by the RTA treatment. The hole doping effect was also observed from Hall measurements. Atomic force microscopy images confirm the PMMA residues and surface roughness reduction by the RTA treatment. Annealing at 300 °C enhances the NO2 sensing response at 1 ppm by 4 times compared to the pristine graphene without RTA. Full recovery of the sensor to the initial baseline could be achieved by the adjustment of UV illumination time.

Identification of high-confidence RNA regulatory elements by combinatorial classification of RNA-protein binding sites.

Crosslinking immunoprecipitation sequencing (CLIP-seq) technologies have enabled researchers to characterize transcriptome-wide binding sites of RNA-binding protein (RBP) with high resolution. We apply a soft-clustering method, RBPgroup, to various CLIP-seq datasets to group together RBPs that specifically bind the same RNA sites. Such combinatorial clustering of RBPs helps interpret CLIP-seq data and suggests functional RNA regulatory elements. Furthermore, we validate two RBP-RBP interactions in cell lines. Our approach links proteins and RNA motifs known to possess similar biochemical and cellular properties and can, when used in conjunction with additional experimental data, identify high-confidence RBP groups and their associated RNA regulatory elements.

Recurrently deregulated lncRNAs in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) cells often invade the portal venous system and subsequently develop into portal vein tumour thrombosis (PVTT). Long noncoding RNAs (lncRNAs) have been associated with HCC, but a comprehensive analysis of their specific association with HCC metastasis has not been conducted. Here, by analysing 60 clinical samples' RNA-seq data from 20 HCC patients, we have identified and characterized 8,603 candidate lncRNAs. The expression patterns of 917 recurrently deregulated lncRNAs are correlated with clinical data in a TCGA cohort and published liver cancer data. Matched array data from the 60 samples show that copy number variations (CNVs) and alterations in DNA methylation contribute to the observed recurrent deregulation of 235 lncRNAs. Many recurrently deregulated lncRNAs are enriched in co-expressed clusters of genes related to cell adhesion, immune response and metabolic processes. Candidate lncRNAs related to metastasis, such as HAND2-AS1, were further validated using RNAi-based loss-of-function assays. Thus, we provide a valuable resource of functional lncRNAs and biomarkers associated with HCC tumorigenesis and metastasis.

POSTAR: a platform for exploring post-transcriptional regulation coordinated by RNA-binding proteins.

We present POSTAR (http://POSTAR.ncrnalab.org), a resource of POST-trAnscriptional Regulation coordinated by RNA-binding proteins (RBPs). Precise characterization of post-transcriptional regulatory maps has accelerated dramatically in the past few years. Based on new studies and resources, POSTAR supplies the largest collection of experimentally probed (∼23 million) and computationally predicted (approximately 117 million) RBP binding sites in the human and mouse transcriptomes. POSTAR annotates every transcript and its RBP binding sites using extensive information regarding various molecular regulatory events (e.g., splicing, editing, and modification), RNA secondary structures, disease-associated variants, and gene expression and function. Moreover, POSTAR provides a friendly, multi-mode, integrated search interface, which helps users to connect multiple RBP binding sites with post-transcriptional regulatory events, phenotypes, and diseases. Based on our platform, we were able to obtain novel insights into post-transcriptional regulation, such as the putative association between CPSF6 binding, RNA structural domains, and Li-Fraumeni syndrome SNPs. In summary, POSTAR represents an early effort to systematically annotate post-transcriptional regulatory maps and explore the putative roles of RBPs in human diseases.

CCG: an integrative resource of cancer protein-coding genes and long noncoding RNAs.

The identification of cancer genes remains a main aim of cancer research. With the advances of high-throughput sequencing technologies, thousands of novel cancer genes were identified through recurrent mutation analyses and differential expression analyses between normal tissues and tumors in large populations. Many databases were developed to document the cancer genes. However, no public database providing both cancer protein-coding genes and cancer lncRNAs is available presently. Here, we present the Catalogue of Cancer Genes (CCG) database (http://ccg.xingene.net), a catalogue of cancer genes. It includes both well-supported and candidate cancer protein-coding genes and cancer lncRNAs collected from literature search and public databases. In addition, uniform genomic aberration information (such as somatic mutation and copy number variation) and drug-gene interactions were assigned to cancer genes in the database. CCG represents an effort on integrative assembly of well-supported and candidate cancer protein-coding and long noncoding RNA genes and takes advantages of high-throughput sequencing results on large populations. With the help of CCG, users can easily access a comprehensive list of cancer genes as well as genomic aberration related with these genes. The availability of integrative information will facilitate the understanding of cancer mechanisms. In addition, drug-gene information in CCG provides a useful guide to the development of new anti-cancer drugs and selection of rational combination therapies.

MicroRNA expression profile of mature dendritic cell in chronic rhinosinusitis.

OBJECTIVE: Chronic rhinosinusitis (CRS), which includes CRS without nasal polyposis (CRSsNP) and with nasal polyposis (CRSwNP), shows imbalance of helper T cells (Th) and regulatory T cells (Treg). The balance of Th and Treg cells is orchestrated by dendritic cells (DCs). Recent studies show functions of DCs can be regulated by microRNAs (miRNAs or miRs). This study is aimed to investigate miRNAs expression profiles of peripheral blood DCs in CRS. METHODS: Peripheral blood samples of 30 patients with CRS and 7 patients with nasal septum deviation alone were collected. CD14(+) monocytes were isolated from these samples and differentiated into dendritic cells (DCs). Small RNAs were extracted from mature DCs and reversely transcribed into cDNA by Mir-XTM miRNA First-Strand synthesis method. MiRNA microarrays were used for miRNA expression analysis. Microarray results were validated by real-time PCR performed on five top list target genes. RESULTS: MiRNA microarrays showed that DCs from different types of patients have different sets of differential expressed miRNAs when comparing with Controls; they also share 31 commonly changed miRNAs among all three groups of CRS patients. Of these 31 miRNAs, 5 miRNAs were up-regulated and 25 miRNAs were down-regulated in all three types of CRS, while MiR-1290 was down-regulated in CRSsNP but up-regulated in both atopic CRSwNP and non-atopic CRSwNP. CONCLUSIONS: By comparing miRNA gene expression patterns in 3 types of CRS patients, we have been able to identify candidate miRNAs that might mediate the core pathogenesis of CRS through regulating dendritic cells. These miRNAs could serve as potential therapeutic targets for CRS.

Fluorescence visualization screening for EBV-LMP1-targeted DNAzymes.

OBJECTIVES: To develop a novel screening method for DNAzymes targeting the LMP1 carboxy region. STUDY DESIGN: To design a method to screen special DNAzymes toward the Epstein-Barr virus (EBV)-associated carcinoma before clinic use. SETTING: Key Laboratory of the Ministry of Education-Molecular Biology of Infectious Diseases in Chongqing Medical University. SUBJECTS AND METHODS: Four novel 10-23 DNAzymes (DZ509, DZ1037, DZ893, and DZ827) targeting the EBV-LMP1 gene were designed and evaluated by detecting enhanced green fluorescence protein (EGFP) expression of LMP1 mRNA and the protein in the nasopharyngeal carcinoma (NPC) cell line CNE2 transfected with the pEGFP-C1-LMP1c vector. The screened specific DNAzymes were then transfected into NPC cell lines C666-1 while a mutant oligonucleotide mutDZ509 and an antisense oligonucleotide ASODN509 were designed as positive and negative controls. Cell proliferation, cell apoptosis, LMP1 mRNA, and the protein were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, Annexin V-fluorescence isothiocyanate (FITC), reverse transcription polymerase chain reaction (RT-PCR), and Western blots. RESULTS: The inhibition rates of fluorescence expression of the DNAzymes DZ509, DZ1037, DZ893, and DZ827 were 91.25%, 65.84%, 49.02%, and 44.56%, respectively. The results were in accordance with the inhibition effects of mRNA and protein expression. The screened DZ509 could effectively knock down endogenous LMP1 expression in C666-1 cells, inhibit cell proliferation, and induce cell apoptosis compared with mutDZ509 and ASODN509. CONCLUSION: LMP1 could present a potential target for DNAzymes toward the EBV-associated carcinoma, and the EGFP expression vector could be a visible method for screening special DNAzymes before clinic use.

[Transposition of orbital fat and orbicularis muscle flap over the orbital rim for correction of lower eyelid pouches complicated with lacrimal groove deformity].

OBJECTIVE: To introduce the experience in the treatment of lower eyelid pouches orbital rim. METHODS: An incision was made along the margin of lower eyelid and dissection was performed under the orbicularis muscle to expose the orbital septum and periosteum of lower orbital rim. The fat released from orbital septum was transposed just below the lower orbital rim and fixed on the periosteum. If lacrimal groove deformity was not corrected completely, the musculocutaneous flap, which may be excised beside the incision, was kept to correct the deformities further with only the muscle portion. RESULTS: 72 cases with lower eyelid pouches complicated with lacrimal groove deformities were treated with transposition of orbital fat and orbicularis muscular flaps. Satisfactory results were achieved in all the patients after a follow-up period of 3-6 months. CONCLUSION: It is an effective and feasible technique to correct lacrimal groove deformities with transposition of orbital fat and orbicularis muscular flaps.

Allergen induced Th17 response in the peripheral blood mononuclear cells (PBMCs) of patients with nasal polyposis.

BACKGROUND: Nasal polyposis (NP) is a chronic inflammatory disease of the nasal cavity and sinuses. Th17 cells have been considered to play roles in allergic airway diseases and various chronic inflammatory disorders. AIM OF THE STUDY: This study aimed to investigate the population and function of peripheral Th17 cells in response to house dust mite extracts (HDM) allergen in NP patients, and evaluate the possible correlation between Th17 cells and atopy, to explore the role of atopy in the pathogenesis of NP. METHODS: Peripheral blood mononuclear cells (PBMCs) obtained from atopic NP patients, non-atopic NP patients, and controls were stimulated by phytohemagglutinin (PHA) or HDM plus PHA. The resulting frequency of Th17 cells was detected by flow cytometry and the expression of RORc was measured by real-time PCR. Then the concentrations of IL-17A, INF-γ, IL-4 and IL-5 in the supernatants were assayed by specific ELISAs. RESULTS: The population and function of Th17 cells in allergen stimulated PBMCs were significantly higher in atopic NP patients. In addition, in atopic group, HDM+PHA stimulation induced significant increase of Th17 population and IL-17A production versus those in PHA stimulated ones. However, the frequency of Th17 cells was not correlated with Th1, Th2 cytokine productions. CONCLUSION: Th17 immunity is involved in the systemic immune responses to allergen in atopic NP and atopy may aggravate NP by stimulating the increase of Th17 population and IL-17A production. The mechanism of Th17 cells response to allergen may be regulated differently from the regulation of Th1 and Th2 immunity in NP.

Significance of interleukin-17A in patients with nasal polyposis.

BACKGROUND: Interleukin-17A (IL-17A) is a key inflammatory cytokine in many disorders, while the significance of IL-17A in nasal polyposis (NP) is still obscure. This study aimed to investigate the expression of IL-17A in nasal polyps from both atopic and nonatopic patients and its associations with clinical and histological features. METHODS: In all, 30 patients with NP were included, and were grouped into atopic and nonatopic patients according to skin prick test (SPT). Disease severity was evaluated by symptom score, endoscopy score and CT score. Histological characteristics were assessed by eosinophilic infiltration, basement membrane (BM) thickness, epithelial damage, squamous metaplasia, and goblet cell hyperplasia. IL-17A expression in polyps was detected by ELISA and immunohistochemistry. RESULTS: Endoscopy score and CT score were significantly higher in atopic NP patients than in nonatopic NP patients (p < 0.05). IL-17A levels were significantly upregulated in both atopic (p < 0.01) and nonatopic (p < 0.05) patients versus controls. Furthermore, IL-17A levels were significantly higher in the atopic group versus nonatopic group. Significantly positive correlations were found between IL-17A levels and CT scores, eosinophilic infiltration and BM thicknesses. CONCLUSIONS: These results indicated that expression of IL-17A was significantly upregulated in NP patients and was more severe in atopic NP patients, suggesting that IL-17A may play an important role in the pathology of NP and atopy may contribute to NP by stimulating the production of IL-17A.

[Preliminary clinical study on the treatment of severe infantile hemangioma with high-dose propranolol in China].

OBJECTIVE: To investigate the clinical results of the treatment of severe infantile hemangioma with high-dose propranolol in Chinese. METHODS: 56 cases with severe infantile hemangioma were treated with propranolol. Clinical evaluation, electrocardiography, and experimental examination of liver function and heart function were performed before treatment. The daily dose of propranolol was increased from 1 mg/kg at the first day to 1.5 mg/kg at the second day, and to 2 mg/kg at the third day. The propranolol was given twice a day. The treatment was lasted for six months. The patients were visited every month. RESULTS: The lesion color was changed after 2-4 days of treatment in all the cases. All the lesions were dramatically improved after one month of treatment. The ulceration were healed, except one case. Until now, complete regression was achieved in 10 cases and marked improvement in 46 cases. Side effects were happened in 3 cases, including one case of abnormal liver function, one case of CK-MB increase and one case of continuous increase of CK-MB, LDH, ALT, GGT. CONCLUSIONS: High-dose Propranolol is very effective in the treatment of infantile hemangioma with minor side effects and short disease period. It might he used as the first-line treatment for infantile hemangioma.

EBV-LMP1-targeted DNAzyme restrains nasopharyngeal carcinoma growth in a mouse C666-1 xenograft model.

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has been demonstrated to be linked to the pathogenesis of nasopharyngeal carcinoma (NPC), one of the most common cancers in southeast Asia as well as in the areas of southern China. RNA-cleaving DNAzymes are catalytic nucleic acids that bind and cleave a target RNA and have been increasingly used to inhibit gene expression. In this study, we aimed to explore the effects of down-regulation of LMP1 by DNAzymes on the NPC growth using a mouse xenograft model derived from human NPC C666-1 cells that constitutively express the LMP1. A specific LMP1-targeted DNAzyme, named DZ509, was synthesized, showing high activities in the inhibition of LMP1 expression, while the control DNAzyme (mutDZ509) had little effect on LMP1 expression. Knockdown of the LMP1 expression by DZ509 reduced cell proliferation and increased apoptosis compared to the cells transfected with mutDZ509. Intratumoral injections of DZ509 into C666-1 xenografts caused a significant suppression of tumor growth compared to mutDZ509-treated xenografts. Examination of the LMP1 expression in the xenografts demonstrated a marked inhibition of LMP1 by DZ509. An antisense oligonucleotide targeting the same site of the LMP1 transcripts was employed in parallel and produced a comparable inhibition on cell proliferation in vitro and tumor growth in vivo. These data demonstrate that LMP1-targeted DNAzyme is efficient in controlling tumor growth in vivo, and thus may have therapeutic implications in the treatment of NPC.

[Effect of endoscopic sinus surgery on asthmatic patients with chronic sinusitis and nasal polyps].

OBJECTIVES: To explore the effect of endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis and asthma. METHODS: Forty-two patients with asthma who underwent ESS and control group were investigated. Interleukin-4 (IL-4), interferon-gamma (IFN-gamma), soluble interleukin-2 receptor (sIL-2R) and soluble CD23 (sCD23) levels in culture supernatant of peripheral blood mononuclear cell (PBMC) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Of these 42 patients 32 (76%), their asthma was relieved greatly after ESS comparing with that before ESS. 14 of 21 patients (67%) taken regular medication for asthma before ESS reported that less medicine was used after operation. CONCLUSION: This study demonstrates that ESS has a favorable effect on asthma in patients with symptomatic chronic sinusitis.