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.

Effects of SENP1-induced deSUMOylation of STAT1 on proliferation and invasion in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is the most common nasopharyngeal squamous cell carcinoma, and recurrence and metastasis are still difficult problems in its current treatment. This study aimed to investigate the effect of SUMO modification of STAT1 protein on the proliferation and invasion of NPC, and to reveal the underlying mechanism. Two gene expression profiles (GSE12452 and GSE53819) of 49 nasopharyngeal carcinomas and 28 normal controls were analyzed to identify differentially expressed genes. In total, 448 up-regulated genes and 622 down-regulated genes were identified. In addition, 16 SUMO-related molecules in the NPC dataset GSE102349 with survival data were analyzed, and it was found that the high expression of SENP1 and SENP2 was closely related to the poor prognosis of NPC. GO and GSEA analysis suggested that immune-related biological processes, IFN-γ-STAT signaling pathway and protein modification-related molecules were significantly enriched in NPC, resulting in poor survival prognosis. In order to verify the results of bioinformatics analysis and explore its underlying molecular mechanisms, western blot, Immunofluorescence, Immunoprecipitation and Immunohistochemistry are conducted in NPC cells, animals and clinical samples. SENP1 and STAT protein levels were increased in NPC tissues. SENP1 inhibited SUMOylation of STAT1, thereby promoting the protein level of STAT1 and the nuclear translocation. SENP1 promoted the proliferation and invasion of NPC by inducing STAT1. Overall, SENP1-induced deSUMOylation of STAT1, resulting in an increased proliferation and invasion of nasopharyngeal carcinoma.

κ-Carrageenan oligosaccharides induce microglia autophagy through AMPK/ULK1 pathway to regulate their immune response.

Microglia are the main effector cells of immune response in central nervous system and are important targets for disease prevention and treatment. Κ-carrageenan Oligosaccharide (KOS), obtained by enzymatic hydrolysis from carrageenan of marine red algae, can inhibit the release of inflammatory factors from the over-activated microglia. The mechanism of microglia autophagy induced by KOS and its relationship with inflammation were studied to explore the development prospect of KOS in the research and treatment of inflammatory related diseases. The effect of KOS on inducing autophagy was detected by the secretion of cytokines by lipopolysaccharide (LPS)-activated microglia, respectively. The protein expression of autophagy-related signaling pathways were detected by Western Blot. The results showed that KOS could significantly protect the microglia from over-activated inflammatory by inducing the autophagy and inhibiting the release of inflammatory cytokines. And KOS could reduce the expression of the protein that related to the AMPK/ULK1 pathways in microglia, so as to regulate the autophagy pathway, and inhibit the inflammatory response of over-activated microglia. The study on the effect of KOS on microglia autophagy and excessive inflammatory response will provide a theoretical basis for further studies on the inhibition of nerve injury by regulating microglia autophagy and inflammatory response.

Altered diversity and composition of gut microbiota in patients with allergic rhinitis.

BACKGROUND: Recently, multiple studies have suggested an association between gut dysbiosis and allergic rhinitis (AR) development. However, the role of gut microbiota in AR development remains obscure. METHODS: The goal of this study was to compare the gut microbiota composition and short-chain fatty acid (SCFAs) differences associated with AR (N = 18) and HCs (healthy controls, N = 17). Gut microbiota 16SrRNA gene sequences were analyzed based on next-generation sequencing. SCFAs in stool samples were analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: Compared with HCs, the gut microbiota composition of AR was significantly different in diversity and richness. At the phylum level, the abundance of Firmicutes in the AR group were significantly lower than those in the HCs group. At the genus level, the abundance of Blautia, Eubacterium_hallii_group, Romboutsia, Collinsella, Dorea, Subdoligranulum and Fusicatenibacter in the AR group were significantly lower than that in the HCs group. The concentrations of SCFAs were significantly lower in the AR group compared with the HCs group. Correlation analysis showed that the Eubacterium-hallii-group and Blautia correlated positively with SCFAs. CONCLUSION: Our results demonstrate compositional and functional alterations of the gut microbiome in AR.

LINC00669 insulates the JAK/STAT suppressor SOCS1 to promote nasopharyngeal cancer cell proliferation and invasion.

Nasopharyngeal carcinoma (NPC) is an epithelial cancer emerging from the lining of nasopharyngeal mucosa, with extremely frequent occurrence in east and southeast Asia. For the purpose of exploring roles of the dysregulated long non-coding RNA (lncRNA) in NPC, we identified a novel lncRNA LINC00669 with an apparent negative correlation to the overall survival from human NPC mRNA expression profiling databases. We further performed RNA pulldown coupled with mass spectrum to find out its target protein, and applied a series of in vitro and in vivo loss-and-gain-of function assays to investigate its oncogenic roles in NPC tumor development and progression. Our results demonstrated that LINC00669 competitively binds to the key JAK/STAT signaling pathway suppressor SOCS1, and insulates it from imposing ubiquitination modification on the pathway component of STAT1, which leads to its abnormal stabilization and activation. The activated STAT1 is then transferred into the nucleus and initiates the transcription of genes related to proliferation and invasion. In summary, our study reveals that the cytoplasmic resident lncRNA LINC00669 confers malignant properties on NPC cancer cells by facilitating a persistent activation of the JAK/STAT signaling pathway. Findings in the current study shed lights on prospects for treating NPC using strategies targeting the novel regulator of the JAK/STAT signaling.

Ophiopogonin D improves osteointegration of titanium alloy implants under diabetic conditions by inhibition of ROS overproduction via Wnt/ß-catenin signaling pathway.

A high failure rate of titanium implants in diabetic patients has been indicated in clinical evidences. Excessive oxidative stress at the bone-implant interface plays an important role in the impaired osteointegration under diabetic conditions. While the underlying mechanisms remain unknown and the targeted treatments are urgently needed. Ophiopogonin D (OP-D), isolated from Chinese herbal Radix Ophiopogon japonicus, is generally reported to be a potent antioxidant agent. In the present study, we hypothesized that OP-D exerted promotive effects on osteointegration against oxidative stress, and investigated the underlying mechanisms associated with alteration of Wnt/ß-catenin signaling pathway. Rabbit osteoblasts incubated on titanium alloy implant were co-cultured with normal serum (NS), diabetic serum (DS), DS + OP-D, DS + NAC (a potent ROS inhibitor) and DS + OP-D + Dkk1 (a Wnt inhibitor) for examinations of osteoblast behaviors. For in vivo study, titanium alloy implants were implanted into the femoral condyle defects on diabetic rabbits. Results demonstrated that diabetes-induced oxidative stress resulted in osteoblast dysfunctions and apoptotic injury at the bone-implant interface, concomitant with the inactivation of Wnt/ß-catenin signaling. Importantly, OP-D administration attenuated oxidative stress, directly reactivating Wnt/ß-catenin signaling. Osteoblast dysfunctions were thus reversed as evidenced by improved osteoblast adhesion, proliferation and differentiation, and ameliorated apoptotic injury, exerting similar effects to NAC treatment. In addition, the positive effects afforded by OP-D were confirmed by improved osteointegration and oetogenesis within the titanium alloy implants in vivo by Micro-CT and histological analyses. Furthermore, the pro-osteogenic effects of OP-D were almost completely abolished by the Wnt inhibitor Dkk1. These results demonstrated, for the first time, OP-D administration alleviated the damaged osteointegration of titanium alloy implants under diabetic conditions by means of inhibiting oxidative stress via a Wnt/ß-catenin-dependent mechanism. The OP-D administration would become a reliable treatment strategy for implant failure therapy in diabetics due to the optimal anti-oxidative and pro-osteogenic properties.

Involvement of FAK-mediated BMP-2/Smad pathway in mediating osteoblast adhesion and differentiation on nano-HA/chitosan composite coated titanium implant under diabetic conditions.

Chitosan (CS)-based hydroxyapatite (HA) composites have emerged as a novel strategy for promoting bone regeneration. Here nanophase HA/CS composite coated porous titanium implants (nCT) were fabricated and their biological behavior under diabetic conditions was investigated. We proposed that the focal adhesion kinase (FAK)-mediated BMP-2/Smad pathway played a role in mediating the promotive effect of nCTs on osteoblast adhesion and differentiation under diabetes-induced high reactive oxygen species (ROS) condition. To confirm the hypothesis, rat osteoblasts on bare titanium implants (Ti) and nCT were subjected to normal serum (NS), diabetic serum (DS), DS + NAC (a potent ROS inhibitor) and DS + cytochalasin D (an actin polymerization inhibitor). In vivo on diabetic sheep implanted with Ti or nCT showed that diabetes-induced ROS overproduction impaired osteoblast adhesion, evidenced by immunostaining of F-actin and vinculin and morphological observation through inhibition of FAK phosphorylation, which contributed to suppressed BMP-2-dependent Smad1/5/8 phosphorylation. nCT substrate reactivated the FAK-BMP-2/Smad pathway, thus reversing osteoblast dysfunction, which exerted a similar effect to NAC treatment on Ti. These effects were further confirmed by improved osteointegration within nCT in diabetic sheep, evidenced by micro-CT and histological examinations. Our study demonstrated that reactivation of the FAK-BMP-2/Smad pathway was involved in improving osteoblast adhesion and differentiation by nano-HA/CS composite coating, potentially directing biomaterial modification and biofunctionalization under diabetic conditions.

Influence of the shape of the micro-finite element model on the mechanical properties calculated from micro-finite element analysis.

Assessing the biomechanical properties of trabecular bone is of major biological and clinical significance for the research of bone diseases, fractures and their treatments. Micro-finite element (µFE) models are becoming increasingly popular for investigating the biomechanical properties of trabecular bone. The shapes of µFE models typically include cube and cylinder. Whether there are differences between cubic and cylindrical µFE models has not yet been studied. In the present study, cubic and cylindrical µFE models of human vertebral trabecular bone were constructed. A 1% strain was prescribed to the model along the superior-inferior direction. E values were calculated from these models, and paired t-tests were performed to determine whether these were any differences between E values obtained from cubic and cylindrical models. The results demonstrated that there were no statistically significant differences in the E values between cubic and cylindrical models, and there were no significant differences in Von Mises stress distributions between the two models. These findings indicated that, to construct µFE models of vertebral trabecular bone, cubic or cylindrical models were both feasible. Choosing between the cubic or cylindrical µFE model is dependent upon the specific study design.

Off-label prescriptions for adult neurological patients: a pilot survey in China.

BACKGROUND: Data concerning the extent of off-label prescriptions for adult neurological patients are limited, and the method of assessing supporting evidence in previous studies has some limitations. OBJECTIVE: To improve the method of assessing supporting evidence, determine the status of off-label prescriptions for adult neurological patients, and evaluate the varying levels of supporting evidence. SETTING: Single, 1,264-bed, tertiary care university hospital in Beijing, China. METHOD: This was a pilot retrospective observational study for adult neurological patients during the period of March 22nd-28th, 2010. Off-label prescriptions were defined according to package inserts. The DRUGDEX system was used to evaluate supporting evidence initially; when information was not available, PubMed/CBM was searched and the grading system proposed by Oxford Centre for Evidence-Based Medicine (OCEBM) was used for categorizing supporting evidence alternatively. MAIN OUTCOME MEASURE: Types, main therapeutic classes and main neurological diseases involved, evidence and recommendation strengths of off-label prescriptions. RESULTS: A total of 418 off-label prescriptions were identified from 3,187 prescriptions for 966 patients, 193 from 759 inpatient (25.4%) and 225 from 2,428 outpatient care (9.3%). Most off-label prescriptions were related to unapproved indications. These off-label prescriptions mainly included drugs labeled for nervous system diseases, cerebrovascular diseases, anemia and ophthalmic conditions; and the medication orders were mostly for cerebrovascular diseases. A total of 155 (37.1%) were initially searched and evaluated in the DRUGDEX system; the remaining 263 (62.9%) prescriptions were found in PubMed/CBM search and evaluated by the OCEBM grading system. Sixty-six (34.2%) off-label prescriptions from inpatients and 103 (45.8%) from outpatients were categorized as Class III or Grade D recommendations. CONCLUSIONS: The improved method provided a supplementary way to study off-label uses. Off-label prescriptions for adult neurological patients mainly concerned unapproved indications, nervous system agents and cerebrovascular diseases, and many of them had inferior level of evidence.

[Health care and disease prevention in Jiujing Tu (Illustration of moxibustion) of the Dunhuang caves].

Figure four of the Jiujing Tu (Illustration of Moxibustion) of the Dunhuang Caves is the earliest and the most complete recording of treatment for five kinds of strain and seven kinds of impairments in the history of acupuncture and moxibustion. Figure 12 is held as a mystery since it only provided illustrations without indications. Through analysis and approved by clinical experiences, it is held that the two figures are companion illustrations on prevention and treatment of five kinds of strain and seven kinds of impairments as well as health keeping with moxibustion. The point prescriptions in these two figures are defined according to the tri-gram in Yijing (The Book of Change), which allowed the maximization of harmony between the human and the nature. Recovery and health are thus fulfilled through regulation on points at the head, trunk and four extremities of the body. And it is considered to have great significance for promoting the development of the present acupuncture and moxibustion theory since it is effective in both preventing and curing diseases caused by deficient and stagnation conditions such as the wei (flaccidity) syndrome, bi (arthralgia) syndrome, paralysis, dementia, asthma and so on.

[Preliminary study on characteristics of the Illustrations of Moxibustion in Dunhuang Caves in treatment of 5 kinds of strain and 7 kinds of impairments].

The Illustrations of Moxibustion, a remained book in Dunhuang Caves, is available the earliest monograph about moxibustion methods with both pictures and writing since recorded writing. In treatment of 5 kinds of strain and 7 kinds of impairments, point association for correspondence between man and universe was adopted human point distribution according to Jiugong and Bagua; and point association method of viewing the situation as a whole according to humam point distribution on the head, the body and the limbs; it wrote and drew available the earliest naked figures for acupuncture and moxibustion in simple natural materialism; and it is the most reasonable, the most complete explanation of sexual science in Chinese medicine, and is a sample for treatment of 5 kinds of strain and 7 kinds of impairments by ancient physicians stressing moxibustion, with convenient point selection and safety.

[Establishment of 2-dimensional gel electrophoresis map and analysis of proteomics from human nasal polyps].

OBJECTIVE: To establish 2-dimensional polyacrylamide gel electrophoresis (2-DE) map from human nasal polyps and normal nasal mucosa, and to identify differential expression proteins of 2-DE map. METHODS: Samples of nasal polyps and nasal mucosa (each sample group containing 7 cases) were obtained. The total proteins were extracted and separated by immobilized pH gradient (IPG)-based 2-DE. The silver-stained 2-DE was scanned with digital Imagescanner and analyzed with ImageMaster 2-DE Elite 4.01 software. To obtain peptide mass fingerprint (PMF) of differential protein spots, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was used. The PMF was searched in Swiss-Prot and TreMBL database by Pept-Ident software, to identify differential expression proteins. RESULTS: The well-resolved, reproducible 2-DE maps of nasal polyps and nasal mucosa were established. For the polyps tissues, the average proteins spot of three 2-DE maps was 825+/-78; and 682+/-96 spot was matched with the average matching rate of 82.7%. The average deviations of matched spot position were (1.13+/-0.16) mm in IEF direction and (1.45+/-0.21) mm in SDS-PAGE direction, respectively. For the nasal mucosa tissues, the average proteins spot of three 2-DE maps was 936+/-62; and 821+/-78 spots were matched with the average matching rate of 87.7%. After comparing the 2-DE maps of nasal polyps and nasal mucosa tissues, the protein spots were 1,458 and 1,617 respectively; and 1,026 protein spots were matched. Forty differential expression protein spots were incised from silver staining gel randomly and digested in the gel by TPCK-Trypsin. Thirty-four PMFs were obtained by MALDI-TOF-MS and 24 differential proteins were identified. CONCLUSION: The well-resolved, reproducible 2-DE maps of human nasal polyps and nasal mucosa have been successfully established. Certain differential proteins related to the pathogenesis of human nasal polyps are identified.

[Determination of differentially expressed proteins and it's significance among chronic sinusitis, nasal polyps and normal nasal mucosa].

OBJECTIVE: To investigate the differentially expressed proteins among chronic sinusitis, nasal polyps and normal nasal mucosa by means of proteomic technology, and select the candidate biomarkers of chronic sinusitis and nasal polyps. METHODS: Proteins extracted from chronic sinusitis, nasal polyps and normal nasal mucosa were separated and the differentially expressed proteins were identified by series of proteomic tools, including immobilized pH4-7 gradient two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis, modified coomassie brilliant blue staining, images scanning by the Image Scanner apparatus, PDQuest analysis software, peptide mass fingerprinting based on matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) by in-gel digestion extract, and Mascot searching in NCBInr and SWISS-PROT databases. RESULTS: The 2-DE patterns with high resolution and reproducibility were obtained. The protein spots separated and visualized in chronic sinusitis, nasal polyps and normal nasal mucosa gel were 1020 +/- 40, 1112 +/- 10 and 1008 +/- 25, respectively. And the match rates were (93 +/- 2)%, (95 +/- 1)% [see text] (90 +/- 3)% respectively. Thirteen differentially expressed spots were found from chronic sinusitis, nasal polyps and normal nasal mucosa gel. We selected and recommend Keratin 8 and APOA1 proteins as candidate biomarkers of nasal polyps, and PLUNC protein, PACAP protein, NKEF-B and SOD as candidate biomarkers of chronic sinusitis. CONCLUSIONS: The differentially expressed proteins among chronic sinusitis, nasal polyps and normal nasal mucosa can be efficiently and relatively reliably identified via the techniques of proteomics. These techniques will play a very important role in the researches for new objective indicators possibly employed in the future classifying, staging and prognosis.

[Experience on clinical application of acupoints in the remained book of the Illustrations of Moxibustion in Dunhuang Caves].

The Illustrations of Moxibustion, a remained book in Dunhuang Caves, is now available the earliest monograph of moxibustion methods since having writing in our country. In this paper, the points selected and therapeutic methods in The Illustrations of Moxibustion are used for treatment of typical cases of cerebral palsy, rheumatoid arthritis, diarrhea due to gastroenteritis, impotence, premature, diabetes, asthma and so on to explore characteristics of using points, find out the law, test and verify the actual effect and find guiding values for modern clinic, indicating that The Illustrations of Moxibustion can be applied for treatment and rehabilitation of many kinds of refractory diseases with unique therapeutic effects and practical significance.