ALOX15+ M2 macrophages contribute to epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: Epithelial remodeling is a prominent feature of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP), and infiltration of M2 macrophages plays a pivotal role in the pathogenesis of eCRSwNP, but the underlying mechanisms remain undefined. OBJECTIVE: We sought to investigate the role of ALOX15+ M2 macrophages in the epithelial remodeling of eCRSwNP. METHODS: Digital spatial transcriptomics and single-cell sequencing analyses were used to characterize the epithelial remodeling and cellular infiltrate in eCRSwNP. Hematoxylin and eosin staining, immunohistochemical staining, and immunofluorescence staining were used to explore the relationship between ALOX15+ M2 (CD68+CD163+) macrophages and epithelial remodeling. A coculture system of primary human nasal epithelial cells (hNECs) and the macrophage cell line THP-1 was used to determine the underlying mechanisms. RESULTS: Spatial transcriptomics analysis showed the upregulation of epithelial remodeling-related genes, such as Vimentin and matrix metalloproteinase 10, and enrichment of epithelial-mesenchymal transition (EMT)-related pathways, in the epithelial areas in eCRSwNP, with more abundance of epithelial basal, goblet, and glandular cells. Single-cell analysis identified that ALOX15+, rather than ALOX15-, M2 macrophages were specifically highly expressed in eCRSwNP. CRSwNP with high ALOX15+ M2THP-1-IL-4+IL-13 macrophages had more obvious epithelial remodeling features and increased genes associated with epithelial remodeling and integrity of epithelial morphology versus that with low ALOX15+ M2THP-1-IL-4+IL-13 macrophages. IL-4/IL-13-polarized M2THP-1-IL-4+IL-13 macrophages upregulated expressions of EMT-related genes in hNECs, including Vimentin, TWIST1, Snail, and ZEB1. ALOX15 inhibition in M2THP-1-IL-4+IL-13 macrophages resulted in reduction of the EMT-related transcripts in hNECs. Blocking chemokine (C-C motif) ligand 13 signaling inhibited M2THP-1-IL-4+IL-13 macrophage-induced EMT alteration in hNECs. CONCLUSIONS: ALOX15+ M2 macrophages are specifically increased in eCRSwNP and may contribute to the pathogenesis of epithelial remodeling via production of chemokine (C-C motif) ligand 13.

Nomogram for predicting the risk of postoperative delirium in elderly patients undergoing orthopedic surgery.

OBJECTIVE: To retrospectively analyze the risk factors for postoperative delirium (POD) after orthopedic surgery in elderly patients and establish an individualized nomogram to predict the risk of POD. METHODS: The data of 1011 patients who underwent orthopedic surgery from January 2019 to January 2022 were retrospectively analyzed. Univariate and multivariate logistic analyses were used to screen for independent risk factors. Stepwise regression was conducted to screen risk factors to construct a nomogram to predict the risk of POD after orthopedic surgery in elderly individuals, and nomogram validation analyses were performed. RESULTS: The logistic regression results showed that age (≥ 75 years old vs. < 75 years old; odds ratio (OR) = 2.889; 95% confidence interval (CI), 1.149, 7.264), sex (male vs. female, OR = 2.368; 95% CI, 1.066, 5.261), and preoperative cognitive impairment (yes vs. no, OR = 13.587; 95% CI, 4.360, 42.338) were independent risk factors for POD in elderly patients who underwent orthopedic surgery (P < 0.05). A nomogram was constructed using 7 risk factors, i.e., age, American Society of Anesthesiologists (ASA) classification, sex, preoperative hemoglobin (Hb), preoperative pulmonary disease, cognitive impairment, and intraoperative infusion volume. The area under the curve (AUC) showed good discrimination (0.867), the slope of the calibration curve was 1.0, and the optimal net benefit of the nomogram from the decision curve analysis (DCA) was 0.01-0.58. CONCLUSION: This study used 7 risk factors to construct a nomogram to predict the risk of POD after major orthopedic surgery in elderly individuals, and the nomogram had good discrimination ability, accuracy, and clinical practicability.

Outcomes of endoscopic sinus surgery in patients with central compartment atopic disease.

Background: Central compartment atopic disease (CCAD) is a subtype of chronic rhinosinusitis (CRS). Research focusing on the endoscopic sinus surgery (ESS) outcomes of CCAD is limited. This study aimed to evaluate the outcomes of ESS in CCAD and compared to 2 following subtypes: chronic rhinosinusitis with nasal polyps (CRSwNP) and concomitant polypoid disease in the central compartment (CRSwNP/CC) and CRSwNP not otherwise specified (CRSwNP NOS). Methods: This case-control study enrolled patients with bilateral CRSwNP who underwent ESS and had at least 1 year of follow-up. Patients were classified into CCAD, CRSwNP/CC, and CRSwNP NOS. The demographic data, preoperative disease severity, and surgery outcomes, including CRS control status, endoscopic score, and symptom scores at 1 year postoperatively, were collected. We defined well controlled and partly controlled as appropriate disease control. Results: This study screened 259 patients and enrolled 138 patients with complete medical records and 1-year follow-up (CCAD N = 51, CRSwNP/CC N = 55, CRSwNP NOS N = 32). Among them, appropriate disease control was achieved in 84.3% of patients (43/51) in the CCAD group, 69.1% (38/55) in the CRSwNP/CC group, and 93.7% (30/32) in the CRSwNP NOS group (P = 0.029). Then we performed post-hoc analysis using appropriate disease control and uncontrolled. There was a significant difference between CRSwNP/CC and CRSwNP NOS (P = 0.007), but no significant difference compared CCAD group to CRSwNP/CC group (P = 0.065) and CRSwNP NOS group (P = 0.199). There were significant differences in endoscopic E-score among groups (P < 0.001). In post-hoc analysis, we found that CRSwNP/CC (Median [IQR], 33.32 [42.14]) had a significantly worse E-score than CCAD (8.33 [16.67]) and CRSwNP NOS (4.17 [8.30]). Also, postoperative olfactory visual analog scale (VAS) scores significantly differed among groups (P = 0.043). However, post-hoc analysis showed no difference between any 2 groups. There were no differences in postoperative VAS scores of obstruction (P = 0.159), rhinorrhea (P = 0.398), and headache/facial pain (P = 0.092). Conclusion: Most CCAD patients had good surgical outcomes 1 year after surgery. Meanwhile, the CRSwNP/CC group had the fewest patients under appropriate disease control.

Acarbose reduces Pseudomonas aeruginosa respiratory tract infection in type 2 diabetic mice.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is widely prevalent worldwide, and respiratory tract infections (RTIs) have become the primary cause of death for T2DM patients who develop concurrent infections. Among these, Pseudomonas aeruginosa infection has been found to exhibit a high mortality rate and poor prognosis and is frequently observed in bacterial infections that are concurrent with COVID-19. Studies have suggested that acarbose can be used to treat T2DM and reduce inflammation. Our objective was to explore the effect of acarbose on P. aeruginosa RTI in T2DM individuals and elucidate its underlying mechanism. METHODS: High-fat diet (HFD) induction and P. aeruginosa inhalation were used to establish a RTI model in T2DM mice. The effect and mechanism of acarbose administered by gavage on P. aeruginosa RTI were investigated in T2DM and nondiabetic mice using survival curves, pathological examination, and transcriptomics. RESULTS: We found that P. aeruginosa RTI was more severe in T2DM mice than in nondiabetic individuals, which could be attributed to the activation of the NF-κB and TREM-1 signaling pathways. When acarbose alleviated P. aeruginosa RTI in T2DM mice, both HIF-1α and NF-κB signaling pathways were inhibited. Furthermore, inhibition of the calcium ion signaling pathway and NF-κB signaling pathway contributed to the attenuation of P. aeruginosa RTI by acarbose in nondiabetic mice. CONCLUSIONS: This study confirmed the attenuating effect of acarbose on P. aeruginosa RTIs in T2DM and nondiabetic mice and investigated its mechanism, providing novel support for its clinical application in related diseases.

Recent advances in mass spectrometry-based proteomics and metabolomics in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex and heterogeneous disease, typically diagnosed through endoscopy and computed tomography and treated with glucocorticoid or surgery. There is an urgent need to develop molecular-level diagnostic or prognostic tools to better understand the pathophysiology of CRSwNP. Proteomics and metabolomics, emerging fields, offer significant potential in elucidating the mechanisms underlying CRSwNP. Mass spectrometry, a powerful and sensitive tool for trace substance detection, is broadly applied for proteomics and metabolomics analysis in CRSwNP research. While previous literature has summarized the advancement of mass spectrometry-based CRSwNP proteomics from 2004 to 2018, recent years have seen new advances in this field, particularly about non-invasive samples and exosomes. Furthermore, mass spectrometry-based CRSwNP metabolomics research has opened new avenues for inquiry. Therefore, we present a comprehensive review of mass spectrometry-based proteomics and metabolomics studies on CRSwNP conducted between 2019 and 2022. Specifically, we highlight protein and metabolic biomarkers that have been utilized as diagnostic or prognostic markers for CRSwNP. Lastly, we conclude with potential directions for future mass spectrometry-based omics studies of CRSwNP.

Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 virus and Staphylococcus aureus infections.

BACKGROUND: Early studies indicated that vitamin D (VD) exerted pleiotropic extra-skeletal effects in the airway, but the definite linkage between VD deficiency and airway host responses remains unclear. METHODS: 142 cases of clinical data from Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, were collected to characterize the relationship between VD deficiency and chronic rhinosinusitis (CRS). Based on the clinical observations, 2.5-D airway epithelial organoids cultured at the air-liquid interface (ALI) were used to simulate the effects of VD treatment in the development of airway epithelium and the modulation of the host responses against influenza H1N1 virus (representing viral infections) and Staphylococcus aureus (representing bacterial infections) infections in the airway. The intrinsic mechanisms of VD deficiency underlying epithelial remodeling were mapped by transcriptomic as well as proteomic analyses. RESULTS: In this study we observed prevailing VD deficiency among inpatients suffering from CRS, a common disease predominantly characterized by epithelial impairment and remodeling. Relative to control organoids cultured without VD, long-term incubation with VD accelerated basal cell proliferation during nasal epithelial development. Under infectious conditions, VD treatment protected the organoids against influenza H1N1 virus and Staphylococcus aureus invasions by reinforcing the respiratory host defenses, including upregulation of LL37, suppression (or inhibition) of proinflammatory cytokines, strengthening of epithelial integrity, and mucociliary clearance. In silico analysis of transcriptomics and proteomics suggested that VD modulated the epithelial development and remodeling, involving epithelial cell proliferation/differentiation, epithelial-mesenchymal transition (EMT), and cytokine signaling in the immune system, as well as responses to microbe, cell junction organization, and extracellular matrix organization via PTEN signaling, independent of TGF-ß signaling. CONCLUSIONS: Our findings emphasize the importance of managing VD deficiency in clinical settings for the sake of alleviating pathological epithelial remodeling. Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 and Staphylococcus aureus infections.

Diagnosis and treatment of transnasal endoscopic optic canal decompression for traumatic optic neuropathy.

Objective: To investigate the clinical efficacy and prognostic factors of transnasal endoscopic optic decompression in the treatment of traumatic optic neuropathy (TON). Methods: A retrospective analysis was performed on 13 TON patients in The Seventh Affiliated Hospital of Sun Yat-sen University and Shenzhen Eye Hospital in Shenzhen City (China) from June 2020 to April 2022. These patients had received transnasal endoscopic optic decompression, and hormonal and neurotrophic drugs were given after surgery. Visual acuity (VA) improvement was used as the criterion to judge clinical efficacy. Results: In a total of 13 patients, 13 injured eyes (12 men and 1 woman; mean age, 28.0 ± 11.8 years) received transnasal endoscopic optic decompression. After surgery, nine patients had improved VA, whereas four patients failed to show any improvement, resulting in a total effective rate of 69.2%. Of the six patients with no light perception preoperatively, three had effective results after the operation, giving an effective rate of 50.0%. Of the seven patients with residual light sensation preoperatively, six had effective results after the operation, giving an effective rate of 85.7%. Of the 10 patients operated on within 7 days after injury, seven had effective results, giving an effective rate of 70%. Of the three patients injured and operated on after 7 days, two had effective results, giving an effective rate of 66.7%. Conclusion: Transnasal endoscopic optic nerve decompression is an effective treatment method for TON. The presence of residual light perception and the timing of surgery within 7 days are crucial to the prognosis.

MIB-ANet: A novel multi-scale deep network for nasal endoscopy-based adenoid hypertrophy grading.

Introduction: To develop a novel deep learning model to automatically grade adenoid hypertrophy, based on nasal endoscopy, and asses its performance with that of E.N.T. clinicians. Methods: A total of 3,179 nasoendoscopic images, including 4-grade adenoid hypertrophy (Parikh grading standard, 2006), were collected to develop and test deep neural networks. MIB-ANet, a novel multi-scale grading network, was created for adenoid hypertrophy grading. A comparison between MIB-ANet and E.N.T. clinicians was conducted. Results: In the SYSU-SZU-EA Dataset, the MIB-ANet achieved 0.76251 F1 score and 0.76807 accuracy, and showed the best classification performance among all of the networks. The visualized heatmaps show that MIB-ANet can detect whether adenoid contact with adjacent tissues, which was interpretable for clinical decision. MIB-ANet achieved at least 6.38% higher F1 score and 4.31% higher accuracy than the junior E.N.T. clinician, with much higher (80× faster) diagnosing speed. Discussion: The novel multi-scale grading network MIB-ANet, designed for adenoid hypertrophy, achieved better classification performance than four classical CNNs and the junior E.N.T. clinician. Nonetheless, further studies are required to improve the accuracy of MIB-ANet.

PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia.

Isocitrate dehydrogenase (IDH) mutation, a known pathologic classifier, initiates metabolic reprogramming in glioma cells and has been linked to the reaction status of glioma-associated microglia/macrophages (GAMs). However, it remains unclear how IDH genotypes contribute to GAM phenotypes. Here, it is demonstrated that gliomas expressing mutant IDH determine M1-like polarization of GAMs, while archetypal IDH induces M2-like polarization. Intriguingly, IDH-mutant gliomas secrete excess cholesterol, resulting in cholesterol-rich, pro-inflammatory GAMs without altering their cholesterol biosynthesis, and simultaneously exhibiting low levels of tumoral cholesterol due to expression remodeling of cholesterol transport molecules, particularly upregulation of ABCA1 and downregulation of LDLR. Mechanistically, a miR-19a/LDLR axis-mediated novel post-transcriptional regulation of cholesterol uptake is identified, modulated by IDH mutation, and influencing tumor cell proliferation and invasion. IDH mutation-induced PERK activation enhances cholesterol export from glioma cells via the miR-19a/LDLR axis and ABCA1/APOE upregulation. Further, a synthetic PERK activator, CCT020312 is introduced, which markedly stimulates cholesterol efflux from IDH wild-type glioma cells, induces M1-like polarization of GAMs, and consequently suppresses glioma cell invasion. The findings reveal an essential role of the PERK/miR-19a/LDLR signaling pathway in orchestrating gliomal cholesterol transport and the subsequent phenotypes of GAMs, thereby highlighting a novel potential target pathway for glioma therapy.

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.

Deep learning-based prediction of treatment prognosis from nasal polyp histology slides.

BACKGROUND: Histopathology of nasal polyps contains rich prognostic information, which is difficult to extract objectively. In the present study, we aimed to develop a prognostic indicator of patient outcomes by analyzing scanned conventional hematoxylin and eosin (H&E)-stained slides alone using deep learning. METHODS: An interpretable supervised deep learning model was developed using 185 H&E-stained whole-slide images (WSIs) of nasal polyps, each from a patient randomly selected from the pool of 232 patients who underwent endoscopic sinus surgery at the First Affiliated Hospital of Sun Yat-Sen University (internal cohort). We internally validated the model on a holdout dataset from the internal cohort (47 H&E-stained WSIs) and externally validated the model on 122 H&E-stained WSIs from the Seventh Affiliated Hospital of Sun Yat-Sen University and the University of Hong Kong-Shenzhen Hospital (external cohort). A poor prognosis score (PPS) was established to evaluate patient outcomes, and then risk activation mapping was applied to visualize the histopathological features underlying PPS. RESULTS: The model yielded a patient-level sensitivity of 79.5%, and specificity of 92.3%, with areas under the receiver operating characteristic curve of 0.943, on the multicenter external cohort. The predictive ability of PPS was superior to that of conventional tissue eosinophil number. Notably, eosinophil infiltration, goblet cell hyperplasia, glandular hyperplasia, squamous metaplasia, and fibrin deposition were identified as the main underlying features of PPS. CONCLUSIONS: Our deep learning model is an effective method for decoding pathological images of nasal polyps, providing a valuable solution for disease prognosis prediction and precise patient treatment.

Clinical characteristics of central compartment atopic disease in Southern China.

BACKGROUND: Central compartment atopic disease (CCAD) is a newly reported subset of chronic rhinosinusitis. It was considered associated with inhalant antigen. However, CCAD in Chinese population is not fully studied yet. DESIGN: Prospective cohort study. OBJECTIVE: This study aimed to describe the clinical manifestations of CCAD and compared the following two subtypes: sinonasal polyps and concomitant polypoid disease in the central compartment (CRSwNP/CC) and CRSwNP not otherwise specified (CRSwNP NOS). Also, we compared the clinical manifestations of atopy CCAD and non-atopy CCAD. METHODS: We consecutively enrolled CRSwNP patients without prior sinus surgery, and assessed the nasal endoscopy and computed tomography of the paranasal sinuses. Allergy was confirmed by skin or serum testing. Eosinophilic CRSwNP (ECRS) was considered as tissue eosinophils to total inflammatory cells >10%. RESULTS: We enrolled a total of 116 patients, including 39 with CCAD, 38 with CRSwNP/CC and 39 with CRSwNP NOS. Atopy was detected in 37.1% of the CCAD group, an incidence showing no significant difference from those in the other two groups (37.1% in the CRSwNP/CC group, 31.0% in the CRSwNP NOS group; p = 0.846). However, the incidence of ECRS in the CCAD group was the highest among the different groups (97.4% in the CCAD group vs. 67.6% in the CRSwNP/CC group vs. 35.1% in the CRSwNP NOS group; p = 0.000). In addition, the incidence of asthma in the CCAD group (33.3%) was significantly higher than that in the CRSwNP NOS group (10.3%), but quite similar to CRSwNP/CC (34.2%). In the subgroup analysis of CCAD, only total serum IgE and sIgE demonstrated significant differences between atopy CCAD and non-atopy CCAD. CONCLUSION: CCAD in Southern China may associate with asthma and significant eosinophilia, with a lower incidence of systemic allergy based on skin and serum testing.

Evaluating Bacterial Pathogenesis Using a Model of Human Airway Organoids Infected with Pseudomonas aeruginosa Biofilms.

Pseudomonas aeruginosa is one of the leading invasive agents of human pulmonary infection, especially in patients with compromised immunity. Prior studies have used various in vitro models to establish P. aeruginosa infection and to analyze transcriptomic profiles of either the host or pathogen, and yet how much those works are relevant to the genuine human airway still raises doubts. In this study, we cultured and differentiated human airway organoids (HAOs) that recapitulate, to a large extent, the histological and physiological features of the native human mucociliary epithelium. HAOs were then employed as a host model to monitor P. aeruginosa biofilm development. Through dual-species transcriptome sequencing (RNA-seq) analyses, we found that quorum sensing (QS) and several associated protein secretion systems were significantly upregulated in HAO-associated bacteria. Cocultures of HAOs and QS-defective mutants further validated the role of QS in the maintenance of a robust biofilm and disruption of host tissue. Simultaneously, the expression magnitude of multiple inflammation-associated signaling pathways was higher in the QS mutant-infected HAOs, suggesting that QS promotes immune evasion at the transcriptional level. Altogether, modeling infection of HAOs by P. aeruginosa captured several crucial facets in host responses and bacterial pathogenesis, with QS being the most dominant virulence pathway showing profound effects on both bacterial biofilm and host immune responses. Our results revealed that HAOs are an optimal model for studying the interaction between the airway epithelium and bacterial pathogens. IMPORTANCE Human airway organoids (HAOs) are an organotypic model of human airway mucociliary epithelium. The HAOs can closely resemble their origin organ in terms of epithelium architecture and physiological function. Accumulating studies have revealed the great values of the HAO cultures in host-pathogen interaction research. In this study, HAOs were used as a host model to grow Pseudomonas aeruginosa biofilm, which is one of the most common pathogens found in pulmonary infection cases. Dual transcriptome sequencing (RNA-seq) analyses showed that the cocultures have changed the gene expression pattern of both sides significantly and simultaneously. Bacterial quorum sensing (QS), the most upregulated pathway, contributed greatly to biofilm formation, disruption of barrier function, and subversion of host immune responses. Our study therefore provides a global insight into the transcriptomic responses of both P. aeruginosa and human airway epithelium.

A nanomaterial targeting the spike protein captures SARS-CoV-2 variants and promotes viral elimination.

The global emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can only be solved with effective and widespread preventive and therapeutic strategies, and both are still insufficient. Here, we describe an ultrathin two-dimensional CuInP2S6 (CIPS) nanosheet as a new agent against SARS-CoV-2 infection. CIPS exhibits an extremely high and selective binding capacity (dissociation constant (KD) < 1 pM) for the receptor binding domain of the spike protein of wild-type SARS-CoV-2 and its variants of concern, including Delta and Omicron, inhibiting virus entry and infection in angiotensin converting enzyme 2 (ACE2)-bearing cells, human airway epithelial organoids and human ACE2-transgenic mice. On association with CIPS, the virus is quickly phagocytosed and eliminated by macrophages, suggesting that CIPS could be successfully used to capture and facilitate virus elimination by the host. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, and as a decontamination agent and surface-coating material to reduce SARS-CoV-2 infectivity.

Gremlin-1 Promotes Colorectal Cancer Cell Metastasis by Activating ATF6 and Inhibiting ATF4 Pathways.

Cancer cell survival, function and fate strongly depend on endoplasmic reticulum (ER) proteostasis. Although previous studies have implicated the ER stress signaling network in all stages of cancer development, its role in cancer metastasis remains to be elucidated. In this study, we investigated the role of Gremlin-1 (GREM1), a secreted protein, in the invasion and metastasis of colorectal cancer (CRC) cells in vitro and in vivo. Firstly, public datasets showed a positive correlation between high expression of GREM1 and a poor prognosis for CRC. Secondly, GREM1 enhanced motility and invasion of CRC cells by epithelial-mesenchymal transition (EMT). Thirdly, GREM1 upregulated expression of activating transcription factor 6 (ATF6) and downregulated that of ATF4, and modulation of the two key players of the unfolded protein response (UPR) was possibly through activation of PI3K/AKT/mTOR and antagonization of BMP2 signaling pathways, respectively. Taken together, our results demonstrate that GREM1 is an invasion-promoting factor via regulation of ATF6 and ATF4 expression in CRC cells, suggesting GREM1 may be a potential pharmacological target for colorectal cancer treatment.

Endoscopic Endonasal Trans-Agger Nasi Approach for Resection of Ossifying Fibroma Involving the Anterior Skull Base: Surgical Anatomy and Technical Note.

OBJECTIVE: A variety of approaches for resection of the ossifying fibromas in sinonasal cavities have been described. However, for those involving the anterior skull base, endoscopic surgery remains challenging because of limitations in identification of tumor boundaries from the anterior skull base and proper control of the tumor-feeding vessel. This study aimed to describe a technique for resection of ossifying fibromas involving the anterior skull base through an endoscopic endonasal trans-agger nasi approach, based on anatomic studies and surgeries. METHODS: Two human cadaveric heads were prepared for study of the anatomic relationship between agger nasi and anterior skull base. Two clinical cases were used to illustrate the technique and feasibility of the approach. RESULTS: The agger nasi was located anterior and inferior to the frontal ostium and the anterior skull base. The frontal ostium and anterior skull base could be visualized and accessed under the 0-degree endoscope by removing the agger nasi. Application of the endoscopic endonasal trans-agger nasi approach in the two patients resulted in complete resection of the tumors with no surgical complications. CONCLUSIONS: An endoscopic endonasal trans-agger nasi approach provides a direct access to the anterior skull base. It would be feasible, effective, and safe for selected cases of ossifying fibroma involving anterior skull base.

Zero Secondary Transmission from Three Traveling COVID-19 Cases in China: A Case for Social Responsibility from the General Public in Stemming the Chain of Transmission.

The number of confirmed COVID-19 cases continues to rise around the world, which is a huge threat to the safety of people and the social economy. Despite the introduction of vaccines, effectively preventing and controlling the epidemic, especially in protecting vulnerable populations, remains a big challenge for countries worldwide. By summarizing the trajectory of several officially reported COVID-19 cases, we found that because the COVID-19 primary routes of transmission consist of respiratory droplets, aerosols and close contacts it remains containable with public health measures. Public health measures to contain the outbreak do not rely on the healthcare institution and government agencies alone but require the concerted efforts of the public with sustained vigilance and social responsibility. People who are showing symptoms or have had suspected contact need to keep wearing masks and be quarantined in time to prevent further chains of transmission.

Generation and Effect Testing of a SARS-CoV-2 RBD-Targeted Polyclonal Therapeutic Antibody Based on a 2-D Airway Organoid Screening System.

Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The US FDA has approved several therapeutics and vaccines worldwide through the emergency use authorization in response to the rapid spread of COVID-19. Nevertheless, the efficacies of these treatments are being challenged by viral escape mutations. There is an urgent need to develop effective treatments protecting against SARS-CoV-2 infection and to establish a stable effect-screening model to test potential drugs. Polyclonal antibodies (pAbs) have an intrinsic advantage in such developments because they can target rapidly mutating viral strains as a result of the complexity of their binding epitopes. In this study, we generated anti-receptor-binding domain (anti-RBD) pAbs from rabbit serum and tested their safety and efficacy in response to SARS-CoV-2 infection both in vivo and ex vivo. Primary human bronchial epithelial two-dimensional (2-D) organoids were cultured and differentiated to a mature morphology and subsequently employed for SARS-CoV-2 infection and drug screening. The pAbs protected the airway organoids from viral infection and tissue damage. Potential side effects were tested in mouse models for both inhalation and vein injection. The pAbs displayed effective viral neutralization effects without significant side effects. Thus, the use of animal immune serum-derived pAbs might be a potential therapy for protection against SARS-CoV-2 infection, with the strategy developed to produce these pAbs providing new insight into the treatment of respiratory tract infections, especially for infections with viruses undergoing rapid mutation.

Cephalometric craniofacial features of patients with Sagliker syndrome: a primary analysis of our experience.

BACKGROUND: Sagliker syndrome (SS) is characterized by a severe uglifying facial appearance resulting from untreated or inadequately treated secondary hyperparathyroidism (SHPT). To date, the craniofacial morphology of patients with SS has yet to be analyzed. The present research sought to cephalometrically evaluate the craniofacial features of patients with SS and to perform an in-depth analysis of their serum biochemical parameters, with the aim of furthering the theoretical basis for the early diagnosis and prevention of SS. METHODS: A retrospective chart review of 9 patients who fulfilled the diagnostic criteria for SS were included in this study, and their serum biochemical parameters were collected. After subjecting standard lateral cephalometric radiographic images to correction for distortions caused by magnification followed by digitization, we conducted a cephalometric analysis. Student's two-tailed t tests or Mann-Whitney U tests were used to analyze the data. Thirty-three patients with patients with SHPT alone were also included as controls. RESULTS: The lower anterior facial height (ANS-ME) and total anterior facial height (N-Me) measurements of patients with SS were significantly increased compared to those of the controls. The angles between the Frankfort horizontal, palatal, and occlusal planes and the mandibular plane, were greater in the SS group than in the control group, as was the gonial angle. Patients with SS also exhibited a significantly larger maxillary protrusion angle and relative position of the maxilla to the mandible. Most patients with SS had class II malocclusion, whereas most of the controls exhibited normal occlusion. Soft tissue largely followed the same pattern as craniofacial changes. Our investigation also showed that among patients with SHPT, female sex, longer duration of dialysis, and higher serum levels of alkaline phosphatase and intact parathyroid hormone were associated with development to SS. CONCLUSIONS: Patients with SS show facial and biochemical differences compared to patients with SHPT. Female sex, long dialysis duration, and high serum levels of intact parathyroid hormone and alkaline phosphatase may be potential risk factors for SS.