Up-regulation of systemic and local BDNF in non-allergic Nasal Polyps in China.

Objective: Although the role of brain-derived neurotrophic factor (BDNF) in allergic rhinitis and/or nasal polyps (NPs) development has been studied, the contribution of BDNF in non-allergic NPs has not been evaluated yet. This study was to investigate the possible role of BDNF in non-allergic NPs pathogenesis. Methods: The study was carried out at The Second Hospital of Shandong University from December 2020 to November 2021. The non-allergic NPs patients (n=26) and the control group (n=22) were included. Lund-Mackay CT scores, nasal endoscopy scores, and pulmonary function testing were evaluated before surgery. Tissue and serum levels of BDNF, eosinophil cationic protein (ECP), and cytokeratins 5 (CK5) were assessed between different groups. Result: The BDNF level in serum and tissue, CK5 count, and eosinophil infiltration in tissue were higher in non-allergic NPs. The eosinophils infiltration, ECP mRNA expression level, as well as BDNF mRNA level were increased in the BDNFhigh subgroup compared with BDNFlow subgroup. Significantly negative correlations between BDNF count and the situation of airway obstruction were found in non-allergic NPs. Conclusion: BDNF may have both local and systemic effects in non-allergic NPs pathogenesis. BDNF may be a possible therapeutic target or an indicator for eosinophilic NPs management.

Epithelial Tight Junction Anomalies in Nasal Inverted Papilloma.

OBJECTIVES: As a critical component of the epithelial barrier, tight junctions (TJs) are essential in nasal mucosa against pathogen invasion. However, the function of TJs has rarely been reported in nasal inverted papilloma (NIP). This study aims to investigate the potential factors of TJs' abnormality in NIP. METHODS: We assessed the expression of ZO-1, occludin, claudin-1, claudin-3, and claudin-7 in healthy controls and NIP by real-time quantitative polymerase chain reaction and immunofluorescent staining. The correlation between TJs expression and neutrophil count, TH 1/TH 2/TH 17 and regulatory T cell biomarkers, and the proportion of nasal epithelial cells was investigated. RESULTS: Upregulation of ZO-1, occludin, claudin-1, and claudin-7, along with downregulation of claudin-3, was found in NIP compared to control (all p < 0.05). An abnormal proportion with a lower number of ciliated cells (control vs. NIP: 37.60 vs. 8.67) and goblet cells (12.52 vs. 0.33) together with a higher number of basal cells (45.58 vs. 124.00) in NIP. Meanwhile, claudin-3 was positively correlated with ciliated and goblet cells (all p < 0.01). Additionally, neutrophils were excessively infiltrated in NIP, negatively correlated with ZO-1, but positively with claudin-3 (all p < 0.05). Furthermore, FOXP3, IL-10, TGF-ß1, IL-5, IL-13, and IL-22 levels were induced in NIP (all p < 0.01). Occludin level was negatively correlated with IL-10, IL-5, IL-13, and IL-22, whereas ZO-1 was positively with TGF-ß1 (all p < 0.05). CONCLUSION: Nasal epithelial barrier dysfunction with TJs anomalies is commonly associated with abnormal proliferation and differentiation of epithelial cells and imbalance of immune and inflammatory patterns in NIP. LEVEL OF EVIDENCE: NA Laryngoscope, 134:552-561, 2024.

Polycephalums A and B, New Anticoagulant Constituents Isolated from Clinopodium polycephalum.

Two previously undescribed compounds (1 and 2) were isolated from Clinopodium polycephalum, a medicinal plant distributed in southwestern and eastern China. Their structures were elucidated using MS analyses and extensive 2D-homo and heteronuclear NMR data interpretations. Both compounds 1 and 2 could significantly shorten APTT and PT, and their procoagulant effect was comparable to that of positive drugs. At the same time, compound 2 had certain antioxidant activity (IC50 value of 2.25±0.05 µM in ABTS assay).

S100A11 regulates nasal epithelial cell remodeling and inflammation in CRSwNPs via the RAGE-mediated AMPK-STAT3 pathway.

Abnormal remodeling of the nasal mucosal epithelium and persistent chronic inflammation are important pathological features of chronic sinusitis with nasal polyps (CRSwNPs). In order to explore the molecular regulation mechanism of CRSwNPs, we performed iTRAQ protein profile analysis on 18 clinical samples collected (9 patients with nasal polyps and 9 healthy patients) and found that S100A11, a Ca2+-binding protein, was significantly higher in CRSwNPs. Subsequently, we demonstrated that S100A11 was mainly located in nasal mucosal epithelial cells and is up-regulated in human nasal epithelial stem/progenitor cells (hNESPCs) from CRSwNPs patients and CRSwNPs epithelial cell model established with S. aureus. To determine the functional role of S100A11 and the signal pathways in epithelial cells, we constructed S100A11 overexpression vector, small interfering RNA, recombinant protein-S100A11 (rh-S100A11) and RAGE inhibitor (sRAGE). Results showed that upregulation of S100A11 inhibited epithelial cell viability and promoted apoptosis and inflammation, in addition, S100A11 can regulate the signal homeostasis of AMPK-STAT3 via RAGE mediation in epithelial cells. Our findings suggest that S100A11 is involved in CRSwNPs epithelial tissue remodeling and inflammatory response regulation and may be a useful target for CRSwNPs therapy.

Abnormal Expression of YAP Is Associated With Proliferation, Differentiation, Neutrophil Infiltration, and Adverse Outcome in Patients With Nasal Inverted Papilloma.

BACKGROUND: Nasal inverted papilloma (NIP) is a common benign tumor. Yes-associated protein (YAP) is the core effector molecule of the Hippo pathway, which regulates the proliferation and differentiation of airway epithelium. While its role in proliferation may be connected to NIP formation, no definitive association has been made between them. METHODS: We compared the difference of YAP expression and proliferation level between the control inferior turbinate, NP (nasal polyps), and NIP groups. In addition, we further used PCR, immunofluorescence, and immunohistochemistry to investigate YAP's role in the proliferation and differentiation of the nasal epithelium and inflammatory cell infiltration, correlating them with different grades of epithelial remodeling. We further used an IL-13 remodeling condition to investigate YAP's role in differentiation in an in vitro air-liquid interface (ALI) human nasal epithelial cell (hNECs) model. Finally, we also explored the correlation between YAP expression and clinical indicators of NIP. RESULTS: The expression of YAP/active YAP in the NIP group was significantly higher than that in the NP group and control group. Moreover, within the NIP group, the higher grade of epithelial remodeling was associated with higher YAP induced proliferation, leading to reduced ciliated cells and goblet cells. The finding was further verified using an IL-13 remodeling condition in differentiating ALI hNECs. Furthermore, YAP expression was positively correlated with proliferation and neutrophil infiltration in NIP. YAP expression was also significantly increased in NIP patients with adverse outcomes. CONCLUSION: Abnormal expression of YAP/active YAP is associated with proliferation, differentiation, neutrophil infiltration, and adverse outcome in NIP and may present a novel target for diagnosis and intervention in NIP.

Mucus composition abnormalities in sinonasal mucosa of chronic rhinosinusitis with and without nasal polyps.

Mucus secretion and its composition are vital in the maintenance of airway health, among which hypoxia-inducible factors (HIFs) are thought to be involved in the regulation of mucin synthesis and regulation. Nasal mucus composition difference between healthy individuals and chronic rhinosinusitis (CRS) patients may contribute to the pathology of chronic nasal diseases, but so far, their role has yet to be completely understood. Nasal biopsy specimens were obtained from 24 healthy subjects and 99 patients with CRS without (CRSsNP, n=36) or with (CRSwNP, n=63) nasal polyps. Immunohistochemical (IHC) and immunofluorescent (IF) staining, quantitative real-time PCR, and western blot were performed to compare the nasal mucus composition between the subjects. Areas of the serous gland and mucous gland were both significantly increased in CRSsNP patients. In CRSwNP patients, a decrease in submucosal gland density and a marked increase in goblet cells were observed. The major gel-forming mucins in the sinonasal mucosa of CRSsNP and CRSwNP are MUC5B and MUC5AC respectively. Mucous cells are found in a higher proportion in both CRSsNP and CRSwNP. The proportion of MUC5AC-positive goblet cells was increased in CRSwNP. The mRNA level of HIF-2α was significantly increased in CRS, and both HIF-1α and HIF-2α were expressed in serous cell but not mucous cell. Over secretion and altered composition of mucus are observed in sinonasal mucosa of CRS, which was mainly associated with glandular hyperplasia in CRSsNP and goblet cell hyperplasia in CRSwNP. Mucus abnormality compromised both non-specific and specific antimicrobial capabilities in the sinonasal mucosa. HIF expression may contribute to differences in mucin synthesis and serous gland regulation, which needs further investigation to understand the pathology of CRS.

Interleukin-13 Alters Tight Junction Proteins Expression Thereby Compromising Barrier Function and Dampens Rhinovirus Induced Immune Responses in Nasal Epithelium.

Tight junctions (TJs) are intercellular structures which are essential for epithelial barrier function and play an important role in antimicrobial defense. Epithelium dysfunction and type-2-skewed inflammation are two main pathological phenomena of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the effect of pro-inflammatory type-2 cytokine IL-13 on TJs in CRSwNP is poorly understood. Nasal biopsies of CRSwNP patients and in vitro IL-13-matured human nasal epithelial cells (hNECs) were used to analyze epithelial markers and TJ proteins. Epithelium permeability, transepithelial electrical resistance (TEER), expression of TJs were quantified for IL-13-matured hNECs and that with RV infection. The expression of occludin, claudin-3, and ZO-1 were significantly decreased in CRSwNP biopsies and in hNECs after IL-13 treatment. IL-13 treatment increased epithelium permeability, decreased TEER and altered hNECs composition resulting in lesser ciliated cells and mucus over-secretion. Interestingly, claudin-3 is selectively expressed on ciliated cells. While RV infection induced minimal changes to TJs, the IL-13-matured hNECs has reduced capacity for upregulation of IFN-λ1 and CXCL10 but further increased the expression of TSLP upon RV infection. These findings suggested that IL-13-mediated dysfunction of TJs and compromised epithelial barrier. IL-13-induced cilia loss conferred lowered viral replication and impaired antiviral responses of nasal epithelium against RV infection.

Registration of in vivo prostate MRI and pseudo-whole mount histology using Local Affine Transformations guided by Internal Structures (LATIS).

PURPOSE: To present a novel registration approach called LATIS (Local Affine Transformation guided by Internal Structures) for coregistering post prostatectomy pseudo-whole mount (PWM) pathological sections with in vivo MRI (magnetic resonance imaging) images. MATERIALS AND METHODS: Thirty-five patients with biopsy-proven prostate cancer were imaged at 3T with an endorectal coil. Excised prostate specimens underwent quarter mount step-section pathologic processing, digitization, annotation, and assembly into a PWM. Manually annotated macro-structures on both pathology and MRI were used to assist registration using a relaxed local affine transformation approximation. Registration accuracy was assessed by calculation of the Dice similarity coefficient (DSC) between transformed and target capsule masks and least-square distance between transformed and target landmark positions. RESULTS: LATIS registration resulted in a DSC value of 0.991 ± 0.004 and registration accuracy of 1.54 ± 0.64 mm based on identified landmarks common to both datasets. Image registration performed without the use of internal structures led to an 87% increase in landmark-based registration error. Derived transformation matrices were used to map regions of pathologically defined disease to MRI. CONCLUSION: LATIS was used to successfully coregister digital pathology with in vivo MRI to facilitate improved correlative studies between pathologically identified features of prostate cancer and multiparametric MRI.

Laser surgery simulation platform: toward full-procedure training and rehearsal for benign prostatic hyperplasia (BPH) therapy.

Recently, photo-selective vaporization of the prostate (PVP) has been a popular alternative to the standard electrocautery - transurethral resection of prostate (TURP). Here we introduce a new training system for practicing the laser therapy by using a virtual reality (VR) simulator. To interactively and realistically simulate PVP on a virtual organ with an order of a quarter million elements, a few novel and practical solutions have been applied to handle the challenges in modeling tissue ablation, contact/collision and deformation; endoscopic instruments tracking, haptic rendering and a web/database curriculum management module are integrated into the system. Over 40 urologists and surgical experts have been invited nationally and participated in the system verification.

Phenomenological model of laser-tissue interaction with application to Benign Prostatic Hyperplasia (BPH) simulation.

Laser-tissue interaction is a multi-physics phenomenon not yet mathematically describable and computationally predictable. It is a challenge to model the laser-tissue interaction for real time laser Benign Prostatic Hyperplasia (BPH) simulation which requires the laser-tissue interaction model to be computationally efficient and accurate. Under the consideration and enforcement of the thermodynamic first law and treating the laser-tissue interaction as a gray-box, utilizing the sensitivity analysis of some key parameters that will affect the laser intensity on the tissue surface with respect to the tissue vaporization rate, a phenomenological model of laser-tissue interaction is developed. The developed laser-tissue interaction model has been implemented for a laser BPH simulator and achieves real time performance (more than 30 frames per second). The model agrees well with the available experimental data.

Volumetric modeling in laser BPH therapy simulation.

In this paper, we introduce a novel application of volume modeling techniques on laser Benign Prostatic Hyperplasia (BPH) therapy simulation. The core technique in our system is an algorithm for simulating the tissue vaporization process by laser heating. Different from classical volume CSG operations, our technique takes experimental data as the guidance to determine the vaporization amount so that only a specified amount of tissue is vaporized in each time. Our algorithm uses a predictor-corrector strategy. First, we apply the classical CSG algorithm on a tetrahedral grid based distance field to estimate the vaporized tissue amount. Then, a volume-correction phase is applied on the distance field. To improve the performance, we further propose optimization approaches for efficient implementation.

A discrete mechanics framework for real time virtual surgical simulations with application to virtual laparoscopic nephrectomy.

The inability to render realistic soft-tissue behavior in real time has remained a barrier to face and content aspects of validity for many virtual reality surgical training systems. Biophysically based models are not only suitable for training purposes but also for patient-specific clinical applications, physiological modeling and surgical planning. When considering the existing approaches for modeling soft tissue for virtual reality surgical simulation, the computer graphics-based approach lacks predictive capability; the mass-spring model (MSM) based approach lacks biophysically realistic soft-tissue dynamic behavior; and the finite element method (FEM) approaches fail to meet the real-time requirement. The present development stems from physics fundamental thermodynamic first law; for a space discrete dynamic system directly formulates the space discrete but time continuous governing equation with embedded material constitutive relation and results in a discrete mechanics framework which possesses a unique balance between the computational efforts and the physically realistic soft-tissue dynamic behavior. We describe the development of the discrete mechanics framework with focused attention towards a virtual laparoscopic nephrectomy application.

Realistic soft tissue deformation strategies for real time surgery simulation.

A volume-preserving deformation method (VPDM) is developed in complement with the mass-spring method (MSM) to improve the deformation quality of the MSM to model soft tissue in surgical simulation. This method can also be implemented as a stand-alone model. The proposed VPDM satisfies the Newton's laws of motion by obtaining the resultant vectors form an equilibrium condition. The proposed method has been tested in virtual surgery systems with haptic rendering demands.