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Mucosal melanoma (MM) poses a significant clinical challenge due to its aggressive nature and limited treatment options. In recent years, immunotherapy has emerged as a promising strategy for MM, with a particular focus on immune checkpoint inhibitors such as PD-1 and CTLA-4 inhibitors. These inhibitors have demonstrated substantial efficacy by harnessing the body's immune response against tumors. Moreover, adoptive cell transfer (ACT), anti-angiogenic therapy, and combination therapies have garnered attention for their potential in MM treatment. ACT involves modifying T cells to target melanoma cells, showing promising antitumor activity. Anti-angiogenic therapy aims to impede tumor growth by inhibiting angiogenesis, while combination therapies, including immune checkpoint inhibitors and targeted therapies, offer a multifaceted approach to overcome treatment resistance. This comprehensive review explores the advancements in immunotherapy for MM, highlighting the role of diverse therapeutic modalities in enhancing treatment outcomes and addressing the challenges posed by this aggressive malignancy.

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OBJECTIVES: Radiation-induced oropharyngeal injury is a dose-limiting toxicity in head and neck cancer patients. Delineation of the "oropharyngeal mucosa" and limiting its dose to spare the oropharynx was investigated. METHODS: In this retrospective study, computed tomography imaging from eight patients with previously untreated head and neck cancer was employed. An adaptive contouring brush within the planning software Monaco was used to create an air cavity within the oropharynx, and then the air cavity was expanded uniformly 2 mm to create the "oropharyngeal mucosa". Three plans were independently generated for each patient: Plan1: dose constraint was applied for the oropharynx; Plan2: dose constraints were applied for the oropharynx and the "oropharyngeal mucosa"; Plan3: dose constraint was applied for the "oropharyngeal mucosa". T-tests were used to compare the dosimetry variables. RESULTS: All plans had adequate target coverage and there were no statistical differences among plans. The mean dose, D30%, D45%, D50%, D85%, D90%, D95%, D100%, V25 Gy, V30 Gy, V35 Gy, V40 Gy, and V45 Gy of the oropharynx and "oropharyngeal mucosa" in Plan1 were significantly higher than those in Plan2 and Plan3. There were no significant differences between Plan2 and Plan3. There were no significant differences in the dosimetric parameters of any other organs at risk. CONCLUSION: Delineation of the "oropharyngeal mucosa" and limiting its dose should be an easy and effective method to spare the oropharynx.

Radiation-induced oropharyngeal injury is dose-limiting toxicity in head and neck cancer patients. Delineation of "oropharyngeal mucosa" and limiting its dose should be an easy and effective method to spare the oropharynx.

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The immunopathogenesis of recurrent vulvovaginal candidiasis (RVVC) is poorly understood. Recently, it was reported that patients with RVVC present a decrease in both the fungicidal capacity of neutrophils and the proliferative capability of peripheral blood mononuclear cells in response to Candida albicans infection, suggesting an alteration in the innate and adaptive immune response. The aim of this study was to determine the in-situ expression, in the vaginal mucosa, of genes associated with the immune response, as well as the serum concentrations of dectin-1, mannose-binding lectin (MBL), and vitamin D in patients with RVVC. A study was carried out on 40 patients with a diagnosis of RVVC and 26 healthy women. Vaginal scrapings were obtained, and the expression of genes that encode cytokines and transcription factors specific for Th1, Th2, Th17, Treg, pro-inflammatory profiles, and enzymes related to oxidative/microbicidal mechanisms was evaluated by quantitiative polymerase chain reaction (qPCR). Additionally, serum levels of vitamin D and the soluble receptors dectin-1 and MBL were determined by enzyme-linked immunosorbent assay (ELISA). In patients with RVVC, a decreased expression of T-bet, RORγ-T, IL-1ß, and IL-17, and an increase in the expression of FOXP3, IL-4, IL-8, IL-10, and IL-18 were observed when compared to healthy women: moreover, decreased levels of MBL were also observed in these patients. These results confirm that patients with RVVC present in-situ alterations in both the specific and adaptive immune response against Candida spp., a fact that could be associated with the exaggerated vaginal inflammatory response.

The study concerns the immune response of women with recurrent vulvovaginal candidiasis; we observed an alteration in the expression of genes that participate in the control of infection, a fact that could be associated with the exaggerated vaginal inflammatory response observed in those patients.

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Effective drug delivery to bacterially infected mucosa remains a challenge due to the combined obstacles of the mucosal barrier, pH variations, and high concentrations of glutathione. However, polysaccharide-based responsive nanogels (NGs) can take advantage of these conditions to deliver specific antimicrobials. We explored the critical features of pH- and redox-responsive NGs to increase drug penetration, residence time, and efficacy in the infected mucosa. We prepared multifunctional NGs using hydroxypropyl cellulose as a template for the cross-linking of methacrylic acid with N,N'-bis(acryloyl)cystamine (BAC) or N,N'-methylenebis(acrylamide) (BIS). Studies of NG-mucin binding and the antibacterial efficacy of doxycycline-loaded NGs revealed the interplay between the response to pH and redox clues. Specifically, higher BAC composition increased mucus binding and controlled release in reductive conditions, while higher BIS composition yielded NGs with higher doxycycline-mediated antibacterial efficacy against Staphylococcus aureus. The findings reveal the potential of multiresponsive NGs in effective antimicrobial delivery in infected mucosa.

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The unconventional type I interferons IFNε and IFNω and type III interferon IFNλ are gradually emerging as tissue-specific cytokines in defence of mucosal tissues. This review provides an overview of the distinct features and functions that define these IFNs as protective factors in the respiratory, gastrointestinal and reproductive tracts, highlighting their immunoregulatory roles against pathogens while maintaining tolerance against commensal microbes. In particular, we discuss recent advances in our understanding of the constitutively expressed IFNε and its role in protecting against mucosal infections, inflammation and cancers. We identify an emerging theme for this unique cytokine as a key contributor to the 'first line of defence' against pathogens and maintenance of mucosal tissue homeostasis, primarily through its regulation of immune cell populations.

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BACKGROUND: This study aimed to explore the impacts of different middle-ear mucosal conditions on the outcomes of type I tympanoplasty. METHODS: A retrospective analysis of 164 patients with chronic otitis media was carried out. The patients were divided into 4 groups according to their mucosal condition. Preoperative hearing levels and air-bone gap (ABG) before and after surgery were compared via the Kruskal‒Wallis H test. The chi-squared test and Fisher's exact test were used to assess the postoperative complications and impact factors of functional success. RESULTS: Preoperatively, neither the air conduction nor bone conduction values differed significantly among groups with different mucosal conditions. All of the ABG closed dramatically after type I tympanoplasty (P < .05) regardless of the mucosal conditions. The functional success rates were lower when the intratympanic mucosa was moderately or severely edematous compared with mildly edematous or normal (P < .05). The disease course, perforation site, and perforation size, as well as the status of the opposite ear, were not related to the auditory functional outcome. The differences in postoperative reotorrhea and reperforation among the 4 groups were not statistically significant. CONCLUSION: Preoperative hearing levels were not affected by middle-ear mucosal conditions. The functional success rate was influenced by mucosal conditions, but hearing levels were significantly enhanced after surgical intervention regardless of the mucosal status. Postoperative complications were not related to the mucosal conditions. Thus, type I tympanoplasty is adoptable for mucosal abnormalities when pharmacotherapy cannot result in a healthy tympanum.

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Infections pose a challenge for the fast growing aquaculture sector. Glycosphingolipids are cell membrane components that pathogens utilize for attachment to the host to initiate infection. Here, we characterized rainbow trout glycosphingolipids from five mucosal tissues using mass spectrometry and nuclear magnetic resonance and investigated binding of radiolabeled Aeromonas salmonicida to the glycosphingolipids on thin-layer chromatograms. 12 neutral and 14 acidic glycosphingolipids were identified. The glycosphingolipids isolated from the stomach and intestine were mainly neutral, whereas glycosphingolipids isolated from the skin, gills and pyloric caeca were largely acidic. Many of the acidic structures were poly-sialylated with shorter glycan structures in the skin compared to the other tissues. The sialic acids found were Neu5Ac and Neu5Gc. Most of the glycosphingolipids had isoglobo and ganglio core chains, or a combination of these. The epitopes on the rainbow trout glycosphingolipid glycans differed between epithelial sites leading to differences in pathogen binding. A major terminal epitope was fucose, that occurred attached to GalNAc in a α1-3 linkage but also in the form of HexNAc-(Fuc-)HexNAc-R. A. salmonicida were shown to bind to neutral glycosphingolipids from the gill and intestine. This study is the first to do a comprehensive investigation of the rainbow trout glycosphingolipids and analyze binding of A. salmonicida to glycosphingolipids. The structural information paves the way for identification of ways of interfering in pathogen colonization processes to protect against infections in aquaculture and contributes towards understanding A. salmonicida infection mechanisms.

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OBJECTIVE: In recent years, the clinical efficacy of medications for adenoid hypertrophy has been demonstrated. Topical nasal steroids have effects to shrink hypertrophic adenoids and improve symptoms of associated diseases. However, the mechanism which topical steroid administrations cause adenoid shrinkage remains unclear, herein, sensitivity for topical steroids in the mucosal epithelium of adenoids was evaluated histologically by comparing with tonsils. METHODS: Histological analysis was performed on adenoids and tonsils removed from 32 pediatric patients with adenoid hypertrophy. In hematoxylin-eosin-stained specimens, the morphology of the mucosal epithelium and eosinophil infiltration were evaluated. The expression of the glucocorticoid receptor (GR), interleukin (IL)-4, and IL-25 in the mucosal epithelium was evaluated, and the staining intensity was scored as 0 (none), 1 (weak), and 2 (strong). The number of eosinophils and expression scores of GR, IL-4, and IL-25 were statistically compared between adenoids and tonsils and analyzed correlations with adenoids sizes. RESULTS: Adenoids were covered with ciliated epithelium, and eosinophils in the mucosal epithelium and submucosal area was higher than tonsils (p < 0.05). GR expression in the most superficial layer of the mucosal epithelium was observed in adenoids, and the expression intensity score was higher than that in tonsils (p < 0.05). IL-4 and IL-25 were more widely expressed in the mucosal epithelium of adenoids than in tonsils, and their expression intensity scores were also higher than in tonsils (p < 0.05). A correlation was found between adenoid size and the intensity of IL-25 expression in the adenoid epithelium (p < 0.05). CONCLUSION: Eosinophilic inflammations in adenoids mucosal epithelium could be one of etiology of adenoid hypertrophy, and the GR and eosinophilic inflammation in the adenoids mucosal epithelium might be target of topical nasal steroids to shrink hypertrophic adenoids.

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Recently, transmucosal drug delivery systems (TDDSs) have been extensively studied because they protect therapeutic agents from degradation; improve drug residence time at the mucosal membranes; and facilitate sustained drug release for a prolonged period. Chitosan is a well-researched polymeric excipient due to its biocompatibility, non-toxicity, biodegradability, mucoadhesive, antimicrobial, and low immunogenicity. Its limited mucoadhesiveness in the physiological environment necessitated its chemical modification. This review highlights the recent advances in the chemical modification of chitosan with various chemical groups to generate various functionalized chitosan derivatives, such as thiolated, acrylated, methacrylated, boronated, catechol, and maleimide-functionalized chitosans with superior mucoadhesive capabilities compared to the parent chitosan. Moreover, it presents the different prepared dosage forms, such as tablets, hydrogels, films, micro/nanoparticles, and liposomes/niosomes for drug administration within various mucosal routes including oral, buccal, nasal, ocular, colonic, intravesical, and vaginal routes. The reported data from preclinical studies of these pharmaceutical formulations have revealed the controlled and target-specific delivery of therapeutics because of their formation of covalent bonds with thiol groups on the mucosal surface. All functionalized chitosan derivatives exhibited long drug residence time on mucosal surfaces and sustainable drug release with excellent cellular permeability, drug efficacy, and biocompatibility. These promising data could be translated from the research laboratories to the clinics with consistent and intensive research effort.

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Current prophylactic and disease control measures in aquaculture highlight the need of alternative strategies to prevent disease and reduce antibiotic use. Mucus covered mucosal surfaces are the first barriers pathogens encounter. Mucus, which is mainly composed of highly glycosylated mucins, has the potential to contribute to disease prevention if we can strengthen this barrier. Therefore, aim of this study was to develop and characterize fish in vitro mucosal surface models based on commercially available cell lines that are functionally relevant for studies on mucin regulation and host-pathogen interactions. The rainbow trout (Oncorhynchus mykiss) gill epithelial cell line RTgill-W1 and the embryonic cell line from Chinook salmon (Oncorhynchus tshawytscha) CHSE-214 were grown on polycarbonate membrane inserts and chemically treated to differentiate the cells into mucus producing cells. RTGill-W1 and CHSE-214 formed an adherent layer at two weeks post-confluence, which further responded to treatment with the γ-secretase inhibitor DAPT and prolonged culture by increasing the mucin production. Mucins were metabolically labelled with N-azidoacetylgalactosamine 6 h post addition to the in vitro membranes. The level of incorporated label was relatively similar between membranes based on RTgill-W1, while larger interindividual variation was observed among the CHSE in vitro membranes. Furthermore, O-glycomics of RTgill-W1 cell lysates identified three sialylated O-glycans, namely Galß1-3(NeuAcα2-6)GalNAcol, NeuAcα-Galß1-3GalNAcol and NeuAcα-Galß1-3(NeuAcα2-6)GalNAcol, resembling the glycosylation present in rainbow trout gill mucin. These glycans were also present in CHSE-214. Additionally, we demonstrated binding of the fish pathogen A. salmonicida to RTgill-W1 and CHSE-214 cell lysates. Thus, these models have similarities to in vivo mucosal surfaces and can be used to investigate the effect of pathogens and modulatory components on mucin production.

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Melanomas affecting acral and mucosal sites have distinct features and are associated with poorer prognosis. Patients of color may be disproportionately affected. Herein we discuss six ethnically diverse cases of acral and mucosal melanoma (AMM). More data on clinical, genetic, and environmental features of AMM are needed, but thorough physical examination can reduce the burden of disease now. J Drugs Dermatol. 2024;23(8):683-685. doi:10.36849/JDD.8311.

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PURPOSE: We investigated the relationship between bile amylase (AMY) levels and biliary epithelial changes in pancreaticobiliary maljunction (PBM), a congenital anomaly characterized by pancreaticobiliary reflux due to duct fusion outside the duodenal wall. METHODS: We enrolled 43 children with congenital biliary dilatation (CBD) of Todani types Ia, Ic, and IVa who underwent surgery at the Hokkaido Medical Center for Child Health and Rehabilitation between November 2007 and June 2023. We defined total AMY exposure in bile as bile AMY levels multiplied by the patient's age (months), representing amount of estimated AMY exposure until surgery. We retrospectively investigated the relationships between bile AMY levels and clinicopathological findings. RESULTS: All patients exhibited hyperplasia in the gallbladder and bile duct epithelium, with dysplasia observed in 13 cases, but no carcinoma. Exposure to bile AMY ≥ 662,400 IU/L × months was an independent risk factor for dysplasia. CONCLUSION: The amount of estimated AMY exposure in bile rather than AMY levels in the bile is an independent risk factor for dysplasia in the biliary mucosa.

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To accurately measure the vaginal mucosa thickness across different age groups using histopathologic techniques and investigate the factors that may influence the thickness changes. This study aims to provide clinicians with objective evidence of variations in vaginal mucosal thickness, facilitating personalized medical decisions for patients. A retrospective analysis was conducted on clinical data from 348 patients who underwent local vaginal wall resection at the West China Second University Hospital, Sichuan University, from January 2021 and May 2022. The thickness of vaginal mucosa, epithelium and lamina propria was measured precisely under the microscope. And the 10th, 25th, 50th, 75th, and 90th percentile values of vaginal mucosa thickness across different age groups were counted and charted a dot-line plot. The percentile values for vaginal mucosa thickness exhibited a decreasing trend with increasing age; vaginal mucosa thickness showed significant correlations with times of delivery (P = 0.031) and age (P < 0.001), both of which were negatively associated. And vaginal mucosa thickness demonstrated no significant correlation with body mass index (BMI) (P = 0.325), times of abortions (P = 0.511), times of gestation (P = 0.101), menstrual cycle (P = 0.533), or types of delivery (P = 0.056); epithelial thickness showed significant associations with age (P < 0.001) and types of delivery (P = 0.017), both of which were negative correlations. Moreover, BMI (P = 0.429), times of abortions (P = 0.764), delivery (P = 0.079), gestation (P = 0.475), and menstrual cycle (P = 0.950) were nonassociated with epithelial thickness; lamina propria thickness displayed a significant correlation only with age (P = 0.002), and there were no obvious correlations observed between lamina propria thickness and BMI (P = 0.374), times of abortion (P = 0.417), delivery (P = 0.053), gestation (P = 0.101), types of delivery (P = 0.132) and menstrual cycle (P = 0.495). Moreover, when the age segmentation was thresholded at 35 and 50 years, both epithelial thickness and vaginal mucosa thickness were significantly correlated with age (P < 0.05). Lamina propria thickness was associated with age when the age threshold was set at 35 years (P = 0.007), whereas it showed no strong link with age when the age threshold was 50 years (P = 0.072). This study has innovatively established percentile reference values for vaginal mucosa thickness based on histopathology, furnishing clinicians with objective evidence of variations in vaginal mucosal thickness to facilitate personalized medical decisions for patients. The findings demonstrated a strong link between vaginal mucosa thickness and age, with epithelium likely playing a predominant role, while the association with lamina propria appeared to be less significant. Further research involving a larger sample size is warranted to elucidate the potential relationship with the lamina propria.

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Interferon epsilon (IFNε) is a unique type I interferon (IFN) that shows distinct constitutive expression in reproductive tract epithelium. Understanding how IFNε expression is regulated is critical for the mechanism of action in protecting the mucosa from infection. Combined computational and experimental investigation of the promoter of IFNε predicted transcription factor binding sites for the ETS family of transcription factors. We demonstrate here that Ifnε is regulated by Elf3, an epithelial restricted member of the ETS family. It is co-expressed with IFNε at the epithelium of uterus, lung and intestine, and we focused on regulation of IFNε expression in the uterus. Promoter reporter studies demonstrated that Elf3 was a strong driver of Ifnε expression; knockdown of Elf3 reduced expression levels of IFNε; Elf3 regulated Ifnε expression and chromatin immunoprecipitation (ChIP) confirmed the direct binding of Elf3 to the IFNε promoter. These data show that Elf3 is important in regulating protective mucosal immunity by driving constitutive expression of IFNε to protect mucosal tissues from infection in at least three organ systems.

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Germinal centers (GCs) that form in mucosal sites are exposed to gut-derived factors that have the potential to influence homeostasis independent of antigen receptor-driven selective processes. The G-protein Gα13 confines B cells to the GC and limits the development of GC-derived lymphoma. We discovered that Gα13-deficiency fuels the GC reaction via increased mTORC1 signaling and Myc protein expression specifically in the mesenteric lymph node (mLN). The competitive advantage of Gα13-deficient GC B cells (GCBs) in mLN was not dependent on T cell help or gut microbiota. Instead, Gα13-deficient GCBs were selectively dependent on dietary nutrients likely due to greater access to gut lymphatics. Specifically, we found that diet-derived glutamine supported proliferation and Myc expression in Gα13-deficient GCBs in the mLN. Thus, GC confinement limits the effects of dietary glutamine on GC dynamics in mucosal tissues. Gα13 pathway mutations coopt these processes to promote the gut tropism of aggressive lymphoma.

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Human cytomegalovirus (CMV) causes serious developmental disabilities in newborns infected in utero following oral acquisition by the mother. Thus, neutralizing antibodies in maternal saliva have potential to prevent maternal infection and, consequently, fetal transmission and disease. Based on standard cell culture models, CMV entry mediators (and hence neutralizing targets) are cell type-dependent: entry into fibroblasts requires glycoprotein B (gB) and a trimeric complex (TC) of glycoproteins H, L, and O, whereas endothelial and epithelial cell entry additionally requires a pentameric complex (PC) of glycoproteins H and L with UL128, UL130, and UL131A. However, as the mediators of mucosal cell entry and the potential impact of cellular differentiation remained unclear, the present studies utilized mutant viruses, neutralizing antibodies, and soluble TC-receptor to determine the entry mediators required for infection of mucocutaneus cell lines and primary tonsil epithelial cells. Entry into undifferentiated cells was largely PC-dependent, but PC-independent entry could be induced by differentiation. TC-independent entry was also observed and varied by cell line and differentiation. Infection of primary tonsil cells from some donors was entirely TC-independent. In contrast, an antibody to gB or disruption of virion attachment using heparin blocked entry into all cells. These findings indicate that CMV entry into the spectrum of cell types encountered in vivo is likely to be more complex than has been suggested by standard cell culture models and may be influenced by the relative abundance of virion envelope glycoprotein complexes as well as by cell type, tissue of origin, and state of differentiation.

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Mucosal melanoma is a rare melanoma subtype, accounting for about 1% of all diagnosed melanomas. It is characterized by an aggressive phenotype with a poor prognosis and a low response rate to approved treatments. We retrospectively analyzed the clinical features, treatments, and outcomes of patients diagnosed with mucosal melanoma treated with axitinib ±â€…anti-programmed cell death protein 1 (PD-1) therapy at a single US referral center between 2018 and 2021. Radiologic response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), v1.1. Twenty-three patients were included in this study. In all, 78% were females with a median age of 62 years. The originating site of mucosal melanoma was the sinonasal (35%), genitourinary (35%), and gastrointestinal (30%) tracts. Sixty-five percent of patients had M1c or M1d disease and 0% had BRAF V600 mutations detected. The majority (96%) had prior treatment inclusive of anti-PD-1, with a median of 2 prior lines, and 78% of patients received a combination of axitinib and PD-1 and the median duration of treatment was 3.2 months. The overall response rate was 13% and the disease control rate was 26%. The median progression-free survival was 3.2 months, and the median overall survival was 8.2 months. Overall, the regimen was well tolerated with 39% of patients requiring dose reduction and 9% requiring treatment cessation. Axitinib with anti-PD-1 therapy has modest clinical activity in heavily pretreated patients with mucosal melanoma outside of Asia, including some with long-term benefits. This data supports the worldwide clinical trials evaluating this combination and the role of incorporating vascular endothelial growth factor-based therapy in the therapeutic paradigm for patients with mucosal melanoma.

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