IgE-Mediated Cannabis Allergy and Cross-Reactivity Syndromes: A Roadmap for Correct Diagnosis and Management.

PURPOSE OF THE REVIEW: With increased access and decriminalization of cannabis use, cases of IgE-dependent cannabis allergy (CA) and cross-reactivity syndromes have been increasingly reported. However, the exact prevalence of cannabis allergy and associated cross-reactive food syndromes (CAFS) remains unknown and is likely to be underestimated due to a lack of awareness and insufficient knowledge of the subject among health care professionals. Therefore, this practical roadmap aims to familiarize the reader with the early recognition and correct management of IgE-dependent cannabis-related allergies. In order to understand the mechanisms underlying these cross-reactivity syndromes and to enable personalized diagnosis and management, special attention is given to the molecular diagnosis of cannabis-related allergies. RECENT FINDINGS: The predominant signs and symptoms of CA are rhinoconjunctivitis and contact urticaria/angioedema. However, CA can also present as a life-threatening condition. In addition, many patients with CA also have distinct cross-reactivity syndromes, mainly involving fruits, vegetables, nuts and cereals. At present, five allergenic components of Cannabis sativa (Can s); Can s 2 (profilin), Can s 3 (a non-specific lipid protein), Can s 4 (oxygen-evolving enhancer protein 2 oxygen), Can s 5 (the Bet v 1 homologue) and Can s 7 (thaumatin-like protein) have been characterized and indexed in the WHO International Union of Immunological Sciences (IUIS) allergen database. However, neither of them is currently readily available for diagnosis, which generally starts by testing crude extracts of native allergens. The road to a clear understanding of CA and the associated cross-reactive food syndromes (CAFS) is still long and winding, but well worth further exploration.

Mast cell secretory granule fusion with amphisomes coordinates their homotypic fusion and release of exosomes.

Secretory granule (SG) fusion is an intermediate step in SG biogenesis. However, the precise mechanism of this process is not completely understood. We show that Golgi-derived mast cell (MC) SGs enlarge through a mechanism that is dependent on phosphoinositide (PI) remodeling and fusion with LC3+ late endosomes (amphisomes), which serve as hubs for the fusion of multiple individual SGs. Amphisome formation is regulated by the tyrosine phosphatase PTPN9, while the subsequent SG fusion event is additionally regulated by the tetraspanin protein CD63 and by PI4K. We also demonstrate that fusion with amphisomes imparts to SGs their capacity of regulated release of exosomes. Finally, we show that conversion of PI(3,4,5)P3 to PI(4,5)P2 and the subsequent recruitment of dynamin stimulate SG fission. Our data unveil a key role for lipid-regulated interactions with the endocytic and autophagic systems in controlling the size and number of SGs and their capacity to release exosomes.

Degranulation and expression of cytokines were modulated by diazinon in activated mast cells.

Diazinon is an organophosphorus (OP) insecticides used in agriculture, home gardening and indoor pest control in Japan. It can activate macrophages and induce pro-inflammatory responses and has been reported to cause airway hyper-reactivity, suggesting the possibility of asthma exacerbation from exposure to OP insecticides. Despite the correlation between insecticide use and the pathogenesis of allergic diseases, there have been no reports on the effects of diazinon on mast cell function. Therefore, in this study, we investigated the effects of diazinon on mast cell function in rat basophilic leukemia (RBL)-2H3 cells. Surprisingly, we found that diazinon inhibited mast cell activation, although the degree of inhibition varied with concentration. Diazinon induced reactive oxygen species (ROS) generation and HO-1 expression at a concentration of 150 µM without affecting cell viability. Diazinon inhibited A23187-mediated degranulation and Tnf and Il4 expression in RBL-2H3 cells but did not affect calcium influx. Suppression of degranulation by diazinon was reversed when the culture supernatant was removed. As a signaling event downstream of calcium influx, diazinon inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) induced by A23187, whereas the phosphorylation of p38 had little effect. IgE cross-linking-mediated degranulation as well as the induction of Tnf and IL4 expression was significantly inhibited by diazinon, while diazinon had little effect on calcium influx. In conclusion, diazinon inhibited mast cell activation, including degranulation and cytokine expression. When evaluating the in vivo effects of diazinon, its potential to inhibit mast cell activation should be considered in the pathophysiology and development of allergic diseases in terms of basic and clinical aspects, respectively, although the effect of diazinon varies depending on the cell type.

Emodin suppresses mast cell migration via modulating the JAK2/STAT3/JMJD3/CXCR3 signaling to prevent cystitis.

AIMS: This study aimed to determine the preventive effects of emodin on cyclophosphamide (CYP)-induced cystitis and to explore the molecular mechanism. METHODS: In vivo, mice were modeled by CYP. Before a half hour of CYP treatment, Jumonji domain-containing protein-3 (JMJD3) inhibitors (GSK-J4) and emodin were used to treat CYP model mice. Bladder samples were stained for hematoxylin-eosin and toluidine blue. Next, JMJD3 was quantified by immunofluorescence staining, RT-PCR, and Western blot. CXCR3 was quantified by Western blot and ELISA. In vitro, before stimulated by lipopolysaccharide (LPS), human bladder smooth muscle cells (hBSMCs) were transfected with pcDNA3.1-JMJD3 plasmids, shRNA-JMJD3 plasmids or pretreated with emodin. Collected cells to detect JMJD3 and CXCR3 ligands again; collected supernatant of culture for Transwell assay. Finally, as the JAK2 inhibitor, AG490 was used to pretreat LPS-induced hBSMCs. Western blot was performed to quantify proteins. RESULTS: Emodin inhibited mast cell migration and suppressed the expression of JMJD3, CXCR3, and CXCR3 ligands, not only in vivo but also in vitro. The pharmacological effects of emodin were similar to GSK-J4 or JMJD3 inhibition. In addition, emodin significantly downregulated the phosphorylation of JAK2 and STAT3, and inhibited JMJD3/CXCR3 axis transduction like AG490. CONCLUSION: Emodin has a preventive effect on cystitis by inhibiting mast cell migration through inhibition of the JAK2/STAT3/JMJD3/CXCR3 signaling pathway.

CCAAT/enhancer-binding protein α-dependent regulation of granule formation in mast cells by intestinal bacteria.

The antiallergic effects of gut microbiota have been attracting attention in recent years, but the underlying cellular and molecular mechanisms have not yet been fully understood. In this study, we aimed to investigate these mechanisms specifically focusing on mast cells. Mast cells retain intracellular granules containing various inflammatory mediators such as histamine, which are released outside the cells upon IgE and allergen stimulation. We previously reported that increased expression of the transcription factor, CCAAT/enhancer-binding protein α (C/EBPα), suppresses granule formation in mast cells and that Lacticaseibacillus casei JCM1134T (LC) upregulates C/EBPα levels. Here, granule formation in mouse bone marrow-derived mast cells was suppressed in a MyD88-dependent manner after LC treatment due to C/EBPα-dependent downregulation of the genes encoding serglycin (SRGN) and mast cell protease 4 (Mcpt4). Furthermore, C/EBPα expression was regulated by DNA methylation in the 5' region far upstream of the transcription start site. LC suppressed DNA methylation of specific CpG motifs in the 5' region of the C/EBPα gene. These results conclude that specific gut microbial components, such as those from LC, suppress granule formation in mast cells by inhibiting SRGN and Mcpt4 expression via reduced C/EBPα gene methylation.

Peripheral mast cells derive the effects of acupuncture in Parkinson's disease.

This research investigates the peripheral mechanisms of acupuncture in treating Parkinson's disease (PD), a progressive neurodegenerative disorder marked by motor impairments. While the central mechanisms of acupuncture have been extensively studied, our focus lies in the peripheral mechanisms at the acupoints, the sites of acupuncture signal initiation. Employing a PD model, we analyzed the local responses to acupuncture stimulation at these points. Our key finding was a significant elevation in both the number and activity of mast cells (MCs) in the peripheral tissues following acupuncture. Intriguingly, pre-treatment with an MC stabilizer diminished the acupuncture's therapeutic effects on PD symptoms. Similarly, local anesthesia with lidocaine at the acupoints attenuated the symptom improvement typically observed with acupuncture. Meanwhile, the augmentation of MC activity induced by acupuncture was significantly impeded by cromolyn, an MC stabilizer, but remained unaffected by lidocaine. This finding suggests that MC activity is a more upstream regulator of acupuncture effects compared to nerve conduction. This study provides groundbreaking insights into the initiation and transmission of acupuncture signals, highlighting the significant role of peripheral MC modulation in PD treatment.

Close relationship between mediators of inflammation and pancreatic cancer: Our experience.

In this editorial, we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer. Cancer of the pancreas remains one of the deadliest cancer types. The highest incidence and mortality rates of pancreatic cancer are found in developed countries. Trends of pancreatic cancer incidence and mortality vary considerably worldwide. A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this disease. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this editorial, we highlight the foundational studies that have driven our understanding of these processes. In our experimental center, we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic cancer. We focused on the role of mast cells (MCs). MCs contain pro-angiogenic factors, including tryptase, that are associated with increased angiogenesis in various tumors. In this editorial, we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue. The assessment includes the density of c-Kit receptor-positive MCs, the density of tryptase-positive MCs, the area of tryptase-positive MCs, and angiogenesis in terms of microvascularization density.

Tail-dependence of masting synchrony results in continent-wide seed scarcity.

Spatial synchrony may be tail-dependent, meaning it is stronger for peaks rather than troughs, or vice versa. High interannual variation in seed production in perennial plants, called masting, can be synchronized at subcontinental scales, triggering extensive resource pulses or famines. We used data from 99 populations of European beech (Fagus sylvatica) to examine whether masting synchrony differs between mast peaks and years of seed scarcity. Our results revealed that seed scarcity occurs simultaneously across the majority of the species range, extending to populations separated by distances up to 1800 km. Mast peaks were spatially synchronized at distances up to 1000 km and synchrony was geographically concentrated in northeastern Europe. Extensive synchrony in the masting lower tail means that famines caused by beech seed scarcity are amplified by their extensive spatial synchrony, with diverse consequences for food web functioning and climate change biology.

Ca2+-Dependent Processes of Innate Immunity in IBD.

IBD is an uncontrolled inflammatory condition of the gastrointestinal tract, which mainly manifests in two forms: ulcerative colitis (UC) and Crohn's disease (CD). The pathogenesis of IBD appears to be associated with an abnormal response of innate and adaptive immune cells. Innate immunity cells, such as macrophages, mast cells, and granulocytes, can produce proinflammatory (e.g., TNF-α) and oxidative stress (ROS) mediators promoting intestinal damage, and their abnormal responses can induce an imbalance in adaptive immunity, leading to the production of inflammatory cytokines that increase innate immune damage, abate intestinal barrier functions, and aggravate inflammation. Considering that Ca2+ signalling plays a key role in a plethora of cellular functions, this review has the purpose of deepening the potential Ca2+ involvement in IBD pathogenesis.

Monensin Suppresses Multiple Features of House Dust Mite-Induced Experimental Asthma in Mice.

Despite intense efforts to develop efficient therapeutic regimes for asthma, there is a large demand for novel treatment strategies in this disease. Here we evaluated the impact of monensin, a drug with potent anti-mast cell effects, in a mouse model of asthma. Allergic airway inflammation was induced by sensitization of mice with house dust mite (HDM) antigen, and effects of monensin on airway hyperreactivity and inflammatory parameters were studied. Following intraperitoneal administration, monensin did not suppress airway hyperreactivity but was shown to have anti-inflammatory properties, as manifested by reduced eosinophil- and lymphocyte infiltration into the airway lumen, and by suppressed inflammation of the lung tissue. After intranasal instillation, monensin exhibited similar anti-inflammatory effects as seen after intraperitoneal administration. Moreover, intranasally administered monensin was demonstrated to suppress goblet cell hyperplasia, and to cause a reduction in the expression of genes coding for key inflammatory markers. Further, monensin blocked mast cell degranulation in the airways of allergen-sensitized mice. Together, this study reveals that monensin has the capacity to suppress key pathological events associated with allergic airway inflammation.

Mast cell activation syndrome: An up-to-date review of literature.

Mast cells are a subtype of white blood cells and are involved in the immune system. These cells contain many chemical substances called mediators, which are involved in the allergic response. The fact that mast cells play a role in many events that require urgent intervention, especially anaphylaxis, has led to a more detailed study of these cells. The diseases also caused by dysfunctions of mast cells have been examined in many circumstances. For instance, mast cell activation syndrome is known as an augmented number of cells due to decreased cell death, resulting in clinical symptoms affecting many systems. The main common symptoms include flushing, hypotension, urticaria, angioedema, headache, vomiting and diarrhea. Although the underlying mechanism is not yet clearly known, we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.

Sulfur dioxide inhibits mast cell degranulation by sulphenylation of galectin-9 at cysteine 74.

Objectives: Mast cell (MC) degranulation is a key process in allergic reactions and inflammatory responses. Aspartate aminotransferase 1 (AAT1)-derived endogenous sulfur dioxide (SO2) is an important regulator of MC function. However, the mechanism underlying its role in MC degranulation remains unclear. This study aimed to investigate the mechanism by which endogenous SO2 controlled MC degranulation. Methods: HMC-1 and Rat basophilic leukemia cell MC line (RBL-2H3) were used in the cell experiments. SO2 content was detected by in situ fluorescent probe. MC degranulation represented by the release rate of MC ß-hexosaminidase was determined using a colorimetric assay. Sulfenylation of galectin-9 (Gal-9) in MCs and purified protein was detected using a biotin switch assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the exact sulfenylation sites of Gal-9 by SO2. Animal models of passive cutaneous anaphylaxis (PCA) and hypoxia-driven pulmonary vascular remodeling were used to investigate the effect of SO2 on mast cell activation in vivo. Site-directed mutation of Gal-9 was conducted to confirm the exact site of SO2 and support the significance of SO2/Gal-9 signal axis in the regulation of MC degranulation. Results: Degranulation was increased in AAT1-knockdowned MCs, and SO2 supplementation reversed the increase in MC degranulation. Furthermore, deficiency of endogenous SO2 contributed to IgE-mediated degranulation in vitro. Besides, SO2 inhibited IgE-mediated and hypoxia-driven MC degranulation in vivo. Mechanistically, LC-MS/MS analysis and site-directed mutation results showed that SO2 sulfenylated Gal-9 at cysteine 74. Sulfenylation of the 74th cysteine of Gal-9 protein was required in the SO2-inhibited MC degranulation under both physiological and pathophysiological conditions. Conclusion: These findings elucidated that SO2 inhibited MC degranulation via sulfenylating Gal-9 under both physiological and pathophysiological conditions, which might provide a novel treatment approach for MC activation-related diseases.

Butyrate promotes visceral hypersensitivity in IBS model via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway.

Emerging evidence indicates that gut dysbiosis is involved in the pathogenesis of visceral hypersensitivity (VH). However, how gut microbiota contributes to the development of VH is unknown. Here, we sought to examine the signal transduction pathways from gut to dorsal root ganglion (DRG) responsible for this. Therefore, abdominal withdrawal reflex (AWR) scores, fecal output, fecal water content, and total gastrointestinal transit time (TGITT) were assessed in Con rats, VH rats, rats treated with NaB, and VH rats treated with VSL#3. Fecal microbiota and its metabolite (short-chain fatty acids, SCFAs), mast cell degranulation in colon, lincRNA-01028, miR-143, and protease kinase C (PKC) and TRPV1 expression in DRGs were further detected. VH rats showed an increased fecal water content, a shortened TGITT, an increased abundance of Clostridium sensu stricto 1 and increased butyrate in fecal samples, an increased mast cell degranulation, an increased expression of lincRNA-01028, PKC, and TRPV1, and a decreased expression of miR-143 in DRGs compared with control rats, which could be restored by the application of probiotic VSL#3. The above-mentioned detection in rats treated with butyrate was similar to that of VH rats. We further confirm whether butyrate sensitized DRG neurons by a lincRNA-01028, miR-143, and PKC-dependent mechanism via mast cell in vitro. In co-cultures, MCs treated with butyrate elicited a higher TRPV1 current, a higher expression of lincRNA-01028, PKC, and a lower expression of miR-143 in DRG neurons, which could be inhibited by a lincRNA-01028 inhibitor. These findings indicate that butyrate promotes visceral hypersensitivity via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway.IMPORTANCEIrritable bowel syndrome (IBS), characterized by visceral hypersensitivity, is a common gastrointestinal dysfunction syndrome. Although the gut microbiota plays a role in the pathogenesis and treatment of irritable bowel syndrome (IBS), the possible underlying mechanisms are unclear. Therefore, it is of critical importance to determine the signal transduction pathways from gut to DRG responsible for this in vitro and in vivo assay. This study demonstrated that butyrate sensitized TRPV1 in DRG neurons via mast cells in vivo and in vitro by a lincRNA-01028, miR-143, and PKC-dependent mechanism. VH rats similarly showed an increased abundance of Clostridium sensu stricto 1, an increased fecal butyrate, an increased mast cell degranulation, and increased expression of TRPV1 compared with control rats, which could be restored by the application of VSL#3. In conclusion, butyrate produced by the altered intestinal microbiota is associated with increased VH.

Successful treatment of a Morbihan's disease patient after a therapeutic challenge: A case report and comprehensive literature review.

Morbihan's disease is a rare condition characterized by chronic facial edema. While its exact cause is unknown, it is thought to involve local cutaneous vascularization and lymphatic drainage imbalance. Traditional treatment options are often ineffective, and no established efficient treatment exists. We present a case study of a 17-year-old male with Morbihan's syndrome who showed resistance to traditional treatments but responded well to a combination of cromolyn sodium nasal spray and oral montelukast after histopathology revealed hyperplasia of plasma cells and mast cells. This combination has not been used before for Morbihan's syndrome. Our review of the literature also provides insight for clinicians seeking to manage this condition.

Mast cell density in Merkel cell carcinoma and its correlation with prognostic features and MCPyV status: a pilot study.

Merkel cell carcinoma (MCC) is a rare, highly aggressive, primitive neuroendocrine carcinoma of the skin, the origin of which is not yet fully understood. Numerous independent prognostic factors have been investigated in an attempt to understand which are the most important parameters to indicate in the histological diagnostic report of MCC. Of these, mast cells have only been studied in one paper before this one. We present a retrospective descriptive study of 13 cases of MCC, received at the Department of Pathology over a 20-year period (2003-2023 inclusive) on which we performed a study using whole-slide (WSI) morphometric analysis scanning platform Aperio Scanscope CS for the detection and spatial distribution of mast cells, using monoclonal anti-tryptase antibody and anti-CD34 monoclonal antibody to study the density of microvessels. In addition, we analyzed MCPyV status with the antibody for MCPyV large T-antigen (Clone CM2B4). We found statistically significant correlation between mast cell density and local recurrence/distant metastasis/death-of-disease (p = 0.008). To our knowledge, we firstly reported that MCPyV ( -) MCC shows higher mast cells density compared to MCPyV ( +) MCC, the latter well known to be less aggressive. Besides, the median vascular density did not show no significant correlation with recurrence/metastasis/death-of-disease, (p = 0.18). Despite the small sample size, this paper prompts future studies investigating the role of mast cell density in MCC.

Treatment of patients with evidence of mast cell-mediated itch in the absence of hives with omalizumab.

PURPOSE: The presence of wheals or hives has been viewed as a hallmark symptom of urticaria, a highly debilitating disease. This study explores our experience with omalizumab in patients with apparent mast-cell mediated pruritus in the absence of hives. MATERIALS AND METHODS: This is a retrospective case series examining all patients with mast cell-mediated pruritus in the absence of hives from April 2022 to May 2024 at a tertiary referral clinic at Icahn School of Medicine at Mount Sinai in New York. Peak pruritus-numerical rating scale (PP-NRS) itch score changes over time were recorded and analyzed. RESULTS: Six patients (67% women; mean [SD] age, 47.67 [13.52] years) were included in the analysis. The median [IQR] pruritus PP-NRS itch score before omalizumab injection was 9 [6 - 10] and the final median [IQR] PP-NRS itch score was 2.5 [0 - 5]. The mean [SD] reduction in the PP-NRS itch score was 6 [3.16]. CONCLUSIONS: This study suggests that patients with evidence of mast cell-mediated pruritus can be identified based on clinical features and may benefit from omalizumab therapy.

Inhibition of Mast Cell Degranulation by Novel Small Molecule MRGPRX2 Antagonists.

BACKGROUND: Mas-related G-protein coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell-mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. OBJECTIVE: We identified and characterized novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease. METHODS: Antagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell-derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-/-) knockout (KO) and Mrgprb2em(MRGPRX2) transgenic human MRGPRX2 knock-in (KI) mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. RESULTS: MRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested, in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 KI mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. CONCLUSION: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.

Vinblastine/prednisolone chemotherapy leads to hematological toxicity in dogs with high-grade or metastatic mast cell tumors.

OBJECTIVE: To determine the myelosuppressive effects/hematological toxicities, other general toxicities, and when these occur during vinblastine/prednisolone chemotherapy in dogs bearing high-grade or metastatic cutaneous/subcutaneous mast cell tumors (MCTs). METHODS: Medical records were retrospectively reviewed between November 1, 2016, and March 1, 2023. Thirty client-owned dogs with histopathologically confirmed cutaneous high-grade MCTs/metastatic subcutaneous MCTs and that subsequently completed a 12-week vinblastine/prednisolone chemotherapy protocol were included. Hematology was assessed before commencing chemotherapy and before each vinblastine treatment. The effect of each treatment upon hematological values was evaluated. Measured outcomes included the type, frequency, and severity of hematological and other more general toxicities. RESULTS: 24 of 30 dogs experienced at least 1 hematological toxicity, 6 experienced gastrointestinal toxicity, and 4 experienced lethargy. The most common toxicity was anemia (15/30 [50%]), with 93.3% (14/15 dogs) classified as Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events grade I and 6.6% (1/15) classified as grade II. The second most common toxicity was neutropenia (14/30 [46.6%]), with 71.4% (10/14) classified as grade I and 28.6% (4/14) as grade III. The least common hematological toxicity was thrombocytopenia (4/30 [13%]), all grade I. Neutropenia mainly occurred during weeks 2 and 3; however, there was no significant decrease in neutrophil count relative to baseline. Neutrophil count increased and Hct decreased during weeks 6 to 12 of treatment when compared to baseline. No change in platelet count was observed. CLINICAL RELEVANCE: Vinblastine/prednisolone chemotherapy leads to hematological toxicity; however, this was mostly low-grade and did not require major intervention. Vinblastine/prednisolone chemotherapy is well tolerated in dogs bearing high-grade or metastatic MCTs.

Inflammatory Cells in Control and Prolapsed Uterosacral Ligament Tissue.

Pelvic organ prolapse (POP), a downward descent of the vagina and/or uterus through the vaginal canal, is a prevalent condition affecting up to 40% of women. Several risk factors of POP have been identified, including childbirth, connective tissue defects, and chronic intra-abdominal pressure; however, the underlying etiologies of POP development are not fully understood, leading to a high burden on patients and the healthcare systems. The uterosacral ligaments are key support structures of the uterus and upper vagina. Our previous work describes observed histopathological changes in uterosacral ligament (USL) tissue and demonstrates the presence of neutrophils in a subgroup of POP individuals. This presence of neutrophils prompted an examination for the presence of a broader spectrum of inflammatory cell types in the USL. Immunohistochemical staining was performed to identify neutrophils, lymphocytes, macrophages, and mast cells outside of the vasculature. All 4 inflammatory cell types were increased in the POP-HQ system-defined POP-Inflammatory (POP-I) phenotype USL tissue relative to the USL tissues of control or other POP-HQ phenotypes. Focal T-lymphocyte and macrophage co-accumulations were observed in the arterial walls from some patients of the POP-vascular (POP-V) phenotype suggesting previous arterial injury. In addition, 1 control and 2 POP-V subjects' USLs contained arterial wall foamy macrophages, evidence of atherosclerosis. These findings further support a complex etiology for POP and indicate that personalized approaches to preventing and treating the condition may be warranted.