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Arteriosclerosis, Thrombosis, and... Mar 2024IgE has been known for mediating endothelial cell dysfunction and mast cell (MC) activation to fuel asthma-aggravated high-fat diet-induced atherosclerosis. However, it...
BACKGROUND
IgE has been known for mediating endothelial cell dysfunction and mast cell (MC) activation to fuel asthma-aggravated high-fat diet-induced atherosclerosis. However, it remains unclear for the mechanism of asthma-mediated atherosclerosis, especially the potential involvement of IgE in the exacerbation of asthma-mediated atherosclerosis with a standard laboratory diet, and the cross talk between endothelial cells and MCs.
METHODS
Asthma-mediated atherosclerosis mice models under a standard laboratory diet and FcεR1 knock-out mice were used to determine the role of IgE-FcεR1 signaling in asthma-mediated atherosclerosis, which was assessed by Oil Red O staining and immunohistochemistry. Various in vitro assays including nanoparticle tracking analysis and transmission electron microscopy were used to evaluate exosome characteristics. Immunofluorescence and fluorescent in situ hybridization approaches were used to evaluate the effect and mechanism of MC-secreted exosomes encapsulated circular RNA CDR1as (cerebellar degeneration-related 1 antisense) on endothelial cells in vivo and in vitro. Finally, cohort studies examined the plasma CDR1as levels in patients with atherosclerosis with or without allergies.
RESULTS
Asthma mice with a standard laboratory diet showed increased atherosclerotic lesions and inflammatory infiltration depending on IgE-FcεR1 signal. FcεR1 knockout mice and blockage of IgE-FcεR1 signaling with IgE monoclonal antibody, omalizumab, all significantly alleviated asthma-mediated atherosclerosis and vascular inflammatory remodeling. Anti-inflammation with dexamethasone and stabilization of MC with cromolyn partially alleviated atherosclerotic lesions and mitigated the inflammatory infiltration in arteries. Mechanistically, IgE stimulation upregulates MC CDR1as expression in exosomes and upregulates the endothelial cell adhesive factors VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) via the CDR1as-FUS (fused in sarcoma)-phos-p65 axis. Knockdown of CDR1as in vivo significantly decreased the endothelial adhesion function and mitigated asthma-mediated atherosclerosis. Furthermore, a cohort study indicated higher plasma CDR1as levels in patients with atherosclerosis with allergies than in patients with atherosclerosis and healthy controls.
CONCLUSIONS
Exosomes from IgE-stimulated MCs aggravated atherosclerosis through circular RNA CDR1as-mediated endothelial dysfunction, providing a novel insight into asthma-mediated atherosclerosis and potential diagnostic and therapeutic targets.
Topics: Animals; Humans; Mice; Asthma; Atherosclerosis; Cohort Studies; Endothelial Cells; Exosomes; Immunoglobulin E; In Situ Hybridization, Fluorescence; Mast Cells; Mice, Knockout; RNA, Circular
PubMed: 38235556
DOI: 10.1161/ATVBAHA.123.319756 -
Journal of Veterinary Internal Medicine 2024The therapeutic role and prognostic relevance of lymphadenectomy in mast cell tumor (MCT) has historically been evaluated on regional rather than sentinel lymph nodes.
BACKGROUND
The therapeutic role and prognostic relevance of lymphadenectomy in mast cell tumor (MCT) has historically been evaluated on regional rather than sentinel lymph nodes.
HYPOTHESIS/OBJECTIVES
To update information about the association of histological nodal (HN) classes with clinical outcome in dogs with MCT after tumor excision and extirpation of normal-sized sentinel nodes (SLN) guided by radiopharmaceutical.
ANIMALS
Ninety-four dogs with histologically-confirmed treatment-naïve MCT (71 cutaneous, 22 subcutaneous and 1 conjunctival MCT) were included if without: distant metastases, lymphadenomegaly, concurrent mixed cutaneous, and subcutaneous MCT.
METHODS
This was a monoistitutional cohort study. Tumors characteristics were retrieved and SLNs were classified according to Weishaar's system. Incidence of MCT-related events (local, nodal, distant relapse), de novo MCT or other tumors and death (MCT-related and non-MCT-related), were recorded. Incidence curves were compared among the HN classes.
RESULTS
Twenty-seven dogs had HN0, 19 HN1, 37 HN2, and 11 HN3 SLN. Thirteen (2 HN0, 4 HN2, and 7 HN3) received adjuvant chemotherapies. Kiupel high grade, increasing number of SLN and lymphocentrums were associated with higher HN classes. Five dogs died for MCT-related causes: 1 low-grade (HN0) and 1 subcutaneous (HN3) had a local relapse, 2 high-grade had distant relapse (HN3-HN0) and 1 dog developed disease progression from a de novo subcutaneous MCT. No nodal relapse was registered. Fourteen dogs developed de novo MCTs.
CONCLUSION/DISCUSSION
Low grade/low-risk MCT with nonpalpable and normal sized SLN have a favorable outcome independently from the HN. Result should be considered strictly related to the successful SLN detection guided pre- and intraoperative by radiopharmaceutical markers.
Topics: Animals; Dogs; Dog Diseases; Female; Male; Lymphatic Metastasis; Sentinel Lymph Node; Lymph Node Excision; Cohort Studies; Mastocytoma; Mast-Cell Sarcoma; Treatment Outcome
PubMed: 38426589
DOI: 10.1111/jvim.16997 -
Veterinary and Comparative Oncology Sep 2023In this study we undertook a comprehensive analysis of a Pet Tumour Registry of the Canary Archipelago (PTR-CA) in Spain to investigate the epidemiology of canine...
In this study we undertook a comprehensive analysis of a Pet Tumour Registry of the Canary Archipelago (PTR-CA) in Spain to investigate the epidemiology of canine cutaneous round cell tumours. From a database of 2526 tumours collected from 2003 to 2020, we conducted a longitudinal analysis of the main trends in diagnosis, age, multiplicity and anatomical distribution as well as a case-control study comparing these cases with the contemporaneous canine population of the Canary Archipelago to analyse breed distribution. In line with former studies, we found histiocytomas mostly affect young dogs (2, IQR 1-5) and mast cell tumours affect middle-to-old dogs (8, IQR 6-10) with grade 1 affecting at younger ages (6.5, IQR 6-8) than both grade 2 (8, IQR 6-10 years) and grade 3 (9, IQR 7-11). Histiocytomas and plasmacytomas showed a similar anatomical distribution appearing mainly on the face, head and neck regions while mast cell tumours occur mainly on limbs and trunk. Higher risk for mast cell tumours and histiocytomas were found for Bulldog-related breeds such as Boxer (OR = 23.61, CI95%: 19.12-29.15, OR = 10.17, CI95%: 6.60-15.67), Boston Terrier (OR 19.47, CI95%: 7.73-49.05, OR 32.61, CI95%: 11.81-90.07) and Pug (OR 8.10, CI95%: 5.92-11.07, OR 7.87, CI95%: 4.66-13.28) while Chihuahua dogs showed significantly less risk (OR 0.18, CI95%: 0.09-0.33, OR 0.41, CI95%: 0.21-0.78). Notably, the Canarian Mastiff, a local breed, had a low risk of suffering from a mast cell tumour which raises the question of whether this relates to a genetic peculiarity of this breed or some husbandry and environmental factor.
Topics: Dogs; Animals; Canaries; Case-Control Studies; Spain; Dog Diseases; Sarcoma; Histiocytoma; Skin Neoplasms
PubMed: 37143410
DOI: 10.1111/vco.12899 -
Cureus Dec 2023KIT gene mutations in Ewing sarcomas are rare; however, they are much more frequent in other neoplasms, namely mastocytosis. We describe a case of an adult male with a...
KIT gene mutations in Ewing sarcomas are rare; however, they are much more frequent in other neoplasms, namely mastocytosis. We describe a case of an adult male with a one-year duration of recurrent episodes of pain, swelling, and redness on the proximal phalanx of the third finger of his right hand. A core biopsy suggested a possible mastocytosis. After four years of recurrent episodes and worsening symptoms, an incisional biopsy revealed an Ewing sarcoma with a KIT gene mutation (M541L, on exon 10). KIT gene mutations with gain-of-function were identified in 2.6% of Ewing sarcomas. In this case, the detection of a KIT mutation in an Ewing sarcoma developed at the site of previous mast cell proliferation raises the hypothesis of a possible sarcomatous evolution of the original lesion. To the best of our knowledge, similar cases are not described in the current literature. This is also the first report describing the KIT M541L mutation (exon 10) in Ewing sarcoma.
PubMed: 38222235
DOI: 10.7759/cureus.50537 -
Scientific Data Jul 2023The prognostic value of mitotic figures in tumor tissue is well-established for many tumor types and automating this task is of high research interest. However,...
The prognostic value of mitotic figures in tumor tissue is well-established for many tumor types and automating this task is of high research interest. However, especially deep learning-based methods face performance deterioration in the presence of domain shifts, which may arise from different tumor types, slide preparation and digitization devices. We introduce the MIDOG++ dataset, an extension of the MIDOG 2021 and 2022 challenge datasets. We provide region of interest images from 503 histological specimens of seven different tumor types with variable morphology with in total labels for 11,937 mitotic figures: breast carcinoma, lung carcinoma, lymphosarcoma, neuroendocrine tumor, cutaneous mast cell tumor, cutaneous melanoma, and (sub)cutaneous soft tissue sarcoma. The specimens were processed in several laboratories utilizing diverse scanners. We evaluated the extent of the domain shift by using state-of-the-art approaches, observing notable differences in single-domain training. In a leave-one-domain-out setting, generalizability improved considerably. This mitotic figure dataset is the first that incorporates a wide domain shift based on different tumor types, laboratories, whole slide image scanners, and species.
Topics: Humans; Algorithms; Prognosis; Mitosis; Neoplasms
PubMed: 37491536
DOI: 10.1038/s41597-023-02327-4 -
Veterinary Pathology Jan 2024Increased or constitutive activation of nuclear factor kappa B (NF-kB) is a feature of many chronic disease processes, including cancer. While NF-kB overactivation has...
Increased or constitutive activation of nuclear factor kappa B (NF-kB) is a feature of many chronic disease processes, including cancer. While NF-kB overactivation has been documented extensively in human oncology, there is a relative paucity of data documenting the same phenomenon in veterinary medicine. To assess NF-kB activity, antibodies to p65 and p100/p52, which are components of NF-kB heterodimers, were first validated for specificity and canine cross-reactivity via Western blot and labeling of immortalized cell pellets. Then, nuclear labeling for these antibodies was assessed via QuPath software in over 200 tumor tissue samples (10 hemangiosarcomas, 94 histiocytic sarcomas, 71 lymphomas, and 28 mast cell tumors) and compared to immunolabeling in appropriate normal tissue counterparts. Greater than 70% of spontaneous canine tumors evaluated in this study had more nuclear p65 and p100/p52 immunoreactivity than was observed in comparable normal cell populations. Specifically, 144/204 (70.58%) of tumors evaluated had positive p65 nuclear labeling and 179/195 (91.79%) had positive p100/p52 nuclear labeling. Surprisingly, greater nuclear p100/p52 reactivity was associated with a longer progression-free survival (PFS) and overall survival (OS) in canine lymphomas. These results provide support and preliminary data to investigate the role of NF-kB signaling in different types of canine cancer.
Topics: Animals; Dogs; Humans; NF-kappa B; Histiocytic Sarcoma; Hemangiosarcoma; Mast Cells; NF-kappa B p52 Subunit; Lymphoma; Dog Diseases
PubMed: 37357953
DOI: 10.1177/03009858231180484 -
European Journal of Medical Research Jan 2024The importance of protein tyrosine phosphatase non-receptor type 3 (PTPN3) in controlling multifaceted tumor cell behaviors throughout cancer development has received...
BACKGROUND
The importance of protein tyrosine phosphatase non-receptor type 3 (PTPN3) in controlling multifaceted tumor cell behaviors throughout cancer development has received widespread attention. Nevertheless, little is known about the biological roles of PTPN3 in drug sensitivity, immunotherapeutic effectiveness, tumor immune microenvironment, and cancer prognosis.
METHODS
The Cancer Genome Atlas (TCGA) database's RNAseq data were used to examine the expression of PTPN3 in 33 different cancer types. In addition, immunohistochemistry (IHC) was performed to validate the expression of PTPN3 across various cancer types within our clinical cohorts. The features of PTPN3 alterations were demonstrated throughout the cBioPortal database. This study focused on examining the prognostic and clinicopathological importance of PTPN3 through the acquisition of clinical data from the TCGA database. The investigation of PTPN3's probable role in the tumor immune microenvironment was demonstrated by the application of CIBERSORT, ESTIMATE algorithms, and the TISIDB database. Using Spearman's rank correlation coefficient, the relationships between PTPN3 expression and tumor mutation burden (TMB) and microsatellite instability (MSI) were evaluated. To further investigate the putative biological activities and downstream pathways of PTPN3 in various cancers in humans, Gene Set Enrichment Analysis (GSEA) was carried out. In addition, an examination was conducted to explore the associations between PTPN3 and the effectiveness of PD-1/PD-L1 inhibitors, utilizing data extracted from the GEO database.
RESULTS
PTPN3 was abnormally expressed in multiple cancer types and was also strictly associated with the prognosis of cancer patients. IHC was used to investigate and confirm the various expression levels of PTPN3 in various malignancies, including breast cancer, lung cancer, sarcoma, and kidney renal clear cell carcinoma in our clinical cohorts. There is a high correlation between the levels of PTPN3 expression in different cancers and infiltrating immune cells, including mast cells, B cells, regulatory T cells, CD8 + T cells, macrophages, and dendritic cells. Infiltrating immune cells, such as regulatory T cells, CD8 + T cells, macrophages, B cells, dendritic cells, and mast cells, are strongly correlated with PTPN3 expression levels in various tumors. The expression of PTPN3 exhibited a substantial correlation with many immune-related biomolecules and the expression of TMB and MSI in multiple types of cancer. In addition, PTPN3 has demonstrated promise in predicting the therapeutic benefits of PD-1/PD-L1 inhibitors and the susceptibility to anti-cancer medications in the treatment of clinical cancer.
CONCLUSIONS
Our findings highlight the importance of PTPN3 as a prognostic biomarker and predictor of immunotherapy success in various forms of cancer. Furthermore, PTPN3 appears to have an important role in modifying the tumor immune microenvironment, highlighting its potential as a promising biomarker for prognosis prediction, immunotherapeutic efficacy evaluation, and identification of immune-related characteristics in diverse cancer types.
Topics: Humans; Female; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Biomarkers; Breast Neoplasms; Carcinoma, Renal Cell; Kidney Neoplasms; Prognosis; Tumor Microenvironment; Protein Tyrosine Phosphatase, Non-Receptor Type 3
PubMed: 38173048
DOI: 10.1186/s40001-023-01587-5 -
Laboratory Investigation; a Journal of... Mar 2024Recent studies have described several molecular subtypes and deregulation of immuno-oncologic signaling pathways in angiosarcoma. Interestingly, mast cells were enriched...
Recent studies have described several molecular subtypes and deregulation of immuno-oncologic signaling pathways in angiosarcoma. Interestingly, mast cells were enriched in subsets of angiosarcoma, although their significance remains unknown. In this study, we aim to verify this observation using immunohistochemistry (H scores) and NanoString transcriptomic profiling and explore the association between mast cells with clinical and biological features. In the study cohort (N = 60), H scores showed a significant moderate correlation with NanoString mast cell scores (r = 0.525; P < .001). Both H score and NanoString mast cell scores showed a significant positive correlation (P < .05) with head and neck location, nonepithelioid morphology, and lower tumor grade. Mast cell enrichment significantly correlated with higher NanoString regulatory T-cell scores (H score, r = 0.32; P = .01; NanoString mast cell score, r = 0.27; P = .04). NanoString mast cell scores positively correlated with signaling pathways relating to antigen presentation (r = 0.264; P = .0414) and negatively correlated with apoptosis (r = -0.366; P = .0040), DNA damage repair (r = -0.348; P = .0064), and cell proliferation (r = -0.542; P < .001). Interestingly, in the metastatic setting, patients with mast cell-enriched angiosarcoma showed poorer progression-free survival (median, 0.2 vs 0.4 years; hazard ratio = 3.05; P = .0489) along with a trend toward worse overall survival (median, 0.2 vs 0.6 years; hazard ratio, 2.86; P = .0574) compared with patients with mast cell-poor angiosarcoma. In conclusion, we demonstrated the presence of mast cells in human angiosarcoma and provided initial evidence of their potential clinical and biological significance. Future research will be required to elucidate their specific roles and mechanisms, which may uncover novel avenues for therapeutic intervention.
Topics: Humans; Hemangiosarcoma; Mast Cells; Signal Transduction; Apoptosis; Prognosis
PubMed: 38218317
DOI: 10.1016/j.labinv.2024.100323 -
Journal of the American Veterinary... Oct 2023To report to what degree narrative operative reports for soft tissue sarcoma (STS) and mast cell tumor (MCT) resections met a predetermined template made up of essential...
OBJECTIVE
To report to what degree narrative operative reports for soft tissue sarcoma (STS) and mast cell tumor (MCT) resections met a predetermined template made up of essential elements.
ANIMALS
197 consecutive client-owned animals between May 1, 2017, and August 1, 2022.
PROCEDURES
A consensus list of 9 elements made up the final synoptic operative report (SR) template. Consecutive narrative surgery reports (NRs) of dogs that underwent MCT or STS resection were then reviewed to determine how many of the SR elements were present in each NR. A score was then determined for each NR out of a maximum total of 9.
RESULTS
Overall, 197 reports (99 MCT and 98 STS) were included. The median score was 5 (56% of elements reported). No report had all 9 elements, and 1 report had none of the elements reported. When MCT and STS were analyzed independently, the median score was 6 (67% of elements reported) for MCT and 5 (56% of elements reported) for STS. There was a trend of more cases with MCT that had a preoperative diagnosis, intraoperative measurements of the tumor, and surgeon margins marked compared to dogs with STS. More dogs with STS had an estimated Enneking dose compared to dogs with MCT.
CLINICAL RELEVANCE
Our data show that essential elements of STS and MCT resection in dogs were inconsistently recorded and no case had all elements present. This mirrors data in people and presses the need for more standardization in reporting of cancer operations in veterinary medicine.
Topics: Dogs; Animals; Mast Cells; Dog Diseases; Sarcoma; Soft Tissue Neoplasms; Retrospective Studies
PubMed: 37290758
DOI: 10.2460/javma.23.03.0152 -
Medicine Jun 2024To explore the expression and prognostic value of UHRF1 gene in soft tissue sarcoma (STS) and its related molecular mechanism. The expression data and...
To explore the expression and prognostic value of UHRF1 gene in soft tissue sarcoma (STS) and its related molecular mechanism. The expression data and clinicopathological parameters of STS were downloaded from the Cancer Genome Atlas (TCGA). The expression level of UHRF1 in STS and adjacent tissues and its relationship with clinicopathological characteristics were analyzed. The expression level of UHRF1 in STS tissues was significantly higher than that in paracancerous tissues (P < .001), and the overall survival (OS) time of patients with high UHRF1 expression was significantly shorter than that of patients with low UHRF1 expression (P = .002). The expression of UHRF1 was correlated with tumor necrosis, histological type and metastasis, and the differences were statistically significant (P = .013; P = .001; P = .002). The area ratio under receiver operating characteristic (ROC) curve between STS tissue and adjacent tissue of UHRF1 expression was 0.994. Number of tumors (HR = 0.416, 95%CI = 0.260-0.666, P < .001), depth of tumor (HR = 2.888, 95%CI = 0.910-9.168, P = .033), metastasis (HR = 2.888, 95% CI = 1.762-4.732, P < .001), residual tumor (HR = 2.637, 95% CI = 1.721-4.038, P < .001) and UHRF1 expression (HR = 1.342, 95% CI = 1.105-1.630, P = .003) were significantly associated with OS, and high expression of UHRF1 (HR = 1.387, 95%CI = 1.008-1.907, P = .044) was an independent risk factor for the prognosis of STS patients. The results of the nomogram exhibited that UHRF1 expression level had a significant effect on the total score value. GSEA enrichment analysis suggested that UHRF1 was involved in 14 signaling pathways regulating mRNA spliceosome, cell cycle, P53 signaling pathway were identified. Single sample gene set enrichment analysis (ssGSEA) exhibited that the expression of UHRF1 in STS was positively correlated with the level of Th2 cell infiltration, and negatively correlated with plasmacytoid dendritic cells (pDC), natural killer cells (NK), Eosinophils, Mast cells, etc. UHRF1 expression is involved in the immune microenvironment of HCC and affects the occurrence and development of HCC. UHRF1 is highly expressed in STS tissues. It is involved in the regulation of multiple tumor-related signaling pathways and immune cell microenvironment, suggesting that UHRF1 may be a potential molecular marker for prognosis prediction and targeted therapy of STS patients.
Topics: Humans; CCAAT-Enhancer-Binding Proteins; Ubiquitin-Protein Ligases; Sarcoma; Female; Prognosis; Male; Middle Aged; Biomarkers, Tumor; Adult; ROC Curve; Aged; Clinical Relevance
PubMed: 38847665
DOI: 10.1097/MD.0000000000038393