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Frontiers in Oncology 2022Uterine leiomyosarcoma (ULMS) is the most common subtype of uterine sarcoma and is difficult to discern from uterine leiomyoma (ULM) preoperatively. The aim of the...
OBJECTIVE
Uterine leiomyosarcoma (ULMS) is the most common subtype of uterine sarcoma and is difficult to discern from uterine leiomyoma (ULM) preoperatively. The aim of the study was to determine the potential and significance of immunerelated diagnostic biomarkers in distinguishing ULMS from ULM.
METHODS
Two public gene expression profiles (GSE36610 and GSE64763) from the GEO datasets containing ULMS and ULM samples were downloaded. Differentially expressed genes (DEGs) were selected and determined among 37 ULMS and 25 ULM control samples. The DEGs were used for Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) and Disease Ontology (DO) enrichment analyses as well as gene set enrichment analysis (GSEA). The candidate biomarkers were identified by least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) analyses. The receiver operating characteristic curve (ROC) was applied to evaluate diagnostic ability. For further confirmation, the biomarker expression levels and diagnostic value in ULMS were verified in the GSE9511 and GSE68295 datasets (12 ULMS and 10 ULM), and validated by immunohistochemistry (IHC). The CIBERSORT algorithm was used to calculate the compositional patterns of 22 types of immune cells in ULMS.
RESULT
In total, 55 DEGs were recognized GO analysis, and KEGG analyses revealed that the DEGs were enriched in nuclear division, and cell cycle. The recognized DEGs were primarily implicated in non-small cell lung carcinoma and breast carcinoma. Gene sets related to the cell cycle and DNA replication were activated in ULMS. and were distinguished as diagnostic biomarkers of ULMS (AUC = 0.957, AUC = 0.899, respectively), and they were verified in the GSE9511 and GSE68295 datasets (AUC = 0.983, AUC = 0.942, respectively). The low expression of and were associated with ULMS. In addition, the analysis of the immune microenvironment indicated that resting mast cells were positively correlated with and expression and that eosinophils and M0 macrophages were negatively correlated with expression (P<0.05).
CONCLUSION
These findings indicated that and are diagnostic biomarkers of ULMS, thereby offering a novel perspective for future studies on the occurrence, function and molecular mechanisms of ULMS.
PubMed: 36531033
DOI: 10.3389/fonc.2022.1084192 -
American Journal of Veterinary Research Nov 2021To determine the effects of morphine on histamine release from 2 canine mast cell tumor (MCT) cell lines and on plasma histamine concentrations in dogs with cutaneous...
OBJECTIVE
To determine the effects of morphine on histamine release from 2 canine mast cell tumor (MCT) cell lines and on plasma histamine concentrations in dogs with cutaneous MCTs.
ANIMALS
10 dogs with cutaneous MCT and 10 dogs with soft tissue sarcoma (STS).
PROCEDURES
The study consisted of 2 phases. First, 2 canine MCT cell lines were exposed to 3 pharmacologically relevant morphine concentrations, and histamine concentrations were determined by an ELISA. Second, dogs with MCT or STS received 0.5 mg of morphine/kg, IM, before surgery for tumor excision. Clinical signs, respiratory rate, heart rate, arterial blood pressure, rectal temperature, and plasma histamine concentrations were recorded before and 5, 15, 30, and 60 minutes after morphine administration but prior to surgery. Data were compared by use of a 2-way ANOVA with the Sidak multiple comparisons test.
RESULTS
In the first phase, canine MCT cell lines did not release histamine when exposed to pharmacologically relevant morphine concentrations. In the second phase, no differences were noted for heart rate, arterial blood pressure, and rectal temperature between MCT and STS groups. Plasma histamine concentrations did not significantly differ over time within groups and between groups.
CONCLUSIONS AND CLINICAL RELEVANCE
No significant changes in histamine concentrations were noted for both in vitro and in vivo study phases, and no hemodynamic changes were noted for the in vivo study phase. These preliminary results suggested that morphine may be used safely in some dogs with MCT.
Topics: Animals; Cell Line; Dog Diseases; Dogs; Histamine; Histamine Release; Mast Cells; Morphine; Neoplasms
PubMed: 34714766
DOI: 10.2460/ajvr.20.08.0137 -
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 -
In Vivo (Athens, Greece) 2016Antibody therapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) is a promising therapy in human cancer, but only limited information...
BACKGROUND
Antibody therapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) is a promising therapy in human cancer, but only limited information on PD-L1 expression in canine tumors is available.
MATERIALS AND METHODS
PD-L1 expression was examined in 31 canine tumor cell lines of various origins by flow cytometry and western blotting, and in canine tumor and normal tissue specimens by immunohistochemistry.
RESULTS
PD-L1 was only expressed on the cell surface of a small number of cell lines but was found expressed within the cells of almost all cell lines. Immunohistochemistry revealed that PD-L1 is frequently expressed in malignant melanoma, mammary gland tumor, mast cell tumor and lymphoma, but less frequently in soft-tissue sarcoma and hemangiosarcoma. PD-L1 was also expressed in some of the cells of normal canine tissue specimens.
CONCLUSION
Canine tumors with PD-L1 expression that were identified in this study are potential candidates for antiPD-1 and antiPD-L1 therapy.
Topics: Animals; B7-H1 Antigen; Blotting, Western; Cell Line, Tumor; Dog Diseases; Dogs; Flow Cytometry; HEK293 Cells; Humans; Immunohistochemistry; Lymphoma; Mammary Neoplasms, Animal; Mastocytoma; Melanoma; Neoplasms; Programmed Cell Death 1 Receptor
PubMed: 27107075
DOI: No ID Found -
The Journal of Dermatology May 2021Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation of neoplastic mast cells in the skin and/or other extracutaneous tissues. Most...
Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation of neoplastic mast cells in the skin and/or other extracutaneous tissues. Most patients with skin involvement can be subclassified into one of the three subtypes of cutaneous mastocytosis currently recognized by the World Health Organization (i.e., mastocytoma, maculopapular cutaneous mastocytosis and diffuse cutaneous mastocytosis); however, some patients may occasionally present with atypical skin lesions that cannot be ascribed to any of these disease subtypes. Here, we report three patients diagnosed with mastocytosis and an unusual cutaneous involvement mimicking Kaposi's sarcoma. Skin biopsies showed neoplastic mast cell infiltrates together with features commonly seen in acroangiodermatitis, and immunohistochemistry for human herpesvirus 8 was negative. One patient fulfilled the criteria for aggressive systemic mastocytosis, showed no response to cytoreductive therapy, and died because of disease progression. The remaining two patients had indolent and smoldering systemic mastocytosis, respectively, but they showed several features associated with an unfavorable prognosis such as extensive involvement of the hematopoiesis by the KIT D816V mutation, increased serum β2-microglobulin, and decreased serum lactate dehydrogenase. The presence of pseudo-Kaposi's sarcoma skin lesions is an uncommon finding in mastocytosis which may alert physicians to the possible existence of underlying features indicative of a poor prognosis.
Topics: Humans; Mast Cells; Mastocytosis; Mastocytosis, Cutaneous; Mastocytosis, Systemic; Proto-Oncogene Proteins c-kit; Sarcoma, Kaposi
PubMed: 33684229
DOI: 10.1111/1346-8138.15734 -
American Journal of Clinical Pathology May 2023Sessions 8 and 9 of the 2021 Society for Hematopathology and the European Association for Haematopathology Workshop aimed to collect examples of transdifferentiation,...
OBJECTIVES
Sessions 8 and 9 of the 2021 Society for Hematopathology and the European Association for Haematopathology Workshop aimed to collect examples of transdifferentiation, lineage infidelity, progression, and transformation in precursor and mature T/natural killer (NK)-cell neoplasms.
METHODS
Twenty-eight cases were submitted and analyzed, with whole-exome sequencing and genome-wide RNA expression analysis performed in a subset of the cases.
RESULTS
In session 8, 7 T-lymphoblastic lymphoma/leukemia cases were received that showed transdifferentiation to clonally related mature myeloid hematopoietic neoplasms, including 6 histiocytic/dendritic cell lineage neoplasms and a mast cell sarcoma. Session 9 included 21 mature T-cell neoplasms that were grouped into 3 themes. The first one addressed phenotypic infidelity in mature T-cell lymphomas (TCLs) and included 8 TCLs expressing aberrant antigens, mimicking classic Hodgkin and non-Hodgkin B-cell lymphomas. The second theme addressed disease progression in TCL and included 5 cutaneous T-cell lymphoproliferative disorders and 2 T-cell large granular lymphocyte proliferations with subsequent progression to systemic TCL. The third theme included 6 patients with TCL with T-follicular helper phenotype, mainly angioimmunoblastic T-cell lymphoma, with concurrent/subsequent clonal hematopoiesis or myeloid neoplasms and/or subsequent/concomitant diffuse large B-cell lymphoma.
CONCLUSIONS
This cohort of cases allowed us to illustrate, discuss, and review current concepts of transdifferentiation, aberrant antigen expression, and progression in various T/NK-cell neoplasms.
PubMed: 37167533
DOI: 10.1093/ajcp/aqad045 -
Molecular Cancer Therapeutics Dec 2019Neurofibromatosis Type 1 (NF1) is one of the most common genetic tumor predisposition syndromes in humans. Mutant results in dysregulated RAS allowing neoplasms...
Neurofibromatosis Type 1 (NF1) is one of the most common genetic tumor predisposition syndromes in humans. Mutant results in dysregulated RAS allowing neoplasms throughout the neuroaxis. Plexiform neurofibromas (pNF) afflict up to 50% of patients with NF1. They are complex tumors of the peripheral nerve that cause major morbidity via nerve dysregulation and mortality via conversion to malignant sarcoma. Genetically engineered mouse models (GEMM) of NF1 provide valuable insights for the identification of therapies that have utility in people with pNF. Preclinical studies in GEMMs implicate mast cells and the c-Kit/Kit ligand pathway in pNF tumorigenesis. Kit ligand is a potent chemokine secreted by tumorigenic, -deficient Schwann cells. Ketotifen is an FDA-approved drug for the treatment of allergic conjunctivitis and asthma that promotes mast cell stabilization and has been used in prior case studies to treat or prevent pNFs. This study investigated the effect of ketotifen on mast cell infiltration and degranulation in the presence and absence of Kit ligand provocation and the effect of ketotifen on shrinking or preventing pNF formation in the ; GEMM. Ketotifen decreased mast cell infiltration in response to exogenous Kit ligand administration, but did not affect mast cell degranulation. Importantly, ketotifen did not reduce mast cells numbers or activity in pNF and did not prevent pNF formation or decrease the volume of established pNF despite administration of pharmacologically active doses. These findings suggest that ketotifen has limited use as monotherapy to prevent or reduce pNF burden in the setting of mutations.
Topics: Animals; Chemotaxis; Histamine H1 Antagonists; Ketotifen; Mast Cells; Mice; Neurofibroma; Neurofibromin 1; Stem Cell Factor
PubMed: 31527226
DOI: 10.1158/1535-7163.MCT-19-0123 -
Molecular Therapy : the Journal of the... Jan 2022Activating mutations in c-KIT are associated with the mast cell (MC) clonal disorders cutaneous mastocytosis and systemic mastocytosis and its variants, including...
Activating mutations in c-KIT are associated with the mast cell (MC) clonal disorders cutaneous mastocytosis and systemic mastocytosis and its variants, including aggressive systemic mastocytosis, MC leukemia, and MC sarcoma. Currently, therapies inhibiting KIT signaling are a leading strategy to treat MC proliferative disorders. However, these approaches may have off-target effects, and in some patients, complete remission or improved survival time cannot be achieved. These limitations led us to develop an approach using chemically stable exon skipping oligonucleotides (ESOs) that induce exon skipping of precursor (pre-)mRNA to alter gene splicing and introduce a frameshift into mature KIT mRNA transcripts. The result of this alternate approach results in marked downregulation of KIT expression, diminished KIT signaling, inhibition of MC proliferation, and rapid induction of apoptosis in neoplastic HMC-1.2 MCs. We demonstrate that in vivo administration of KIT targeting ESOs significantly inhibits tumor growth and systemic organ infiltration using both an allograft mastocytosis model and a humanized xenograft MC tumor model. We propose that our innovative approach, which employs well-tolerated, chemically stable oligonucleotides to target KIT expression through unconventional pathways, has potential as a KIT-targeted therapeutic alone, or in combination with agents that target KIT signaling, in the treatment of KIT-associated malignancies.
Topics: Humans; Mast Cells; Mastocytosis; Proto-Oncogene Proteins c-kit; RNA, Messenger; Receptor Protein-Tyrosine Kinases
PubMed: 34371183
DOI: 10.1016/j.ymthe.2021.08.009 -
Acta Clinica Belgica Feb 2023Systemic mastocytosis (SM) is a rare myeloproliferative disease that results from a clonal proliferation of abnormal mast cells in one or more extra-cutaneous organs.... (Review)
Review
BACKGROUND
Systemic mastocytosis (SM) is a rare myeloproliferative disease that results from a clonal proliferation of abnormal mast cells in one or more extra-cutaneous organs. Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) is the second most common subgroup and is diagnosed when WHO criteria for both SM and a hematological neoplasm of non-mast cell lineage are met. The SM-AHN category as currently proposed is highly heterogeneous in terms of pathogenesis, clinical presentation, and prognosis.
CASE PRESENTATION
We present the first reported case of SM-AHN associated with two hematological malignancies of different lineages, a monocytic myeloid sarcoma and a B-cell chronic lymphatic leukemia. Cytogenetic and molecular analyses revealed a distinct clonal origin of the two associated malignancies. The SM-myeloid sarcoma clone demonstrated an abnormal karyotype, trisomy 8 and del(13)(q12.3q14.3), as well as mutations in and . The mutation could be detected years before disease onset, supporting its potential role as early driver of leukemogenesis. No genetic aberrations could be identified in the CLL clone, which is assumed to present coincidentally.
CONCLUSIONS
This report highlights the importance of full diagnostic work-up in SM patients in whom an associated hematological malignancy is suspected. Moreover, the importance of genetic analysis is highlighted, as it provides additional insights in the underlying clonal pathogenesis of different phenotypes, can aid in risk stratification, and may help identify potential therapy targets.
Topics: Humans; Mastocytosis, Systemic; Leukemia, Lymphocytic, Chronic, B-Cell; Sarcoma, Myeloid; Hematologic Neoplasms; Clone Cells
PubMed: 35098906
DOI: 10.1080/17843286.2022.2033919 -
The Journal of Pharmacology and... Dec 2018G-quadruplexes (G4) are nucleic acid secondary structures frequently assumed by G-rich sequences located mostly at telomeres and proto-oncogenes promoters. Recently, we...
G-quadruplexes (G4) are nucleic acid secondary structures frequently assumed by G-rich sequences located mostly at telomeres and proto-oncogenes promoters. Recently, we identified, in canine (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) promoter, two G-rich sequences able to fold into G4: d_kit1 and d_kit2_A16. In this study, an anthraquinone (AQ1) and an anthracene derivative (AN6), known to stabilize the G4 structures of the corresponding human h_kit1 and h_kit2, were tested on the canine G4 and in two canine mast cell tumor (MCT) cell lines (C2 and NI-1) to verify their capability to down-regulate expression. The cytotoxicity of AQ1 and AN6 was determined using the Alamar Blue test; also the constitutive expression of and other proto-oncogenes containing G4 structures in their promoter (, , , , and ) was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Then the time- and dose-dependent effects of both ligands on target gene expression were assessed by qRT-PCR. All target genes were constitutively expressed up to 96 hours of culture. Both ligands decreased mRNA levels and c-kit protein amount, and AN6 was comparatively fairly more effective. DNA interaction studies and a dual-luciferase gene reporter assay performed on a noncancerous canine cell line (Madin-Darby Canine Kidney cells) proved that this down-regulation was the result of the interaction of AN6 with proximal promoter. Interestingly, our results only partially overlap with those previously obtained in human cell lines, where AQ1 was found as the most effective compound. These preliminary data might suggest AN6 as a promising candidate for the selective targeting of canine -dependent tumors.
Topics: Animals; Anthracenes; Anthraquinones; Cell Line; DNA; Dog Diseases; Dogs; Down-Regulation; G-Quadruplexes; Gene Expression; Ligands; Madin Darby Canine Kidney Cells; Oncogenes; Promoter Regions, Genetic; Proto-Oncogene Proteins c-kit; RNA, Messenger
PubMed: 30275152
DOI: 10.1124/jpet.118.248997