42 research outputs found
Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA
<p>Abstract</p> <p>Background</p> <p>Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA.</p> <p>Methods</p> <p>Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p.) 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.). IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later.</p> <p>Results</p> <p>Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v.) prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical) given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning.</p> <p>Conclusions</p> <p>These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA.</p
Changes in interleukin-1 signal modulators induced by 3,4-methylenedioxymethamphetamine (MDMA): regulation by CB2 receptors and implications for neurotoxicity
CD30 expression by bone marrow mast cells from different diagnostic variants of systemic mastocytosis
[Aims]: CD30 expression by bone marrow (BM) mast cells (MC) has been reported recently in systemic mastocytosis (SM) patients. The aim of this study was to investigate the potential diagnostic and prognostic value of CD30 expression in SM as assessed by multiparameter flow cytometry. [Methods and results]: A total of 163 consecutive BM samples corresponding to 142 SM patients and 21 non-mastocytosis cases were studied. CD30 was positive in most SM patients (80%), but in only one non-mastocytosis case (4.8%). When combined with CD25, CD30 contributed to an improved accuracy over that of CD25 alone (98% versus 93%) mainly because most (eight of nine) of the well-differentiated SM (WDSM), who lacked CD25, were CD30+. Similar levels of expression of CD30 were observed among all different subgroups of SM except mast cell leukaemia; among indolent SM (ISM) patients, no significant association was observed between the levels of CD30 expression and other clinical and biological features of the disease. [Conclusions]: The increased expression of CD30 associated with absence of CD25 contributes to the diagnosis of WDSM and its distinction from other subtypes of SM. By contrast, CD30 expression did not contribute either to prognostic stratification of ISM or to the differential diagnosis between ISM and aggressive SM cases.This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS) PI11/02399, PS09/00032 and RETICs RD09/0076/00133, RD09/0076/00074 and RD12/0036/0048 (FEDER) from the Instituto de Salud Carlos III, Ministerio de Economía
y Competitividad, Spain; Fundacion Sociosanitaria de Castilla-La Mancha (2010/008 y G-2010/C-002); Fundación Espanola de Mastocitosis (FEM 2010); and by a grant from Fundaçao para a Ciência e Tecnologia (FCT) of Portugal (SFRH/BD/22972/2005).Peer Reviewe
Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis
[Background]: Well-differentiated systemic mastocytosis (WDSM) is a rare variant of systemic mastocytosis (SM) characterized by bone marrow (BM) infiltration by mature-appearing mast cells (MCs) often lacking exon 17 KIT mutations. Because of its rarity, the clinical and biological features of WDSM remain poorly defined. [Objective]: We sought to determine the clinical, biological, and molecular features of a cohort of 33 patients with mastocytosis in the skin in association with BM infiltration by well-differentiated MCs and to establish potential diagnostic criteria for WDSM. Methods Thirty-three patients with mastocytosis in the skin plus BM aggregates of round, fully granulated MCs lacking strong CD25 and CD2 expression in association with clonal MC features were studied. [Results]: Our cohort of patients showed female predominance (female/male ratio, 4:1) and childhood onset of the disease (91%) with frequent familial aggregation (39%). Skin involvement was heterogeneous, including maculopapular (82%), nodular (6%), and diffuse cutaneous (12%) mastocytosis. KIT mutations were detected in only 10 (30%) of 33 patients, including the KIT D816V (n = 5), K509I (n = 3), N819Y (n = 1), and I817V (n = 1) mutations. BM MCs displayed a unique immunophenotypic pattern consisting of increased light scatter features, overexpression of cytoplasmic carboxypeptidase, and aberrant expression of CD30, together with absent (79%) or low (21%) positivity for CD25, CD2, or both. Despite only 9 (27%) of 33 patients fulfilling the World Health Organization criteria for SM, our findings allowed us to establish the systemic nature of the disease, which fit with the definition of WDSM. [Conclusions]: WDSM represents a rare clinically and molecularly heterogeneous variant of SM that requires unique diagnostic criteria to avoid a misdiagnosis of cutaneous mastocytosis per current World Health Organization criteria.Supported by grants from Asociación Española de Mastocitosis, Madrid, Spain (grant AEDM 2014); Instituto de Salud Carlos III, FEDER, Ministry of Economy and Competitivity, Madrid, Spain (grant PI11/02399); Fundación Ramón Areces, Madrid, Spain (grant CIVP16A1806); and Novartis Farmacéutica, S.A., Spain. I. Alvarez-Twose has received research support from Novartis Farmacéutica, S.A., Spain. A. García-Montero has received
research support from Fundacion Ramon Areces (grant no. CIVP16A1806) and ISCIII
Ministerio de Economia y Competitividad (grant no. PI11/02399). A. Orfao has
received research support from Fundacion Ramon Areces (grant no. CIVP16A1806).Peer Reviewe
Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications
Recent studies have found the KIT D816V mutation in peripheral blood of virtually all adult systemic mastocytosis patients once highly sensitive PCR techniques were used; thus, detection of the KIT D816V mutation in peripheral blood has been proposed to be included in the diagnostic work-up of systemic mastocytosis algorithms. However, the precise frequency of the mutation, the biological significance of peripheral blood-mutated cells and their potential association with involvement of bone marrow hematopoietic cells other than mast cells still remain to be investigated. Here, we determined the frequency of peripheral blood involvement by the KIT D816V mutation, as assessed by two highly sensitive PCR methods, and investigated its relationship with multilineage involvement of bone marrow hematopoiesis. Overall, our results confirmed the presence of the KIT D816V mutation in peripheral blood of most systemic mastocytosis cases (161/190; 85%)-with an increasing frequency from indolent systemic mastocytosis without skin lesions (29/44; 66%) to indolent systemic mastocytosis with skin involvement (124/135; 92%), and more aggressive disease subtypes (11/11; 100%)-as assessed by the allele-specific oligonucleotide-qPCR method, which was more sensitive (P<.0001) than the peptide nucleic acid-mediated PCR approach (84/190; 44%). Although the presence of the KIT mutation in peripheral blood, as assessed by the allele-specific oligonucleotide-qPCR technique, did not accurately predict for multilineage bone marrow involvement of hematopoiesis, the allele-specific oligonucleotide-qPCR allele burden and the peptide nucleic acid-mediated-PCR approach did. These results suggest that both methods provide clinically useful and complementary information through the identification and/or quantification of the KIT D816V mutation in peripheral blood of patients suspected of systemic mastocytosis.This work was supported in part by grants from the Fondo de Investigaciones Sanitarias (FIS; grant number PI11/02399, FEDER) and Red Temática de
Investigación Cooperativa en Cancer (RTICC; grant number RD12/0036/0048, FEDER) of the Instituto deSalud Carlos III (Ministry of Economy and Competitivity, Madrid, Spain), from Fundacion Ramon Areces (Madrid, Spain; grant number CIVP16A1806) and from Ayudas a Proyectos de Investigación en
Salud de la Fundación Mutua Madrileña 2014 and Asociación Española de Enfermos de Mastocitosis (AEDM 2014). The National DNA Bank is supported
by grants from the Instituto de Salud Carlos III of the Ministerio de Economia y Competitividad of Spain (grand numbers PT13/0001/0037 and PT13/0010/
0067, FEDER). AM was supported by RTICC.Peer Reviewe
KITD816V mutation in blood for the diagnostic screening of systemic mastocytosis and mast cell activation syndromes
[Background]: Current diagnostic algorithms for systemic mastocytosis (SM) rely on the detection of KITD816V in blood to trigger subsequent bone marrow (BM) investigations.
[Methods]: Here, we correlated the KITD816V mutational status of paired blood and BM samples from 368 adults diagnosed with mast cell activation syndrome (MCAS) and mastocytosis and determined the potential utility of investigating KITD816V in genomic DNA from blood-purified myeloid cell populations to increase diagnostic sensitivity. In a subset of 69 patients, we further evaluated the kinetics of the KITD816V cell burden during follow-up and its association with disease outcome.
[Results]: Our results showed a high correlation (P < .0001) between the KITD816V mutation burden in blood and BM (74% concordant samples), but with a lower mean of KITD816V-mutated cells in blood (P = .0004) and a high rate of discordant BM+/blood− samples particularly among clonal MCAS (73%) and BM mastocytosis (51%), but also in cutaneous mastocytosis (9%), indolent SM (15%), and well-differentiated variants of indolent SM (7%). Purification of different compartments of blood-derived myeloid cells was done in 28 patients who were BM mast cell (MC)+/blood− for KITD816V, revealing KITD816V-mutated eosinophils (56%), basophils (25%), neutrophils (29%), and/or monocytes (31%) in most (61%) patients. Prognostically, the presence of ≥3.5% KITD816V-mutated cells (P < .0001) and an unstable KITD816V mutation cell burden (P < .0001) in blood and/or BM were both associated with a significantly shortened progression-free survival (PFS).
[Conclusions]: These results confirm the high specificity but limited sensitivity of KITD816V analysis in whole blood for the diagnostic screening of SM and other primary MCAS, which might be overcome by assessing the mutation in blood-purified myeloid cell populations.This work was supported by grants from the Fundación Española de Mastocitosis (Madrid, Spain; grant number: FEM2021-SAM) and Blueprint Medicines Corporation (Cambridge, MA). PNN was supported by a grant of Government of Castilla y León (Orden EDU 875 2021), Spain; co-financed with the European Social Fund (BDNS (Identif.): 540787). We also thank the Agencia Estatal de Investigación (AEI) and European Regional Development Fund (FEDER) for the grant (EQC2019-005419-P) within the Subprograma Estatal de Infraestructuras de Investigación y Equipamiento Científico Técnico de 2019
Frequency and prognostic impact of blood-circulating tumor mast cells in mastocytosis
Circulating tumor mast cells (CTMCs) have been identified in the blood of a small number of patients with advanced systemic mastocytosis (SM). However, data are limited about their frequency and prognostic impact in patients with MC activation syndrome (MCAS), cutaneous mastocytosis (CM) and nonadvanced SM. We investigated the presence of CTMCs and MC-committed CD34+ precursors in the blood of 214 patients with MCAS, CM, or SM using highly sensitive next-generation flow cytometry. CTMCs were detected at progressively lower counts in almost all patients with advanced SM (96%) and smoldering SM (SSM; 100%), nearly half of the patients (45%) with indolent SM (ISM), and a few patients (7%) with bone marrow (BM) mastocytosis but were systematically absent in patients with CM and MCAS (P < .0001). In contrast to CTMC counts, the number of MC-committed CD34+ precursors progressively decreased from MCAS, CM, and BM mastocytosis to ISM, SSM, and advanced SM (P < .0001). Clinically, the presence (and number) of CTMCs in blood of patients with SM in general and nonadvanced SM (ISM and BM mastocytosis) in particular was associated with more adverse features of the disease, poorer-risk prognostic subgroups as defined by the International Prognostic Scoring System for advanced SM (P < .0001) and the Global Prognostic Score for mastocytosis (P < .0001), and a significantly shortened progression-free survival (P < .0001) and overall survival (P = .01). On the basis of our results, CTMCs emerge as a novel candidate biomarker of disseminated disease in SM that is strongly associated with advanced SM and poorer prognosis in patients with ISM
Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM
Spanish Network on Mastocytosis (REMA): et al.[Background]: Indolent systemic mastocytosis (ISM) without skin lesions (ISMs-) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs+). Interestingly, in almost one-half of ISMs- patients, MC-mediator release episodes are triggered exclusively by insects. [Objective]: We aimed to determine the clinical and laboratory features of ISMs- associated with insect-induced anaphylaxis (insectISMs-) versus other patients with ISM. [Methods]: A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs-, 72 ISMs- triggered by other factors (otherISMs-), 56 ISMs+, and 64 nonclonal MC activation syndrome, were studied. [Results]: Compared with otherISMs- and ISMs+ patients, insectISMs- cases showed marked male predominance (78% vs 53% and 46%; P <.001), a distinct pattern of MC-related symptoms, and significantly lower median serum baseline tryptase levels (22.4 vs 28.7 and 45.8 μg/L; P ≤.009). Moreover, insectISMs- less frequently presented BM MC aggregates (46% vs 70% and 81%; P ≤.001), and they systematically showed MC-restricted KIT mutation. [Conclusions]: ISMs- patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs- and ISMs+ patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors.Supported by Fondo de Investigaciones Sanitarias –FIS– of the Instituto de Salud Carlos
III, Ministery of Economy and Competitivity, Madrid, Spain grant PS09/00032;
Fundación Sociosanitaria de Castilla-La Mancha grants 2010/008 and G-2010/
C-002; Fundacióon Española de Mastocitosis grant FEM 2011; BioB-HVS is supported
by grant RETICS (Redes Temáticas de Investigación Cooperativa en Salud) RD09/
00760074 (Toledo, Spain); RTICC (Red Temática de Investigación Cooperativa en
Cáncer) grants RD09/0076/00133, RD12/0036/0048; FIS; FEDER, Ministery of
Economy and Competitivity, Madrid, Spain grant PI11/02399; and Fundación Ramón
Areces, Madrid, Spain grant CIVP16A1806; and by Associazione Italiana Leucemie e
Linfomi of Verona (AIL-Verona) and ASIMAS (Associazione Italiana Mastocitosi). L. Escribano has been supported by one or more grants from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Fundacion Sociosanitaria de Castilla La Mancha, and from FEM. A. García-Montero has been supported by one or more grants from ISCIII. M. Mollejo and A. Orfao have been supported by one or more grants from Instituto de Salud Carlos III, Ministerio de Economía y Competitividad. L. Sánchez-Muñoz has been supported by one or more grants from Fundacion Sociosanitaria de Castilla La Mancha.Peer Reviewe
Complete response to gemtuzumab ozogamicin in a patient with refractory mast cell leukemia
Mast cell (MC) leukemia (MCL) is a subtype of systemic mastocytosis (SM) defined by the World Health Organization as ⩾ 20% of MCs in the bone marrow (BM) aspirate, with (leukemic variant) or without (aleukemic variant) ⩾ 10% of MCs in peripheral blood (PB). The European/American Consensus Group on Mastocytosis has recently proposed a new subclassification of MCL that distinguishes acute vs chronic MCL based on the presence vs absence of organ damage, respectively.Peer Reviewe
Characterization of CD34+ hematopoietic cells in systemic mastocytosis: Potential role in disease dissemination
[Background]: Recent studies show that most systemic mastocytosis (SM) patients, including indolent SM (ISM) with (ISMs+) and without skin lesions (ISMs−), carry the KIT D816V mutation in PB leukocytes. We investigated the potential association between the degree of involvement of BM hematopoiesis by the KIT D816V mutation and the distribution of different maturation-associated compartments of bone marrow (BM) and peripheral blood (PB) CD34+ hematopoietic precursors (HPC) in ISM and identified the specific PB cell compartments that carry this mutation.
[Methods]: The distribution of different maturation-associated subsets of BM and PB CD34+ HPC from 64 newly diagnosed (KIT-mutated) ISM patients and 14 healthy controls was analyzed by flow cytometry. In 18 patients, distinct FACS-purified PB cell compartments were also investigated for the KIT mutation.
[Results]: ISM patients showed higher percentages of both BM and PB MC-committed CD34+ HPC vs controls, particularly among ISM cases with MC-restricted KIT mutation (ISMMC); this was associated with progressive blockade of maturation of CD34+ HPC to the neutrophil lineage from ISMMC to multilineage KIT-mutated cases (ISMML). Regarding the frequency of KIT-mutated cases and cell populations in PB, variable patterns were observed, the percentage of KIT-mutated PB CD34+ HPC, eosinophils, neutrophils, monocytes and T cells increasing from ISMs−MC and ISMs+MC to ISMML patients.
[Conclusion]: The presence of the KIT D816V mutation in PB of ISM patients is associated with (early) involvement of circulating CD34+ HPC and multiple myeloid cell subpopulations, KIT-mutated PB CD34+ HPC potentially contributing to early dissemination of the disease.This work was supported by Fondo de Investigaciones Sanitarias—FIS—of the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain (grant numbers PI11/02399 and PI16/00642, FEDER); Consejería de Educación (Regional Government of Castilla y León, Spain; grant number SA013U16); Biomedical Research Networking Centre Consortium–CIBER-CIBERONC (CB16/12/00400) of the Instituto de Salud Carlos III, Madrid, Spain; and Fundacion Ramon Areces, Madrid, Spain (grant CIVP16A1806). AM was supported by a RTICC (Red Tematica de Investigacion Cooperativa en Cancer) grant (RD12/0036/0048, FIS, FEDER)