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1.
Blood ; 139(16): 2483-2498, 2022 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-35020836

RESUMO

NOTCH1 is a well-established lineage specifier for T cells and among the most frequently mutated genes throughout all subclasses of T cell acute lymphoblastic leukemia (T-ALL). How oncogenic NOTCH1 signaling launches a leukemia-prone chromatin landscape during T-ALL initiation is unknown. Here we demonstrate an essential role for the high-mobility-group transcription factor Tcf1 in orchestrating chromatin accessibility and topology, allowing aberrant Notch1 signaling to convey its oncogenic function. Although essential, Tcf1 is not sufficient to initiate leukemia. The formation of a leukemia-prone epigenetic landscape at the distal Notch1-regulated Myc enhancer, which is fundamental to this disease, is Tcf1-dependent and occurs within the earliest progenitor stage even before cells adopt a T lymphocyte or leukemic fate. Moreover, we discovered a unique evolutionarily conserved Tcf1-regulated enhancer element in the distal Myc-enhancer, which is important for the transition of preleukemic cells to full-blown disease.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Carcinogênese/genética , Linhagem Celular Tumoral , Cromatina/genética , Humanos , Oncogenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética
2.
Cytometry A ; 103(1): 71-81, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35796000

RESUMO

Technical artifacts such as clogging that occur during the data acquisition process of flow cytometry data can cause spurious events and fluorescence intensity shifting that impact the quality of the data and its analysis results. These events should be identified and potentially removed before being passed to the next stage of analysis. flowCut, an R package, automatically detects anomaly events in flow cytometry experiments and flags files for potential review. Its results are on par with manual analysis and it outperforms existing automated approaches.


Assuntos
Citometria de Fluxo , Citometria de Fluxo/métodos , Biologia Computacional
3.
Invest New Drugs ; 38(4): 977-989, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31493129

RESUMO

Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo pharmacokinetic profiles of the most promising compounds were determined in CD-1 mice, while the in vivo antitumour efficacies were evaluated using the A375 melanoma xenograft model in nude mice. MTT assays revealed that all compounds presented concentration-dependent cytotoxicity against the A375 cell line. AKS 61 produced the most favourable antiproliferative activity according to the sulphorhodamine B and clonogenic assays. AKS 61 treatment resulted in decreased mitochondrial membrane potential and increased apoptosis and autophagy in the A375 cell line. However, AKS 61 failed to prevent in vivo tumour growth in a melanoma xenograft, whereas compound AKS 7 was able to inhibit tumour growth when administered orally. These in vivo findings may be explained by a more favourable pharmacokinetic profile presented by AKS 7 when compared to AKS 61. Taken together, these results suggest that acetohydroxamates have potential anticancer effects and will guide future optimisation of these molecules to allow for further non-clinical development.


Assuntos
Antineoplásicos/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Melanoma/tratamento farmacológico , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/farmacologia , Masculino , Melanoma/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Carga Tumoral/efeitos dos fármacos
4.
Nat Commun ; 13(1): 6772, 2022 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-36351924

RESUMO

Follicular lymphoma (FL) is an indolent cancer of mature B-cells but with ongoing risk of transformation to more aggressive histology over time. Recurrent mutations associated with transformation have been identified; however, prognostic features that can be discerned at diagnosis could be clinically useful. We present here comprehensive profiling of both tumor and immune compartments in 155 diagnostic FL biopsies at single-cell resolution by mass cytometry. This revealed a diversity of phenotypes but included two recurrent patterns, one which closely resembles germinal center B-cells (GCB) and another which appears more related to memory B-cells (MB). GCB-type tumors are enriched for EZH2, TNFRSF14, and MEF2B mutations, while MB-type tumors contain increased follicular helper T-cells. MB-type and intratumoral phenotypic diversity are independently associated with increased risk of transformation, supporting biological relevance of these features. Notably, a reduced 26-marker panel retains sufficient information to allow phenotypic profiling of future cohorts by conventional flow cytometry.


Assuntos
Linfoma Folicular , Humanos , Linfoma Folicular/genética , Células B de Memória , Centro Germinativo , Linfócitos B , Mutação
5.
Mol Neurobiol ; 55(3): 2150-2161, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28283888

RESUMO

Kinin B1 (B1R) and B2 receptors (B2R) and the transient receptor potential vanilloid 4 (TRPV4) channel are known to play a critical role in the peripheral neuropathy induced by paclitaxel (PTX) in rodents. However, the downstream pathways activated by kinin receptors as well as the sensitizers of the TRPV4 channel involved in this process remain unknown. Herein, we investigated whether kinins sensitize TRPV4 channels in order to maintain PTX-induced peripheral neuropathy in mice. The mechanical hyperalgesia induced by bradykinin (BK, a B2R agonist) or des-Arg9-BK (DABK, a B1R agonist) was inhibited by the selective TRPV4 antagonist HC-067047. Additionally, BK was able to sensitize TRPV4, thus contributing to mechanical hyperalgesia. This response was dependent on phospholipase C/protein kinase C (PKC) activation. The selective kinin B1R (des-Arg9-[Leu8]-bradykinin) and B2R (HOE 140) antagonists reduced the mechanical hyperalgesia induced by PTX, with efficacies and time response profiles similar to those observed for the TRPV4 antagonist (HC-067047). Additionally, both kinin receptor antagonists inhibited the overt nociception induced by hypotonic solution in PTX-injected animals. The same animals presented lower PKCε levels in skin and dorsal root ganglion samples. The selective PKCε inhibitor (εV1-2) reduced the hypotonicity-induced overt nociception in PTX-treated mice with the same magnitude observed for the kinin receptor antagonists. These findings suggest that B1R or B2R agonists sensitize TRPV4 channels to induce mechanical hyperalgesia in mice. This mechanism of interaction may contribute to PTX-induced peripheral neuropathy through the activation of PKCε. We suggest these targets represent new opportunities for the development of effective analgesics to treat chronic pain.


Assuntos
Hiperalgesia/metabolismo , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/metabolismo , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Antagonistas de Receptor B2 da Bradicinina/farmacologia , Hiperalgesia/etiologia , Masculino , Camundongos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estimulação Física/efeitos adversos , Receptor B1 da Bradicinina/agonistas , Receptor B2 da Bradicinina/agonistas , Moduladores de Tubulina/toxicidade
6.
Neuropharmacology ; 125: 207-219, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28729222

RESUMO

Painful peripheral neuropathy is a common side effect of paclitaxel (PTX). The use of analgesics is an important component for management of PTX-induced peripheral neuropathy (PINP). However, currently employed analgesics have several side effects and are poorly effective. ß-caryophyllene (BCP), a dietary selective CB2 agonist, has shown analgesic effect in neuropathic pain models, but its role in chemotherapy-induced neuropathic pain has not yet been investigated. Herein, we used the mouse model of PINP to show the therapeutic effects of BCP in this neuropathy. Male Swiss mice receiving PTX (2 mg kg-1, ip, four alternate days) were treated with BCP (25 mg kg-1, po, twice a day) either during or after PTX administration. Some groups were also pretreated with AM630 (CB2 antagonist, 3 mg kg-1, ip) or AM251 (CB1 antagonist, 1 mg kg-1, ip). Spinal cord samples were collected in different time points to perform immunohistochemical analysis. BCP attenuated the established mechanical allodynia induced by PTX (p < 0.0001) in a CB2-dependent manner. Of note, when given concomitantly with PTX, BCP was able to attenuate the development of PINP (p < 0.0001). Spinal cord immunohistochemistry revealed that preventive treatment with BCP reduced p38 MAPK and NF-κB activation, as well as the increased Iba-1 and IL-1ß immunoreactivity promoted by PTX. Our findings show that BCP effectively attenuated PINP, possibly through CB2-activation in the CNS and posterior inhibition of p38 MAPK/NF-κB activation and cytokine release. Taken together, our results suggest that BCP could be used to attenuate the establishment and/or treat PINP.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Sesquiterpenos/farmacologia , Administração Oral , Animais , Antineoplásicos Fitogênicos/toxicidade , Moduladores de Receptores de Canabinoides/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Hiperalgesia/imunologia , Hiperalgesia/patologia , Indóis/farmacologia , Masculino , Neuralgia/induzido quimicamente , Neuralgia/imunologia , Neuralgia/patologia , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/patologia , Piperidinas/farmacologia , Sesquiterpenos Policíclicos , Pirazóis/farmacologia , Distribuição Aleatória , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia
7.
J Invest Dermatol ; 135(10): 2484-2491, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25955385

RESUMO

A role for proteinase-activated receptor-4 (PAR-4) was recently suggested in itch sensation. Here, we investigated the mechanisms underlying the pruriceptive actions of the selective PAR-4 agonist AYPGKF-NH2 (AYP) in mice. Dorsal intradermal (i.d.) administration of AYP elicited intense scratching behavior in mice, which was prevented by the selective PAR-4 antagonist (pepducin P4pal-10). PAR-4 was found to be coexpressed in 32% of tryptase-positive skin mast cells, and AYP caused a 2-fold increase in mast cell degranulation. However, neither the treatment with cromolyn nor the deficiency of mast cells (WBB6F1-Kit(W/Wv) mice) was able to affect AYP-induced itch. PAR-4 was also found on gastrin-releasing peptide (GRP)-positive neurons (pruriceptive fibers), and AYP-induced itch was reduced by the selective GRP receptor antagonist RC-3095. In addition, AYP evoked calcium influx in ∼1.5% of cultured DRG neurons also sensitive to TRPV1 (capsaicin) and/or TRPA1 (AITC) agonists. Importantly, AYP-induced itch was reduced by treatment with either the selective TRPV1 (SB366791), TRPA1 (HC-030031), or NK1 (FK888) receptor antagonists. However, genetic loss of TRPV1, but not of TRPA1, diminished AYP-induced calcium influx in DRG neurons and the scratching behavior in mice. These findings provide evidence that PAR-4 activation by AYP causes pruriceptive itch in mice via a TRPV1/TRPA1-dependent mechanism.


Assuntos
Capsaicina/farmacologia , Prurido/fisiopatologia , Receptores da Bombesina/metabolismo , Receptores de Trombina/metabolismo , Canais de Potencial de Receptor Transitório/efeitos dos fármacos , Animais , Comportamento Animal , Células Cultivadas , Modelos Animais de Doenças , Feminino , Gânglios Espinais/citologia , Imuno-Histoquímica , Injeções Intradérmicas , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prurido/induzido quimicamente , Prurido/psicologia , Distribuição Aleatória , Valores de Referência , Transdução de Sinais , Canais de Potencial de Receptor Transitório/metabolismo
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