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Front Immunol ; 12: 671904, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489930


To assess patients with multiple myeloma (MM), the whole-body positron-emission tomography/computed tomography (PET/CT) occupies a pivotal position for diagnostic stratification, response evaluation, and survival prediction, while important limitations are recognized as incapable of representing tumor microenvironment. Regulatory B cells (Bregs) have been reported to have an inhibitory immune function, contributing to bone marrow (BM)-immunosuppressive microenvironment for MM. Therefore, to investigate the role of PET/CT in combination with Bregs' ratios to predict therapeutic response and survival, we sequentially enrolled 120 patients with newly diagnosed MM (NDMM) who were treated with novel agents in our center, while conventional PET/CT parameters including maximum standard uptake value (SUVmax), ratios of BM-derived Bregs within CD19+ B cells, and patients' clinical characteristics were collected. After a median follow-up of 28.20 months (range 7.00-46.93 months), SUVmax > 4.2 at onset, accounting for 53.2% of NDMM, was uncovered to predict inferior progression-free survival (PFS) as well as overall survival (OS). With regard to the ratios of BM-derived Bregs within CD19+ B cells, the cohort with the Bregs' proportions lower than 10%, accounting for 46.2%, exerted poorer OS. Additionally, the patients with both SUVmax > 4.2 and Bregs' ratios < 10%, accounting for 31.7%, yielded compromised therapeutic response and long-term survival. Collectively, this study may draw attention on the prognostic value of combination of PET/CT and Bregs' ratios when clinical decisions are made for MM in the era of novel agents.

Linfócitos B Reguladores/imunologia , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Adulto , Idoso , Antineoplásicos/uso terapêutico , Dexametasona/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
J Cancer ; 12(9): 2633-2642, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854623


Multiple myeloma (MM) is a heterogeneous disease that remains incurable with significant interpatient variability in outcomes. Regulatory B cells (Bregs) were observed to be involved into specific defects in MM. Here, we provide our risk-adapted approach to newly diagnosed MM (NDMM), combining with the fundamental dysfunction of Bregs. We reported one hundred consecutive patients with NDMM from South-Western China, primarily treated with bortezomib plus dexamethasone with or without a 3rd agent, were enrolled from 2017. Bone marrow aspirates were obtained and flow cytometry (FCM) was used to quantify the percentage of Bregs from the bone marrow. The correlation between Bregs and clinical characters were further analyzed. This study found using bortezomib plus dexamethasone as backbone showed promising efficacy with acceptable tolerability in NDMM. The relatively compromised progression free survival (PFS) points to the essential synergy of bortezomib and lenalidomide here. This study also found that altered proportions of Bregs were closely correlated with treatment efficacy and prognosis in MM. Further understanding of Bregs biology might provide new opportunities to develop immunotherapy, which could prove beneficial in treating MM.

Ann Hematol ; 100(1): 135-141, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33083863


The aim of this study was to investigate the effect of low-dose ruxolitinib (daily dose ≤ 10 mg) for the treatment of myelofibrosis (MF). A retrospective analysis was performed on a total of 88 patients with myeloproliferative neoplasm-associated MF (MPN-MF) who were diagnosed and treated in West China Hospital, Sichuan University, China. A total of 44 MPN-MF patients received a low dose of ruxolitinib (daily dose ≤ 10 mg), while another 44 patients received 10-25 mg twice daily. Low-dose ruxolitinib treatment resulted in slow, but gradual spleen response. Compared with baseline, the mean changes in palpable spleen length in the low- and high-dose groups were -26.9 and -49.0% after 12 weeks of treatment, respectively, and -46.7 and -64.1% after 48 weeks of treatment, respectively. In the low dose group, the median myeloproliferative neoplasm symptom assessment form (MPN-SAF) total symptom score (TSS) decreased by 37.8 and 35.9% at the 12 weeks and 48 weeks after treatment, respectively. No statistical difference was observed in MPN-SAF TSS among different dose groups. After 48 weeks of treatment, bone marrow (BM) fibrosis improved in 43.3% (13/30) of evaluated patients and was stable in 56.7% (17/30) patients. In the low-dose treated group, BM fibrosis improved in 50% patients and was stable in remaining 50%. Low-dose ruxolitinib is effective in treating MF.

Inibidores de Janus Quinases/administração & dosagem , Mielofibrose Primária/tratamento farmacológico , Pirazóis/administração & dosagem , Baço/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/patologia , Estudos Retrospectivos , Baço/patologia , Resultado do Tratamento
Cell Signal ; 72: 109643, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32320859


Transient Receptor Potential Melastatin Subfamily Member 4 (TRPM4) has been demonstrated to be aberrantly expressed in several cancers but seldom reported in acute leukemia. Based on database mining and validated experiments, our present data show that TRPM4 is selectively overexpressed in AML patients and cell lines with the MLL gene rearrangement. We analyzed the correlation between TRPM4 expression and clinical parameters in a validated cohort of AML patients. Increased TRPM4 expression was associated with significant leukocytosis (p = .028), M4/M5 subtype (p = .000), FLT3-ITD mutation (p = .034), MLL status (p = .007) and a higher risk stratification (p = .001). Knockdown of TRPM4 mediated by siRNA impaired proliferation and arrested the cell cycle at the G0/G1 phase in MLL-rearranged leukemia cells. We suggested that TRPM4 may be involved in the pathogenesis of MLL-rearranged leukemia through regulating the AKT/GLI1/Cyclin D1 pathway. The transcription factor HOXA9 was found to be responsible for upregulation of TRPM4 expression by binding to its promoter. In conclusion, TRPM4 is overexpressed in MLL-rearranged AML and blockade of TRPM4 may be an alternative therapeutic approach in AML patients with high TRPM4 expression.

Pontos de Checagem do Ciclo Celular/genética , Ciclina D1/metabolismo , Rearranjo Gênico/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Canais de Cátion TRPM/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Adulto , Estudos de Casos e Controles , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/metabolismo , Regiões Promotoras Genéticas/genética , Transdução de Sinais , Canais de Cátion TRPM/metabolismo , Transcrição Genética , Regulação para Cima/genética