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1.
J Environ Pathol Toxicol Oncol ; 39(3): 281-290, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865918

RESUMO

Objective-To investigate cystathionine ß synthase (CBS)/hydrogen sulfide (H2S) signaling in multiple myeloma (MM) patients and to identify its effect on the proliferation of U266 cells. Methods-Bone marrow samples of 19 MM patients and 23 healthy donors were collected. qRT-PCR was performed to measure the mRNA expression levels of H2S synthases, cystathionine ß synthase, and cystathionine γ lyase. ELISA assays quantified the amount of H2S produced by the two enzymes CBS and CSE. CCK-8 experiment was used to investigate the influence of the CBS inhibitor amino oxyacetic acid and the CSE inhibitor propargylglycine on the proliferation of U266 cells. Flow cytometry and western blotting were performed to determine the effects of AOAA, PAG, and NaHS on cell cycle distribution as well as Caspase-3 and Bcl-2 expression. Results-Patients with MM had higher level of CBS compared with healthy donors. AOAA significantly inhibited cell proliferation in both a time and concentration dependent characteristic, whereas PAG does not. After 24 hours of treatment, AOAA significantly elevated the G0/G1 phase proportion of cells, and reduced the cell distribution in both S and G2/M phases, while NaHS accelerated cell cycle progression by reducing the relative number of cells in G0/G1 phase and increasing the proportion of cells in the G2/M phase. Moreover, AOAA abolished the impact of NaHS on cell cycle progression of U266 cells. AOAA treatment also led to a significant decrease in Bcl-2 expression and dramatic increase in Caspase-3 expression, though NaHS reversed these effects. Conclusion-CBS/H2S system might have a certain effect on the proliferation and apoptosis of MM cells.


Assuntos
Apoptose , Proliferação de Células , Cistationina beta-Sintase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Mieloma Múltiplo/metabolismo , Adulto , Idoso , Alquinos/farmacologia , Ácido Amino-Oxiacético/farmacologia , Apoptose/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Estudos de Casos e Controles , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Transdução de Sinais
2.
Orv Hetil ; 161(38): 1623-1628, 2020 09.
Artigo em Húngaro | MEDLINE | ID: mdl-32924966

RESUMO

Maintenance therapy has been the strong and standard element of many acute lymphoblastic leukaemia protocols, used much less frequently and systematically in adult oncohematological disorders. The first adult maintenance efforts appeared in follicular and mantle cell lymphoma (mostly monoclonal antibody based), along with an early maintenance effort to prolong the plateau phase of myeloma. For the time being, after a long debate, the prognosis-dependent type of consolidation and maintenance became - sometimes until relapse - the standard approach in myeloma patients. The so-called small molecules, which turned out to be effective as induction and relapse agents, are continuously moving toward maintenance settings. Moreover, maintenance efforts seem to be more and more considered and used in transplanted or some non-transplanted acute myeloid leukaemia patients as well. Nevertheless, maintenance should be patient-friendly, easy to use (e.g., tablets) by enabling short outpatient office time, done not very frequently, and as much quality-of-life-based as possible. Orv Hetil. 2020; 161(38): 1623-1628.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Humanos , Leucemia Mieloide Aguda/patologia , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
3.
Anticancer Res ; 40(10): 5727-5734, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988898

RESUMO

BACKGROUND/AIM: To examine the impact of ACA and the association of socioeconomic factors on delay in initial treatment for multiple myeloma (MM). PATIENTS AND METHODS: Patients diagnosed with MM between 2004-2016 were identified in the National Cancer Database (NCDB). Time-to-initial treatment (TTI) was defined as the number of days from diagnosis to initial therapy. Patients were classified into quartiles and those belonging to the fourth quartile for TTI constituted the delayed treatment group. Study period was divided into pre-ACA and post-ACA using 2010 as the cut-off. RESULTS: A total of 65,723 patients met the eligibility criteria. Median TTI was 13 (IQR=5-27) days. Racial-ethnic minorities were associated with delayed-TTI. Delayed treatment was more likely for Hispanics pre-ACA but not post-ACA, while non-Hispanic Blacks (NHB) were more likely to have delayed treatment both, pre- and post-ACA. CONCLUSION: While ACA has been shown to help mitigate healthcare disparities in certain cancer diagnoses, the study suggests that the effect is still limited among MM patients.


Assuntos
Disparidades em Assistência à Saúde/normas , Cobertura do Seguro/normas , Mieloma Múltiplo/epidemiologia , Patient Protection and Affordable Care Act , Idoso , Grupos de Populações Continentais , Grupos Étnicos , Grupo com Ancestrais do Continente Europeu , Feminino , Hispano-Americanos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Fatores Socioeconômicos , Estados Unidos/epidemiologia
4.
Anticancer Res ; 40(9): 4979-4987, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878786

RESUMO

BACKGROUND/AIM: Multiple myeloma is a highly heterogeneous disease of clonal plasma cells. Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their precise mechanisms of actions are not well understood. MATERIALS AND METHODS: Cell-cycle regulation and pro-apoptotic effects of two histone deacetylase inhibitors, suberohydroxamic acid (SAHA) and suberoylanilide hydroxamic acid (SBHA), were analyzed in multiple myeloma cell lines RPMI8226 and U266 with differing TP53 status using gene-expression analysis. RESULTS: Enhanced expression of cyclin-dependent kinase inhibitor 1A (CDKN1A/p21WAF/CIP1) detected in the TP53-deleted U266 cell line after SAHA treatment indicates the P53-independent mode of transcriptional activation of CDKN1A gene. In contrast, CDKN1A gene expression was significantly increased by both SBHA and SAHA treatment of TP53-mutated RPMI8226 cells. CONCLUSION: SAHA appears to be a potentially effective pro-apoptotic and anticancer drug with universal application in the treatment of heterogeneous populations of multiple myeloma cells.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Mieloma Múltiplo/patologia , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Proteína Supressora de Tumor p53/genética
5.
Ann Hematol ; 99(11): 2589-2598, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892275

RESUMO

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Indução de Remissão , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
6.
Ann Hematol ; 99(11): 2599-2609, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32935190

RESUMO

Methods to estimate bone marrow plasma cells (BMPC) basically include histopathology, cytomorphology, and flow cytometry. The present study compares the outcomes of these methods with special focus on the impact of BMPC-specific characteristics on their recovery by either method. Laboratory reports of diagnostic samples from 238 consecutive patients with suspected or known plasma cell disease were retrospectively analyzed. The median (IQR) proportion of BMPC was 30.0% (15.0-70.0%) by histological review (hBMPC), 7.0% (2.0-16.0%) by smear review (sBMPC), and 3.0% (0.8-10.0%) by flow cytometry (fBMPC). The disparity of results between core biopsy and aspirate smear was enhanced in case of poor quality of the smear, increased BM fiber content, higher grade cell atypia, expression of CD56 (all P < 0.0001), the number of cytogenetic aberrations (P = 0.0002), and abnormalities of the MYC gene (P = 0.0002). Conversely, expression of CD19 and a non-clonal plasma cell phenotype were associated with a lower difference between hBMPC and sBMPC (both P < 0.0001). The disparity between the percentages of sBMPC and fBMPC was associated with the quality of the smear (P = 0.0007) and expression of CD56 (P < 0.0001). Our results suggest that the recovery of BMPC in aspirate specimens not only is a matter of sampling quality but also depends on biological cell properties. Aspiration failure due to malignant type features of BMPC may lead to misclassification of plasma cell disorders and represent a bias for the detection of minimal residual disease after therapy.


Assuntos
Antígenos CD19/biossíntese , Células da Medula Óssea , Antígeno CD56/biossíntese , Mieloma Múltiplo , Proteínas de Neoplasias/biossíntese , Plasmócitos , Adulto , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/classificação , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Neoplasia Residual , Plasmócitos/metabolismo , Plasmócitos/patologia , Estudos Retrospectivos
7.
Anticancer Res ; 40(10): 5437-5443, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988865

RESUMO

BACKGROUND: Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor A (VEGFA), and has been reported to be overexpressed in several malignancies. Since angiogenesis plays an important role in pathogenesis of multiple myeloma (MM) and the role of NRP1 in MM has not been studied yet, we characterized the expression of NRP1 in this disease. MATERIALS AND METHODS: The expression level of NRP1 was measured in 140 patients newly diagnosed with MM and 28 healthy controls by flow cytometry and quantitative reverse transcriptase polymerase chain reaction. RESULTS: Expression of NRP1 was significantly reduced on plasma cells (median=2.05%) compared to that on B-cells (median=10.05%, p<0.0001) in bone marrow of patients with MM. In MM, the expression of NRP1 was high on plasmacytoid dendritic cells (median=85.85%) and low on regulatory T-cells (median=0.6%). CONCLUSION: In MM, NRP1 is regulated differentially as compared to other B-cell malignancies at both the RNA and protein level.


Assuntos
Mieloma Múltiplo/genética , Neovascularização Patológica/genética , Neuropilina-1/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Linfócitos B/metabolismo , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Neovascularização Patológica/sangue , Neovascularização Patológica/patologia , Neuropilina-1/sangue , Transdução de Sinais/genética
8.
Adv Exp Med Biol ; 1207: 625-631, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671780

RESUMO

Multiple myeloma is a hematological malignancy. It is characterized by the abnormal clonal proliferation of malignant plasma cells in the bone marrow and the secretion of a large number of monoclonal immunoglobulins or light chains, causing bone destruction, elevated blood calcium levels, anemia, and renal dysfunction. Autophagy has a dual role in the autophagy of myeloma cells. On the one hand, autophagy eliminates abnormal proteins and organelles in cells, prevents gene damage, and inhibits tumorigenesis. On the other hand, once tumors are formed, tumor cells use autophagy to ensure their survival under nutrient-deficient and hypoxic conditions. Excessive autophagy promotes another form of death in tumor cells, autophagic cell death. Targeted autophagy is becoming another new myeloma treatment strategy.


Assuntos
Autofagia , Mieloma Múltiplo/patologia , Autofagia/efeitos dos fármacos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo
10.
Life Sci ; 257: 118088, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663573

RESUMO

AIMS: Bone marrow stromal cells (BMSCs) have been reported to interact with multiple myeloma (MM) and exert a vital function of the survival of MM cells. Heme oxygenase-1 (HO-1), a cytoprotective enzyme, has the potential to become a hematological malignancies targeted gene. This study aimed to investigate the role of HO-1 in MM resistance of BMSCs and its possible mechanisms. MAIN METHODS: In this study, the expression of related proteins was detected by RT-qPCR and Western blot. HO-1 expression was regulated by lentivirus transfection. Cell viability and apoptosis were detected by Flow cytometry and CCK-8. Cytokine secretion was assayed by ELISA. The survival and carcinogenic abilities was detected by clone formation assay. KEY FINDINGS: HO-1 expression in the BMSCs of stage III MM patients was substantially increased, compared with that of healthy donors and stage I/II patients. The results of co-culture of BMSCs and MM cells indicated that, the upregulated HO-1 inhibited the apoptosis of co-cultured MM cells, while downregulated HO-1 promoted the chemosensitivity of co-cultured MM cells, moreover, the upregulated HO-1 in BMSCs increased the colony-formation ability of MM cells. This protective capability may be regulated by CXCL12/CXCR4 signaling. High HO-1 expression in BMSCs can promote the phosphorylation of the JAK2/STAT3 pathway, thereby increasing secretion of SDF-1 in BMSCs and activating CXCL12/CXCR4 signaling. In addition, direct contact between BMSCs and MM cells may cause drug resistance. SIGNIFICANCE: These results indicated that the regulation of HO-1 in BMSCs may be a new effective method of MM therapy.


Assuntos
Antineoplásicos/farmacologia , Heme Oxigenase-1/genética , Células-Tronco Mesenquimais/citologia , Mieloma Múltiplo/patologia , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Estudos de Casos e Controles , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Estadiamento de Neoplasias , Fator de Transcrição STAT3/metabolismo
11.
Nat Commun ; 11(1): 3617, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32680998

RESUMO

Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient's life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Evolução Clonal/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Progressão da Doença , Relação Dose-Resposta a Droga , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico por imagem , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Mutação/efeitos dos fármacos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Análise de Célula Única , Análise Espaço-Temporal , Transplante Autólogo/efeitos adversos , Sequenciamento Completo do Genoma
13.
PLoS One ; 15(6): e0232068, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559187

RESUMO

Cyclin Dependent Kinase 9 (CDK9) associates with Bromodomain and Extra-Terminal Domain (BET) proteins to promote transcriptional elongation by phosphorylation of serine 2 of RNAP II C-terminal domain. We examined the therapeutic potential of selective CDK9 inhibitors (AZD 4573 and MC180295) against human multiple myeloma cells in vitro. Short-hairpin RNA silencing of CDK9 in Multiple Myeloma (MM) cell lines reduced cell viability compared to control cells showing the dependency of MM cells on CDK9. In order to explore synergy with the CDK9 inhibitor, proteolysis targeting chimeric molecule (PROTAC) ARV 825 was added. This latter drug causes ubiquitination of BET proteins resulting in their rapid and efficient degradation. Combination treatment of MM cells with ARV 825 and AZD 4573 markedly reduced their protein expression of BRD 2, BRD 4, MYC and phosphorylated RNA pol II as compared to each single agent alone. Combination treatment synergistically inhibited multiple myeloma cells both in vitro and in vivo with insignificant weight loss. The combination also resulted in marked increase of apoptotic cells at low dose compared to single agent alone. Taken together, our studies show for the first time that the combination of a BET PROTAC (ARV 825) plus AZD 4573 (CDK9 inhibitor) is effective against MM cells.


Assuntos
Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas/metabolismo , Proteólise/efeitos dos fármacos , Animais , Azepinas/farmacologia , Azepinas/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 9 Dependente de Ciclina/genética , Quinase 9 Dependente de Ciclina/metabolismo , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Camundongos , Camundongos SCID , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , RNA Polimerase II/metabolismo , RNA Interferente Pequeno/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacologia , Talidomida/uso terapêutico , Transplante Heterólogo
14.
Life Sci ; 256: 117971, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32553925

RESUMO

AIMS: Multiple myeloma (MM) was recently reported to rely on increased oxidative phosphorylation (OXPHOS) for survival, providing a potential opportunity for MM therapy. Herein, we aimed to propose a novel targeted drug for MM treatment, followed by the exploration of reason for OXPHOS enhancement in MM cells. MATERIALS AND METHODS: The expression of OXPHOS genes and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was analyzed using bioinformatics analyses, followed by verification in MM cell lines. The effects of SR18292 on OXPHOS were measured by qRT-PCR, Western blot, transmission electron microscopy, oxygen consumption rate and so on. The proliferation and apoptosis were evaluated by CCK-8, flow cytometry and Western blot. The efficiency and safety of SR18292 were assessed in a mouse model of MM. KEY FINDINGS: The OXPHOS genes were generally overexpressed in MM cells, which was associated with poorer prognosis of MM patients. PGC-1α, a transcriptional coactivator, was upregulated in MM cells, and MM patients with higher PGC-1α expression exhibited increased enrichment of the OXPHOS gene set. Treatment with SR18292 (an inhibitor of PGC-1α) significantly impaired the proliferation and survival of MM cells due to OXPHOS metabolism dysfunction, which leads to energy exhaustion and oxidative damage. Besides, SR18292 potently inhibited tumor growth at a well-tolerated dose in MM model mice. SIGNIFICANCE: The overexpression of OXPHOS gene set mediated by upregulated PGC-1α provides a structural basis for enhanced OXPHOS in MM cells, and SR18292 (a PGC-1α inhibitor) exerts potent antimyeloma effects, offering a potential tangible avenue for MM therapy.


Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Fosforilação Oxidativa , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Metabolismo Energético/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Mieloma Múltiplo/ultraestrutura , Fosforilação Oxidativa/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Br J Radiol ; 93(1112): 20190891, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32462885

RESUMO

OBJECTIVE: To explore the value of related parameters in monoexponential, biexponential, and stretched-exponential models of diffusion-weighted imaging (DWI) in differentiating metastases and myeloma in the spine. METHODS: 53 metastases and 16 myeloma patients underwent MRI with 10 b-values (0-1500 s/mm2). Parameters of apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), the distribution diffusion coefficient (DDC), and intravoxel water diffusion heterogeneity (α) from DWI were calculated. The independent sample t test and the Mann-Whiney U test were used to compare the statistical difference of the parameter values between the two. Receiver operating characteristics (ROC) curve analysis was used to identify the diagnostic efficacy. Then substituted each parameter into the decision tree model and logistic regression model, identified meaningful parameters, and evaluated their joint diagnostic performance. RESULTS: The ADC, D, and α values of metastases were higher than those of myeloma, whereas the D* value was lower than that of myeloma, and the difference was significant (p < 0.05); the area under the ROC curve for the above parameters was 0.661, 0.710, 0.781, and 0.743, respectively. There was no significant difference in the f and DDC values (p > 0.05). D and α were found to conform to the decision tree model, and the accuracy of model diagnosis was 84.1%. ADC and α were found to conform to the logistic regression model, and the accuracy was 87.0%. CONCLUSION: The 3 models of DWI have certain values indifferentiating metastases and myeloma in spine, and the diagnostic performance of ADC, D, α and D*was better. Combining ADC with α may markedly aid in the differential diagnosis of the two. ADVANCES IN KNOWLEDGE: Monoexponential, biexponential, and stretched-exponential models can offer additional information in the differential diagnosis of metastases and myeloma in the spine. Decision tree model and logistic regression model are effective methods to help further distinguish the two.


Assuntos
Imagem de Difusão por Ressonância Magnética , Mieloma Múltiplo/diagnóstico por imagem , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Análise Multivariada , Curva ROC , Neoplasias da Coluna Vertebral/diagnóstico , Neoplasias da Coluna Vertebral/secundário , Coluna Vertebral/diagnóstico por imagem
18.
Am J Hematol ; 95(8): 966-977, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32350883

RESUMO

With rapid advancements in the diagnosis and treatment of multiple myeloma (MM), imaging has become instrumental in detection of intramedullary and extramedullary disease, providing prognostic information, and assessing therapeutic efficacy. Whole-body low dose computed tomography (WBLDCT) has emerged as the study of choice to detect osteolytic bone disease. Positron emission tomography/computed tomography (PET/CT) combines functional and morphologic information to identify MM disease activity and assess treatment response. Magnetic resonance imaging (MRI) has excellent soft-tissue contrast and is the modality of choice for bone marrow evaluation. This review focuses on the imaging modalities available for MM patient management, highlighting advantages, disadvantages, and applications of each.


Assuntos
Mieloma Múltiplo/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Estudos Retrospectivos
19.
J Cancer Res Ther ; 16(1): 88-93, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362614

RESUMO

Introduction: The impact of rapid reduction in paraprotein levels, with induction chemotherapy in myeloma, on treatment outcomes is less clear. There are very few studies in transplant ineligible patients treated with novel agents, correlating an early reduction in paraprotein with survival duration. Methods: In this retrospective analysis of newly diagnosed multiple myeloma, ineligible for stem cell transplant, paraprotein levels at baseline and 3 months were noted with percentage reduction. Survival analysis was performed with Kaplan-Meier curves and Cox proportional hazard model. Results: Among a total of 121 patients, 42 (35%), 29 (24%), and 50 (41%) had paraprotein reduction of 100%, 90%-99%, and <90%, respectively from baseline levels at 3 months. Patients with complete disappearance of paraprotein (100% reduction) when compared against those with <100% reduction at 3 months had a trend toward higher overall survival (OS) (3-year OS of 81% vs. 69%, hazard ratio [HR] = 0.54, P = 0.182). However, the progression-free survival (PFS) was significantly higher when these two groups were compared (median PFS of 51 vs. 17 months, HR = 0.33, P ≤ 0.001). When patients with ≥90% reduction were compared with <90% reduction at 3 months, there was significant improvement in both OS and PFS (3-year OS of 80% vs. 48%, HR = 0.24, P = 0.001, median PFS of 38 vs. 14 months, HR = 0.13, P < 0.001). Conclusions: Achieving a faster and deeper reduction in paraprotein as early as 3 months could lead to significant improvement in PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Quimioterapia de Indução/métodos , Mieloma Múltiplo/mortalidade , Paraproteínas/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Centros de Atenção Terciária , Resultado do Tratamento
20.
J Cancer Res Ther ; 16(1): 98-101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362616

RESUMO

Context: The fluctuations of proteins in multiple myeloma (MM) are well-known markers for checking the status of the patients. Aims: The objective of this study was to examine three proteins that have an important role in disease progression. Subjects and Methods: The study was performed with two groups: 30 MM stage I patients' (14 females/16 males; aged 60.83 ± 12.38 years) as case group and 40 healthy individuals (18 females/22 males; aged 57.65 ± 6.43 years) as control group. Both groups have been matched in gender and age. Bone sialoprotein (BSP), osteopontin (OPN), and ß2-microglobulin (ß2M) were measured with an enzyme-linked immunosorbent assay. Results: Serum BSP levels of MM-I patients was significantly higher than that of healthy controls (29.24 ± 5.57 vs. 20.89 ± 3.67, P = 0.001). OPN levels of MM-I patients were significantly lower than that of healthy individuals (12.03 ± 3.45 vs. 19.35 ± 4.67, P = 0.001). ß2M levels of patients and controls were similar (1.49 ± 0.67 vs. 1.29 ± 0.55, P = 0.193). Conclusions: The results suggested that myeloma cells may affect the production of BSP and OPN, which possibly contributes to osteoclastic bone resorption in MM-I patients. Their levels may be a useful biomarker for assessing bone destruction in MM-I patients and distinguishing MM-I from healthy individuals.


Assuntos
Biomarcadores Tumorais/sangue , Sialoproteína de Ligação à Integrina/sangue , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Osteopontina/sangue , Microglobulina beta-2/sangue , Estudos de Casos e Controles , Progressão da Doença , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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