RESUMO
A chemotherapy-based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single-arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18-75 years. The EAP regimen consisted of etoposide 75 mg/m2/day on days 1-2, cytarabine 300 mg/m2 every 12 h on days 1-2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1-92.7) × 106/kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2-3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina , Etoposídeo , Filgrastim , Mobilização de Células-Tronco Hematopoéticas , Linfoma , Mieloma Múltiplo , Polietilenoglicóis , Humanos , Filgrastim/administração & dosagem , Filgrastim/uso terapêutico , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Feminino , Masculino , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Adulto , Linfoma/tratamento farmacológico , Linfoma/terapia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/terapia , Estudos Prospectivos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/métodos , Adulto Jovem , AdolescenteRESUMO
Although CD19-specific chimeric antigen receptor (CAR) T cells are curative for patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), disease relapse with tumor antigen-positive remains a challenge. Cytokine/chemokine-expressing CAR-T cells could overcome a suppressive milieu, but the clinical safety and efficacy of this CAR-T therapy remain unclear. Here we report the preclinical development of CD19-specific CAR-T cells capable of expressing interleukin (IL)-7 and chemokine (C-C motif) ligand (CCL)-19 upon CD19 engagement (referred to as 7 × 19 CAR-T cells) and results from a phase 1 and expansion phase trial of 7 × 19 CAR-T cell therapy in patients with R/R LBCL (NCT03258047). In dose-escalation phase, there were no dose-limiting toxicities observed. 39 patients with R/R LBCL received 7 × 19 CAR-T with doses ranged from 0.5 × 106-4.0 × 106 cells per kg body weight. Grade 3 cytokine release syndrome occurred in 5 (12.8%) patients and ≥ grade 3 neurotoxicity in 4 (10.3%) patients. The overall response rate at 3 months post-single infusion was 79.5% (complete remission, 56.4%; partial response, 23.1%). With a median follow-up of 32 months, the median progression-free survival was 13 months, and median overall survival was not reached, with an estimated rate of 53.8% (95% CI, 40.3% to 72.0%) at two years. Together, these long-term follow-up data from the multicenter clinical study suggest that 7 × 19 CAR-T cells can induce durable responses with a median overall survival of greater than 2 years, and have a manageable safety profile in patients with R/R LBCL.
RESUMO
Patients with hematologic malignancies are often immunodeficient and therefore have a higher risk of severe symptoms from coronavirus disease 2019 (COVID-19). We retrospectively examined a cohort of 289 patients from 16 hospitals in Zhejiang Province who had hematologic malignancies and COVID-19 during a period when the Omicron variant was predominant. Univariate analysis showed that some clinical characteristics, including elder age (P = 0.014), multiple comorbid conditions (P = 0.011), and receipt of active antineoplastic therapy (P = 0.018) were associated with an increased risk of severe COVID-19. Patients with severe/critical COVID-19 had significantly lower levels of lymphocytes and serum albumin, and significantly higher levels of D-dimer, lactate dehydrogenase, C-reactive protein, and interleukin-6 (all P < 0.05). Fifty-four patients (18.7%) had symptoms lasting ≥3 weeks, suggesting that persistent long-term COVID-19 infection is likely present in a significant proportion of patients. Receipt of the inactivated vaccine was unrelated to disease severity (P = 0.143), which indicated that many patients with hematologic malignancies may not have effective humoral immunity to inactivated vaccines.
Assuntos
COVID-19 , Neoplasias Hematológicas , Humanos , COVID-19/complicações , População do Leste Asiático , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/epidemiologia , Estudos RetrospectivosRESUMO
Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.
Assuntos
Adenocarcinoma , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Junção Esofagogástrica , Neoplasias Gástricas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoglobulina G/imunologia , Método Duplo-Cego , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Oxaloacetatos/administração & dosagem , Oxaloacetatos/efeitos adversosRESUMO
BACKGROUND: The tumor immune microenvironment plays a crucial role in the efficacy of various therapeutics. However, their correlation is not yet completely understood in Clear cell renal cell carcinoma (ccRCC). This study aimed to investigate the potential of TREM-1 as a potential novel biomarker for ccRCC. METHODS: We constructed a ccRCC immune prognostic signature. The clinical characteristics, the status of the tumor microenvironment, and immune infiltration were analyzed through the ESTIMATE and CIBERSORT algorithms for the hub gene, while the Gene Set Enrichment Analysis and PPI analysis were performed to predict the function of the hub gene. Immunohistochemical staining was used to detect the expression of TREM-1 in renal clear cell carcinoma tissues. RESULTS: The CIBERSORT and ESTIMATE algorithms revealed that TREM-1 was correlated with the infiltration of 12 types of immune cells. Therefore, it was determined that TREM-1 was involved in numerous classical pathways in the immune response via GSEA analysis. In Immunohistochemical staining, we found that the expression of TREM-1 was significantly upregulated with increasing tumor grade in renal clear cell carcinoma, and elevated TREM-1 expression was associated with poor prognosis. CONCLUSIONS: The results suggest that TREM-1 may act as an implicit novel prognostic biomarker in ccRCC that could be utilized to facilitate immunotherapeutic strategy.
Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Prognóstico , Receptor Gatilho 1 Expresso em Células Mieloides , Neoplasias Renais/genética , Microambiente TumoralRESUMO
Wild boars (Sus scrofa) are extremely common in southern China, but little study has been conducted regarding reporting the dietary habits of wild boars using high-throughput sequencing technology, especially in karst areas, due to the difficulty in obtaining stomach contents of wild boars. In our study, the stomach contents of 14 wild boars in southern China were analyzed by DNA metabarcoding. The results showed that there were 153 genera, 93 families, and 48 orders of plant food sources for wild boars. The main plant food component were Cissus, Dioscorea, Quercus, Actinidia, and Houttuynia. The most numerous taxa of animal food sources were Elaphodus, Amynthas, Chonaphe, Rattus, and Tanytarsus. It is noteworthy that Elaphodus cephalophus were detected in most of the stomach samples, accounting for a large portion of animal food sources. The results showed that there were significant differences in the diets of wild boars in different regions; however, no significant differences were noted between male and female wild boars. Our study revealed the dietary preference of wild boars under the special forest conditions in the mountainous area of southwest China, as well as the relationship between the dietary habits of wild boars and their habitats from the perspective of resource utilization, thus providing a key scientific basis for the prevention and control of wild boars, along with resource protection.
RESUMO
Background: Diffuse large B-cell lymphoma (DLBCL) is a common aggressive B-cell non-Hodgkin lymphoma (B-NHL). While combined chemotherapy has improved the outcomes of DLBCL, it remains a highly detrimental disease. Pyroptosis, an inflammatory programmed cell death, is considered to have both tumor-promoting and tumor-suppressing effects. The role of pyroptosis in DLBCL has been gradually appreciated, but its value needs further investigation. Methods: We analyzed mutations and copy number variation (CNV) alterations of pyroptosis-related genes (PRGs) from The Cancer Genome Atlas (TCGA) cohort and evaluated the differences in expression in normal B cells and DLBCL patients in two Gene Expression Omnibus (GEO) datasets (GSE12195 and GSE56315). Based on the expression of 52 PRGs, we divided 421 DLBCL patients from the GSE31312 dataset into distinct clusters using consensus clustering. The Kaplan-Meier method was used to prognosis among the three clusters, and GSVA was used to explore differences in the biological functions. ESTIMATE and single-sample gene-set enrichment analysis (ssGSEA) were used to analyze the tumor immune microenvironment (TME) in different clusters. A risk score signature was developed using a univariate survival analysis and multivariate regression analysis, and the reliability and validity of the signature were verified. By combining the signature with clinical factors, a nomogram was established to predict the prognosis of DLBCL patients. The alluvial diagram and correlation matrix were used to explore the relationship between pyroptosis risk score, clinical features and TME. Results: A large proportion of PRGs are dysregulated in DLBCL and associated with the prognosis. We found three distinct pyroptosis-related clusters (cluster A, B, and C) that differed significantly with regard to the prognosis, biological process, clinical characteristics, chemotherapeutic drug sensitivity, and TME. Furthermore, we developed a risk score signature that effectively differentiates high and low-risk patients. The nomogram combining this signature with several clinical indicators showed an excellent ability to predict the prognosis of DCBCL patients. Conclusions: This work demonstrates that pyroptosis plays an important role in the diversity and complexity of the TME in DLBCL. The risk signature of pyroptosis is a promising predictive tool. A correct and comprehensive assessment of the mode of action of pyroptosis in individuals will help guide more effective treatment.
RESUMO
BACKGROUND: Multiple myeloma (MM) is a malignant hematopoietic disease that is usually incurable. RNA-binding proteins (RBPs) are involved in the development of many tumors, but their prognostic significance has not been systematically described in MM. Here, we developed a prognostic signature based on eight RBP-related genes to distinguish MM cohorts with different prognoses. METHOD: After screening the differentially expressed RBPs, univariate Cox regression was performed to evaluate the prognostic relevance of each gene using The Cancer Genome Atlas (TCGA)-Multiple Myeloma Research Foundation (MMRF) dataset. Lasso and stepwise Cox regressions were used to establish a risk prediction model through the training set, and they were validated in three Gene Expression Omnibus (GEO) datasets. We developed a signature based on eight RBP-related genes, which could classify MM patients into high- and low-score groups. The predictive ability was evaluated using bioinformatics methods. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and gene set enrichment analyses were performed to identify potentially significant biological processes (BPs) in MM. RESULT: The prognostic signature performed well in the TCGA-MMRF dataset. The signature includes eight hub genes: HNRNPC, RPLP2, SNRPB, EXOSC8, RARS2, MRPS31, ZC3H6, and DROSHA. Kaplan-Meier survival curves showed that the prognosis of the risk status showed significant differences. A nomogram was constructed with age; B2M, LDH, and ALB levels; and risk status as prognostic parameters. Receiver operating characteristic (ROC) curve, C-index, calibration analysis, and decision curve analysis (DCA) showed that the risk module and nomogram performed well in 1, 3, 5, and 7-year overall survival (OS). Functional analysis suggested that the spliceosome pathway may be a major pathway by which RBPs are involved in myeloma development. Moreover, our signature can improve on the R-International Staging System (ISS)/ISS scoring system (especially for stage II), which may have guiding significance for the future. CONCLUSION: We constructed and verified the 8-RBP signature, which can effectively predict the prognosis of myeloma patients, and suggested that RBPs are promising biomarkers for MM.
RESUMO
PURPOSE: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is effective against refractory or relapsed (R/R) B-cell lymphoma, but the efficacy is hindered by the existence of PD-1/PD-L1 pathway. PATIENTS AND METHODS: Here, we generated a novel anti-CD19 CAR-expressing PD-1/CD28 chimeric switch-receptor (CD19-PD-1/CD28-CAR). We then conducted a phase Ib study to evaluate safety and efficacy of CD19-PD-1/CD28-CAR T cells in the treatment of PD-L1+ B-cell lymphoma. RESULTS: We found that CD19-PD-1/CD28-CAR T cells had superior T-cell proliferation, cytokine production, and sequentially capability of killing PD-L1+ B-cell lymphoma cells in vitro and in vivo relative to the prototype, CD19-CAR T cells. Among 17 adult patients with R/R lymphoma who received the CAR T therapy, 10 patients had objective response (58.8%), including seven patients with complete remission (41.2%). At a median follow-up 15 months, median overall survival for all patients was not reached. Remarkably, no severe neurologic toxicity or cytokine release syndrome was observed. CONCLUSIONS: This first-in-human study demonstrates the tolerability, safety, and encouraging efficacy of CD19-PD-1/CD28-CART in PD-L1+ large B-cell lymphoma.
Assuntos
Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Estimativa de Kaplan-Meier , Leucopenia/etiologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Acute myelogenous leukemia (AML) is a class of malignant tumors derived from hematopoietic stem or progenitor cells. The H2.0-like homeobox gene (HLX) encodes transcription factors that function in promoting normal hematopoietic cell proliferation and tumor immunity. The present study analyzed the effect of downregulating the HLX on cell cycle distribution and cell proliferation in AML. Moreover, the current study detected changes in the expression of genes and proteins in the Janus kinase (JAK)/STAT signaling pathway to investigate the mechanism of the action of HLX in tumor immunity in AML. HLX expression in AML cell lines was silenced using small interfering siRNA, and MTS/PMS-assay colorimetric assays were used to assess the effect of knockdown of HLX on AML cell proliferation. Flow cytometry was used to analyze changes in cell cycle distribution, while reverse transcription-quantitative PCR and western blotting were used to detect changes in the expression levels of key components of the JAK/STAT signaling pathway, such as p21-activated kinase 1 (PAK1), neuropilin 1 (NRP1), B-cell translocation gene 1 (BTG1) and STAT5. It was found that HLX was differentially expressed in AML cell lines of various subtypes, and HLX expression was higher in the AML/M3 subtype NB4 cell line compared with the control group. Knockdown of HLX in NB4 cells significantly inhibited cell proliferation and arrested cells in the G0/G1 phase. Moreover, STAT5 protein expression, as well as NRP1 and PAK1 expression levels were downregulated, while BTG1 expression was upregulated when HLX was knocked out by siRNA. Collectively, the results suggested that downregulation of HLX may cause G0/G1 phase arrest and inhibit the proliferation of AML cells by activating the JAK/STAT signaling pathway.
RESUMO
Objective: To investigate the hyaluronic acid (HA) modified, doxorubicin (DOX) and gallic acid (GA) co-delivered lipid-polymeric hybrid nano-system for leukemia therapy. Methods: We produced a kind of lipid-polymer hybrid nanoparticle (LPHN) with a core-shell structure in which DOX and GA were co-loaded. In vitro and in vivo leukemia therapeutic effects of the HA modified, DOX and GA co-delivered LPHNs (HA-DOX/GA-LPHNs) were evaluated in DOX resistant human HL-60 promyelocytic leukemia cells (HL-60/ADR cells), DOX resistant human K562 chronic myeloid leukemia cells (K562/ADR cells), and HL-60/ADR cells bearing mouse model. Results: The sizes and zeta potentials of HA modified LPHNs were about 160 nm and -40 mV. HA-DOX/GA-LPHNs showed the most prominent cytotoxicity and the best synergistic effect was obtained when DOX/GA ratio was 2/1. In vivo studies revealed that HA-DOX/GA-LPHNs inhibited tumor growth from 956 mm3 to 213 mm3, with an inhibition rate of 77.7%. Conclusion: In summary, the study showed that HA-DOX/GA-LPHNs can be applied as a promising leukemia therapy system.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Ácido Gálico/farmacologia , Ácido Hialurônico/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Liberação Controlada de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Gálico/administração & dosagem , Ácido Gálico/química , Células HL-60 , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Injeções Intravenosas , Células K562 , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Lipídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Tamanho da Partícula , Polímeros/química , Propriedades de SuperfícieRESUMO
INTRODUCTION: This systematic review and meta-analysis aims to explore the influence of ferumoxytol versus placebo on iron deficiency anemia. METHODS: We search for randomized controlled trials (RCTs) assessing the effect of ferumoxytol on iron deficiency anemia on PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases. This meta-analysis is performed using the random-effects model. RESULTS: Four RCTs are included in the meta-analysis. Compared with the control group for iron deficiency anemia, intravenous ferumoxytol can significantly improve the proportion of patients with a ≥20 g/L hemoglobin (Hb) increase (RR = 18.43; 95% CI = 7.29-46.57; p < 0.00001), the proportion of patients with an Hb level ≥120 g/L (RR = 18.55; 95% CI = 8.66-39.72; p < 0.00001), transferrin saturation (mean difference = 11.08; 95% CI = 9.86-12.31; p < 0.00001) and FACIT-fatigue score (mean difference = 4.60; 95% CI = 3.21-6.00; p < 0.00001), but has no remarkable influence on adverse events (RR = 1.33; 95% CI = 0.84-2.10; p = 0.22), serious adverse events (RR = 1.22; 95% CI = 0.74-2.02; p = 0.44), and death (RR = 0.32; 95% CI = 0.05-1.95; p = 0.22). CONCLUSIONS: Intravenous ferumoxytol can provide the important benefits for iron deficiency anemia.
Assuntos
Anemia Ferropriva , Óxido Ferroso-Férrico/uso terapêutico , Anemia Ferropriva/sangue , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/fisiopatologia , Óxido Ferroso-Férrico/efeitos adversos , Hemoglobinas/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy caused by abnormal proliferation of immature T cell progenitors. Chemotherapy of T-ALL usually consists of induction, consolidation, and long-term maintenance. Diacetyl hexamethylene diamine (CAHB) is a newly developed agent that induces the differentiation of malignant cells and deprives their clonal growth ability. Since its effect on T-ALL has not been previously determined, we evaluated its potential function in the Jurkat cell line. MATERIAL AND METHODS MTT assay was conducted to evaluate the cytotoxicity and anti-proliferative effect of CAHB. The apoptosis level of CAHB-treated Jurkat cells was evaluated using flow cytometry via staining with Annexin V/PI or cleaved-caspase-3. The alteration of mitochondrial membrane potential was determined by flow cytometry. The expression of Bax and Bcl-2 was evaluated by RT-PCR and Western blot. Western blot was also used to assess the activation of Akt. RESULTS CAHB inhibited the proliferation and promoted the apoptosis of Jurkat cells in a time- and dose-dependent manner by decreasing activation of Akt, reducing the mitochondrial membrane potential, and downregulating the Bcl-2/Bax ratio. CONCLUSIONS Our data suggest that CAHB might be regarded as a novel treatment agent for T-ALL since it can induce apoptosis and inhibit proliferation of the T-ALL cell line at a relatively low level.
Assuntos
Diaminas/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diacetil , Diaminas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Células Jurkat , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The study aims to investigate the effect and safety of sustained-release oxycodone hydrochloride as background dose on pain titration in patients with moderate-to-severe cancer pain. MATERIAL AND METHODS: Adult patients scheduled with a regular strong opioid for cancer-related pain were recruited and randomly assigned to sustained-release oxycodone group (tablets, 12 hourly) and immediate-release morphine group (5âmg initially, hourly). All patients were hourly reassessed for efficacy and dose titration. RESULTS: The primary end point was the number of titration cycles required to achieve adequate pain relief (numerical rating scale, NRS ≤ 3). Secondary end points included the proportion of patients achieving adequate pain relief during each cycle, potential predictive factors for titration performance, and side effects. Ninety (94.7%) patients in oxycodone group and 78 (86.7%) patients in morphine group achieved adequate pain control during 1 to 4 cycles of titration. Patients in oxycodone group reached adequate pain control within the first 2 cycles of titration, which was significantly shorter than morphine group wherein the number of titration cycles ranged from 1 to 4 (P = .034). Oxycodone prescription significantly increased the response rate of patients to morphine titration during the first cycle of titration (Pâ=â.010). The initial NRS score and oxycodone administration were significantly associated with titration performance. The mild or moderate adverse effects were similar in 2 groups, while severe adverse effects were only identified in morphine group (Pâ=â.001). CONCLUSION: Use of background sustained-release oxycodone is more efficient and better tolerated on dose titration than immediate-release morphine.
Assuntos
Dor do Câncer/tratamento farmacológico , Morfina/administração & dosagem , Oxicodona/administração & dosagem , Idoso , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/uso terapêutico , Oxicodona/uso terapêutico , Medição da Dor , Resultado do TratamentoRESUMO
Long noncoding RNAs (lncRNAs) have been confirmed to be strongly associated with the progression of various types of cancer. LncRNA LINC01234 (LINC01234) is a newly identified tumor-related lncRNA whose upregulation has been confirmed in some tumors. However, its potential expressions and possible functions in non-small-cell lung cancer (NSCLC) have not been explored. In this study, we first found that LINC01234 expressions were distinctly upregulated in both NSCLC samples and cell lines using RT-PCR. Our group also showed that LINC01234 upregulations were modulated by nuclear transcription factor SP1. The results form clinical investigations indicated that high LINC01234 expressions were associated with positively lymph node metastasis and advanced tumor-metastasis-node (TMN) stage. Kaplan-Meier assays indicated that patients with NSCLC having high LINC01234 expressions tend to have unfavorable clinical prognosis. Using multivariate assays, it was confirmed that LINC01234 was an independent prognostic factor for patients with NSCLC. In vitro assays showed that inhibition of LINC01234 suppressed NSCLC cell proliferation, cell colony formation and metastasis, and greatly promoted apoptosis. Mechanistic investigations revealed LINC01234 promotes the progression of NSCLC cells by the modulation of miR-140 to positively regulate OTUB1 expression. Taken together our findings, they provided an exhaustive assay of LINC01234 in NSCLC and imperative clues for insights into the potential effects of lncRNAs-miRNAs regulatory network in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Cisteína Endopeptidases/metabolismo , Neoplasias Pulmonares/enzimologia , RNA Longo não Codificante/metabolismo , Fator de Transcrição Sp1/metabolismo , Células A549 , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Movimento Celular , Proliferação de Células , Cisteína Endopeptidases/genética , Enzimas Desubiquitinantes , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Invasividade Neoplásica , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Transdução de Sinais , Fator de Transcrição Sp1/genéticaRESUMO
The study aimed to investigate the reason of HCT116 cell resistance to MEK inhibitor, and the combination treatment effects of MEK inhibitor AZD6244 and JAK2/STAT3 inhibitor AG490 on colon cancer in vitro and in vivo, including cell viability, apoptosis, and explore the partial mechanisms focused on AZD6244 promoted the activation of JAK2-STAT3 pathways. In vitro, we examined the HCT116 cell viability by CCK8, cell apoptosis by flow cytometry; Western blot measured p-ERK, p-JAK2, p-STAT3 and STAT3 expression. In vivo, nude mice were subcutaneously injected by HCT116 cells. The tumor volume and weight were detected. HCT116 cell resistance to MEK inhibitor AZD6244, which inhibited the activation of ERK and promoted the activation of JAK2-STAT3 signaling. The combination treatment of AZD6244 and AG490 significantly inhibited cell viability and induced cell apoptosis, and completely inhibited the activation of ERK and JAK2-STAT3 signaling. Combination treatment of AZD6244 and AG490 had a stronger effect than that of AZD6244 as a monotherapy in vitro and in vivo. The treatment of AZD6244 on K-Ras mutations HCT116 cells promoted the activation of JAK2/STAT3 signaling. JAK2/STAT3 inhibitor AG490 synergistically increases effects of AZD6244 on colon cancer in vitro and in vivo. Collectively, these results provide a rationale for combining inhibitors of the JAK/STAT pathway and MEK inhibitors to reduce the potential impact of drug resistance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/patologia , Janus Quinase 2/antagonistas & inibidores , MAP Quinase Quinase Quinases/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Benzimidazóis/antagonistas & inibidores , Células HCT116 , Humanos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tirfostinas/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
RESUMO
OBJECTIVE: To investigate the effects of anti-CD44 mAb A3D8 on the cell proliferation of human acute monocytic leukemia cell line THP-1 and its mechanism. METHODS: Cell proliferation was assayed with MTT method, the expression of CD33, CD15, CD11b, CD14, Annexin-V, caspase-3 and cell cycle with flow cytometry, and the expression of p-Akt, p-ERK, bcl-2 and p27kip1 with Western blot. RESULTS: A3D8 could remarkably inhibit the proliferation capacity of the THP-1 cells in a dosage- and time-dependent manner. THP-1 differentiation was observed when treated with A3D8 (2.0 µg/ml) for one to six days. Expression of CD33 (68.9 ± 2.0 vs 39.3 ± 1.5), CD15 (61.7 ± 5.5 vs 12.9 ± 2.6), CD11b (67.3 ± 3.8 vs 14.0 ± 2.0) and CD14 (83.0 ± 5.7 vs 8.0 ± 1.0) was significantly increased at day 4 compared with the control group (all P < 0.01). Cell cycle of the THP-1 cells was arrested in G(0)/G(1). Expression of the Annexin-V \[(32.5 ± 2.5)% vs (2.4 ± 0.3)%\] and caspase-3 \[(33.3 ± 2.5)% vs (3.6 ± 0.3)%\] was much higher than that in normal controls (all P < 0.01), and apoptosis was observed in THP-1 cells at day 5. Expression of p-Akt (0.24 ± 0.06 vs 1.20 ± 0.15), p-ERK (0.32 ± 0.05 vs 1.24 ± 0.09), and bcl-2 (0.11 ± 0.05 vs 0.65 ± 0.07) was much lower than that of the controls (all P < 0.01), while p27kip1 (1.08 ± 0.09 vs 0.10 ± 0.02) was significantly increased at day 4 (P < 0.05). CONCLUSION: Anti-CD44 antibody can induce the differentiation and apoptosis of THP-1 cell through inhibiting PI3K/AKt and ERK1/2 signaling pathway.
Assuntos
Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Humanos , Receptores de Hialuronatos/imunologia , Leucemia Monocítica Aguda/patologia , Transdução de SinaisRESUMO
The aim of this study was to investigate the effect of rapamycin on cell growth and apoptosis in the myelodysplastic syndrome (MDS) cell line MUTZ-1 and possible mechanism. MUTZ-1 cells were treated with rapamycin, cell proliferation capability was determined with MTT, protein expression including Annexin V/PI, caspase 3, PTEN, p-Akt, p-mTOR and the cell cycle were analyzed with flow cytometry. The results indicated that the proliferation of MUTZ-1 cells was inhibited by rapamycin in concentration-and time-dependent manners (r=0.67, 0.61, 0.72). After treatment with rapamycin for 24-72 hours, cell count in G0/G1 were significantly higher than that of the control (p<0.01), and this effect showed a time-and concentration-dependency (r=0.94, 0.93, 0.92), the cell cycle was blocked in G0/G1 phase. As compared with control group, the proportion of Annexin V+PI-MUTZ-1 cells and the cellular PTEN levels increased in the treated group dramatically and in time-and dose-dependent manners (p<0.01). To the contrary, level of p-mTOR expression markedly decreased as compared with control group (p<0.05). It is concluded that the rapamycin inhibits the proliferation of MUTZ-1 cells, down-regulates the PTEN/PI3K-Akt/mTOR signaling pathway by interaction with mTOR, which induces the apoptosis of mUTZ-1 cells.