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1.
BMC Cancer ; 24(1): 46, 2024 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-38195455

RESUMEN

BACKGROUND: Prompt response to induction chemotherapy is a prognostic factor in pediatric acute myeloid leukemia. In this study, we aimed to evaluate the prognostic significance of multiparametric flow cytometry-minimal residual disease (MFC-MRD), assessed at the end of the first and second induction courses. METHODS: MFC-MRD was performed at the end of the first induction (TP1) in 524 patients and second induction (TP2) in 467 patients who were treated according to the modified Medical Research Council (UK) acute myeloid leukemia 15 protocol. RESULTS: Using a 0.1% cutoff level, patients with MFC-MRD at the two time points had lower event-free survival and overall survival. Only the TP2 MFC-MRD level could predict the outcome in a separate analysis of high and intermediate risks based on European LeukemiaNet risk stratification and KMT2A rearrangement. The TP2 MFC-MRD level could further differentiate the prognosis of patients into complete remission or non-complete remission based on morphological evaluation. Multivariate analysis indicated the TP2 MFC-MRD level as an independent adverse prognostic factor for event-free survival and overall survival. When comparing patients with MFC-MRD ≥ 0.1%, those who underwent hematopoietic stem cell transplant during the first complete remission had significantly higher 5-year event-free survival and overall survival and lower cumulative incidence of relapse than those who only received consolidation chemotherapy. CONCLUSIONS: The TP2 MFC-MRD level can predict the outcomes in pediatric patients with acute myeloid leukemia and help stratify post-remission treatment.


Asunto(s)
Leucemia Mieloide , Humanos , Niño , Citometría de Flujo , Neoplasia Residual , Pronóstico , Movimiento Celular , Respuesta Patológica Completa
2.
Eur J Haematol ; 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38847134

RESUMEN

BACKGROUND: IKZF1 deletion (IKZF1del) is associated with poor prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). But the prognosis of IKZF1del combined with other prognostic stratification factors remains unclear. Whether intensified treatment improves BCP-ALL prognosis has not been determined. METHODS: A retrospective analysis was performed on 1291 pediatric patients diagnosed with BCP-ALL and treated with the South China Children's Leukemia 2016 protocol. Patients were stratified based on IKZF1 status for comparison of characteristics and outcome. Additionally, IKZF1del patients were further divided based on chemotherapy intensity for outcome assessments. RESULTS: The BCP-ALL pediatric patients with IKZF1del in south China showed poorer early response. Notably, the DFS and OS for IKZF1del patients were markedly lower than IKZF1wt group (3-year DFS: 88.7% [95% CI: 83.4%-94.0%] vs. 93.5% [95% CI: 92.0%-94.9%], P = .021; 3-year OS: 90.7% [95% CI: 85.8% to 95.6%] vs. 96.1% [95% CI: 95% to 97.2%, P = .003]), with a concurrent increase in 3-year TRM (6.4% [95% CI: 2.3%-10.5%] vs. 2.9% [95% CI: 1.9%-3.8%], P = .025). However, the 3-year CIR was comparable between the two groups (5.7% [95% CI: 1.8%-9.5%] vs. 3.7% [95% CI: 2.6%-4.7%], P = .138). Subgroup analyses reveal no factor significantly influenced the prognosis of the IKZF1del cohort. Noteworthy, intensive chemotherapy improved DFS from 85.7% ± 4.1% to 94.1% ± 0.7% in IKZF1del group (P = .084). Particularly in BCR::ABL positive subgroup, the 3-year DFS was remarkably improved from 53.6% ± 20.1% with non-intensive chemotherapy to 100% with intensive chemotherapy (P = .026). CONCLUSIONS: Pediatric BCP-ALL patients with IKZF1del in South China manifest poor outcomes without independent prognostic significance. While no factor substantially alters the prognosis in the IKZF1del group. Intensified chemotherapy may reduce relapse rates and improve DFS in patients with IKZF1del subset, particularly in IKZFdel patients with BCR::ABL positive.

3.
Bioorg Med Chem ; 103: 117650, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38492540

RESUMEN

Reactions for drug synthesis under cell-like conditions or even inside living cells can potentially be used e.g., to minimize toxic side effects, to maximize bioactive compound efficacy and/or to address drug delivery problems. Those reactions should be bioorthogonal to enable the generation of drug-like compounds with sufficiently good yields. In the known bioorthogonal Michael reactions, using thiols and phosphines as nucleophiles (e.g., in CS and CP bond formation reactions) is very common. No bioorthogonal Michael addition with a carbon nucleophile is known yet. Therefore, the development of such a reaction might be interesting for future drug discovery research. In this work, the metal-free Michael addition between cyclohexanone and various trans-ß-nitrostyrenes (CC bond formation reaction), catalysed by a dipeptide salt H-Pro-Phe-O-Na+, was investigated for the first time in the presence of glutathione (GSH) and in phosphate-buffered saline (PBS). We demonstrated that with electron-withdrawing substituents on the aromatic ring and in ß-position of the trans-ß-nitrostyrene yields up to 64% can be obtained under physiological conditions, indicating a potential bioorthogonality of the studied Michael reaction. In addition, the selected Michael products demonstrated activity against human ovarian cancer cells A2780. This study opens up a new vista for forming bioactive compounds via CC bond formation Michael reactions under physiological (cell-like) conditions.


Asunto(s)
Neoplasias Ováricas , Humanos , Femenino , Línea Celular Tumoral , Carbono/química , Compuestos de Sulfhidrilo
4.
BMC Cancer ; 23(1): 476, 2023 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-37231380

RESUMEN

PURPOSE: To explore the outcome and prognostic factors between inv(16) and t(8;21) disrupt core binding factor (CBF) in acute myeloid leukemia (AML). METHODS: The clinical characteristic, probability of achieving complete remission (CR), overall survival (OS) and cumulative incidence of relapse (CIR) were compared between inv(16) and (8;21). RESULTS: The CR rate was 95.2%, 10-year OS was 84.4% and CIR was 29.4%. Subgroup analysis showed that patients with t(8;21) had significant lower 10-year OS and CIR than patients with inv(16). Unexpectedly, there was a trend for pediatric AML receiving five courses cytarabine to have a lower CIR than four courses cytarabine (19.8% vs 29.3%, P = 0.06). Among the cohort of no-gemtuzumab ozogamicin(GO) treatment, inv (16) patients showed a similar 10-year OS (78.9% vs 83.5%; P = 0.69) and an inferior outcome on 10-year CIR (58.6% vs 28.9%, P = 0.01) than those patients with t(8;21). In contrast, inv (16) and t(8;21) patients receiving GO treatment had comparable OS (OS: 90.5% vs. 86.5%, P = 0.66) as well as CIR (40.4% vs. 21.4%, P = 0.13). CONCLUSION: Our data demonstrated that more cumulative cytarabine exposure could improve the outcome of childhood patients with t(8;21), while GO treatment was beneficial to the pediatric patients with inv(16).


Asunto(s)
Leucemia Mieloide Aguda , Humanos , Niño , Pronóstico , Supervivencia sin Enfermedad , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Citarabina/uso terapéutico , Inducción de Remisión , Recurrencia
5.
Chemistry ; 28(30): e202104420, 2022 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-35419888

RESUMEN

Elevated levels of reactive oxygen species (ROS) and deficient mitochondria are two weak points of cancer cells. Their simultaneous targeting is a valid therapeutic strategy to design highly potent anticancer drugs. The remaining challenge is to limit the drug effects to cancer cells without affecting normal ones. We have previously developed three aminoferrocene (AF)-based derivatives, which are activated in the presence of elevated levels of ROS present in cancer cells with formation of electron-rich compounds able to generate ROS and reduce mitochondrial membrane potential (MMP). All of them exhibit important drawbacks including either low efficacy or high unspecific toxicity that prevents their application in vivo up to date. Herein we describe unusual AF-derivatives lacking these drawbacks. These compounds act via an alternative mechanism: they are chemically stable in the presence of ROS, generate mitochondrial ROS in cancer cells, but not normal cells and exhibit anticancer effect in vivo.


Asunto(s)
Antineoplásicos , Mitocondrias , Antineoplásicos/química , Apoptosis , Potencial de la Membrana Mitocondrial , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo
6.
BMC Cancer ; 22(1): 1257, 2022 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-36461002

RESUMEN

PURPOSE: To evaluate the prognostic factors and outcome for acute lymphoblastic leukemia (ALL) in children with MLL rearrangement (MLL-r). METHODS: A total of 124 pediatric patients who were diagnosed with ALL were classified into two groups based on the MLL-r status by using a retrospective case-control study method from June 2008 to June 2020. RESULTS: The prevalence of MLL-r positive in the whole cohort was 4.9%. The complete remission (CR) rate on Day 33 in the MLL-r positive group was not statistically different from the negative group (96.8% vs 97.8%, P = 0.736). Multivariate analysis showed that T-cell, white blood cell counts (WBC) ≥ 50 × 109/L, MLL-AF4, and D15 minimal residual disease (MRD) positive were independent risk factors affecting the prognosis of MLL-r positive children. Stem cell transplantation (SCT) was a favorable independent prognostic factor affecting event-free survival (EFS) in MLL-r positive patients (P = 0.027), and there was a trend toward an independent prognostic effect on overall survival (OS) (P = 0.065). The 10-year predicted EFS for patients with MLL-AF4, MLL-PTD, MLL-ENL, other MLL partner genes, and MLL-r negative cases were 46.67 ± 28.61%, 85.71 ± 22.37%, 75 ± 32.41%, 75 ± 32.41%, and 77.33 ± 10.81%, respectively (P = 0.048). The 10-year predicted OS were 46.67 ± 28.61%, 85.71 ± 22.37%, 75 ± 32.41%, 75 ± 32.41%, and 85.2 ± 9.77%, respectively (P = 0.049). The 124 patients with ALL were followed up and eventually 5 (4%) cases relapsed, with a median relapse time of 3.9 years. CONCLUSION: Patients with MLL-r positive ALL have moderate remission rates, but are prone to relapse with low overall survival. The outcome of MLL-r positive ALL was closely related to the partner genes, and clinical attention should be paid to screening for MLL partner genes and combining them with other prognostic factors for accurate risk stratification.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Estudios de Casos y Controles , Pronóstico , Estudios Retrospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Aberraciones Cromosómicas , Recurrencia
7.
BMC Cancer ; 22(1): 1190, 2022 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-36401208

RESUMEN

BACKGROUND: Umbilical cord blood transplantation (UCBT) from unrelated donors is one of the successful treatments for acute leukemia in childhood. The most frequent side effect of UCBT is peri-engraftment syndrome (PES), which is directly associated with the greater prevalence of acute and chronic graft-versus-host-disease (aGvHD and cGvHD). In haploidentical stem cell transplantation, posttransplant cyclophosphamide (PTCY) has been demonstrated to be an effective method against GvHD. However, the effects of PTCY as a GvHD prophylactic in UCBT had not been investigated. This study aimed to evaluate the effects of PTCY on the outcomes of UCBT for pediatric acute leukemia. METHODS: This retrospective study included 52 children with acute leukemia who underwent unrelated single-unit UCBT after myeloablative conditioning regimens. The results from the PTCY and non-PTCY groups were compared. RESULTS: The incidence of transplantation-related mortality in non-PTCY and PTCY were 5% and 10% (p = 0.525), respectively. The incidence of relapse in non-PTCY and PTCY were 5% and 23% (p = 0.095), respectively. Second complete remission status (CR2) was an independent risk factor for relapse-free survival (hazard ratio = 9.782, p = 0.001). The odds ratio for sepsis or bacteremia incidence was significantly greater in the PTCY group (9.524, p = 0.017). PTCY group had increased rates of cytomegalovirus activity and fungal infection. The incidence of PES, aGvHD, cGvHD, and hemorrhagic cystitis in the PTCY group was lower than that in the non-PTCY group, although it was not significantly different. Additionally, higher doses of PTCY (29 mg/kg and 40 mg/kg) were associated with lower incidences of aGvHD and severe GvHD (65% and 29%, respectively) than lower doses (93% and 57%, respectively). Engraftment time and graft failure incidence were similar across groups. CONCLUSION: The results support the safety and efficiency of PTCY as part of PES controlling and GvHD prophylaxis in single-unit UCBT for children with acute leukemia. A PTCY dosage of 29 mg/kg to 40 mg/kg appears to be more effective in GvHD prophylaxis for UCBT patients.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Leucemia Mieloide Aguda , Humanos , Niño , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Estudios Retrospectivos , Ciclofosfamida , Leucemia Mieloide Aguda/tratamiento farmacológico , Enfermedad Aguda , Recurrencia , Enfermedad Crónica
8.
BMC Cancer ; 21(1): 59, 2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33435902

RESUMEN

BACKGROUND: The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70-85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL. METHODS: The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs. RESULTS: The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group (n=7) was 28.6%, while in the MRD Day 33 negative group (n=67) was 7.5% (p=0.129). CONCLUSIONS: The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/mortalidad , Neoplasia Residual/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Adolescente , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Mercaptopurina/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Prednisona/administración & dosificación , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia
9.
Br J Clin Pharmacol ; 87(4): 2023-2031, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33080064

RESUMEN

AIMS: The purpose of this study is to examine the safety and efficacy of eltrombopag as first-line treatment for thrombocytopenia among paediatric patients after haematopoietic stem cell transplantation (HSCT). METHODS: Forty-three childhood patients with thrombocytopenia after HSCT who received eltrombopag were retrospectively analysed. RESULT: Eltrombopag was began at the median of 27 days after HSCT and lasted for 24 days. Thirty-five children responded to eltrombopag therapy, and the cumulative platelet recovery rate was 88.9%. The cumulative incidence of platelet recovery was lower (83.9 vs 100%; P = .035) in patients with decreased numbers of megakaryocytes before starting eltrombopag than in those with normal. Factors associated with a significantly elevated response to eltrobopag from univariate analysis were donor type. Results from the multiple regression analysis found that weight (hazard ratio [HR] = 0.7, 95% confidence interval [CI] 0.5-0.9, P = .022), platelet engraftment time (HR = 1.0, 95%CI 1.0-1.0, P = .012) and bone marrow megakaryocytes (HR = 8.0, 95%CI 1.5-43.3, P = .016) before starting eltrombopag were the independent risk factors. Based on Youden's index algorithm in the receiver-operating characteristic curve, the optimal cut-off value of the maintenance dose of eltrombopag in predicting nonresponders was 4 mg/kg. The area under the receiver-operating characteristic curve was 0.923 with sensitivity of 97.8%, specificity of 87.9%, positive predictive value of 72.3%, and negative predictive value of 92%. None of the paediatric patients stopped using eltrombopag due to side effect or intolerability. CONCLUSION: Eltrombopag is effective and safe in paediatric patients with thrombocytopenia after HSCT. The number of megakaryocytes in bone marrow before eltrombopag treatment may serve as a predictor of the response to eltrombopag. We recommend that the maintenance dose of eltrombopag should not exceed 4 mg/kg/d.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Trombocitopenia , Benzoatos/uso terapéutico , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Hidrazinas , Pirazoles , Estudios Retrospectivos , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/etiología
10.
Pediatr Blood Cancer ; 68(8): e29097, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34031980

RESUMEN

OBJECTIVE: Cytokine storms are central to the development of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Previous studies have shown that single-nucleotide polymorphisms (SNPs) of cytokine genes may be associated with the development of EBV-HLH in children. As such, we investigated the association between susceptibility to EBV-HLH in children and SNPs and haplotypes of genes encoding interleukin-2 receptor subunit alpha (IL2RA), interleukin-10 (IL10), interferon gamma (IFNG), interferon regulatory factor 5 (IRF5), and C-C chemokine receptor 2 (CCR2). METHODS: Sixty-six children with EBV-HLH and 58 healthy EBV-seropositive controls were enrolled in this study. SNPs of IL2RA rs2104286, rs12722489, and rs11594656; IL10 rs1800896, rs1800871, and rs1800872; IFNG rs2430561, IRF5 rs2004640, and CCR2 rs1799864 were assayed and genotyped using the SNaPshot technique. RESULTS: Frequencies of the A allele of IL2RA rs2104286 and IL10 rs1800896, and C allele of IL-10 rs1800872 were significantly higher in the EBV-HLH group than in the control group. The AA genotype of IL2RA rs2104286 and IL10 rs1800896, and the CC genotype of IL10 rs1800872 might be associated with a significantly high risk of EBV-HLH. However, the frequencies of genotypes and alleles of IL2RA rs2104286, IL10 rs1800871, IFNG rs2430561, IRF5 rs2004640, and CCR2 rs1799864 were similar in both groups. Additionally, IL2RA AGT (rs2104286-rs12722489-rs11594656) and IL10 ACC (rs1800896-rs1800871-rs1800872) haplotypes were also associated with an increased risk of EBV-HLH. CONCLUSIONS: SNPs of IL2RA rs2104286, IL10 rs1800896 and rs1800872 and the haplotypes of IL2RA AGT and IL10 ACC were highly associated with susceptibility to EBV-HLH in children.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Interleucina-10 , Subunidad alfa del Receptor de Interleucina-2 , Linfohistiocitosis Hemofagocítica , Niño , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Haplotipos , Herpesvirus Humano 4 , Humanos , Factores Reguladores del Interferón/genética , Interferón gamma/genética , Interleucina-10/genética , Subunidad alfa del Receptor de Interleucina-2/genética , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/virología , Polimorfismo de Nucleótido Simple , Receptores CCR2/genética , Receptores de Quimiocina
11.
Pediatr Transplant ; 25(7): e14078, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34255916

RESUMEN

BACKGROUND: Pyruvate kinase deficiency (PKD) is an autosomal recessive disorder caused by a PK-LR gene mutation. Allogeneic hematopoietic cell transplantation (HCT) is an effective cure for PKD. However, the experience of applying HCT in PKD is limited. METHODS: We present a child with novel PK-LR gene mutations who was successfully cured by matched unrelated donor peripheral blood stem cell transplantation (MUD-PBSCT). RESULTS: A 4-year-old, male patient suffered severe hemolytic anemia and jaundice 5 h after birth. Gene sequencing showed that the pyruvate kinase-liver and RBC (PK-LR) gene had a nonsense mutation in exon 5: c.602G>A (p.W201X), and large deletions in exons 3-9. Both of them were novel pathogenic mutations of the PK-LR gene. After transplantation, the hemoglobin level became normal and the nonsense mutation was undetectable. Grade Ⅳ acute graft-versus-host disease (aGVHD) and extensive chronic graft-versus-host disease (cGVHD) occurred in the patient. However, the GVHD was controlled effectively. The patient is alive and has good quality of life 22 months post-transplant, but has mild oral lichen planus-like lesion. CONCLUSION: Gene sequencing contributes to the diagnosis of PKD. HCT is an effective method for curing PKD, but we should explore how to reduce severe GVHD.


Asunto(s)
Anemia Hemolítica Congénita no Esferocítica/terapia , Trasplante de Células Madre de Sangre Periférica , Piruvato Quinasa/deficiencia , Piruvato Quinasa/genética , Errores Innatos del Metabolismo del Piruvato/terapia , Preescolar , Humanos , Masculino , Mutación , Donante no Emparentado
12.
Angew Chem Int Ed Engl ; 60(20): 11158-11162, 2021 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-33656236

RESUMEN

The folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in the endoplasmic reticulum (ER) of cancer cells, leading to so-called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading, for example, to accumulation of reactive oxygen species (ROS). To address this problem, we have developed ER-targeted prodrugs activated only in cancer cells in the presence of elevated ROS amounts. These compounds are conjugates of cholic acid with N-alkylaminoferrocene-based prodrugs. We confirmed their accumulation in the ER of cancer cells, their anticancer efficacy, and cancer cell specificity. These prodrugs induce ER stress, attenuate mitochondrial membrane potential, and generate mitochondrial ROS leading to cell death via necrosis. We also demonstrated that the new prodrugs are activated in vivo in Nemeth-Kellner lymphoma (NK/Ly) murine model.


Asunto(s)
Antineoplásicos/farmacología , Retículo Endoplásmico/efectos de los fármacos , Linfoma/tratamiento farmacológico , Profármacos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/química , Retículo Endoplásmico/metabolismo , Humanos , Linfoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Profármacos/química
13.
Pediatr Transplant ; 24(8): e13876, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33098346

RESUMEN

BACKGROUND: Early-onset mixed chimerism (MC) with a high proportion of residual host cells is considered a signal of graft rejection in patients undergoing allogenic hematopoietic stem cell transplantation for transfusion-dependent thalassemia. In order to prevent graft rejection and minimize the risk of treatment-related graft-versus-host disease (GVHD), we established a hierarchical management system based on chimerism analysis. METHOD: This retrospective study provides a comprehensive review of the characteristics, interventions, and outcomes of the 38 patients who developed MC after transplantation among the 144 pediatric thalassemia patients between July 2007 and January 2019 at our center. RESULTS: A sibling donor, a blood type-matched donor, conditioning regimens without fludarabine, and transplants containing <10 × 108 total nucleated cells/kg were identified to be associated with the development of MC. Among the 38 patients developing MC, only four patients rejected the grafts. The response rate to donor lymphocyte infusion (DLI, only for patients receiving sibling donor transplantation) and cytokine immunomodulation without DLI was 70.6% and 42.9%, respectively. Patients that developed GVHD after DLI or cytokine therapy had a more significant increase in donor cell chimerism (16%, range 0%-35%) than those without (8.5%, range -21% to 40%, P = .049). However, even when treatment-related GVHD was included, patients with MC had a lower cumulative incidence of total acute GVHD than patients with complete donor chimerism (29.2% vs 48.0%, P = .030). CONCLUSIONS: Interventions based on chimerism analysis were effective in preventing graft rejection and did not increase treatment-related GVHD in thalassemia patients with MC.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Talasemia/terapia , Quimera por Trasplante , Adolescente , Niño , Preescolar , Femenino , Rechazo de Injerto/etiología , Enfermedad Injerto contra Huésped/etiología , Humanos , Lactante , Masculino , Pronóstico
14.
Clin Transplant ; 33(8): e13641, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31211850

RESUMEN

OBJECTIVE: The purpose of our study was to evaluate the diagnostic value of serum galactomannan antigen (GM) testing combined with chest computed tomography (CT) of invasive pulmonary aspergillosis (IPA) in pediatric patients after hematopoietic stem cell transplantation. METHODS: A retrospective nested case-control study was conducted in the identifying IPA among pediatric patients. RESULTS: A total of 141 eligible pediatric recipients with febrile neutropenia were enrolled in this study. All patients in the cases were diagnosed with proven-probable IPA(PP-IPA), while only 9 patients in the controls. GM testing was positive in 38 pediatric recipients in the cases and nine recipients in the controls with sensitivity of 62.3%, specificity of 81.8%. Among all patients with IPA, 46 patients in the cases and 9 patients in the controls had typical features of CT imaging with sensitivity of 79.3%, specificity of 85.2%. For discrimination of participants' GM testing combined with CT evaluation, the AUC of the diagnostic model was 0.887 with PPV of 0.764, and NPV of 0.872. Sensitivity was 0.793, and specificity was 0.852 in IPA. CONCLUSION: The combination methods with serum GM and CT scan might be used as a valuable marker for early diagnosis of IPA in pediatric patients after HSCT.


Asunto(s)
Biomarcadores/sangre , Diagnóstico Precoz , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Aspergilosis Pulmonar Invasiva/diagnóstico , Mananos/sangre , Radiografía Torácica/métodos , Tomografía Computarizada por Rayos X/métodos , Adolescente , Aspergillus/aislamiento & purificación , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Estudios de Seguimiento , Galactosa/análogos & derivados , Humanos , Lactante , Recién Nacido , Aspergilosis Pulmonar Invasiva/sangre , Aspergilosis Pulmonar Invasiva/diagnóstico por imagen , Aspergilosis Pulmonar Invasiva/etiología , Masculino , Pronóstico , Estudios Retrospectivos
15.
Clin Transplant ; 33(1): e13459, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30506735

RESUMEN

BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is an increasingly recognized serious complication of cyclosporine A (CSA) and tacrolimus (TAC) use in hematopoietic cell transplantation (HCT) recipients. PROCEDURE: A retrospective study was carried out, including 84 cases of HCT for TM from January 2012 to January 2017. Eleven cases were diagnosed with PRES. RESULTS: The cumulative incidence of PRES was 13.4% (95% confidence interval (CI) 9.7%-17.2%). The median onset time of the symptoms was 63 [20, 143] days after transplantation. Lumber puncture found that CSF was normal. Univariate analysis showed that patients who received methylprednisolone (MP) (OR = 10.629 95% CI, 1.360-83.071, P = 0.024), female patients (OR = 4.275, 95% CI, 1.154-15.843, P = 0.032), patients who had severe hypertension (OR = 5.162, 95% CI, 1.042 to 25.559, P = 0.029) had significantly higher risks of PRES. Multivariate analysis showed that severe hypertension (hazard ratio [HR], 12.793; 95% CI, 1.477 to 110.813; P  = 0.021), and Pesaro class 3 (HR, 3.367; 95% CI, 1.210 to 9.368; P  =  0.020) were associated with PRES. CONCLUSIONS: The severe hypertension is an independent risk factor for PRES post-HCT in children with thalassemia major. Patients of Pesaro class 3 may benefit from optimum control of blood pressure post-HCT for prophylaxis of PRES.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hipertensión/complicaciones , Síndrome de Leucoencefalopatía Posterior/diagnóstico , Síndrome de Leucoencefalopatía Posterior/etiología , Talasemia beta/terapia , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/fisiopatología , Masculino , Pronóstico , Estudios Retrospectivos , Factores de Riesgo
16.
Org Biomol Chem ; 17(46): 9883-9891, 2019 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-31710325

RESUMEN

Singlet oxygen (1O2) plays an important role in human innate immune response, plant physiology and anticancer photodynamic therapy (PDT). Therefore, its monitoring by convenient and sensitive methods (e.g. by detecting a fluorescence signal) by using non-toxic reagents would be advantageous. Known fluorogenic 1O2-chemodosimeters can potentially consume reducing agents in cells leading to the generation of toxic side products that limit their applications. In this paper we report on a series of 9-anthracenyl-fluorescein hybrids, which do not require any reducing agents for their reaction with 1O2. The selected compound 8d at a very low concentration of 100 nM is able to detect 1O2 in live human promyelocytic leukemia HL-60 cells with over 35-fold fluorescence signal enhancement within only 20 min assay time. This chemodosimeter is not toxic to HL-60 cells at concentrations ≤1 µM (higher concentrations were not tested) even at long incubation times ≤48 h.


Asunto(s)
Antracenos/análisis , Antracenos/química , Técnicas de Química Analítica , Fluoresceína/análisis , Fluoresceína/química , Colorantes Fluorescentes/análisis , Oxígeno Singlete/análisis , Supervivencia Celular , Técnicas Electroquímicas , Colorantes Fluorescentes/química , Células HL-60 , Humanos , Estructura Molecular , Imagen Óptica , Espectrometría de Fluorescencia
17.
Transpl Infect Dis ; 21(3): e13066, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30859662

RESUMEN

BACKGROUND: Invasive fungal disease (IFD) has a poor prognosis in children with hematological disorders after hematopoietic stem cell transplantation (HSCT). We assessed if drug combinations with different targets may improve the outcome. METHODS: Retrospective study to assess the outcome of combination antifungal therapy (CAT) for proven-probable IFD (PP-IFD) in children with hematological disorders after HSCT from January 2008 to June 2018. RESULTS: Over the 10-year period, 95 PP-IFD were diagnosed in pediatric recipients, median age of 5.6 years. Twenty-seven patients received combinations of caspofungin and voriconazole, 28 patients received combinations of caspofungin and amphotericin B, and 40 patients received combinations of voriconazole and amphotericin B. The overall response rate of PP-IFD was 77.9%, while the 100-day overall survival rates were 66.8%. Univariate analysis showed that factors that significantly affected the response to combination treatments were type of combination (P = 0.02), the stem cell source (P = 0.04), the donor type (P = 0.03), HLA-match (P = 0.03), aGVHD (P = 0.02), period of treatment (P = 0.044), use of corticosteroids (0.036), CD4:CD8 ratio (P = 0.014), and CMV viremia (P = 0.033). In addition, multivariate analysis demonstrated that only the type of combination remained a significant factor (odds ratio = 0.335, 95% confidence interval: 0.071-0.812, P = 0.042). Forty-three children suffered from mild and reversible adverse reactions, no serious side effects during treatment. CONCLUSION: A variety of factors can affect the outcome of CAT. Combination of caspofungin with voriconazole is a safe and helpful treatment option for HSCT recipients with IFD.


Asunto(s)
Antifúngicos/uso terapéutico , Enfermedades Hematológicas/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Micosis/tratamiento farmacológico , Adolescente , Anfotericina B/uso terapéutico , Caspofungina/uso terapéutico , Niño , Preescolar , Quimioterapia Combinada , Femenino , Enfermedades Hematológicas/microbiología , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/microbiología , Humanos , Lactante , Masculino , Micosis/etiología , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento , Voriconazol/uso terapéutico
18.
J Pediatr Hematol Oncol ; 41(2): 96-104, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30688831

RESUMEN

OBJECTIVE: Hyperglycemia increases the risk of early recurrence and high mortality in some adult blood cancers. In response to increased glucose levels, insulin is secreted, and several studies have shown that insulin-induced AKT signaling can regulate tumor cell proliferation and apoptosis. The AKT pathway is aberrantly activated in adult acute lymphoblastic leukemia (ALL), but the mechanisms underlying this activation and its impact in pediatric patients with ALL are unclear. MATERIALS AND METHODS: We evaluated the insulin-induced chemoresistance and AKT pathway activation by measuring cell proliferation, apoptosis, and other parameters in ALL cell lines (Jurkat and Reh cells), as well as in primary pediatric leukemic cell samples, after culture with insulin, the chemotherapeutic drugs daunorubicin (DNR), vincristine (VCR), and L-asparaginase (L-Asp), or anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody. RESULTS: DNR, VCR, and L-Asp-induced toxicity in Jurkat and Reh cells was reduced in the presence of insulin. DNR promoted cell proliferation, whereas DNR, VCR, and L-Asp all reduced apoptosis in both cell lines cotreated with insulin compared with that in cell lines treated with chemotherapeutics alone (P<0.05). Furthermore, addition of an anti-IGF-1R monoclonal antibody promoted apoptosis, downregulated IGF-1R expression, and decreased the phosphorylation of AKT, P70S6K, and mTOR intracellular signaling pathway proteins in both cell lines, as well as in primary cultures (P<0.05). CONCLUSIONS: Our results suggest that insulin-induced chemoresistance and activation of the AKT signaling pathway in pediatric ALL cells.


Asunto(s)
Apoptosis , Resistencia a Antineoplásicos , Insulina/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Antineoplásicos Inmunológicos/farmacología , Asparaginasa/farmacología , Niño , Preescolar , Daunorrubicina/farmacología , Femenino , Humanos , Células Jurkat , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Receptor IGF Tipo 1 , Receptores de Somatomedina/antagonistas & inhibidores , Receptores de Somatomedina/metabolismo , Vincristina/farmacología
19.
Hemoglobin ; 43(1): 38-41, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30915867

RESUMEN

To evaluate the iron metabolism and oxidative status in patients with Hb H disease, we investigated 43 patients with Hb H disease, including eight deletional Hb H disease patients and 35 nondeletional Hb H disease patients and 20 healthy controls. The levels of hematological parameters, serum ferritin, hepcidin, superoxide dismutase (SOD), malondialdehyde (MDA) and total antioxidant capacity (TAC), were examined. We found higher serum ferritin levels and lower hepcidin, MDA and TAC levels in Hb H disease patients than in controls. The hepcidin level in Hb H disease patients was positively correlated with MDA and TAC levels but not with serum ferritin and SOD levels. The patients with nondeletional Hb H disease showed higher serum ferritin and Hb H concentrations than those patients with deletional Hb H disease. However, no statistically significant differences in SOD, MDA and TAC levels were found in patients with deletional and nondeletional Hb H disease. Oxidative stress and antioxidant defense were related to hepcidin levels. Our study indicated that hepcidin might be an important parameter for monitoring the iron metabolism and oxidative status of Hb H disease patients.


Asunto(s)
Hierro/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Talasemia alfa/metabolismo , Adolescente , Antioxidantes/metabolismo , Biomarcadores , Estudios de Casos y Controles , Niño , Preescolar , Índices de Eritrocitos , Femenino , Humanos , Hígado/metabolismo , Masculino , Talasemia alfa/sangre
20.
Bioorg Med Chem Lett ; 28(20): 3391-3394, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30181060

RESUMEN

Arenobufagin is a naturally occurring bufadienolide showing promising antitumor activity accompanied however with apparent cardiac toxicity. Following the recent discovery that oxidative damage possibly be an important cause of the cardiac toxicity of cardenolides, a strategy fusing the antitumor agent arenobufagin with a benzoisoselenazol fragment, a reactive oxygen species (ROS) scavenger, has been developed. Six novel hybrids were synthesized and their ROS scavenging activities as well as their in vitro cytotoxicity against the human hepatocellular carcinoma cell line HepG2, an adriamycin-resistant subline HepG2/ADM, and the human myocardial cell line AC16 were evaluated. The results indicate that the hybrids exhibit various degrees of in vitro ROS scavenging activities, and weaker cytotoxicity than that of arenobufagin against the myocardial cell line AC16. These findings suggest the feasibility of a strategy in which the cardiotoxicity of the potential antitumor agent arenobufagin is reduced.


Asunto(s)
Antineoplásicos/farmacología , Bufanólidos/farmacología , Cardiotoxicidad/prevención & control , Depuradores de Radicales Libres/farmacología , Compuestos de Organoselenio/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/toxicidad , Bufanólidos/síntesis química , Bufanólidos/química , Bufanólidos/toxicidad , Línea Celular Tumoral , Diseño de Fármacos , Depuradores de Radicales Libres/síntesis química , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/toxicidad , Humanos , Estructura Molecular , Miocitos Cardíacos/patología , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/química , Compuestos de Organoselenio/toxicidad , Especies Reactivas de Oxígeno/metabolismo
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