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1.
Mol Biol Rep ; 51(1): 595, 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38683436

RESUMEN

BACKGROUND: Mesenchymal stem cells (MSCs) have the ability to self-renew and are multi-potent. They are a primary candidate for cell-based therapy due to their potential anti-cancer effects. The aim of this study was to evaluate the in vitro anti-leukemic effect of Wharton's Jelly-derived MSC (WJ-MSC) on the leukemic cell lines K562 and HL-60. METHODS: In this present study, WJ-MSCs were isolated from human umbilical cord. The cells were incubated according to the standard culture conditions and characterized by flow cytometry. For experiments, WJ-MSC and leukemic cells were incubated in the direct co-culture at a ratio of 1:5 (leukemia cells: WJ-MSC). HUVEC cells were used as a non-cancerous cell line model. The apoptotic effect of WJ-MSCs on the cell lines was analyzed using Annexin V/PI apoptosis assay. RESULTS: After the direct co-culture of WJ-MSCs on leukemic cell lines, we observed anti-leukemic effects by inducing apoptosis. We had two groups of determination apoptosis with and without WJ-MSCs for all cell lines. Increased apoptosis rates were observed in K562 and HL-60 cell lines, whereas the apoptosis rates in HUVEC cells were low. CONCLUSIONS: MSCs are known to inhibit the growth of tumors of both hematopoietic and non-hematopoietic origin in vitro. In our study, WJ-MSC treatment strongly inhibited the viability of HL-60 and K562 and induced apoptosis. Our results also provided new insights into the inhibition of tumor growth by WJ-MSCs in vitro. In the future, WJ-MSCs could be used to inhibit cancer cells in clinical applications.


Asunto(s)
Apoptosis , Técnicas de Cocultivo , Células Endoteliales de la Vena Umbilical Humana , Células Madre Mesenquimatosas , Gelatina de Wharton , Humanos , Células Madre Mesenquimatosas/metabolismo , Gelatina de Wharton/citología , Células K562 , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células HL-60 , Cordón Umbilical/citología , Leucemia/patología , Leucemia/terapia , Proliferación Celular
2.
Heliyon ; 10(7): e28788, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38586343

RESUMEN

Background and aim: Leptin is mainly produced in adipose tissue and released into systemic circulation. Leptin and its receptor LEPR activate the Janus kinase/signal transducers and activators of transcription signaling cascade and increase cytokine discharge. In our study, we aimed to examine the role of leptin gene (LEP) rs7799039 and LEPR rs1137101 polymorphisms on the susceptibility for febrile neutropenia (FEN) attacks and their relationship with clinical findings during the course of FEN. Methods: This study included pediatric patients with a diagnosis of malignancy who applied to the pediatric emergency department between December 2019 and June 2022 and healthy controls. The genotypes of the LEP rs7799039 and LEPR rs1137101 genes were statistically compared between patients and healthy controls. In addition, the relationship between the genotype distribution of LEP rs7799039 and LEPR rs1137101 polymorphisms and clinical features during the course of FEN was investigated. Results: In the statistical analysis in terms of LEP rs7799039 and LEPR rs1137101 genotype distributions between the patient and healthy groups, there was no significant difference. Patients with the AA genotype of LEPR rs1137101 polymorphism had significantly more commonly a body mass index (BMI) value of <25, and all the patients with the AG/GG genotype had a BMI value of 25 and above. LEP rs7799039 and LEPR rs1137101 genotype distributions were not statistically significant with other clinical features. Conclusions: It was revealed that leptin gene polymorphisms did not have a significant effect during the course of FEN.

3.
Eur J Haematol ; 113(1): 82-89, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38556258

RESUMEN

OBJECTIVES: In congenital hemolytic anemias (CHA), it is not always possible to determine the specific diagnosis by evaluating clinical findings and conventional laboratory tests. The aim of this study is to evaluate the utility of next-generation sequencing (NGS) and clinical-exome-based copy number variant (CNV) analysis in patients with CHA. METHODS: One hundred and forty-three CHA cases from 115 unrelated families referred for molecular analysis were enrolled in the study. Molecular analysis was performed using two different clinical exome panels in 130 patients, and whole-exome sequencing in nine patients. Exome-based CNV calling was incorporated into the traditional single-nucleotide variant and small insertion/deletion analysis pipeline for NGS data in 92 cases. In four patients from the same family, the PK Gypsy variant was investigated using long-range polymerase chain reaction. RESULTS: Molecular diagnosis was established in 86% of the study group. The most frequently mutated genes were SPTB (31.7%) and PKLR (28.5%). CNV analysis of 92 cases revealed that three patients had different sizes of large deletions in the SPTB and six patients had a deletion in the PKLR. CONCLUSIONS: In this study, NGS provided a high molecular diagnostic rate in cases with rare CHA. Analysis of the CNVs contributed to the diagnostic success.


Asunto(s)
Anemia Hemolítica Congénita , Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Humanos , Masculino , Femenino , Anemia Hemolítica Congénita/genética , Anemia Hemolítica Congénita/diagnóstico , Exoma , Niño , Preescolar , Lactante , Predisposición Genética a la Enfermedad , Adulto , Adolescente , Estudios de Asociación Genética , Adulto Joven
4.
Nat Med ; 30(2): 488-497, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38355973

RESUMEN

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .


Asunto(s)
Agammaglobulinemia , Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Humanos , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/terapia , Adenosina Desaminasa/genética , Adenosina Desaminasa/uso terapéutico , Busulfano/efectos adversos , Terapia Genética , Retroviridae/genética
5.
Blood Adv ; 7(23): 7279-7289, 2023 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-37738125

RESUMEN

The efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.


Asunto(s)
Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Niño , Antineoplásicos/uso terapéutico , Mesilato de Imatinib/efectos adversos , Pirimidinas/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico
6.
Clin Hemorheol Microcirc ; 85(1): 1-12, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37482986

RESUMEN

BACKGROUND: Thalassemia patients have reduced red cell deformability and decreased plasma zinc levels in their blood. OBJECTIVE: This study aimed to evaluate the effects of zinc (Zn) on the hemorheological parameters and antioxidant enzyme activities in ß-thalassemia major (TM) and healthy volunteers (HV). METHODS: Hemorheological parameters were measured using LORCA (laser-assisted optical rotational cell analyzer) after adjusting the hematocrit to 40%. Zinc sulfate (ZnSO4.7H2O) was used for Zn incubation with a concentration of 0.5µg/dl. Oxidative stress and antioxidant status were determined using commercial kits. RESULTS: Data showed that after Zn incubation, EImax, the area under the EI-osmolarity curve (Area), and Omax decreased in TM. However, no significant difference was observed in the osmotic deformability parameters of HV. The increased elongation index was obtained at different shear stresses for TM and HV, and SS1/2 decreased in both groups. The AMP and aggregation index (AI) decreased in TM, and the required time for half of the maximum aggregation (t1/2) increased in HV. However, Zn did not affect oxidative parameters in both groups. CONCLUSIONS: This study showed that Zn incubation increased deformability and decreased aggregation in thalassemic erythrocytes. It means that Zn supplementation will contribute to microcirculation in thalassemia patients.


Asunto(s)
Deformación Eritrocítica , Talasemia beta , Humanos , Talasemia beta/tratamiento farmacológico , Antioxidantes/farmacología , Zinc/farmacología , Agregación Eritrocitaria , Eritrocitos
7.
Mediterr J Hematol Infect Dis ; 15(1): e2023036, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37435033

RESUMEN

Acute lymphoblastic leukemia (ALL) is a malignant disease of hematopoietic stem cells. B cell ALL (B-ALL) is characterized by highly proliferative and poorly differentiated progenitor B cells in the bone marrow. Chromosomal rearrangements, aberrant cell signaling, and mutations lead to dysregulated cell cycle and clonal proliferation of abnormal B cell progenitors. In this study, we aimed to examine hot spot genetic variations in the RUNX1, IDH2, and IL2RA genes in a group of (n=52) pediatric B-ALL. Sanger sequencing results revealed a rare RUNX1 variant p.Leu148Gln in one B-ALL patient with disease recurrence. Additionally, common intronic variations rs12358961 and rs11256369 of IL2RA were determined in two patients. None of the patients had the IDH2 variant. RUNX1, IDH2, and IL2RA variations were rare events in ALL. This study detected a novel pathogenic RUNX1 variation in a patient with a poor prognosis. Examining prognostically important genetic anomalies of childhood lymphoblastic leukemia patients and the signaling pathway components will pilot more accurate prognosis estimations.

8.
Adv Lab Med ; 4(1): 92-104, 2023 Apr.
Artículo en Inglés, Español | MEDLINE | ID: mdl-37359898

RESUMEN

Objectives: Acute myeloid leukemia (AML) is a highly heterogeneous disease. Although patients can be classified into risk groups based on their genetic changes, the prognosis of disease within these categories varies widely. This situation raises the need to search for new molecular markers related to AML. Serine peptidase inhibitor Kazal type 2 (SPINK2) has recently been reported to be upregulated in AML and associated with poor outcomes by meta-analysis and in a limited number of AML patients. Methods: We analyzed SPINK2 mRNA expression in 62 patients (45 adult and 17 pediatric) with AML and 11 cell lines using quantitative Real-Time PCR (qRT-PCR). SPINK2 protein level was determined using ELISA in cell lines. Results: We found that the expression of SPINK2 mRNA and protein levels in AML cell lines (HL60 and NB4) have increased compared to other cell lines (K562, Jurkat and NALM6, MCF7, HeLa, HUVEC, hFOB, 293T, U87). SPINK2 mRNA expression was upregulated in patients with AML compared to controls (p=0.004) and significantly lower in t(8;21)-positive patients compared to negative patients (p=0.0006). Conclusions: Our results suggest that SPINK2 serves an important role in AML development. Further studies are needed to evaluate SPINK2 expression in AML patients with t(8.21) and investigate to clarify its prognostic value in various subgroups of AML.

9.
Artículo en Inglés | MEDLINE | ID: mdl-37117150

RESUMEN

INTRODUCTION: Epidemiologic studies on pediatric acute lymphoblastic leukemias (ALL) have been conducted to evaluate the possible risk factors including genetic, infectious and environmental factors with the objective of idenfying the etiology. Mannose-binding lectin 2 (MBL2) plays an important role in first-line immune defense. HLA DRB1 alleles play a role in presentation of peptides to T cells and in activation of the adaptive immune response. OBJECTIVE: In our study, we aimed to investigate both the MBL2 gene variant and HLA-DRB1 alleles in pediatric ALL patients. MATERIALS: In this study, 86 high-risk ALL patients and 100 controls were included. Polymerase Chain Reaction (PCR)-Restriction Fragment Length Polymorphism (PCR-RFLP) and PCR-sequence specific primer (SSP) methods were used for detection of polymorphism of the MBL2 and HLA-DRB1 alleles, respectively. RESULTS: The frequency of the MBL2 AB genotype was lower in female ALL patients, compared to male ALL patients (p = 0.034). An association was found between the MBL2 BB genotype and DRB1*07 and among patients with the MBL2 BB genotype; those who also carried the DRB1*07 and *04 alleles were significantly higher than those without the DRB1*07 and *04 alleles. (p = 0.048, p = 0.022, respectively). CONCLUSION: This is the first study suggesting that the MBL2 BB genotype in association with the DRB1*07 or co-inheritance of the HLA-DRB1*04 and HLA DRB1*07 may have an impact on the etiopathogenesis of the disease.

10.
Scand J Clin Lab Invest ; 83(3): 187-193, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37029683

RESUMEN

The tumor suppressor protein 53 (TP53) gene is one of the most studied genes in cancer. Although TP53 variants are rare events in acute leukemia, recent observations showed that relapse samples might harbor TP53 variants. Here, we aimed to determine TP53 variants (hotspot region, exon 4-11) in childhood acute lymphoblastic leukemia (B and T-ALL) patients (n = 94) including diagnostic-relapse pairs (n = 15) by amplicon sequencing and evaluate the clinical impact of these variants. In total, nine different (E298*, R283C, R273H, L252F, C229F, I195T, E286G, c.955_956insC, and c.920-1G > C) variants were identified in 17 (18%) childhood ALL patients. c.(920-1G> C) splice site variant and c.(955_956insC) insertion were reported for the first time. In diagnose-relapse pair samples, we identified acquired and/or loss of TP53 variants in the samples at the time of relapse. TP53 variants were found to be more common in T-ALL (37%) than in B-ALL patients (9%). Pathogenic TP53 variants were associated with a shorter overall survival time (p = 0.001).TP53 variants were found to be associated with inferior outcomes in our cohort and can be an independent risk factor for poor prognosis in childhood acute leukemia patients. Identification of low-frequent variants with next-generation sequencing approaches enables better knowledge of the clonal dynamics of ALL.


Asunto(s)
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Genes p53 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Mutación , Proteína p53 Supresora de Tumor/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Leucemia Mieloide Aguda/genética , Recurrencia
11.
Leuk Lymphoma ; 63(12): 2931-2939, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35921545

RESUMEN

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous malignancy and consists of several genetic abnormalities. Some of these abnormalities are used in clinics for risk calculation and treatment decisions. Patients with ZNF384 rearrangements had a distinct expression profile regardless of their diagnosis, BCP-ALL or mixed phenotype acute leukemia (MPAL) and defined as a new subtype of ALL. In this study, we screened 42 MPAL and 91 BCP-ALL patients for the most common ZNF384 fusions; ZNF384::TCF3, ZNF384::EP300 and ZNF384::TAF15 by using PCR. We identified ZNF384 fusions in 9.5% of MPAL and 7.6% of BCP-ALL. A novel breakpoint was identified in ZNF384::TCF3 fusion in one BCP-ALL patient. T-myeloid MPAL patients showed significantly lower ZNF384 expression compared to lymphoid groups. Patients with ZNF384r had intermediate survival rates based on other subtypes. Prognostic and patient-specific treatment evaluation of ZNF384 fusions in both ALL and MPAL might help to improve risk characterization of patients.


Asunto(s)
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Transactivadores/genética , Transactivadores/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Factores de Transcripción/genética , Fenotipo , Dedos de Zinc
12.
J Pediatr Hematol Oncol ; 44(8): e1039-e1045, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36036521

RESUMEN

BACKGROUND: Central nervous system fungal infections (CNSFI) are seen in patients with hematologic malignancies and have high morbidity and mortality. Because of their rarity, there is limited data on CNSFI in children with no established treatment protocols or guidelines. MATERIALS AND METHODS: In this multicenter retrospective study, 51 pediatric patients with leukemia, 6 of whom had undergone bone marrow transplantation, with proven or probable CNSFI were evaluated. Fungal infections were defined as proven or probable based on European Organisation for Research and Treatment of Cancer criteria. Proven CNSFI was diagnosed by appropriate central nervous system (CNS) imaging or tissue sample findings in combination with positive microbiological results of cerebrospinal fluid. A positive culture, microscopic evidence of hyphae, a positive result of the galactomannan assays are defined as positive microbiological evidence. Probable CNSFI was defined as appropriate CNS imaging findings together with proven or probable invasive fungal infections at another focus without CNS when there is no other explanatory condition. Data was collected by using the questionnaire form (Supplemental Digital Content 1, http://links.lww.com/JPHO/A541 ). RESULTS: Seventeen patients had proven, 34 patients had probable CNSFI. Headaches and seizures were the most common clinical findings. The median time between the onset of fever and diagnosis was 5 days. The most common fungal agent identified was Aspergillus . Sixteen patients received single-agent, 35 received combination antifungal therapy. Surgery was performed in 23 patients. Twenty-two patients (43%) died, 29 of the CNSFI episodes recovered with a 20% neurological sequelae. CONCLUSION: CNSFIs should be considered in the differential diagnosis in patients with leukemia and refractory/recurrent fever, headache, neurologicalocular symptoms, and a radiologic-serological evaluation should be performed immediately. Early diagnosis and prompt management, both medical and surgical, are essential for improving clinical outcomes.


Asunto(s)
Infecciones Fúngicas del Sistema Nervioso Central , Trasplante de Células Madre Hematopoyéticas , Infecciones Fúngicas Invasoras , Leucemia , Niño , Humanos , Estudios Retrospectivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/etiología , Infecciones Fúngicas del Sistema Nervioso Central/diagnóstico , Infecciones Fúngicas del Sistema Nervioso Central/terapia , Antifúngicos/uso terapéutico , Leucemia/tratamiento farmacológico
14.
Turk J Pediatr ; 64(1): 152-159, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35286044

RESUMEN

BACKGROUND: Granulocytic sarcoma (GS) is an extramedullary solid tumor composed of immature myeloid cells. GS has been associated with acute myeloid leukemia (AML), myelodysplastic syndromes or myeloproliferative diseases. Although GS can affect various tissues of the human body, it has rarely been reported in other soft tissues such as the breast, gastrointestinal, respiratory and genitourinary tracts. We report a pediatric case diagnosed with granulocytic sarcoma of the bladder and concomitant AML. CASE: A twelve-year-old previously healthy girl was admitted to the pediatric urology clinic with a ten-day history of hematuria and pollakiuria. Laboratory examinations revealed anemia, thrombocytopenia and neutrophilic leukocytosis. Bone marrow aspiration results were consistent with acute myeloid leukemia -FAB subtype M2-. Abdominal magnetic resonance imaging (MRI) showed an irregularly bounded 12 cm mass on the right side of the bladder. Transurethral resection (TUR) pathology was consistent with granulocytic sarcoma. After a multimodal treatment approach, complete remission was achieved. CONCLUSIONS: Malignant bladder masses are rare causes of macroscopic hematuria in childhood. The diagnostic spectrum is wide, ranging from rhabdomyosarcoma to leukemia involvement. The bladder is a rare site of extramedullary involvement in pediatric patients with AML. Multimodal treatment should be considered on a per-patient basis.


Asunto(s)
Anemia , Leucemia Mieloide Aguda , Sarcoma Mieloide , Neoplasias de la Vejiga Urinaria , Niño , Femenino , Hematuria , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/terapia , Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/terapia
15.
J Appl Clin Med Phys ; 23(5): e13563, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35194924

RESUMEN

PURPOSE: To determine the possibility of further improving clinical stereotactic body radiotherapy (SBRT) plans using normal tissue complication probability (NTCP) objectives in order to minimize the risk for carotid blowout syndrome (CBOS). METHODS: 10 patients with inoperable locally recurrent head and neck cancer, who underwent SBRT using CyberKnife were analyzed. For each patient, three treatment plans were examined: (1) cone-based without delineation of the ipsilateral internal carotid (clinical plan used to treat the patients); (2) cone-based with the carotid retrospectively delineated and spared; and (3) Iris-based with carotid sparing. The dose-volume histograms of the target and primary organs at risk were calculated. The three sets of plans were compared based on dosimetric and TCP/NTCP (tumor control and normal tissue complication probabilities) metrics. For the NTCP values of carotid, the relative seriality model was used with the following parameters: D50 = 40 Gy, γ = 0.75, and s = 1.0. RESULTS: Across the 10 patient plans, the average TCP did not significantly change when the plans were re-optimized to spare the carotid. The estimated risk of CBOS was significantly decreased in the re-optimized plans, by 14.9% ± 7.4% for the cone-based plans and 17.7% ± 7.1% for the iris-based plans (p = 0.002 for both). The iris-based plans had significant (p = 0.02) reduced CBOS risk and delivery time (20.1% ± 7.4% time reduction, p = 0.002) compared to the cone-based plans. CONCLUSION: A significant improvement in the quality of the clinical plans could be achieved through the delineation of the internal carotids and the use of more modern treatment delivery modalities. In this way, for the same target coverage, a significant reduction in the risk of CBOS could be achieved. The range of risk reduction varied depending on the proximity of carotid artery to the target.


Asunto(s)
Radiocirugia , Radioterapia de Intensidad Modulada , Arterias Carótidas/patología , Arterias Carótidas/cirugía , Humanos , Recurrencia Local de Neoplasia , Probabilidad , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Estudios Retrospectivos
16.
Anticancer Agents Med Chem ; 22(2): 349-355, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-33653255

RESUMEN

AIM: The present study aims to identify the anticancer effect of novel 1H-indole-2,3-dione 3- thiosemicarbazone derivatives. These compounds could be promising anticancer agents in leukemia treatment. BACKGROUND: Conventional chemotherapeutic agents accumulate in both normal and tumor cells due to nonspecificity. For effective cancer treatment, new drugs need to be developed to make chemotherapeutics selective for cancer cells. The ultimate goal of cancer treatment is to reduce systemic toxicity and improve the quality of life. METHODS: In this study, the anticancer effects of 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives (A-L) were investigated in chronic myelogenous leukemia K562, Burkitt's lymphoma P3HR1, acute promyelocytic leukemia HL60 cells, and vincristine-resistant sublines of K562 and P3HR1 cells. Additionally, the compounds were tested on lymphoid-derived cells from ALL patients. In order to investigate the particular mechanism of death caused by the cytotoxic effects of the compounds, immunohistochemical caspase 3 staining was performed in P3HR1 cells, and the resulting apoptotic activities were demonstrated. RESULTS: All tested compounds have been found to have cytotoxic effects against lymphoma cells at submicromolar concentrations (IC50= 0.89-1.80 µM). Most compounds show significant selectivity for the P3HR1 and P3HR1 Vin resistance. The most effective and selective compound is 4-bromophenyl substituted compound I (IC50=0.96 and 0.89 µM). Cyclohexyl and benzyl substituted compounds D and E have also been found to have cytotoxic effects against K562 cell lines (IC50=2.38 µM), while the allyl substituted compound C is effective on all cell lines (IC50=1.13-2.21 µM). 4-Fluorophenyl substituted F compound has been observed to be effective on all cells (IC50=1.00-2.41 µM) except K562 cell. Compound C is the only compound that shows inhibition of HL-60 cells (IC50= 1.13 µM). Additionally, all compounds exhibited cytotoxic effects on lymphoidderived cells at 1µM concentration. These results are in accordance with the results obtained in lymphoma cells. CONCLUSION: All compounds tested have submicromolar concentrations of cytotoxic effects on cells. These compounds hold potential for use in future treatments of leukemia.


Asunto(s)
Antineoplásicos/farmacología , Indoles/farmacología , Tiosemicarbazonas/farmacología , Adolescente , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Indoles/síntesis química , Indoles/química , Masculino , Estructura Molecular , Relación Estructura-Actividad , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/química , Células Tumorales Cultivadas
17.
Clin Exp Med ; 22(1): 95-101, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34245399

RESUMEN

Iron deposition in various organs can cause endocrine complications in patients with transfusion-dependent beta-thalassemia. The aim was to investigate the relationship between endocrine complications and pancreatic iron overload using magnetic resonance imaging (MRI). Forty patients with transfusion-dependent thalassemia (TDT) were enrolled in the study. The magnetic resonance imagings of the patients were performed using a 1.5 Tesla Philips MRI scanner. Two out of three patients had at least one clinical endocrine complication. The rate of iron deposition was 62.5% in liver, and 45% in pancreas tissue, and was 12.5% in heart tissue. Pancreatic T2* and hepatic T2* values were significantly positively correlated (p = 0.006). Pancreatic T2* and ferritin were significantly negatively correlated (p = 0.03). Cardiac T2* values were negatively correlated with fasting blood glucose (p = 0.03). Patients with short stature had significantly higher cardiac iron burden (22.3 vs. 36.6 T2*ms; p 0.01), and patients with hypothyroidism had higher liver iron concentrations (9.9 vs. 6.4 LIC mg/g; p = 0.05). The ferritin level of 841 ng/mL and liver iron concentration (LIC) value of 8.7 mg/g were detected as the threshold level for severe pancreatic iron burden (AUC 70%, p:0.04, AUC 80%, p = 0.002, respectively). Moreover, males were found to have decreased pancreas T2* values compared with the values in females (T2* 19.3 vs. 29.9, p = 0.05). Patients with higher ferritin levels over than 840 ng/mL should be closely monitored for pancreatic iron deposition, and patients with endocrine complications should be assessed in terms of cardiac iron burden.


Asunto(s)
Sobrecarga de Hierro , Talasemia beta , Femenino , Ferritinas , Humanos , Sobrecarga de Hierro/diagnóstico por imagen , Sobrecarga de Hierro/etiología , Hígado/diagnóstico por imagen , Hígado/patología , Imagen por Resonancia Magnética/métodos , Masculino , Miocardio/patología , Páncreas/diagnóstico por imagen , Páncreas/patología , Talasemia beta/complicaciones , Talasemia beta/diagnóstico por imagen
18.
North Clin Istanb ; 9(6): 616-621, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36685621

RESUMEN

OBJECTIVE: Patients with hemoglobinopathy are prone to cerebrovascular event. Our aim was to screen the peak systolic flow velocity (PSV) using transcranial Doppler ultrasonography (TCD) in terms of cerebrovascular event risk in patients with beta thalassemia (ß-thal) and sickle cell anemia (SCA). METHODS: PSV and resistive index (RI) values were determined at internal carotid artery (ICA) and middle cerebral artery (MCA)-from both temporal regions using TCD. RESULTS: A total of 55 participants (40 patients and 15 healthy people) were included in the study. Thirty-three (60%) of the participants were female. Among 40 patients, 12 patients (30%) had NTDT, 14 patients (35%) had SCA, and 14 patients (35%) had TDT diagnosis. Bilateral ICA and MCA were open in all patients and had a normal flow pattern. PSV and RI were not significantly different between study and control groups in right and left MCA and ICA. Patients with high platelet level (>450.000/mm3) had significantly higher PSV values in right MCA (96 vs.70 cm/s, p=0.05). Among patients with TDT, age of starting iron chelation and right ICA PSV values was significantly negatively correlated (r=-0.56; p=0.04). Clinical symptoms (headache and pain crisis), hydroxyurea, and chelation therapy did not effect PSV values. CONCLUSION: Platelet level and age of starting iron chelation might be an influencing factor for PSV. Regular follow-up of patients, appropriate therapy and lack of other factors causing cerebrovascular events might be possible reason for these acceptable results.

19.
Blood Adv ; 5(14): 2925-2934, 2021 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-34309636

RESUMEN

The phase 2, open-label study (DIALOG) of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) met its coprimary end points, showing sustained nilotinib efficacy in patients with newly diagnosed (ND) or imatinib/dasatinib resistant/intolerant (R/I) CML. This update assessed growth and safety profiles in patients who had completed ≥48, 28-day treatment cycles of nilotinib 230 mg/m2 twice daily, or previously discontinued the study. Height was assessed regularly and reported using standard deviation scores (SDSs) based on World Health Organization growth charts. All data were summarized descriptively (cutoff, 6 March 2019). Overall, 33 patients in the R/I cohort and 25 patients in the ND cohort received nilotinib. Each cohort showed a negative slope in height SDS over the course of the study, indicating attenuated growth rates during nilotinib treatment: overall median change from baseline in height SDS after 48 cycles was -0.54 SDS (range, - 1.6 to 0.4) and -0.91 SDS (-1.4 to -0.1) in R/I and ND cohorts, respectively. Patients in the R/I cohort were shorter at baseline than those in the ND cohort, and remained so throughout the study. The most common all-cause adverse events were increased blood bilirubin (53.4%), headache (46.6%), pyrexia (37.9%), and increased alanine transferase (36.2%). Apart from the impact on growth, the safety profile of nilotinib was generally consistent with previous reports. This study was registered on www.clinicaltrials.gov at #NCT01844765.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Pirimidinas , Niño , Trastornos del Crecimiento , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Pirimidinas/efectos adversos
20.
Int J Lab Hematol ; 43(5): 1093-1103, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33844466

RESUMEN

INTRODUCTION: The lymphoid enhancer factor 1 (LEF1) is a DNA-binding transcription factor that functions in the Wnt signaling pathway. Increased LEF1 activity is associated with progression of several types of cancer including leukemia. Here, we investigated LEF1 isoform expression and genomic variations in acute lymphoblastic leukemia (ALL). METHODS: LEF1 isoform expression was evaluated by quantitative real-time PCR in 87 newly diagnosed childhood ALL patients and controls. Moreover, Western blot analysis was performed for detection of LEF1 expression and the hotspot region of LEF1 was screened by deep sequencing. RESULTS: The LEF1 mRNA expression of B cell ALL patients was higher than the controls (LEF1-total P = .011, LEF1-long P = .026). Moreover, B-ALL samples showing higher total LEF1 expression had significantly shorter relapse-free survival (P = .008) and overall survival (P = .011). Although full-length LEF1 expression was similar to the controls in T-ALL, 50% (n = 15) of the ALL patients had increased full-length LEF1 protein expression. Imbalance between short- and full-length LEF1 isoforms may lead to cell survival in ALL. Beside the LEF1 activation, LEF1 gene variations were rarely observed in our cohort. CONCLUSION: The results indicate that the Wnt pathway may have a pathogenic function in a group of ALL patients and high LEF1-total expression might be a marker for shorter relapse-free survival time in B cell ALL.


Asunto(s)
Factor de Unión 1 al Potenciador Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudios de Casos y Controles , Línea Celular Tumoral , Niño , Preescolar , Femenino , Regulación Leucémica de la Expresión Génica , Variación Genética , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Pronóstico , Isoformas de Proteínas/genética
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