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Toll-like receptor-4 (TLR4) is known to influence growth and migration of hepatocellular tumors; however, its role in hepatoblastoma remains poorly understood. This study investigated the regulatory role of TLR4 in proliferation and chemoresistance of HepG2 hepatoblastoma cells. Treatment with lipopolysaccharide (LPS), a TLR4 agonist, was found to significantly upregulate TLR4 expression in HepG2 cells, but not in malignant Huh-7 and Sk-Hep1 hepatocellular carcinoma cells. Additionally, IL-6 enhanced LPS-induced TLR4 upregulation. LPS-stimulated TLR4 activation increased proliferation, nitric oxide synthase (NOS) expression, and NO production in HepG2 cells. Chemotherapeutic agents, cisplatin and doxorubicin, effectively inhibited TLR4 expression in HepG2 cells. Characterization of LPS-induced signaling activation and blockade with kinase inhibitors revealed the involvement of Akt and MAPK pathways in LPS-enhanced NO release from, and proliferation of HepG2 cells. Mechanistically, gene modifications as a result of TLR4 transfection and siRNA-mediated knockdown further demonstrated a crucial role for TLR4 in the regulation of NOS expression, cell proliferation, and chemoresistance in HepG2 cells. These findings suggest that targeting TLR4 expression and its cognate signaling may modulate proliferation and chemosensitivity in hepatoblastoma cells and serve as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β2 (TGF-β2) has been implicated in the pathogenesis of proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), due to its ability to stimulate the overproduction of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), and remodeling of the extracellular matrix (ECM). Although intravitreal triamcinolone acetonide (TA) is clinically useful in the treatment of PVR and PDR, its molecular mechanism has yet to be fully elucidated. The present study investigated whether TA treatment altered TGF-β2-driven biological effects on the behavior of cultured human retinal pigment epithelial (RPE) cells, in order to determine which signaling pathway may be essential for the pharmacological action of TA. The R-50 human RPE cell line was treated with TA in the presence of TGF-β2, followed by analyses of cell viability and contraction using cell viability and collagen gel contraction assays. VEGF mRNA expression and protein production were measured using reverse transcription-quantitative PCR and ELISA, respectively. The phosphorylation status of signaling mediators and the protein expression of type I collagen (COL1A1), α-smooth muscle actin (α-SMA), and ECM-remodeling enzymes, including MMP-2 and MMP-9, were analyzed using western blotting. The gelatinolytic activity of MMPs was detected using gelatin zymography. TA treatment exhibited no prominent cytotoxicity but markedly antagonized TGF-β2-induced cytostatic effects on RPE cell viability and TGF-β2-enhanced contractility in collagen gels. In the context of TGF-β2-related signaling, TA significantly attenuated TGF-β2-elicited Smad2, extracellular-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, TA markedly mitigated TGF-β2-induced VEGF upregulation through ablation of p38 signaling activity. TA also partially attenuated TGF-β2-elicted expression of COL1A1, α-SMA, MMP-2, and MMP-9, but only suppressed TGF-β2-induced MMP-9 gelatinolytic activity. Mechanistically, the MEK/ERK signaling pathway may have a critical role in the TGF-β2-induced upregulation of COL1A1, α-SMA and MMP-9. In conclusion, TA may be considered a useful therapeutic agent for treating TGF-β2-associated intraocular angiogenesis and tissue remodeling, the underlying mechanism of which may involve the ERK and p38 MAPK signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract: Minimal residual disease (MRD) in 56 children with acute lymphoblastic leukemia (ALL) was quantified simultaneously by flow cytometry and by RQ-PCR of WT1 transcripts. Six patients failed remission induction, all had detectable MRD by flow cytometry, and two had undetectable MRD by WT1 assay. Among 41 patients, who achieved remission and had overexpression of WT1 transcripts at diagnosis, the two techniques gave concordant MRD results in 26 and discordant MRD results in 15. Nine patients did not show overexpression of WT1 at diagnosis. Our results indicate that RQ-PCR measurements of WT1 may be of limited value for monitoring MRD in childhood ALL. [Copyright &y& Elsevier]

Objective: Although Epstein-Barr virus (EBV) is known to cause immune thrombocytopenic purpura (ITP), the epidemiology of this pathogen in children with ITP is not known. In the present study, the clinicoepidemiology and laboratory characteristics of EBV-associated ITP in childhood were analysed retrospectively.Methods: The study cohort consisted of 108 children in whom ITP was diagnosed between 1990 and 1998. Patients were divided into EBV or non-EBV groups according to their serological status at diagnosis.Results: Thirty-five (32.4%) of 108 children had ITP associated with acute EBV infection. The clinical manifestations and laboratory data were similar in children with and without acute EBV. Responses to various modalities of therapy were analysed. The average time to achieve complete remission (platelet count > or =150 x 10(9)/L) in EBV and non-EBV groups was 26 and 16 days, respectively.Conclusions: The incidence of childhood ITP associated with acute EBV infection is relatively high in Taiwan. Patients with EBV-associated ITP tended to resolve more slowly than those without EBV infection. [ABSTRACT FROM AUTHOR]

Background/Objectives: Relapsed B-cell acute lymphoblastic leukemia (B-ALL) remains an unresolved matter of concern regarding adverse outcomes. This case study aimed to evaluate the effectiveness of blinatumomab, with or without door lymphocyte infusion (DLI), in treating measurable residual disease (MRD)-positive B-ALL. Methods: All patients who received blinatumomab salvage therapy were included in this study. Eleven patients were included in the study. All patients were evaluated for MRD-negativity. Results: Before starting blinatumomab therapy, seven patients tested positive for MRD, three tested negative, and one had refractory disease. Hematopoietic cell transplantation (HCT) was reserved for five patients with persistent MRD. Six patients became MRD-negative and subsequent HCT was not performed. Only two patients relapsed; one patient died of relapse, and the other one received carfilzomib-based therapy and was MRD-negative thereafter. Nine patients were MRD-negative at a median follow-up of 28 months (15–52 months). Two of three MRD-positive post-transplant patients remained in complete molecular remission after preemptive DLI at the last follow-up date. In the first salvage, blinatumomab may achieve complete remission and bridging to HCT in pediatric patients with end-of-induction MRD-positive B-cell precursor ALL. Conclusions: The decision on how to treat post-transplant relapse continues to affect survival outcomes. Blinatumomab combined with DLI may extend the armamentarium of release options for high-risk pediatric patients. This approach is encouraging for high-risk ALL patients who are MRD-positive post-transplantation. [ABSTRACT FROM AUTHOR]

Summary: This study investigates the potential utility of IKZF1 deletion as an additional high‐risk marker for paediatric acute lymphoblastic leukaemia (ALL). The prognostic impact of IKZF1 status, in conjunction with minimal/measurable residual disease (MRD), was evaluated within the MRD‐guided TPOG‐ALL‐2013 protocol using 412 newly diagnosed B‐ALL patients aged 1–18. IKZF1 status was determined using multiplex ligation‐dependent probe amplification. IKZF1 deletions, when co‐occurring with CDKN2A, CDKN2B, PAX5 or PAR1 region deletions in the absence of ERG deletions, were termed IKZF1plus. Both IKZF1 deletion (14.6%) and IKZF1plus (7.8%) independently predicted poorer outcomes in B‐ALL. IKZF1plus was observed in 4.1% of Philadelphia‐negative ALL, with a significantly lower 5‐year event‐free survival (53.9%) compared to IKZF1 deletion alone (83.8%) and wild‐type IKZF1 (91.3%) (p < 0.0001). Among patients with Day 15 MRD ≥0.01%, provisional high‐risk patients with IKZF1plus exhibited the worst outcomes in event‐free survival (42.0%), relapse‐free survival (48.0%) and overall survival (72.7%) compared to other groups (p < 0.0001). Integration of IKZF1plus and positive Day 15 MRD identified a subgroup of Philadelphia‐negative B‐ALL with a 50% risk of relapse. This study highlights the importance of assessing IKZF1plus alongside Day 15 MRD positivity to identify patients at increased risk of adverse outcomes, potentially minimizing overtreatment. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. Methods: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. Results and discussion: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5–578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p <.01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p <.01). Twenty‐seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p <.01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug‐related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. Conclusions: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed. [ABSTRACT FROM AUTHOR]

Background: Primary malignant mediastinal germ cell tumors (GCTs) are rare pediatric tumors that have a poorer prognosis compared to GCTs occurring elsewhere in the body. The current study aimed to assess the prognostic factors and treatment outcomes of children with primary malignant mediastinal GCT in Taiwan. Methods: The authors retrospectively reviewed children 0–18 years old who were newly diagnosed with primary malignant mediastinal GCT between January 1, 2005 and December 31, 2019 and were registered in the Taiwan Pediatric Oncology Group patient registry. The impact of presenting characteristics, including sex, age, tumor stage, histology subtype, surgical treatment, and chemotherapy regimens of the patients were analyzed. Results: This study enrolled 52 children with malignant mediastinal GCT who had a median age of 16.0 (range, 6.0–17.9) years at diagnosis. The most common histological subtypes were mixed GCTs (n = 20) and yolk sac tumors (n = 15). Advanced disease stage and choriocarcinoma histology subtype were associated inferior outcomes. Children who received surgical treatment exhibited better outcomes compared to those who did not (5‐year overall survival, 78% vs. 7%, p <.001). After comparing patients who received first‐line cisplatin‐ and carboplatin‐based chemotherapy, no difference in treatment outcomes was observed. Multivariate analysis showed that surgical management was the only independent predictor for superior OS. Conclusions: Surgical treatment is recommended for mediastinal GCT. Cisplatin‐based chemotherapy was not superior to carboplatin‐based chemotherapy as first‐line treatment and may be avoided due to toxicity concerns. Surgical treatment is recommended for pediatric malignant mediastinal germ cell tumors. Cisplatin‐based chemotherapy was not superior to carboplatin‐based chemotherapy as first‐line treatment. [ABSTRACT FROM AUTHOR]

The cement industry is the most energy intensive of Taiwan's manufacturing industries. This paper presents a case study of the greenhouse gas (GHG) inventory in Taiwan's cement industry, which includes an analysis of GHG emission intensity (EI) and the testing of raw meal calcination. The GHG inventory analysis results show that direct GHG emissions (Scope 1) are the largest emission source of the study subject, the H plant. As regards the EI analysis results of Taiwan's cement plants, only one cement plant (H plant) meets the EI limit announced by the Environmental Protection Administration (EPA) of Taiwan. According to the calcination test, the major calcination reaction occurs in the 700–900°C temperature range and accounts for nearly 87% of total CO2emissions. Finally, a modified and feasible process is proposed as a base case for simulating options for GHG reductions in the cement industry. The modified process can reduce coal consumption and pipeline corrosion, and increase the efficiency of waste heat recovery and the calcination rate; these procedures require low investment and operating cost. [ABSTRACT FROM PUBLISHER]

Introduction: The large interpatient variability in the pharmacokinetic (PK) parameters of recombinant Factor VIII (rFVIII) observed in haemophilia A hinders efficient and cost‐beneficial prophylactic regimen initiation. Identification of factors influencing the PK of rFVIII may shed more light on personalised treatment. Aim: This study aimed to develop a population PK model in the Taiwanese haemophilia A and evaluate the current national health insurance (NHI) reimbursement guidelines of Taiwan for haemophilia treatment. Methods: A population PK analysis was established based on 69 Taiwanese with moderate or severe haemophilia A. A nonlinear mixed‐effects modelling (NONMEM®) was used to estimate PK parameters and their variabilities. A Monte Carlo simulation was performed to evaluate different prophylactic regimens. Results: A two‐compartment model with first‐order elimination best described the rFVIII data. Weight‐based allometric scaling was related to clearance and central volume of distribution. Blood type and baseline von Willebrand factor (VWF) were significant covariates for clearance. For single dose simulations, a time achieving target level (> 1 IU/dL) was associated with increasing rFVIII dose and VWF level. The multiple dose simulations showed that > 96.4% of patients with high VWF level (> 200%) had predicted trough level > 1 IU/dL for all dosing regimens (15‐40 IU/kg, two to three times weekly). However, for twice weekly dosing, lower percentage (47.62‐62.20%) of patients with blood group O and low VWF level (< 50%) achieved a predicted trough level > 1 IU/dL. Conclusion: The population PK of rFVIII was successfully developed. Dose adjustment based on blood type and VWF level should be considered. [ABSTRACT FROM AUTHOR]

Improvement in outcomes of children with acute myeloid leukemia (AML) is attributed to several refinements in clinical management. We evaluated treatment outcomes of Taiwanese pediatric AML patients in the past 20 years. Overall, 860 de novo AML patients aged 0–18 years and registered in the Childhood Cancer Foundation of R.O.C during January 1996–December 2019 were included. Survival analysis was performed to identify factors that improved treatment outcomes. Regardless of treatment modalities used, patients during 2008–2019 had better 5-year event-free survival (EFS) and overall survival (OS) rates than patients during 1996–2007. For patients received the TPOG-AML-97A treatment, only 5-year OS rates were significantly different between patients diagnosed before and after 2008. Patients with RUNX1–RUNX1T1 had similar relapse-free survival rates, but 5-year OS rates were better during 2008–2019. However, the survival of patients who received hematopoietic stem-cell transplantations (HSCT) did not differ significantly before and after 2008. For patients without relapse, the 5-year OS improved during 2008–2019. Non-relapse mortality decreased annually, and cumulative relapse rates were similar. In conclusion, 5-year EFS and OS rates improved during 2008–2019, though intensities of chemotherapy treatments were similar before and after 2008. Non-relapse mortality decreased gradually. Further treatment strategies including more intensive chemotherapy, novel agents' use, identification of high-risk patients using genotyping and minimal residual disease, early intervention of HSCT, and antibiotic prophylaxis can be considered for future clinical protocol designs in Taiwan. [ABSTRACT FROM AUTHOR]

Background: To eliminate cranial irradiation (CrRT)-related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)-directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL).Methods: This study compared the treatment outcomes of patients overall and patients with a non-CNS-1 status (CNS-2, CNS-3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG-ALL-2002 protocol by the introduction of the modification (era 1 [2002-2008] with CrRT and era 2 [2009-2012] with delayed first TIT and no CrRT).Results: There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5-year event-free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non-CNS-1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5-year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2.Conclusions: The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non-CNS-1 status. [ABSTRACT FROM AUTHOR]

In the study, the novel fan-out wafer level packaging (FOWLP) technology is presented in which the through silicon via (TSV) array interposer layer is manufactured. Compared to conventional FOWLP technology, the present novel FOWLP technology has several advantages of better signal integrity, higher electrical performance, and easier customization. However, similar to the conventional FOWLP technology, the process-induced warpage resulted from the mismatch of the coefficient of thermal expansion (CTE) among the constituent materials is also an essential issue during the fan-out fabrication process, which is notably for successful process integration. This study proposes a comprehensive assessment of the process-induced warpage of the novel FOWLP during the fan-out fabrication process. A process-dependent simulation methodology is introduced, which integrates nonlinear finite element (FE) analysis incorporated with the element death-birth technique. The study starts from establishing a silicon interposer layer with TSV array, attachment of glass carrier, multiple redistribution layers (RDLs), and dielectric layers. The warpage evolution during the fan-out fabrication process is thoroughly evaluated according to the temperature loading profile. To demonstrate the effectiveness of the proposed theoretical model, the novel FOWLP test vehicle is manufactured for experimental measurement. Finally, the parametric study together with response surface methodology is further applied to provide guidelines for suppressing the warpage. Overall, the simulation modeling represents a feasible approach for predicting the process-induced warpage during the fan-out fabrication process. • A thorough investigation of the process-induced warpage of the novel FOWLP during fabrication process is performed. • The nonlinear finite element analysis with the element death-birth technique is used to assess the process-induced warpage. • The process-induced warpage is affected by the glass carrier CTE and Cu volume fraction in RDL. • Warpage of the novel FOWLP test vehicle is measured by the optical profilometry system using infrared interferometry. • The parametric study with response surface methodology is used to provide guidelines for suppressing the warpage. [ABSTRACT FROM AUTHOR]

Aims To evaluate the acceptability and efficacy of a psycho-educational intervention designed to improve effective coping and reduce symptom severity in children with cancer. Background Cancer treatments increase survival rates and also cause physical and psychological effects on children with cancer. A psycho-educational intervention is used to assist children and adolescents with these effects and its efficacy has been described in several studies. Design A randomized controlled trial. Methods Participants being treated were recruited and randomly assigned to two groups from September 2011-February 2013 in Taiwan. The intervention group received a psycho-educational intervention in addition to standard care, while the control group received only standard care. Each participant was assessed using a paediatric cancer coping scale and perceived symptom severity was evaluated at three time points (baseline, 1 month and 3 months). A repeated-measures analysis of variance was used to estimate the effects of intervention. Qualitative findings were analysed using content analysis. Results No significant difference in coping scores was found between groups, but the experimental group reported significantly lower scores in gastrointestinal problems and pain. Most symptoms decreased significantly over time in both groups, except for gastrointestinal problems. The scores in pain, bone marrow suppression and body image showed significant interaction effects between groups on changes over time. Qualitative results reported that participants evaluated the intervention positively, especially about receipt of psychological support and learnt coping skills. Conclusions The psycho-educational intervention administered was acceptable for children with cancer and was found to reduce gastrointestinal problems and pain. [ABSTRACT FROM AUTHOR]

Aims. To report a study examining the relationships among coping, anxiety and resilience and to identify predictors of anxiety and resilience in adolescents undergoing cancer treatment. Background. Anxiety is the main psychological disturbance in adolescents with cancer, but predictors in the context of anxiety related cancer treatments have not been investigated. Design. Cross-sectional study. Methods. Adolescents ( n = 131) recruited from three medical centres between 2010-2011. The eligible participants were diagnosed with cancer, without mental disease and receiving chemotherapy. Participants were assessed with the paediatric cancer coping scale, revised children's manifest anxiety scale, second edition, and the Haase adolescent resilience in illness scale. Results. Over 20% of participants scored high on worry. The most commonly used coping strategy was cognitive coping, followed by problem-oriented coping and finally by defensive coping. There was a statistically significant correlation between defensive coping and level of worry. Resilience was positively correlated with cognitive coping and problem-oriented coping. The cognitive coping and defensive coping were found to predict anxiety and resilience significantly by a step-wise multiple regression analysis and accounted for 40·9% and 46·5% of total variance, respectively. Conclusions. Cognitive coping and defensive coping are predictors for the level of anxiety and resilience in adolescents undergoing cancer treatment. Health providers should evaluate coping behaviour in patients and work towards a cognitive and problem-oriented coping style that will benefit the patient's mental health during treatment. [ABSTRACT FROM AUTHOR]

Over the past few decades, Taiwan has seen striking improvements in the life expectancy of its 400 registered β-thalassemia major (β-TM) patients due mainly to adequate transfusion regimens and effective iron chelation therapy. Since 1995, Taiwanese citizens have enjoyed universal health care through National Health Insurance (NIH), receiving comprehensive treatment at minimal cost. In 1984, a national program for thalassemia prevention, control, and hematopoietic stem cell transplantation (HSCT) was initiated. Recent data show 1- and 2-year event-free survival rates of 85 and 78%, respectively. Chelation agents like deferoxamine (DFO), deferiprone (L1) and deferasirox (DFRA) are available in Taiwan, and therapy is tailored to individuals based on drug availability and tissue distribution of iron load. Intensive chelation regimens combining L1 and DFO are recommended in patients with cardiac complications, while DFRA has been found to be effective in reducing serum ferritin, with acceptable side effects. Here, we report advances in thalassemia treatment in Taiwan and suggest treatment guidelines. [ABSTRACT FROM AUTHOR]

Deferiprone (L1) has been recommended as an effective oral chelation therapy for patients with ß-thalassemia major (TM). From 1999 to 2004, 114 patients with TM from five treatment centers were enrolled in this program: iron (Fe) was chelated with L1 in 57 patients, deferoxamine (DFO) in 26, and combined L1/DFO therapy in 31. We found that serum ferritin (SF) was significantly lower in nine patients receiving L1 for more than 5 years ( p = 0.04), 22 patients receiving L1 for 1–2 years ( p [ABSTRACT FROM AUTHOR]

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways. [ABSTRACT FROM AUTHOR]

With the improvement of the survival rates in children acute lymphoblastic leukemia (ALL), some children ALL survivors show impaired cognitive function. Methotrexate (MTX), an essential component in ALL treatment, has been reported to be related to neurologic sequelae and to increased oxidative stress through its interactions with enzymes in the folate pathway. Asymmetric dimethylarginine (ADMA) is the main endogenous inhibitor of nitric oxide synthase, and increased ADMA may result from increased oxidants. Melatonin is an antioxidant; however, its role in MTX neuropathy is not well studied. We developed a rat model mimicking child ALL treatment to explore peripheral and central homocysteine and ADMA regulation after MTX and found potential treatment choice. Preweaning male Sprague-Dawley rats were used in this study. Experiment 1 evaluated spatial performance in rats with intrathecal (IT) MTX, intraperitoneal (IP) MTX, or combined IT and IP MTX, protocols mimicking ALL treatment in children. Experiment 2 focused on rats with combined IT and IP MTX, evaluating spatial performance and plasma and dorsal hippocampal homocysteine and ADMA levels, their regulation, and the protective effect of melatonin. Combined IT and IP MTX treatment caused in spatial deficits in developing rats, and melatonin restored the spatial performance. Alterations in peripheral and central homocysteine and ADMA concentrations and their regulation were found and could be alleviated by melatonin treatment. Combined IP and IT MTX treatment caused spatial deficits in developing rats. Melatonin could restore spatial performance through alleviating the effects on the imbalance of oxidative stress. [ABSTRACT FROM AUTHOR]