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Background: Pyrethroid chemicals are one of the main acaricides used against ticks. Resistance to these chemicals has been reported to be associated with mutations in the voltage-gated sodium channel (VGSC) gene of the Rhipicephalus microplus. This study investigates R. microplus resistance to pyrethroids in Guangxi region of China, marking one of the first research efforts in this area. The findings are intended to provide vital baseline for the effective implementation of localized tick control strategies., Methods: From March to July 2021, 447 R. microplus tick samples were collected from five prefecture-level cities in Guangxi. Allele-specific polymerase chain reaction (AS-PCR) was used to amplify segments C190A and G215T of the domain II S4-5 linker and T2134A of domain III S6 in the VGSC, to detect nucleotide mutations associated with resistance to pyrethroid acaricides. Subsequent analyses were conducted to ascertain the prevalence, types of mutations, and genotypic distributions within the sampled populations., Results: Mutations within VGSC gene were identified across all five studied populations of R. microplus, although the mutation rates remained generally low. Specifically, the most prevalent mutation was C190A, observed in 4.9% of the samples (22/447), followed by G215T at 4.0% (18/447), and T2134A at 1.3% (6/447). The distribution of mutations across three critical sites of the VGSC gene revealed four distinct mutation types: C190A, G215T, C190A + G215T, and T2134A. Notably, the single mutation C190A had the highest mutation frequency, accounting for 4.3%, and the C190A + G215T combination had the lowest, at only 0.7%. The analysis further identified seven genotypic combinations, with the wild-type combination C/C + G/G + T/T predominating at a frequency of 90.4%. Subsequently, the C/A + G/G + T/T combination was observed at a frequency of 4.3%, whereas the C/C + T/T + T/T combination exhibited the lowest frequency (0.2%). Additionally, no instances of simultaneous mutations at all three sites were detected. Geographical differences in mutation types were apparent. Both samples from Hechi to Chongzuo cities exhibited the same three mutation types; however, C190A was the most prevalent in Hechi, while G215T dominated in Chongzuo. In contrast, samples from Beihai to Guilin each exhibited only one mutation type: G215T occurred in 12.5% (4/32) of Beihai samples, and C190A in 7.5% (4/53) of Guilin samples., Conclusions: These findings underscore the relatively low frequency of VGSC gene mutations in R. microplus associated with pyrethroid resistance in the Guangxi, China. Moreover, the variation in mutation types and genotypic distributions across different locales highlights the need for regionalized strategies in monitoring and managing pyrethroid resistance in tick populations. This molecular surveillance is crucial for informing targeted control measures and mitigating the risk of widespread resistance emergence., (© 2024. The Author(s).)

Ticks are a hematophagous parasite and a vector of pathogens for numerous human and animal diseases of significant importance. The expansion of tick distribution and the increased risk of tick-borne diseases due to global climate change necessitates further study of the spatial distribution trend of ticks and their potential influencing factors. This study constructed a dataset of tick species distribution in Xinjiang for 60 years based on literature database retrieval and historical data collection (January 1963-January 2023). The distribution data were extracted, corrected, and deduplicated. The dominant tick species were selected for analysis using the MaxEnt model to assess their potential distribution in different periods under the current and BCC-CSM2.MR mode scenarios. The results indicated that there are eight genera and 48 species of ticks in 108 cities and counties of Xinjiang, with Hyalomma asiaticum, Rhipicephalus turanicus, Dermacentor marginatus, and Haemaphysalis punctatus being the top four dominant species. The MaxEnt model analysis revealed that the suitability areas of the four dominant ticks were mainly distributed in the north of Xinjiang, in areas such as Altay and Tacheng Prefecture. Over the next four periods, the medium and high suitable areas within the potential distribution range of the four tick species will expand towards the northwest. Additionally, new suitability areas will emerge in Altay, Changji Hui Autonomous Prefecture, and other local areas. The 60-year tick dataset in this study provides a map of preliminary tick distribution in Xinjiang, with a diverse array of tick species and distribution patterns throughout the area. In addition, the MaxEnt model revealed the spatial change characteristics and future distribution trend of ticks in Xinjiang, which can provide an instrumental data reference for tick monitoring and tick-borne disease risk prediction not only in the region but also in other countries participating in the Belt and Road Initiative., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© 2024. The Author(s).)

Background: Brucellosis is a zoonotic affliction instigated by bacteria belonging to the genus Brucella and is characterized by a diverse range of pervasiveness, multiple transmission routes, and serious hazards. It is imperative to amalgamate the current knowledge and identify gaps pertaining to the role of ticks in brucellosis transmission., Methods: We systematically searched China National Knowledge Infrastructure (CNKI), WanFang, Google Scholar, and PubMed on the topic published until April 23, 2022. The procedure was performed in accordance with the Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. The selected articles were categorized across three major topic areas, and the potential data was extracted to describe evidence-practice gaps by two reviewers., Results: The search identified 83 eligible studies for the final analyses. The results highlighted the potential capacity of ticks in brucellosis transmission as evidenced by the detection of Brucella in 16 different tick species. The pooled overall prevalence of Brucella in ticks was 33.87% (range: 0.00-87.80%). The review also revealed the capability of Brucella to circulate in parasitic ticks' different developmental stages, thus posing a potential threat to animal and human health. Empirical evidence from in vitro rodent infection experiments has revealed that ticks possess the capability to transmit Brucella to uninfected animals (range: 45.00-80.00%). Moreover, significant epidemiological associations have been found between the occurrence of brucellosis in animals and tick control in rangelands, which further suggests that ticks may serve as potential vectors for brucellosis transmission in ruminants. Notably, a mere three cases of human brucellosis resulting from potential tick bites were identified in search of global clinical case reports from 1963 to 2019., Conclusions: It is imperative to improve the techniques used to identify Brucella in ticks, particularly by developing a novel, efficient, precise approach that can be applied in a field setting. Furthermore, due to the lack of adequate evidence of tick-borne brucellosis, it is essential to integrate various disciplines, including experimental animal science, epidemiology, molecular genetics, and others, to better understand the efficacy of tick-borne brucellosis. By amalgamating multiple disciplines, we can enhance our comprehension and proficiency in tackling tick-borne brucellosis., (© 2024. The Author(s).)

To investigate the possible risk factors for death at post-treatment in children with acute lymphoblastic leukemia (ALL). A multivariate competing risk analysis was performed to retrospectively analyze the data of children with ALL who died after treatment with CCCG-ALL-2015 in China and to determine the possible risk factors for death at post-treatment in children with ALL. Age at the first diagnosis of ≥10 years; final risk level of high-risk; D19 minimal residual disease (MRD) (≥0.01%) and D46 MRD (≥0.01%); genetic abnormalities, such as KMT2A-rearrangement, c-Myc rearrangement, and PDGFRB rearrangement; and the presence of CNS3 (all P values, <0.05) were identified as independent risk factors, whereas the risk level at the first diagnosis of low-risk (LR) and ETV6::RUNX1 positivity was considered as independent protective factors of death in children with ALL. Among the 471 cases of death, 45 cases were treated with CCCG-ALL-2015 only, and 163 (34.61%) were treatment-related, with 62.42% due to severe infections. 55.83% of treatment-related mortality (TRM) occurred in the early phase of treatment (induction phase). TRM has a significant impact on the overall survival of pediatric patients with ALL. Moreover, the CCCG-ALL-2015 regimen has a better safety profile for treating children with ALL, with rates close to those in developed countries (registration number: ChiCTR-IPR-14005706; date of registration: June 4, 2014)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Ticks are known to transmit a wide range of diseases, including those caused by bacteria, viruses, and protozoa. The expansion of tick habitats has been intensified in recent years due to various factors such as global warming, alterations in microclimate, and human activities. Consequently, the probability of human exposure to diseases transmitted by ticks has increased, leading to a higher degree of risk associated with such diseases., Methods: In this study, we conducted a comprehensive review of domestic and international literature databases to determine the current distribution of tick species in Inner Mongolia. Next, we employed the MaxEnt model to analyze vital climatic and environmental factors influencing dominant tick distribution. Subsequently, we predicted the potential suitability areas of these dominant tick species under the near current conditions and the BCC-CSM2.MR model SSP245 scenario for the future periods of 2021-2040, 2041-2060, 2061-2080, and 2081-2100., Results: Our study revealed the presence of 23 tick species from six genera in Inner Mongolia, including four dominant tick species (Dermacentor nuttalli, Ixodes persulcatus, Dermacentor silvarum, and Hyalomma asiaticum). Dermacentor nuttalli, D. silvarum, and I. persulcatus are predominantly found in regions such as Xilin Gol and Hulunbuir. Temperature seasonality (Bio4), elevation (elev), and precipitation seasonality (Bio15) were the primary variables impacting the distribution of three tick species. In contrast, H. asiaticum is mainly distributed in Alxa and Bayannur and demonstrates heightened sensitivity to precipitation and other climatic factors. Our modeling results suggested that the potential suitability areas of these tick species would experience fluctuations over the four future periods (2021-2040, 2041-2060, 2061-2080, and 2081-2100). Specifically, by 2081-2100, the centroid of suitable habitat for D. nuttalli, H. asiaticum, and I. persulcatus was predicted to shift westward, with new suitability areas emerging in regions such as Chifeng and Xilin Gol. The centroid of suitable habitat for H. asiaticum will move northeastward, and new suitability areas are likely to appear in areas such as Ordos and Bayannur., Conclusions: This study provided a comprehensive overview of the tick species distribution patterns in Inner Mongolia. Our research has revealed a significant diversity of tick species in the region, exhibiting a wide distribution but with notable regional disparities. Our modeling results suggested that the dominant tick species' suitable habitats will significantly expand in the future compared to their existing distribution under the near current conditions. Temperature and precipitation are the primary variables influencing these shifts in distribution. These findings can provide a valuable reference for future research on tick distribution and the surveillance of tick-borne diseases in the region., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Because of successful thalassaemia prevention programmes in resource-rich countries and it's huge population China now has the greatest number of new cases of thalassaemia globally as well as more people with thalassaemia than any other country. 30 million Chinese have thalassaemia-associated mutations and about 300,000 have thalassaemia major or intermedia requiring medical intervention. Over the past 2 decades there has been tremendous economic growth in China including per capita spending on health care. There is now nation-wide availability and partial or full insurance for prenatal genetic testing, RBC-transfusions, iron-chelating drugs and haematopoietic cell transplants. Prenatal screening and educational programmes have reduced the incidence of new cases. However, substantial challenges remain. For example, regional differences in access to medical care and unequal economic development require innovations to reduce the medical, financial and psychological burdens of Chinese with thalassaemia and their families. In this review we discuss success in preventing and treating thalassaemia in China highlighting remaining challenges. Our discussion has important implications for resource-poor geospaces challenged with preventing and treating thalassaemia., Competing Interests: Declaration of Competing Interest RPG is a consultant to NexImmune Inc. and Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd., (Copyright © 2023. Published by Elsevier Ltd.)

Background: ASXL1 mutation is an independent prognostic factor in adult acute myeloid leukemia (AML), but its effect on the prognosis of pediatric AML is poorly understood., Aims: This study aimed to investigate the clinical characteristics and prognostic factors of ASXL1-mutant pediatric AML from a large Chinese multicenter cohort., Methods: A total of 584 pediatric patients with newly diagnosed AML from 10 centers in South China were enrolled. The exon 13 of ASXL1 was amplified by polymerase chain reaction (PCR), and then analyzed the mutation status of the locus. (n = 59 for ASXL1-mut group, n = 487 for ASXL1-wt group)., Results: ASXL1 mutations were found in 10.81% of all patients with AML. A complex karyotype was significantly less common in the ASXL1-mut AML group than in the ASXL1-wt group (1.7% vs. 11.9%, p = 0.013). Furthermore, TET2 or TP53 mutations were predominantly found in the ASXL1+ group (p = 0.003 and 0.023, respectively). The 5-year overall survival (OS) and event-free survival (EFS) of the total cohort were 76.9% and 69.9%. In ASXL1-mut AML patients, a white blood cell (WBC) count ≥50 × 10 9 /L had significantly poorer 5-year OS and EFS than a WBC count <50 × 10 9 /L (78.0% vs. 44.6%, p = 0.001; 74.8% vs. 44.6%, p = 0.003, respectively), while receiving hematopoietic stem cell transplantation (HSCT) had a higher 5-year OS and EFS (84.5% vs. 48.5%, p = 0.024; 79.5% vs. 49.3%, p = 0.047, respectively). In the multivariate Cox regression analysis, patients with high-risk AML undergoing HSCT tended to have a better 5-year OS and EFS than those receiving chemotherapy as a consolidation (HR = 0.168 and 0.260, both p < 0.001), and WBC count ≥50 × 10 9 /L or failure to achieve complete response after the first course were independent adverse predictors of OS and EFS (HR = 1.784 and 1.870, p = 0.042 and 0.018; HR = 3.242 and 3.235, both p < 0.001)., Conclusion: The C-HUANA-AML-15 protocol is a well-tolerated and effective in the treatment of pediatric AML. ASXL1 mutation is not an independent adverse prognosis predictor for survival in AML, whereas ASXL1-mut patients tend to have a poor prognosis if WBC count ≥50 × 10 9 /L, but they can benefit from HSCT., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: The purpose of this study was to examine the effect of iron overload on the mobilization of peripheral blood stem cells (PBSCs) in pediatric patients with β-thalassemia major (TM)., Methods: We retrospectively reviewed the records of 226 patients with TM from whom PBSCs were collected. Iron overload was based on serum ferritin level, and liver and cardiac iron overload was measured by magnetic resonance imaging (MRI) T2*., Results: The mean age of the TM patients was 7.35 ± 3.41 years. Of the patients, only 171 received MRI. Of the 171 patients, 35 had normal liver iron levels, 39 mild liver iron overload, 90 intermediate liver iron overload, and 7 severe liver iron overload. The intermediate + severe group was associated with significantly higher age and BMI and lower leukapheresis product white blood cell count and CD34+ cell levels (all, p &lt; 0.05)., Conclusion: Leukapheresis indices were similar between patients with different degrees of iron overload according to the ferritin level and cardiac iron overload, in which the later might be due to the small number of patients with cardiac overload. In patients with TM, the intermediate and severe liver iron overload was associated with poorer mobilization of PBSCs., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Many cytogenetic changes and gene mutations are associated with acute myeloid leukemia (AML) survival outcomes. CD56 is related to poor prognosis when expressed in adult AML patients. However, the prognostic value of CD56 in children with AML has rarely been reported. In this research, we aimed to evaluate the prognostic value of CD56 in childhood AML., Methods: The present retrospective study included 145 newly diagnosed pediatric patients with de novo AML (excluding AML-M3) in two hospitals between January 2015 and April 2021., Results: The total median (range) age was 75 (8-176) months, and the median follow-up time was 35 months. No significant difference in the 3-year overall survival rate was noted between the CD56-positive and CD56-negative groups (67.0% vs. 79.3%, P = 0.157) who received chemotherapy. However, among high-risk patients, the CD56-positive group had a worse overall survival rate and event-free survival rate (P < 0.05). Furthermore, among high-risk patients, the CD56-positive group had higher relapse and mortality rates than the CD56-negative group (P < 0.05)., Conclusions: CD56 represents a potential factor of poor prognosis in specific groups of children with AML and should be considered in the risk stratification of the disease. Given the independent prognostic value of CD56 expression, we should consider integrating this marker with some immunophenotypic or cytogenetic abnormalities for comprehensive analysis., (© 2022. The Author(s).)

Objective: This study attempted to investigate miR-92a-3p expression in peripheral blood of patients with severe β-thalassemia, and the effect and action mechanism of miR-92a-3p on γ-globin expression and oxidative stress in erythroid precursor cells., Methods: CD34 + hematopoietic progenitor cells (HPCs) were isolated from peripheral blood of healthy volunteers and patients with severe β-thalassemia. The levels of miR-92a-3p, BCL11A, and γ-globin were measured in erythroid precursor cells. High-performance liquid chromatography (HPLC) was used to analyze hemoglobin F (HbF) content. HPCs were induced with erythroid differentiation and erythroid precursor cells were then obtained. The relevance between miR-92a-3p and BCL11A was studied using dual luciferase reporter gene assay, and the correlation between miR-92a-3p and HbF was assayed by Pearson correlation analysis. Reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) in erythroid precursor cells were tested to evaluate oxidative stress. Cell apoptosis was examined by flow cytometry., Results: Remarkably higher expression of miR-92a-3p was observed in erythroid precursor cells. Increased expression of miR-92a-3p resulted in elevated levels of γ-globin, GSH, and SOD, reduced expression of ROS and MDA, and decreased cell apoptosis. BCL11A was identified as a target of miR-92a-3p and to be downregulated by miR-92a-3p. Moreover, BCL11A knockdown alone increased the expression of γ-globin, SOD and GSH, and repressed the levels of ROS and MDA and cell apoptosis, and the following inhibition of miR-92a-3p changed these patterns., Conclusions: Our data indicated that miR-92a-3p might increase γ-globin level and reduce oxidative stress and apoptosis in erythroid precursor cells by downregulating BCL11A.

Background: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment for thalassaemia major (TM). Cord blood (CB) from a sibling has different characteristics from marrow and has potential advantages and disadvantages as a stem cell source., Methods: We retrospectively analyzed 68 children with beta-thalassaemia major (β-TM) who underwent fresh cord blood transplantation (F-CBT) from an HLA-matched sibling donor (MSD) between June 2010 and July 2018 in the Department of Pediatrics, Nanfang Hospital and Haematology-Oncology, Shenzhen Children's Hospital., Results: The median infused doses of total nucleated cells (TNCs) and CD34 + cells were 8.51×10 7 /kg and 3.16×10 5 /kg, respectively. The median time to neutrophil and platelet engraftment were, respectively, 27 and 31 days. The cumulative probabilities of acute and chronic graft-versus-host disease (GVHD) were very low after F-CBT (7.8% and 0.0%, respectively). Of the 68 paediatric patients, 67 patients survived during a median follow-up period of 61 months. The estimated 5-year probability of overall survival (OS) and disease-free survival (DFS) were 98.5% and 87.9%, respectively. Three patients experienced graft rejection (GR) (4.5%), and we identified CD34 + cell dose as a significant risk factor for graft failure ( p  = 0.036) in stratify analysis., Conclusions: The above results indicate that patients with β-TM have excellent outcomes after F-CBT from an HLA-MSD.

C-type lectin-like molecule-1 (CLL1) is preferentially expressed on acute myeloid leukemia (AML) stem cells and AML blasts, which can be considered as AML-associated antigen. Anti-CLL1-based CAR-T cells exhibited effective tumor-killing capacity in vitro and in AML-bearing mouse model. In this report, eight children with relapsed or refractory AML (R/R-AML) were recruited for a phase 1/2 clinical trial of autologous anti-CLL1 CAR-T cell immunotherapy. The objectives of this clinical trial were to evaluate the safety and the preliminary efficacy of anti-CLL1 CAR-T cell treatment. Patients received one dose of autologous anti-CLL1 CAR-T cells after lymphodepletion conditioning. After CAR-T treatment, patients developed grade 1-2 cytokine release syndrome (CRS) but without any lethal events. 4 out of 8 patients achieved morphologic leukemia-free state (MLFS) and minimal residual disease (MRD) negativity, 1 patient with MLFS and MRD positivity, 1 patient achieved complete remission with incomplete hematologic recovery (CRi) but MRD positivity, 1 patient with partial remission (PR), and 1 patient remained at stable disease (SD) status but had CLL1-positive AML blast clearance. These results suggested that anti-CLL1-based CAR-T cell immunotherapy can be considered as a well-tolerated and effective option for treating children with R/R-AML., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Haematopoietic cell transplantation (HCT) is the only curative treatment for haematological complications in patients with Fanconi anaemia (FA). Haploidentical (haplo-) HCT is a promising alternative for FA. We aimed to analyse the outcomes of unmanipulated haplo-HCT in patients with FA with radiation-free conditioning. A total of 56 patients from 11 centres between 2013 and 2021 in China were retrospectively analysed. The mean (SD) cumulative incidence was 96.4% (0.08%) for 30-day neutrophil engraftment and 85.5% (0.24%) for 100-day platelet engraftment. With a median (range) follow-up of 2.4 (0.2-5.8) years, favourable mean (SD) overall survival of 80.9% (5.5%) and event-free survival of 79.3% (5.6%) were achieved. The mean (SD) incidences of acute graft-versus-host disease (aGvHD) Grade II-IV and Grade III-IV were 55.4% (0.45%) and 42.9 (0.45%) respectively. The mean (SD) cumulative incidence of 3-year chronic graft-versus-host disease (cGvHD) was 34.7% (0.86%) and that of moderate-to-severe cGvHD was 9.0% (0.19%). Our data demonstrate that in unmanipulated haplo-HCT for patients with FA, radiation-free regimens based on fludarabine and low-dose cyclophosphamide ± busulfan achieved favourable engraftment and survival with relatively high incidences of aGvHD and cGvHD. These results prompt the use of low-intensity conditioning without radiation and intensive GvHD prophylaxis when considering unmanipulated haplo-HCT in patients with FA., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: To compare the therapeutic effect of transumbilical single-port laparoscopic surgery (TSPLS) and three-port laparoscopic surgery (TPLS) on ovarian cyst., Methods: Clinical data of 60 patients with ovarian cyst admitted to our hospital were respectively analyzed. The patients were divided into a TPLS group (n=30) and a TSPLS group (n=30) according to surgical methods. Clinical indicators, visual analogue scale (VAS), self-rating anxiety scale (SAS), self-rating depression scale (SDS) and satisfaction regarding aesthetic appearance of the incision were compared between the two groups., Results: The operation time, time to anal exhaust and hospital stay in the TSPLS group were shorter than those in the TPLS group, and lower postoperative VAS, SAS and SDS scores and higher quality-of-life score were seen in the TSPLS group (all P<0.05). The incidence of postoperative complications in the TSPLS group was lower than that in the TPLS group (P<0.05). The overall satisfaction in the TSPLS group was significantly higher than that in the TPLS group (93.33% vs. 66.67%; χ 2 =51.526, P=0.001)., Conclusion: Compared with TPLS, TSPLS has better therapeutic effect on ovarian cyst. TSPLS can improve the clinical indications of patients with higher safety., Competing Interests: None., (AJTR Copyright © 2021.)

Background: A prophylactic antimalarial drug that is both effective for protection and improves compliance is in high demand., Methods: We conducted a randomized, placebo-controlled, double-blinded phase 3 trial to evaluate the 1:1 fixed-dose combination of naphthoquine-azithromycin (NQAZ) for safety and protection against Plasmodium infections in villages along the China-Myanmar border. A total of 631 residents, 5-65 years of age, were randomized into the drug group (n = 319) and the placebo group (n = 312) to receive NZAQ and placebo, respectively, as a single-dose monthly treatment. Follow-ups were conducted weekly to monitor for adverse events and malaria infections., Results: Of the 531 subjects completing the trial, there were 46 and 3 blood smear-positive Plasmodium infections in the placebo and treatment groups, respectively. For the intent-to-treat analysis, the single-dose monthly NQAZ treatment had 93.62% protective efficacy (95% confidence interval [CI]: 91.72%-95.52%). For the per-protocol analysis, NQAZ treatment provided a 93.04% protective efficacy (95% CI: 90.98%-95.1%). Three smear-positive cases in the NQAZ group were all due to acute falciparum malaria. In comparison, NQAZ treatment provided 100% protection against the relapsing malaria Plasmodium vivax and Plasmodium ovale. The treatment group had 5.6% of participants experiencing transient elevation of liver aminotransferases compared with 2.2% in the placebo group (P > .05)., Conclusions: Monthly prophylaxis with NQAZ tablets was well tolerated and highly effective for preventing Plasmodium infections. It may prove useful for eliminating P. vivax in areas with a high prevalence of glucose-6-phosphate dehydrogenase deficiency in the population., Clinical Trials Registration: ChiCTR1800020140., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: A high ecotropic viral integration site 1 ( EVI1) expression ( EVI1 high ) is an independent prognostic factor in adult acute myeloid leukemia (AML). However, little is known of the prognostic value of EVI1 high in pediatric AML. This study aimed to examine the biological and prognostic significance of EVI1 high in uniformly treated pediatric patients with AML from a large cohort of seven centers in China., Methods: A diagnostic assay was developed to determine the relative EVI1 expression using a single real-time quantitative polymerase chain reaction in 421 newly diagnosed pediatric AML patients younger than 14 years from seven centers in southern China. All patients were treated with a uniform protocol, but only 383 patients were evaluated for their treatment response. The survival data were included in the subsequent analysis (n = 35 for EVI1 high , n = 348 for EVI1 low )., Results: EVI1 high was found in 9.0% of all 421 pediatric patients with de novo AML. EVI1 high was predominantly found in acute megakaryoblastic leukemia (FAB M7), MLL rearrangements, and unfavorable cytogenetic aberrance, whereas it was mutually exclusive with t (8; 21), inv (16)/t (16; 16), CEBPA , NPM1 , or C-KIT mutations. In the univariate Cox regression analysis, EVI1 high had a significantly adverse 5-year event-free survival (EFS) and overall survival (OS) [hazard ratio (HR) = 1.821 and 2.401, p = 0.036 and 0.005, respectively]. In the multivariate Cox regression analysis, EVI1 high was an independent prognostic factor for the OS (HR = 2.447, p = 0.015) but not EFS (HR = 1.556, p = 0.174). Furthermore, EVI1 high was an independent adverse predictor of the OS and EFS of patients with MLL rearrangements (univariate analysis: HR = 9.921 and 7.253, both p < 0.001; multivariate analysis: HR = 7.186 and 7.315, p = 0.005 and 0.001, respectively). Hematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) provided EVI1 high patients with a tendential survival benefit when compared with chemotherapy as a consolidation (5-year EFS: 68.4% vs. 50.8%, p = 0.26; 5-year OS: 65.9% vs. 54.8%, p = 0.45)., Conclusion: It could be concluded that EVI1 high can be detected in approximately 10% of pediatric AML cases. It is predominantly present in unfavorable cytogenetic subtypes and predicts adverse outcomes. Whether pediatric patients with EVI1 high AML can benefit from HSCT in CR1 needs to be researched further., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zheng, Huang, Le, Zheng, Hua, Chen, Feng, Li, Zheng, Xu, He, He, Li and Hu.)

Background: Vincristine plus dexamethasone pulses are generally used throughout maintenance treatment for childhood acute lymphoblastic leukaemia. However, previous studies remain inconclusive about the benefit of this maintenance therapy and the absence of randomised, controlled trials in patients with low-risk or high-risk acute lymphoblastic leukaemia provides uncertainty. We therefore aimed to determine if this therapy could be safely omitted beyond 1 year of treatment without leading to an inferior outcome in any risk subgroup of childhood acute lymphoblastic leukaemia., Methods: This open-label, multicentre, randomised, phase 3, non-inferiority trial involved 20 major medical centres across China. We enrolled patients who were aged 0-18 years with newly diagnosed acute lymphoblastic leukaemia that was subsequently in continuous remission for 1 year after initial treatment. Patients with secondary malignancy or primary immunodeficiency were excluded. Eligible patients were classified as having low-risk, intermediate-risk, or high-risk acute lymphoblastic leukaemia based on minimal residual disease and immunophenotypic and genetic features of leukaemic cells. Randomisation and analyses were done separately for the low-risk and intermediate-to-high-risk cohorts. Randomisation was generated by the study biostatistician with a block size of six. Stratification factors included participating centre, sex, and age at diagnosis; the low-risk cohort was additionally stratified for ETV6-RUNX1 status, and the intermediate-to-high-risk cohort for cell lineage. Patients in each risk cohort were randomly assigned (1:1) to either receive (ie, the control group) or not receive (ie, the experimental group) seven pulses of intravenous vincristine (1·5 mg/m 2 ) plus oral dexamethasone (6 mg/m 2 per day for 7 days) during the second year of treatment. The primary endpoint was difference in 5-year event-free survival between the experimental group and the control group for both the low-risk and intermediate-to-high-risk cohorts, with a non-inferiority margin of 0·05 (5%). The analysis was by intention to treat. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-14005706., Findings: Between Jan 1, 2015, and Feb 20, 2020, 6141 paediatric patients with newly diagnosed acute lymphoblastic leukaemia were registered to this study. Approximately 1 year after diagnosis and treatment, 5054 patients in continuous remission were randomly assigned, including 2923 (1442 in the control group and 1481 in the experimental group) with low-risk acute lymphoblastic leukaemia and 2131 (1071 control, 1060 experimental) with intermediate-to-high risk acute lymphoblastic leukaemia. Median follow-up for patients who were alive at the time of analysis was 3·7 years (IQR 2·8-4·7). Among patients with low-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (90·3% [95% CI 88·4-92·2] vs 90·2% [88·2-92·2]; p=0·90). The one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·024, establishing non-inferiority. Among patients with intermediate-to-high-risk acute lymphoblastic leukaemia, no difference was observed in 5-year event-free survival between the control group and the experimental group (82·8% [95% CI 80·0-85·7] vs 80·8% [77·7-84·0]; p=0·90), but the one-sided 95% upper confidence bound for the difference in 5-year event-free survival probability was 0·055, giving a borderline inferior result for those in the experimental group. In the low-risk cohort, we found no differences in the rates of infections, symptomatic osteonecrosis, or other complications during the second year of maintenance treatment between patients in the control and experimental groups. Patients with intermediate-to-high-risk acute lymphoblastic leukaemia in the control group were more likely to develop grade 3-4 pneumonia (26 [2·4%] of 1071 vs ten [0·9%] of 1060) and vincristine-related peripheral neuropathy (17 [1·6%] vs six [0·6%]) compared with the experimental group. Incidence of grade 5 fatal infection was similar between the control group and the experimental group in both the low-risk cohort (two [0·1%] of 1442 vs five [0·3%] of 1481) and intermediate-to-high risk cohort (six [0·6%] of 1071 vs five [0·5%] of 1060)., Interpretation: Vincristine plus dexamethasone pulses might be omitted beyond 1 year of treatment for children with low-risk acute lymphoblastic leukaemia. Additional studies are needed for intermediate-to-high-risk acute lymphoblastic leukaemia., Funding: VIVA China Children's Cancer Foundation, the National Natural Science Foundation of China, the China fourth round of Three-Year Public Health Action Plan (2015-2017), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, US National Cancer Institute, St Baldrick's Foundation, and the American Lebanese Syrian Associated Charities., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests C-HP is on the scientific advisory board of Adaptive Biotechnology and the Data Monitoring Committee of Novartis; and has received honorariums from Amgen and Erytech. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706)., (© 2021 by The American Society of Hematology.)

Lab-attenuated rabies virus (RABV) is a highly cellular adaptation and less pathogenic than wild-type RABV. However, the molecular mechanisms that regulate the cellular adaptation and pathogenicity remain obscure. In this work, we isolated a wild-type RABV (CNIM1701) from a rabid bovine in northern China. The original CNIM1701 was lethal in adult mice and restricted replication in cell cultures. After 20 serial passages in the brains of suckling mice, the virus was renamed CNIM1701-P20, which was safe in adult mice and replicated well in cell cultures. In addition, sequence comparison analysis of the original CNIM1701 and CNIM1701-P20 identified 2 amino acid substitutions on G protein (Lys83 → Arg83 and Pro367 → Ser 367) related to pathogenesis and cellular adaptation. Using site-directed mutagenesis to exchange Lys83 with Arg83 and Pro367 with Ser 367 in the G protein of the RABV SAD strain, the pathogenicity of rSAD-K83R was significantly decreased. Our data indicate that the decreased pathogenicity of rSAD-K83R is due to increasing the expression of RABV-G, which also induced a higher level of apoptosis in infected cells. Furthermore, the K83 mutation induced high expression of MMP-2 and MMP-9 on DCs and promoted blood-brain barrier (BBB) permeability. These results demonstrate that the pathogenesis of RABV is partially dependent on G expression and BBB permeability, which may help in the design and development of highly safe, live-RABV vaccines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Wang, Liu, Zhang, Baolige, Zhao, Hu and Yang.)

Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL)., Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation., Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019., Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy., Main Outcomes and Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival., Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups., Conclusions and Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation., Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.

We studied 1110 patients with β-thalassemia major aged ≤25 years who received transplants with grafts from HLA-matched related (n = 677; 61%), HLA-mismatched related (n = 78; 7%), HLA-matched unrelated (n = 252; 23%), and HLA-mismatched unrelated (n = 103; 9%) donors between 2000 and 2016. Ninety percent of transplants were performed in the last decade. Eight-five percent of patients received ≥20 transfusions and 88% were inadequately chelated. All patients received myeloablative-conditioning regimen. Overall and event-free survival were highest for patients aged ≤6 years and after HLA-matched related and HLA-matched unrelated donor transplantation. The 5-year probabilities of overall survival for patients aged ≤6 years, 7 to 15 years, and 16 to 25 years, adjusted for donor type and conditioning regimen were 90%, 84%, and 63%, respectively ( P < .001). The corresponding probabilities for event-free survival were 86%, 80%, and 63% ( P < .001). Overall and event-free survival did not differ between HLA-matched related and HLA-matched unrelated donor transplantation (89% vs 87% and 86% vs 82%, respectively). Corresponding probabilities after mismatched related and mismatched unrelated donor transplantation were 73% vs 83% and 70% vs 78%. In conclusion, if transplantation is considered as a treatment option it should be offered early (age ≤6 years). An HLA-matched unrelated donor is a suitable alternative if an HLA-matched relative is not available., (© 2019 by The American Society of Hematology.)

FOS is component of the AP-1 complex and has been reported to be involved in many cellular functions, including cell proliferation, differentiation, survival, angiogenesis, hematopoiesis and cancer progress. To further understand the exact role of FOS in these processes, here we created two FOS knockout human embryonic stem cell lines by CRISPR/Cas9 mediated gene targeting. These cell lines retained normal morphology and karyotype, normal expression of pluripotent markers, and differentiation potential both in vivo and in vitro. These cell lines can be used to verify whether the FOS mutated produces any affect on endothelial cells and hematopoietic progenitor cells during the hematopoietic differentiation., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

To provide a detailed insight into the early biological process of tobacco mosaic disease, transcriptomic changes in tobacco leaves were surveyed at 1, 3 and 5 days after mono-infected by Tobacco mosaic virus (TMV) and co-infected by Cucumber mosaic virus (CMV) and TMV. At the three different stages, there were 2372, 3168 and 2045 differentially expressed genes (DEGs) in mono-infected leaves, and 2388, 3281 and 3417 DEGs were identified in co-infected leaves. There were 836, 1538 and 1185 common DEGs between the mono-infection and co-infection at the three time points, respectively. These common DEGs were enriched in the pathways, such as photosynthesis, biosynthesis of secondary metabolites, plant-pathogen interaction, porphyrin and chlorophyll metabolism, phenylalanine metabolism and phenylpropanoid biosynthesis. Photosynthesis pathway was observably down-regulated, and defense response pathways were markedly up-regulated. These pathways have been found to be related to tobacco mosaic disease. Of these common DEGs, the changes in expression of argonaute proteins, thioredoxins and peroxidases showed that the activation of RNA silencing and the destruction of redox balance can be induced by tobacco mosaic virus infection, resulting in the reset of biology process and damage in tobacco plants. Additionally, the occurrence of symptoms in co-infected tobacco plants was more early and serious than mono-infection, indicating that there is synergy between TMV and CMV in co-infected tobacco plants. The timely usage of antiviral agents and plant resistance inducers can decrease the incidence of tobacco mosaic disease through changing the expression of some DEGs, indicating that these genes can be used to screen novel plant resistance inducers and antiviral agents. Overall, our results were helpful in clarifying the mechanism of tobacco mosaic disease and provided novel strategies for the prevention of tobacco mosaic disease., Competing Interests: Conflict of interestThe authors declare no competing or financial interests.

Objectives: Before 2003, most children with acute lymphoblastic leukaemia (ALL) abandoned treatment, with only approximately 30% treated in China. With the development of national insurance for underprivileged patients, we assessed the current frequency and causes of treatment abandonment among patients with ALL who were enrolled in the Chinese Children's Cancer Group ALL protocol between 2015 and 2016., Methods: Demographic, clinical and laboratory data on patients who abandoned treatment, as well as economic and sociocultural data of their families were collected and analysed. General health-related statistics were retrieved from publicly accessible databanks maintained by the Chinese government., Results: At a median follow-up of 119 weeks, 83 (3.1%, 95% CI 2.5% to 3.8%) of the 2641 patients abandoned treatment. Factors independently associated with abandonment included standard/high-risk ALL (OR 2.62, 95% CI 1.43 to 4.77), presence of minimal residual disease at the end of remission induction (OR 3.57, 95% CI 1.90 to 6.74) and low-income economic region (OR 3.7, 95% CI 1.89 to 7.05). According to the family members, economic constraints (50.6%, p=0.0001) were the main reason for treatment abandonment, followed by the belief of incurability, severe side effects and concern over late complications., Conclusions: The rate of ALL treatment abandonment has been greatly reduced in China. Standard/high-risk ALL, residence in a low-income region and economic difficulties were associated with treatment abandonment., Clinical Trial Registration Number: ChiCTR-IPR-14005706, pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous studies have shown that wild-type (wt) rabies virus (RABV) evades the host immune response by restricting expression of glycoprotein (G), which blocks activation of dendritic cells (DCs) and induces production of virus-neutralizing antibodies (VNAs). In the present study, wt RABVs not only restricted G expression but also reduced incorporation of G into mature virions compared with laboratory-adapted viruses. A recombinant RABV expressing triple G was used to further determine whether G expression relates to incorporation. The recombinant virus showed higher expression and incorporation of G and activated more DCs than the virus that expressed a single copy of G. Removal of G from viruses using subtilisin or Dithiothreitol (DTT)/ Nonidet P-40 (NP40) almost completely abolishes DC activation and VNA production. Consequently, these G-depleted viruses cause lethal infection in mice. Thus, wt RABVs can subvert DC-induced antiviral immune response and maintain pathogenicity by decreasing G expression in infected cells and G incorporation into virions.

The aim of this study was to investigate the function of Cystic fibrosis transmembrane conductance regulator (CFTR) in human glioblastoma (GBM) cells. Data dining results of the Human Protein Atlas showed that low CFTR expression was associated with poor prognosis for GBM patients. We found that CFTR protein expression was lower in U87 and U251 GBM cells than that in normal humane astrocyte cells. CFTR activation significantly reduced GBM cell proliferation. In addition, CFTR activation significantly abrogated migration and invasion of GBM cells. Besides, CFTR activator Forskolin treatment markedly reduced MMP-2 protein expression. These effects of CFTR activation were significantly inhibited by CFTR inhibitor CFTRinh-172 pretreatment. Our findings suggested that JAK2/STAT3 signaling was involved in the anti-glioblastoma effects of CFTR activation. Moreover, CFTR overexpression in combination with Forskolin induced a synergistic anti-proliferative response in U87 cells. Overall, our findings demonstrated that CFTR activation suppressed GBM cell proliferation, migration and invasion likely through the inhibition of JAK2/STAT3 signaling., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The present study is to evaluate the biological functions of long non-coding RNA (lncRNA), X-inactive specific transcript, X-inactive specific transcript (XIST) in human epithelial ovarian cancer (EOC)., Methods: XIST was upregulated in EOC cell lines, CAOV3 and OVCAR3 cells by lentiviral transduction. The effects of XIST overexpression on cancer cell proliferation, invasion, chemosensitivity and in vivo tumor growth were investigated, respectively. Possible sponging interaction between XIST and human microRNA hsa-miR-214-3p was further evaluated. Furthermore, hsa-miR-214-3p was overexpressed in XIST-upregulated CAOV3 and OVCAR3 cells to evaluate its effect on XIST-mediated EOC regulation., Results: Lentivirus-mediated XIST upregulation had significant anticancer effects in CAOV3 and OVCAR3 cells by suppressing cancer cell proliferation, invasion, increasing cisplatin chemosensitivity and inhibiting in vivo tumor growth. Hsa-miR-214-3p was confirmed to directly bind XIST, and inversely downregulated in XIST-upregulated EOC cells. In EOC cells with XIST upregulation, secondary lentiviral transduction successfully upregulated hsa-miR-214-3p expression. Subsequently, hsa-miR-214-3p upregulation functionally reversed the anticancer effects of XIST-upregulation in EOC., Conclusion: Upregulation of lncRNA XIST may suppress EOC development, possibly through sponging effect to induce hsa-miR-214-3p downregulation., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2018. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Objectives: This meta-analysis evaluated the impact of granulocyte colony-stimulating factor (G-CSF) added to chemotherapy on treatment outcomes including survival and disease recurrence in patients with acute myeloid leukemia (AML)., Methods: Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 19 September 2016 using search terms. Studies that investigated patients with AML who underwent stem-cell transplantation were included., Results: The overall analysis revealed a significant improvement in overall survival (OS) (P = .019) and disease-free survival (DFS) (P = .002) for patients receiving G-CSF with chemotherapy. Among patients without prior AML treatment, there was a significant improvement in DFS (P = .014) and reduction in incidence of relapse (P = .015) for those who received G-CSF. However, subgroup analyses found no significant difference between G-CSF (+) and G-CSF (-) treatments in rates of OS (P = .104) and complete remission (CR) (P = .572) for patients without prior AML treatment. Among patients with relapsed/refractory AML, there was no significant difference found between G-CSF (+) and G-CSF (-) groups for OS (P = .225), DFS (P = .209), and CR (P = .208)., Discussion: Treatment with chemotherapy plus G-CSF appears to provide better survival and treatment responses compared with chemotherapy alone, particularly for patients with previously untreated AML., Abbreviations: AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; DFS, disease-free survival; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; HR, hazard ratio; MDS, myelodysplastic syndrome; OR, odds ratio; OS, overall survival; RCTs, randomized control trials; RR, relative risk.

New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for 2 months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated, without any serious adverse events. Four adverse events (transient and slight elevations of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, against Plasmodium falciparum infections, whereas both offered 100% prophylactic efficacy against Plasmodium vivax and Plasmodium ovale These trials showed that NQAZ had a good safety profile, and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species., (Copyright © 2018 American Society for Microbiology.)

The use of chemotherapeutic agents prior to treatment with infusion of cluster of differentiation (CD)19-chimeric antigen receptor (CAR)‑T cells is important for the efficacy of clinical therapies against hematological malignancies. However, the effect of chemotherapeutic agents on CD19‑CAR‑T cells and the associated underlying mechanisms remain unknown. The first aim of the present study was to determine the effect of chemotherapeutic agents on CAR‑T cells using the in vitro Cell Counting kit 8 assay. The second aim was to evaluate the abilities of fludarabine (FDR) and mafosfamide (MFA; a metabolite of cyclophosphamide) to induce apoptosis of CD19‑CAR‑T cells via the use of Annexin V/propidium iodide double staining. In addition, a JC‑1 fluorescent probe was used to detect alterations in cell membrane potential, and flow cytometry analysis was used to measure concentrations of caspase‑3/7 to identify apoptotic pathways of CD19‑CAR‑T cells. The data of the present study suggested that FDR and MFA inhibit the activities of CD19‑CAR‑T cells. Alterations to the mitochondrial membrane potential and an increase in the concentration of caspase‑3/7 indicated early apoptosis of FDR‑ and MFA‑treated CD19‑CAR‑T cells. The present study laid a theoretical foundation for the development of programs for clinical treatment.

The aim of the present study was to investigate the function of long non‑coding RNA TUG1 in hypoxia‑induced myocardial cell injury and to explore the potential molecular mechanisms. The cardiomyocyte cell line H9c2 was cultured under hypoxic and normoxic conditions. TUG1 expression under hypoxic conditions was then detected. The effects of TUG1 overexpression on viability, apoptosis, migration and invasion were assayed. In addition, the microRNA (miR)‑145‑5p expression was detected. Following H9c2 cell transfection with miR‑145‑5p mimics, the H9c2 cell viability, apoptosis, migration and invasion were also detected. Additionally, the target gene of miR‑145‑5p was assayed by Luciferase reporter assay. The protein expressions of Wnt‑3a, Wnt5a, and β‑catenin in H9c2 cells under hypoxic conditions were also determined. The results revealed that hypoxia induced injury in H9c2 cells, including inhibiting cell viability, migration and invasion, and promoting cell apoptosis. Overexpression of TUG1 aggravated hypoxia‑induced injury in H9c2 cells. In addition, miR‑145‑5p was negatively regulated by TUG1, and TUG1 overexpression aggravated hypoxia‑induced injury via the downregulation of miR‑145‑5p. Furthermore, B‑cell lymphoma 2 interacting protein 3 (Bnip3) was a target of miR‑145‑5p, and overexpression of Bnip3 aggravated hypoxia‑induced cell injury by activating Wnt/β‑catenin signaling pathways in H9c2 cells. In conclusion, overexpression of TUG1 aggravated hypoxia‑induced injury in cardiomyocytes by regulating the miR‑145‑5p‑Binp3 axis. Activation of the Wnt/β‑catenin signaling pathway may be a key mechanism to mediate the role of TUG1 in regulating hypoxia‑induced myocardial injury. TUG1 may be an effective diagnostic marker and therapeutic target for myocardial ischemia.

Background: Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for thalassemia majorTM. Graft rejection (GR) and graft-versus-host disease (GVHD) are the primary obstacles to a successful outcome., Methods: We conducted a retrospective study of HSCT in 29 children (median age at transplantation: 6 years) with Beta-thalassemia (β-TM) after the combined infusion of granulocyte colony-stimulating factor-primed bone marrow (G-BM) and cord blood (CB) from the human leukocyte antigen (HLA)-identical sibling donors. We also compared the outcomes of the co-transplanted children with those of children with β-TM who received G-BM alone from an HLA-identical sibling donor (n = 26)., Results: Compared to the G-BM transplant (G-BMT) recipients, those who received a co-transplant had a lower incidence of grade ≥II acute (17.24 vs. 30.7%, p = 0.047) and limited chronic (0 vs.15.4%, p = 0.022) GVHD as well as a lower incidence of GR (0 vs. 7.7%, p = 0.132). Neutrophil recovery time was faster in the co-transplant group (18.5 vs. 21 days, p = 0.04). All the patients were monitored until December 31, 2016; the median follow-up time was 74 months, and the 5-year thalassemia-free survival rate was 89.7% in the co-transplant group and 84.6% in the G-BMT-alone group (p = 0.590)., Conclusions: A combined CB and G-BM graft from an HLA-identical sibling donor is an effective treatment option for TM in children, with less acute and chronic GVHD., (© 2018 S. Karger AG, Basel.)

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver condition worldwide. However, its etiology and fundamental pathophysiology for the disease process are poorly understood. In this study, we thus used bioinformatics to identify candidate genes potentially causative of severe NAFLD., Methods: Gene expression profile data GSE49541 were downloaded from the Gene Expression Omnibus database. Tissues samples from 32 severe and 40 mild NAFLD patients were evaluated to identify differentially expressed genes (DEGs) between the 2 groups, followed by analyses of Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes pathways. Then, a weighted protein-protein interaction (PPI) network was constructed, and subnetworks and candidate genes were screened. Moreover, the GSE48452 data (14 normal liver tissue samples and 18 nonalcoholic steatohepatitis samples) were used to verify the results obtained from the above analyses., Results: A total of 100 upregulated genes and 24 downregulated ones were identified in severe NAFLD. Functional enrichment and pathway analyses showed that these DEGs were mainly associated with cell adhesion, inflammatory response, and chemokine activity. The top 5 subnetworks were selected based on the PPI network. A total of 5 hub genes, including ubiquilin 4 (UBQLN4), amyloid-beta precursor protein (APP), sex hormone-binding globulin (SHBG), cadherin-associated protein beta 1 (CTNNB1) and collagen type I alpha 1 (COL1A1), were considered to be candidate genes for NAFLD. In addition, the verification data confirmed the status of COL1A1, SHBG, and APP as candidate genes., Conclusion: UBQLN4, APP, CTNNB1, SHBG, and COL1A1 might be involved in the development of NAFLD, and are proposed as the potential markers for predicting the development of this condition.

Background: Acute renal failure (ARF) developed due to various causes and may lead to significant morbidity and mortality among pediatric patients., Objectives: The study was conducted to determine the incidence, etiology, outcome of treatment and clinical presentation of ARF in pediatric patients in Somalia., Methods: Comprehensive case history of 39 pediatric patients below 12 years of age, admitted with renal diseases in four tertiary care hospitals in Hargeisa and Borama cities in Somalia during December 2015 to November 2016. They were subjected to clinical investigation and laboratory test analysis based on the inclusion criteria of renal insufficiency characterized by serum creatinine level more than 1.5 mg/dl., Results: ARF was most commonly found in five to 12 years age group (53.8%) compared to infant (zero to one year) and pre-school (one to five years) children (23.08%). Mean age of presentation was 6.14 years. Male female ratio in this study was 1.2: 1. Most common presenting clinical feature in our study was oliguria (97.43%), swelling (69.2%), fever (84.1%), abdomen pain and nausea-vomiting (41.02%). Common clinical signs were edema (66.66%), altered sensorium (51.28%), hematuria (48.71%) and hypertension (38.46%). Snake bite and acute post streptococcal glomerulonephritis were the two most common causes of ARF in children in our study. Common complications were hypertension (38.46%), anemia (35.89%), hyperkalemia (25.64%) and infection (20.51%), all of which were within the previously reported range. The factors which correlated positively with increased mortality and morbidity were females with age below one year , etiology like septicemia and systemic lupus erythematosus (SLE), high peak serum creatinine concentration and complicated by disseminated intravascular coagulation (DIC)., Conclusion: Many causes of ARF are preventable and it should be possible to reduce mortality and morbidity due to ARF through purposive preventive measure and availability of the better medical facility., Competing Interests: The authors have declared that no competing interests exist.

The delivery of combination chemotherapy by nanoscale platforms has been demonstrated to enhance cancer treatment in the clinic. Cisplatin (CDDP)-crosslinked, glutathione-sensitive, tumor-targeting micelles based on carboxymethyl chitosan were designed for synergistic cisplatin-doxorubicin (DOX) combination chemotherapy. In our study, DOX was conjugated to carboxymethyl chitosan through a disulfide bond, which was structurally characterized by 1 H NMR. The micelles formed by self-assembly were spherical, with the mean diameter of 274nm. The in vitro release studies revealed that the micelles were highly glutathione-sensitive. Cytotoxicity analysis demonstrated that the cisplatin-crosslinked micelles loaded with DOX exhibited enhanced therapeutic efficacy compared with the DOX-loaded nanoparticles, free DOX, and free CDDP. Cellular uptake and intracellular release revealed that the cisplatin-crosslinked micelles loaded with DOX could efficiently deliver and release DOX into the cancer cells. These results clearly indicate that tumor-targeting and glutathione-sensitive micelles provide means for combination drug delivery in cancer treatment., (Copyright © 2016. Published by Elsevier Ltd.)

Novel glutathione (GSH)-dependent micelles based on carboxymethyl chitosan (CMCS) were developed for triggered intracellular release of doxorubicin (DOX). DOX-33'-Dithiobis (N-hydroxysuccinimidyl propionate)-CMCS (DOX-DSP-CMCS) prodrugs were synthesized. DOX was attached to the amino group on CMCS via disulfide bonds and drug-loaded micelles were formed by self-assembly. The micelles formed core-shell structure with CMCS and DOX as the shell and core, respectively, in aqueous media. The structure of the prodrugs was confirmed by IR and proton nuclear magnetic resonance ( 1 H NMR) spectroscopy. The drug-loading capacity determined by UV spectrophotometry was 4.96% and the critical micelle concentration of polymer prodrugs determined by pyrene fluorescence was 0.089 mg/mL. Micelles were spherical and the mean size of the nanoparticles was 174 nm, with a narrow polydispersity index of 0.106. Moreover, in vitro drug release experiments showed that the micelles were highly GSH-sensitive owing to the reductively degradable disulfide bonds. Cell counting kit (CCK-8) assays revealed that DOX-DSP-CMCS micelles exhibited effective cytotoxicity against HeLa cells. Moreover, confocal laser scanning microscopy (CLSM) demonstrated that DOX-DSP-CMCS micelles could efficiently deliver and release DOX in the cancer cells. In conclusion, the DOX-DSP-CMCS nanosystem is a promising drug delivery vehicle for cancer therapy.

Background: Long-term health-related quality of life (HRQoL) of pediatric patients after hematopoietic stem cell transplantation (HSCT) is increasingly studied worldwide. However, few studies have been performed in China, where no uniform scale is available; the PedsQL™ Cancer Module 3.0 Chinese Mandarin version has been used to evaluate HRQoL of patients after HSCT in China. This study aimed to assess the reliability and validity of the Chinese Mandarin version of PedsQL™ 3.0 Transplant Module., Methods: Patients between 2 and 18 years old, who underwent HSCT from January 2006 to June 2014, were recruited in Beijing Children's Hospital affiliated to Capital Medical University, the First Affiliated Hospital of Southern Medical University and Beijing Daopei Hospital. 207 parent reports and 182 child self-reports of the PedsQL™ 3.0 Transplant Module Chinese Mandarin version were assigned, of which 362 were returned., Results: No missing item response was observed in the returned reports. Cronbach's alpha coefficient exceeded 0.7 in total scale and every dimension. The intraclass correlation coefficient exceeded 0.8 in all dimensions of child self-reports and parent reports. Spearman's rank correlation coefficients of items and their respective dimensions were 0.6-0.94 in parent reports, and 0.62-0.93 in child self-reports, while a weak association was found between the items and other dimensions. Exploratory factor analysis indicated a good extraction effect, and construct validity of the scale was >60 %., Conclusions: The Chinese Mandarin version of PedsQL™ 3.0 Transplant Module has good feasibility, reliability and validity. Its use may help improve the HRQoL of children after HSCT in China.

Objective: To observe the status of iron deposition in patient with β thalassemia major, and to formulate appropriate treatment strategies., Method: The data of status of transfusion and chelation in 135 patients aged from 6 years and 4 months to 17 years and 11 months with β thalassemia major were collected and analyzed. Serum ferritin levels were determined and cardiac and hepatic iron deposition was determined using MRI T2(*) technology., Result: Of the 135 cases studied, 66 were male, and 69 were female, their average age was 12.1 years. Serum ferritin (SF) was determined for 111 cases, it varied from 1 086.8 µg/L to 15 011.5 µg/L. Among them, 16 cases had SF level <2 000 µg/L (14.5%) , in 41 cases SF were between 2 000 and 4 000 µg/L (36.0%) ;in 54 cases SF >4 000 µg/L (48.7%) . Liver MRI T2(*) results showed that in only 8 cases (5.9%) iron content in the liver was in normal range, 19 cases (14.9%) showed mild liver iron deposition;34 (25.2%) moderate and 74 (54.8%, the youngest one was only 6 years and 4 months of age) had severe iron deposition respectively. Cardiac MRI T2(*) showed that in 89 cases (65.9%) iron content in the heart was in normal range;19 cases (14.1%) had mild cardiac iron deposition and 27 (20.0%) presented severe iron deposition (the youngest one was only 9 years and 3 months of age) . SF level was obviously related to liver and cardiac iron deposition (MRI T2(*)) r and P value were -0.284, 0.003 and -0.374, 0.000 respectively. In 108 cases regular transfusion and chelation were delayed due to financial problem. The late and insufficient dosage administered and irregular chelation caused the higher SF level and the severe iron deposition., Conclusion: The survival status of β thalassemia major in China is worrisome. Majority of them had not received regular transfusion and chelation. Liver and cardiac iron deposition occur early and had a high incidence.

Background/aims: There exists few pediatric data on the safety and efficacy of prophylactic antibiotics during chemotherapy-induced agranulocytosis., Methods: We prospectively studied the incidence of infection-related fever in 38 children, aged 2-16 years, with acute myeloid leukemia (AML) over 121 chemotherapy treatment cycles. A prophylactic group (n = 18) was given either vancomycin/cefepime (400 mg/m(2), q12 h/50 mg/kg, q12 h) or piperacillin/tazobactam (110 mg/kg, q12 h). Control patients (n = 20) received no preventive antibiotics., Results: The prophylactic group (59 treatment cycles) experienced fever less frequently than the control group (0.4 vs. 0.9 events; p < 0.001), had a longer interval between agranulocytosis and fever (6.4 vs. 3.8 days; p = 0.007), had a shorter duration of hospitalization (21.5 vs. 28.5 days; p < 0.001), and had a lower rate of lung infection (38.8 vs. 80.0%; p < 0.001). One patient taking vancomycin experienced a skin rash and 3 patients taking piperacillin/tazobactam had diarrhea; these side effects subsided after antibiotics were discontinued., Conclusions: In children with AML, prophylactic antibiotics during the period of chemotherapy-induced agranulocytosis can effectively reduce the incidence of infectious fever and can shorten the average length of hospital stay, improving treatment success and quality of life., (© 2014 S. Karger AG, Basel.)

Objective: To assess the value of magnetic resonance imaging T2* tests in the detection of myocardial and liver iron overload in patients with β-thalassemia major (β-TM)., Methods: From 2010 to 2011, 28 β-TM patients over 10 years old under blood transfusion therapy and chelation care with serum ferritin (SF)>1000 µg/L underwent myocardial and liver MRI T2* tests on a voluntary basis. The results were analyzed in relation with age, SF, and left ventricular ejection fraction (LVEF)., Results: Fourteen out of the 28 cases (50%) were found to have myocardial iron overload, including 7 severe cases, 2 moderate cases, and 5 mild cases. All the 28 cases had liver iron overload, including 2 mild cases, 7 moderate cases, and 19 severe cases. Two out of the 28 cases had lowered LVEF (7.14%), and one of them had severe myocardial iron overload. There was a negative correlation between myocardial MRI T2* and SF (r=-0.479, P=0.01). Myocardial MRI T2* was positively correlated with liver MRI T2* (r=0.378, P=0.047). Age was not significantly correlated with SF, LVEF, or liver MRI T2*., Conclusion: Magnetic resonance imaging (T2*) detection is an effective and non-invasive means for detecting myocardial and liver iron overload in patients with β-thalassemia major receiving blood transfusion. T2* combined with SF is the main diagnostic indicator to assess iron overload in the vital organs.

We used a novel NF-08-TM transplant protocol based on intravenous busulfan, cyclophosphamide, fludarabine, and thiotepa in 82 consecutive patients with β-thalassemia major (TM), including 52 with allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors (UDs) with well-matched human leukocyte antigens and 30 with hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSDs). The median age at transplantation was 6.0 years (range, 0.6-15.0 years), and the ratio of male-to-female patients was 56:26. The median follow-up time was 24 months (range, 12-39 months). The estimated 3-year overall survival and TM-free survival were 92.3% and 90.4% in the UD-PBSCT group and 90.0% and 83.3% in the MSD-HSCT group. The cumulative incidences of graft rejection and grades III-IV acute graft-versus-host disease were 1.9% and 9.6%, respectively, in the UD-PBSCT group and 6.9% and 3.6%, respectively, in the MSD-HSCT group. The cumulative incidence of transplant-related mortality was 7.7% in the UD-PBSCT group and 10.0% in the MSD-HSCT group. In conclusion, UD-PBSCTs using the well-tolerated NF-08-TM protocol show similar results to MSD-HSCTs and can be used to treat β-thalassemia patients in the absence of MSDs.