The influence of methotrexate-related transporter and metabolizing enzyme gene polymorphisms on peri-engraftment syndrome and graft-versus-host disease after haplo-hematopoietic stem cell transplantation in pediatric patients with malignant hematological diseases

BackgroundMethotrexate (MTX), utilized as a graft-versus-host disease (GvHD) prophylactic agent in allogeneic hematopoietic stem cell transplantation (allo-HSCT), has been proven to effectively decrease the occurrence of the peri-engraftment syndrome (Peri-ES) and acute GvHD (aGvHD). Changes in the pharmacodynamics of MTX are closely associated with gene polymorphisms in genes encoding drug-metabolizing enzymes and transporters. Nevertheless, the current studies mainly concentrate on leukemia or autoimmune diseases, and limited studies on allo-HSCT were reported.MethodsHere, we retrospectively assessed the relationship between MTX-related transporter and metabolizing enzyme gene polymorphisms, clinical characteristics, and outcomes in 57 pediatric patients who received haploid HSCT (haplo-HSCT) with malignant tumors at a single center.ResultsWe discovered all gene polymorphisms were in the Hardy–Weinberg equilibrium in our cohort. We discovered a significant correlation between platelet recovery time and ABCB1 (1236C>T) (p = 0.042). Compared with patients with SLCO1B1 (1865+4846T>C) TT, patients with SLCO1B1 (1865+4846T>C) TC/CC had an increased incidence of Peri-ES (p = 0.030). Based on the multivariate Cox analysis, we discovered that SLCO1B1 (1865+4846T>C) TT genotype was an independent protective factor for Peri-ES morbidity (hazard ratio (HR) = 0.464, p = 0.031), and the dose of mononuclear cells reinfused was significantly correlated with II–IV aGvHD (HR = 2.604, p = 0.039).ConclusionIn summary, our findings prove that the host’s genotypes might modify the risk of developing Peri-ES, contribute to a better understanding of the inter-individual difference in efficacy, and facilitate the development of individualized approaches to GvHD prophylaxis

Event-Triggered Adaptive Neural Network Tracking Control with Dynamic Gain and Prespecified Tracking Accuracy for a Class of Pure-Feedback Systems

This paper studies the event-triggered adaptive tracking control problem of a class of pure-feedback systems. Via the backstepping method and the neural network approximation with the central symmetric distribution, an event-triggered adaptive neural network controller is designed. In particular, a dynamic gain driven by the tracking error is introduced into the event-triggering mechanism. Then, by using the Lyapunov stability theory, the boundedness of all the closed-loop signals is proved, and the tracking error falls into a prespecified ϵ-neighbourhood of zero. Meanwhile, the Zeno behaviour is avoided. Finally, two simulations verify the effectiveness of the proposed control scheme

Ten-Year Change in Disorders of Consciousness: A Bibliometric Analysis

Objectives: Disorders of consciousness (DoC) is a dynamic and challenging discipline, presenting intriguing challenges to clinicians and neurorehabilitation specialists for the lack of reliable assessment methods and interventions. Understanding DoC keeps pace with scientific research is urgent to need. We quantitively analyzed publications on DoC over the recent 10 years via bibliometrics analysis, to summarize the intellectual structure, current research hotspots, and future research trends in the field of DoC. Methods: Literature was obtained from the Science Citation Index Expanded of Web of Science Core Collection (WoSCC). To illustrate the knowledge structure of DoC, CiteSpace 5.8.R3 was used to conduct a co-occurrence analysis of countries, institutions, and keywords, and a co-citation analysis of references and journals. Also, Gephi 0.9.2 contributed to the author and co-cited author analysis. We found the most influential journals, authors, and countries and the most talked about keywords in the last decade of research. Results: A total of 1919 publications were collected. Over the past 10 years, the total number of annual publications has continued to increase, with the largest circulation in 2018. We found most DoC research and close cooperation originated from developed countries, e.g., the USA, Canada, and Italy. Academics from Belgium appear to have a strong presence in the field of DoC. The most influential journals were also mainly distributed in the USA and some European countries. Conclusions: This bibliometric study sheds light on the knowledge architecture of DoC research over the past decade, reflecting current hotspots and emerging trends, and providing new insights for clinicians and academics interested in DoC. The hot issues in DoC were diagnosing and differentiating the level of consciousness, and detecting covert awareness in early severe brain-injured patients. New trends focus on exploring the recovery mechanism of DoC and neuromodulation techniques

Initial indicators for the prognosis of Acinetobacter Baumannii bacteremia in children

Abstract Background Risk factors related to mortality due to Acinetobacter baumannii (AB) bacteremia have been unveiled previously, but early clinical manifestations of AB bacteremia based on prognosis remain uncovered. Methods The demographic characteristics, clinical features, antibiotic susceptibility, and outcomes of 37 hospitalized children with laboratory-confirmed AB bacteremia from Suzhou, China, were collected and analyzed retrospectively. Results Of the 37 children with AB bacteremia included in this study, 23 were males and 14 were females, with a median age of 4.83 (0.60 to 10.15) years. Among the children, 18 died (48.65%, 18/37) and 19 survived (51.35%, 19/37). The dead group had a significantly higher incidence of respiratory failure (p = 0.008), shock (P = 0.000), MODS (p = 0.000), neutropenia (< 1.5 × 109/L) (p = 0.000) and serious neutropenia (< 0.5 × 109/L) (p = 0.000) than those in the survival group. The death group had significantly more invasive procedures (2 or more) than that in the survival group at 2 weeks before onset (p = 0.005). The proportion of MDR-AB in the death group was significantly higher than that in the survival group (p = 0.000), while the PICS score was significantly lower in the survival group than that in the death group (p = 0.000). There was no significant difference in effective antibiotic use within 24 h between these two groups (p = 0.295). Among the 37 children with bloodstream infection of AB, 56.76% (21/37) of the underlying diseases were hematological diseases and oncology. Among them, 17 (81.00%) were died in the hospital. The proportion of white blood cells (p = 0.000), neutrophils (p = 0.042), eosinophils (p = 0.029), the ANC (p = 0.000) and lymphocyte (p = 0.000), the NLR(p = 0.011), hemoglobin (p = 0.001), platelets (p = 0.000), prealbumin (P = 0.000), LDH (p = 0.017), blood gas pH (p = 0.000), and serum potassium (p = 0.002) in the death group were significantly lower than those in the survival group. However, CRP (p = 0.000) and blood glucose(p = 0.036) were significantly higher in the death group than those in the survival group. By further multivariate analysis, CRP [OR (95% CI): 1.022(1.003, 1.041), p = 0.021] and neutropenia [OR (95% CI): 21.634 (2.05, 228.313, p = 0.011] within 24 h of infection were independent risk factors for death in children with AB bacteremia. When CRP was higher than 59.02 mg/L, the sensitivity of predicting mortality was 88.9%, and the specificity was 78.9%. And the sensitivity and specificity of neutropenia for predicting mortality were 83.3% and 84.2%. Conclusions AB bacteremia has a high mortality in children, especially in patients with hematological diseases and oncology. Many early indicators were associated with poor prognosis, while elevated CRP and neutropenia were the independent predictors for the 30-day mortality of children with laboratory-confirmed AB bacteremia

Differences between Yaks and Qaidam Cattle in Digestibilities of Nutrients and Ruminal Concentration of Volatile Fatty Acids Are not Dependent on Feed Level

The Qinghai–Tibetan Plateau (QTP) is characterized by highly fluctuating seasonal pastures. Yaks (Bos grunniens) graze at higher altitudes than Qaidam cattle (Bos taurus), but the two bovine species co-graze in their overlapping ranges. We hypothesized that yaks would digest nutrients to a greater extent and utilize energy more efficiently than cattle at low dietary intakes, but the difference between bovine species would not be apparent at high intakes. To test this hypothesis, six yaks (203 ± 6.0 kg) and six Qaidam cattle (214 ± 9.0 kg), all 3.5-year-old castrated males, were used in two concurrent 4 × 4 Latin square designs with two extra steers of each species in each period. The digestibilities of dry matter, organic matter, crude protein, ether extract, neutral and acid detergent fiber were greater (p p p p −0.75 d−1, which was lesser (p −0.75 d−1 in cattle. We concluded that: (1) when differences between breeds emerged, the differences existed for all FLs; (2) maintenance energy requirement was lesser and ADG was greater in yaks than in cattle; (3) the digestibilities of nutrients were greater in yaks than in cattle when consuming only oat hay pellets. These findings indicate that yaks adapt to fluctuating dietary intakes in harsh environments by having a low energy requirement and high digestibility of nutrients, independent of the FL

Atypical features and de novo heterozygous mutations in two siblings with Cockayne syndrome

Abstract Background Cockayne syndrome (CS) is a rare autosomal recessive disorder which displays multiorgan dysfunction, especially within the nervous system including psychomotor retardation, cerebral atrophy, microcephaly, cognitive dysfunction, mental retardation, and seizures. Many genetic variations reported were related to this syndrome, but splicing mutations with cardiac anomalies have not been found in previous studies. Methods Herein, we described a pair of brothers and sisters who present essential manifestations of CS including premature feature, developmental delay, growth failure, microcephaly, and characteristic facial features, such as sunken eyes and a beaked nose. Interestingly, the brother also presented with atypical features which included cardiac anomalies such as left atrioventricular enlargement and cardiac dysfunction such as dilated cardiomyopathy. In addition, whole exome sequencing and RNA sequencing were employed to analyze their genetic landscape. Results WES analysis showed that these two cases carried double unreported heterozygous spliced mutations in the excision repair cross‐complementing group 8 (ERCC8, also known as CSA, NM_000082) gene, which were c.78‐2 (IVS1) A>T and c.1042‐1 (IVS10) G>A, respectively. Moreover, transcript sequencing analysis validated these mutation sites. In this study, Gene Ontology enrichment and KEGG pathway analyses from RNA sequencing demonstrated similarities but some differences when compared with previous studies. Conclusion For patients with Cockayne syndrome, cardiac changes need to be monitored carefully, especially for cases with splicing mutations of the ERCC8 gene

Successful Treatment of Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Status in an Infant with KCNJ11-Related Neonatal Diabetes Mellitus via Continuous Renal Replacement Therapy

<p><b> </b></p> <p></p><p><strong>Article full text</strong></p> <p><br> The full text of this article can be found <a href="https://link.springer.com/article/10.1007/s13300-018-0484-3"><b>here</b>.</a><br> <br> <strong>Provide enhanced digital features for this article</strong><br> If you are an author of this publication and would like to provide additional enhanced digital features for your article then please contact <u>[email protected]</u>.<br> <br> The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.<br> <br> Other enhanced features include, but are not limited to:<br> • Slide decks<br> • Videos and animations<br> • Audio abstracts<br> • Audio slides<u></u></p><br><p></p

BRD4 PROTAC degrader MZ1 exhibits anti-B-cell acute lymphoblastic leukemia effects via targeting CCND3

ABSTRACTIntroduction B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent malignant tumor affecting children. While the majority of B-ALL patients (90%) experience successful recovery, early relapse cases of B-ALL continue to exhibit high mortality rates. MZ1, a novel inhibitor of Bromodomains and extra-terminal (BET) proteins, has demonstrated potent antitumor activity against hematological malignancies. The objective of this study was to examine the role and therapeutic potential of MZ1 in the treatment of B-ALL.Methods In order to ascertain the fundamental mechanism of MZ1, a sequence of in vitro assays was conducted on B-ALL cell lines, encompassing Cell Counting Kit 8 (CCK8) assay, Propidium iodide (PI) staining, and Annexin V/PI staining. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to examine protein and mRNA expression levels. Transcriptomic RNA sequencing (RNA-seq) was utilized to screen the target genes of MZ1, and lentiviral transfection was employed to establish stably-expressing/knockdown cell lines.Results MZ1 has been observed to induce the degradation of Bromodomain Containing 4 (BRD4), Bromodomain Containing 3 (BRD3), and Bromodomain Containing 2 (BRD2) in B-ALL cell strains, leading to inhibited cell growth and induction of cell apoptosis and cycle arrest in vitro. These findings suggest that MZ1 exhibits cytotoxic effects on two distinct molecular subtypes of B-ALL, namely 697 (TCF3/PBX1) and RS4;11 (MLL-AF4) B-ALL cell lines. Additionally, RNA-sequencing analysis revealed that MZ1 significantly downregulated the expression of Cyclin D3 (CCND3) gene in B-ALL cell lines, which in turn promoted cell apoptosis, blocked cell cycle, and caused cell proliferation inhibition.Conclusion Our results suggest that MZ1 has potential anti-B-ALL effects and might be a novel therapeutic target