Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1­G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1­G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7­G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9­G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion.

Recurrent MEF2D fusions with poor prognosis have been identified in B-cell precursor ALL (BCP-ALL). The molecular mechanisms underlying the pathogenic function of MEF2D fusions are poorly understood. Here, we show that MEF2D-HNRNPUL1 (MH) knock-in mice developed a progressive disease from impaired B-cell development at the pre-pro-B stage to pre-leukemia over 10 to 12 months. When cooperating with NRASG12D, MH drove an outbreak of BCP-ALL, with a more aggressive phenotype than the NRASG12D-induced leukemia. RNA-sequencing identified key networks involved in disease mechanisms. In chromatin immunoprecipitation-sequencing experiments, MH acquired increased chromatin-binding ability, mostly through MEF2D-responsive element (MRE) motifs in target genes, compared with wild-type MEF2D. Using X-ray crystallography, the MEF2D-MRE complex was characterized in atomic resolution, whereas disrupting the MH-DNA interaction alleviated the aberrant target gene expression and the B-cell differentiation arrest. The C-terminal moiety (HNRNPUL1 part) of MH was proven to contribute to the fusion protein's trans-regulatory activity, cofactor recruitment, and homodimerization. Furthermore, targeting MH-driven transactivation of the HDAC family by using the histone deacetylase inhibitor panobinostat in combination with chemotherapy improved the overall survival of MH/NRASG12D BCP-ALL mice. Altogether, these results not only highlight MH as an important driver in leukemogenesis but also provoke targeted intervention against BCP-ALL with MEF2D fusions.

Long-Term Highly Stable High-Voltage LiCoO2 Synthesized via a Solid Sulfur-Assisted One-Pot Approach.

Commercialized lithium cobalt oxide (LCO) only shows a relatively low capacity of ≈175 mAh g-1 despite a high theoretical capacity of ≈274 mAh g-1 . As an effective and direct strategy, increasing its charge cutoff voltage can, in principle, escalate the capacity, which is however precluded by the irreversible phase transition, oxygen loss, and severe side reactions with electrolytes normally. Herein, an in situ sulfur-assisted solid-state approach is proposed for one-pot synthesis of long-term highly stable high-voltage LCO with a novel compound structure. The coating of coherent spinel Lix Co2 O4 shells on and the gradient doping of SO4 2- polyanions into LCO are in situ realized simultaneously in terms of gas-solid interface reactions between metal oxides and generated SO2 gas from sulfur during synthesis. At 4.6 V, this LCO shows the discharge capacities of 232.4 mAh g-1 at 0.1 C (1 C = 280 mA g-1 ), 215 mAh g-1 at 1 C and 139 mAh g-1 even at 20 C and the capacity retentions of 97.4% (89.7%) after 100 (300) cycles at 1 C. This approach is facile, low-cost and up-scalable and may provide a route to improve the performance of LCO and other electrode materials greatly.

The pathogenic role of MEF2D-SS18 fusion gene in B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) is characterized by various fusion genes resulted from chromosome translocations, and MEF2D related fusions are recently identified in a B-ALL subtype with relatively worse survival. In this study, we investigated the pathogenic role of MEF2D-SS18 fusion in B-ALL. The recombinant retrovirus and lentivirus plasmids containing the MEF2D-SS18 transcript were constructed for functional studies. Immuno-fluorescent staining presented the nuclear localization of MEF2D-SS18. In vitro B cell differentiation assay showed MEF2D-SS18 significantly inhibited the differentiation of mouse common lymphoid progenitors into CD19 positive B cells. The data of RBMT mouse model also showed B cell developmental arrest. In REH cells overexpressing MEF2D-SS18, genes related to B cell development were down-regulated, while genes related to drug sensitivity and B cell survival were up-regulated. In conclusion, MEF2D-SS18 fusion gene blocked the differentiation of B cells, thus exerted a funding role in the pathogenesis and prognosis of B-ALL.

Prediction of LncRNA-Protein Interactions Based on Kernel Combinations and Graph Convolutional Networks.

The complexes of long non-coding RNAs bound to proteins can be involved in regulating life activities at various stages of organisms. However, in the face of the growing number of lncRNAs and proteins, verifying LncRNA-Protein Interactions (LPI) based on traditional biological experiments is time-consuming and laborious. Therefore, with the improvement of computing power, predicting LPI has met new development opportunity. In virtue of the state-of-the-art works, a framework called LncRNA-Protein Interactions based on Kernel Combinations and Graph Convolutional Networks (LPI-KCGCN) has been proposed in this article. We first construct kernel matrices by taking advantage of extracting both the lncRNAs and protein concerning the sequence features, sequence similarity features, expression features, and gene ontology. Then reconstruct the existent kernel matrices as the input of the next step. Combined with known LPI interactions, the reconstructed similarity matrices, which can be used as features of the topology map of the LPI network, are exploited in extracting potential representations in the lncRNA and protein space using a two-layer Graph Convolutional Network. The predicted matrix can be finally obtained by training the network to produce scoring matrices w.r.t. lncRNAs and proteins. Different LPI-KCGCN variants are ensemble to derive the final prediction results and testify on balanced and unbalanced datasets. The 5-fold cross-validation shows that the optimal feature information combination on a dataset with 15.5% positive samples has an AUC value of 0.9714 and an AUPR value of 0.9216. On another highly unbalanced dataset with only 5% positive samples, LPI-KCGCN also has outperformed the state-of-the-art works, which achieved an AUC value of 0.9907 and an AUPR value of 0.9267.

Unveiling the Roles of Trace Fe and F Co-doped into High-Ni Li-Rich Layered Oxides in Performance Improvement.

High-Ni Li-rich layered oxides (HNLOs) derived from Li-rich Mn-based layered oxides (LRMLOs) can effectively mitigate the voltage decay of LRMLOs but normally suffered from decreased capacity and cycling stability. Herein, an effective, simple, and up-scalable co-doping strategy of trace Fe and F ions via a facile expanded graphite template-sacrificed approach was proposed for improving the performance of HNLOs. The trace Fe and F co-doping can far more effectively improve both its rate capability and cycling stability in a synergistic manner compared to the introduction of individual Fe cations and F anions. The co-doping of Fe and F increased the Li-O bonds by a magnitude far larger than the summation of the increments by their individual doping, quite favorable for the performance. The trace Fe doping can escalate the capacity and enhance the rate capability significantly by increasing the components of lower valence transition metals to activate their redox reactions more effectively and improving both the electronic and ionic conduction. In contrast, trace F can improve the cycling stability remarkably by lowering the O 2p band top to suppress the lattice oxygen escape effectively which were revealed by density functional theory calculations. The co-doped cathode exhibited excellent cycling stability with a superior capacity retention of 90% after 200 cycles at 1 C, much higher than 64% for the pristine sample. This study offers an idea for synergistically improving the performance of Li-rich layered oxides by co-doping trace Fe cations and F anions simultaneously, which play a complementary role in performance improvement.

The clinical efficacy and safety of equipment-assisted intravesical instillation of mitomycin C after transurethral resection of bladder tumour in patients with nonmuscular invasive bladder cancer: A meta-analysis.

BACKGROUND: This review and meta-analysis aimed to systematically evaluate the clinical efficacy and safety of equipment-assisted intravesical instillation of mitomycin C (MMC) in patients with nonmuscular invasive bladder cancer (NMIBC) after transurethral resection of bladder tumour (TURBT). METHODS: The Embase, PubMed, CNKI, CBM, WANGFANG, VIP, Cochrane Library, and Clinicaltrial.com databases were searched for articles published before April 2022. The experimental group was treated with intravesical instillation of MMC assisted by equipment, including radiofrequency-induced thermochemotherapy, conductive thermochemical therapy, electromotive drug administration, or locoregional hyperthermia. The control group was treated with simple MMC perfusion. The outcomes of interest in the meta-analysis were recurrence, progression, side-effects, gross haematuria, and bladder irritation. RESULTS: A total of 15 studies that enrolled 1,190 patients were included in the meta-analysis. Compared to that of the control group, device-assisted intravesical instillation of MMC significantly reduced both tumour recurrence (odds ratio [OR] = 0.32, 95% confidence interval [CI] [0.24, 0.42], P <0.00001) and progression (OR = 0.29, 95% CI [0.12, 0.67], P = 0.004). There were no significant differences between the two groups in terms of safety (OR = 1.21, 95% CI [0.66,2.21], P = 0.54), bladder irritation (OR = 1.06, 95% CI [0.72,1.55], P = 0.78), or gross haematuria (OR = 1.11, 95% CI [0.64,1.94], P = 0.72). CONCLUSIONS: Equipment-assisted intravesical instillation of MMC significantly reduced the recurrence and progression of patients with NMIBC who underwent TURBT and improved their quality of life. Given the significant heterogeneity in research quality and sample size among earlier studies, more prospective, multicentre, large sample randomized controlled trials are needed to supplement and verify this in the future.

Clinical analysis of transurethral holmium laser enucleation in the treatment of benign prostatic hyperplasia with prostatic inflammation: A prospective research study.

Objective: To investigate the clinical efficacy of holmium laser enucleation of the prostate (HoLEP) in the treatment of benign prostatic hyperplasia (BPH) with prostatic inflammation (PI). Methods: We prospectively collected and followed up data on patients with BPH who underwent HoLEP at the Affiliated Hospital of Weifang Medical University between July 2021 and July 2022. According to the postoperative pathological results, the patients were divided into two groups: BPH without PI group (BPH group) and BPH with PI group. Statistical analysis was performed on clinical data, including age and body mass index (BMI), prostate volume (PV), postoperative residual urine volume (PVR), preoperative serum total prostate-specific antigen (tPSA), serum-free prostate-specific antigen (fPSA), preoperative and postoperative maximum urinary flow rate (Qmax), International Prostate Symptom Score (IPSS) before and 3 months after surgery, quality of life index (QoL) before and 3 months after surgery, and postoperative complications. Results: A total of 41 patients were included in this study, including 16 in the BPH group and 25 in the BPH with PI group. There were no significant differences in preoperative age, BMI, PV, PVR, tPSA, fPSA, and f/tPSA between the BPH and BPH with PI groups (P > 0.05). The preoperative mean Qmax of the BPH and BPH with PI groups were 9.44 ± 2.449 and 7.52 ± 2.946 [mean ± standard deviation (SD)] ml/s, mean IPSS were 17.75 ± 5.335 and 24.24 ± 5.861 (mean ± SD), and mean QoL were 4.13 ± 0.806 and 4.48 ± 0.8 (mean ± SD), respectively. The postoperative mean Qmax of the BPH and BPH with PI groups were 20.38 ± 4.787 and 14.32 ± 3.827 (mean ± SD) ml/s, mean IPSS were 2.69 ± 1.25 and 5.84 ± 3.579 (mean ± SD), and mean QoL were 0.13 ± 0.342 and 0.92 ± 0.759 (mean ± SD), respectively. In both groups, Qmax significantly increased (P < 0.05) and IPSS and QoL significantly decreased after HoLEP (P < 0.05). Before and after surgery, the Qmax in the BPH with PI group was lower than that in the BPH group, and the IPSS and QoL levels in the BPH with PI group were higher than those in the BPH group (P < 0.05). Compared with the BPH group, the increase in Qmax in the BPH with PI group was smaller and the decrease in IPSS was larger (P < 0.05), but the variation in QoL was not statistically significant (P > 0.05). Conclusion: Improvements in Qmax, IPSS, and QoL in BPH patients with PI after HoLEP surgery were lower than those in BPH patients alone. PI may be a predictor of a worse response to surgical treatment. However, more multicenter randomized controlled trials with larger samples and long-term follow-up are needed to verify this.

Lithium Antievaporation-Loss Engineering via Sodium/Potassium Doping Enables Superior Electrochemical Performance of High-Nickel Li-Rich Layered Oxide Cathodes.

Low-cost Mn- and Li-rich layered oxides suffer from rapid voltage decay, which can be improved by increasing the nickel content to derive high nickel Li-rich layered oxides (HNLO) but is normally accompanied by reduced capacity and inferior cycling stability. Herein, Na or K ions are successfully doped into the lattice of high nickel Li-rich Li1.2-xMxNi0.32Mn0.48O2 (M = Na, K) layered oxides via a facile expanded graphite template-sacrificed approach. Both Na- and K-doped samples exhibit excellent rate capability and cycling stability compared with the un-doped one. The Na-doped sample shows a capacity retention of 93% after 200 cycles at 1C, which is quite outstanding for HNLO. The greatly improved electrochemical performances are attributed to the increased effective Li content in the lattice via Li antievaporation-loss engineering, the expanded Li slab, the pillaring effect, the increased C2/m component, and the improved electronic conductivity. Different performances by the introduction of sodium and potassium ions may be ascribed to their different ionic radii, which give rise to their different doping behaviors and threshold doping amounts. This work provides a new idea of enhancing electrochemical performance of HNLO by doping proper alien elements to increase the lattice lithium content effectively.

Integrated bioinformatics analysis of the NEDD4 family reveals a prognostic value of NEDD4L in clear-cell renal cell cancer.

The members of the Nedd4-like E3 family participate in various biological processes. However, their role in clear cell renal cell carcinoma (ccRCC) is not clear. This study systematically analyzed the Nedd4-like E3 family members in ccRCC data sets from multiple publicly available databases. NEDD4L was identified as the only NEDD4 family member differentially expressed in ccRCC compared with normal samples. Bioinformatics tools were used to characterize the function of NEDD4L in ccRCC. It indicated that NEDD4L might regulate cellular energy metabolism by co-expression analysis, and subsequent gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. A prognostic model developed by the LASSO Cox regression method showed a relatively good predictive value in training and testing data sets. The result revealed that NEDD4L was associated with biosynthesis and metabolism of ccRCC. Since NEDD4L is downregulated and dysregulation of metabolism is involved in tumor progression, NEDD4L might be a potential therapeutic target in ccRCC.

The complete chloroplast genome sequence of Manglietia yuyuanensis (Magnoliaceae).

Manglietia yuyuanensis is an important afforestation and excellent broad-leaved tree species in southern China. In this study, we assembled the complete chloroplast genome of M. yuyuanensis based on the Illumina sequences, sequence analysis showed the genome was 160,078 bp in length presenting a typical quadripartite structure and contains an inverted repeat region (IR, 26,467 b), a small single-copy (SSC) region, and a large single-copy (LSC) region (18,785 and 88,359 bp, respectively). The overall GC content was 39.27%. The sequence contained 128 unique genes, including 81 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. The maximum-likelihood (ML) phylogenetic analysis revealed that M. maudiae was closely related to Manglietia insignis. A phylogenetic analysis revealed that M. yuyuanensis is closely related to Manglietia glaucifolia, with the genus Manglietia.

Effect of acupuncture on chronic bronchitis: A protocol for systematic review and meta-analysis.

INTRODUCTION: Chronic bronchitis (CB) is a clinically common and recurrent respiratory disease. However, many trials have shown that acupuncture can effectively treat CB. There is currently no systematic review of this therapy. The plan is to evaluate the effectiveness and safety of this treatment in patients with CB. METHODS AND ANALYSIS: This systematic evaluation will entail an electronic and manual search of all acupuncture for CB from inception to December 31, 2020, regardless of the publication status or language. Databases include PubMed, Embase, Springer, Web of Science, the Cochrane Library, the World Health Organization International Clinical Trial Registration Platform, the Chinese Medicine Database, the China National Knowledge Infrastructure, the Chinese Biomedical Literature Database, the China Science Journal Database, and the Wanfang Database. Other sources of information, including bibliographies and meeting minutes for identified publications, will also be searched. A manual search for grey literature, including unpublished conference articles will be performed. Additionally, any clinical randomized controlled trials related to acupuncture for CB, regardless of the publication status and language limitations, will be included in the study. Study selection, data extraction, and research quality assessments will be conducted independently by 2 researchers. The main result was the Change in cystic fibrosis transmembrane conductance regulator function as measured by sweat chloride analysis or treatment effect. Secondary outcomes included Quality of life (eg, SF-36), change in Breathlessness, Cough, and Sputum Scale score, follow-up relapse rate, and adverse events. The system searches for randomized controlled trials of this therapy for CB. Implement the Cochrane RevMan V5.3 bias assessment tool to assess bias risk, data integration risk, meta-analysis risk, and subgroup analysis risk (if conditions are met). Mean difference, standard mean deviation, and binary data will be used to represent continuous results. RESULTS: This study will provide a comprehensive review and evaluation of the available evidence for the treatment of CB using this therapy. CONCLUSION: This study will provide new evidence to evaluate the effectiveness and side effects of acupuncture on CB. Because the data are not personalized, no formal ethical approval is required. PROSPERO REGISTRATION NUMBER: CRD42020170287.

The effects of exercise on COVID-19 therapeutics: A protocol for systematic review and meta-analysis.

BACKGROUND: At the end of 2019, peoples normal lives were disrupted by a sudden plague (COVID-19), the huge impact of COVID-19 on society has never been appeared. How to effectively prevent and treat COVID-19 is a concern for all health care workers. Exercise as a green and cheap complementary therapy, which has been proven to improve the immune capacity of the body and prevent infection. The main purpose of this study is to provide a reliable methodological guidance and credible evidence for exercise on COVID-19 therapeutic. METHODS: This protocol is guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. We will search the following database sources for the Randomized controlled trials: the Cochrane Library, PubMed, EMBASE, Web of Science, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure Database (CNKI), Chinese Science and the Wanfang Database. All randomized controlled trials of exercise therapy for COVID-19 in the above database will be considered for inclusion, and high-quality articles will be screened for data extraction and analysis, to summarize the therapeutic effect of exercise on COVID-19 patients. RESULTS: In this study, we hope to find strong evidence for the treatment of COVID-19 by exercise. CONCLUSION: The conclusion of our study will provide credible evidence to judge whether exercise is an effective intervention on the COVID-19 patients therapeutic, and guide future researches.PROSPERO registration number: CRD42020200883.