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.

Correlation of Gut Microbiota with Children Obesity and Weight Loss.

Children obesity is a serious public health problem drawing much attention around the world. Recent research indicated that gut microbiota plays a vital role in children obesity, and disturbed gut microbiota is a prominent characteristic of obese children. Diet and exercise are efficient intervention for weight loss in obesity children, however, how the gut microbiota is modulated which remains largely unknown. To characterize the feature of gut microbiota in obese children and explore the effect of dietary and exercise on gut microbiota in simple obese children, 107 healthy children and 86 obese children were recruited, and among of the obese children 39 received the dietary-exercise combined weight loss intervention (DEI). The gut microbiota composition was detected by the 16S amplicon sequencing method. The gut microbiota composition was significantly different between obese children and the healthy cohort, and DEI significantly reduced the body weight and ameliorated the gut microbiota dysbiosis. After DEI, the abundance of the Akkermansia muciniphila was increased, while the abundance of the Sutterella genus was decreased in simple obese children. Our results may provide theoretical reference for future personalized obesity interventions based on gut microbiota. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01088-3.

[Mechanism of active components of "Notoginseng Radix et Rhizoma-Drynariae Rhizoma" in treatment of osteoporosis based on network pharmacology and in vitro cell experiment].

The present study aimed to explore the main active components and potential mechanisms of Panax notoginseng saponins(PNS) and osteopractic total flavone(OTF) in the treatment of osteoporosis(OP) through network pharmacology, molecular docking and in vitro cell experiments, which was expected to provide a theoretical basis for clinical applications. The blood-entering components of PNS and OTF were obtained from literature search and online database, and their potential targets were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The OP targets were obtained by means of searching Online Mendelian Inheritance in Man(OMIM) and GeneCards. The common targets of the drug and disease were screened by Venn. Cytoscape was used to construct a "drug-component-target-disease" network, and the core components were screened according to the node degree. The protein-protein interaction(PPI) network of the common targets was constructed by STRING and Cytoscape, and the core targets were screened according to the node degree. GO and KEGG enrichment analysis of potential therapeutic targets were carried out by R language. Molecular docking was used to determine the binding activity of some active components to key targets by AutoDock Vina. Finally, HIF-1 signaling pathway was selected for in vitro experimental verification according to the results of KEGG pathway analysis. Network pharmacology showed that there were 45 active components such as leachianone A, kurarinone, 20(R)-protopanaxatriol, 20(S)-protopanaxatriol, and kaempferol, and 103 therapeutic targets such as IL6, AKT1, TNF, VEGFA and MAPK3 involved. PI3K-AKT, HIF-1, TNF and other signaling pathways were enriched. Molecular docking revealed that the core components had good binding ability to the core targets. In vitro experiments found that PNS-OTF could up-regulate the mRNA expression levels of HIF-1α, VEGFA and Runx2, indicating that the mechanism of PNS-OTF in treating OP may be related to the activation of HIF-1 signaling pathway, and thus PNS-OTF played a role in promoting angiogenesis and osteogenic differentiation. In conclusion, this study predicted the core targets and pathways of PNS-OTF in treating OP based on network pharmacology and carried out in vitro experimental verification, which reflected the characteristics of multi-component, multi-target and multi-pathway synergy of PNS-OTF, and provided new ideas for the future clinical treatment of OP.

Ectopic expression of a combination of 5 genes detects high risk forms of T-cell acute lymphoblastic leukemia.

BACKGROUND: T cell acute lymphoblastic leukemia (T-ALL) defines a group of hematological malignancies with heterogeneous aggressiveness and highly variable outcome, making therapeutic decisions a challenging task. We tried to discover new predictive model for T-ALL before treatment by using a specific pipeline designed to discover aberrantly active gene. RESULTS: The expression of 18 genes was significantly associated with shorter survival, including ACTRT2, GOT1L1, SPATA45, TOPAZ1 and ZPBP (5-GEC), which were used as a basis to design a prognostic classifier for T-ALL patients. The molecular characterization of the 5-GEC positive T-ALL unveiled specific characteristics inherent to the most aggressive T leukemic cells, including a drastic shut-down of genes located on the mitochondrial genome and an upregulation of histone genes, the latter characterizing high risk forms in adult patients. These cases fail to respond to the induction treatment, since 5-GEC either predicted positive minimal residual disease (MRD) or a short-term relapse in MRD negative patients. CONCLUSION: Overall, our investigations led to the discovery of a homogenous group of leukemic cells with profound alterations of their biology. It also resulted in an accurate predictive tool that could significantly improve the management of T-ALL patients.

Catalytic asymmetric Michael/cyclization reaction of 3-isothiocyanato thiobutyrolactone: an approach to the construction of a library of bispiro[pyrazolone-thiobutyrolactone] skeletons.

Here, we demonstrate the first example of 3-isothiocyanato thiobutyrolactone serving as a useful building block in the Michael/cyclization reaction with alkylidene pyrazolones for the enantioselective construction of optically active structural bispiro[pyrazolone-thiobutyrolactone] skeletons containing three contiguous stereocenters with two spiroquaternary stereocenters. These products were smoothly afforded in up to 90% yield, >20 : 1 dr and >99% ee with chiral squaramide as the catalyst under mild conditions. Notably, this is also the first example of the merger of a spirocyclic pyrazolone scaffold with a spirocyclic thiobutyrolactone scaffold, potentially useful in medicinal chemistry.

Ring opening and skeletal reconstruction of 3-vinyl benzofuranone-chromone synthons: catalyst-free access to skeletally-diverse 2-pyridone and optically active imidazoline derivatives.

Herein is reported the first example of ring opening and skeletal reconstruction of 3-vinyl benzofuranone-chromones 1 as versatile synthons, which can react with ammonia or primary aliphatic amines as binucleophiles, for the eco-friendly and atom-economical synthesis of diverse and functionalized 2-pyridones 3 with potential biological activity in good to excellent yields (77-93%). When using optically active 1,2-diphenylethylenediamine 2 as the binucleophile, the in situ generated 2-pyridone intermediates are successfully transformed to novel optically active functionalized imidazoline derivatives 4 with high efficiency (up to 87% yield). In particular, this is the first report on the catalyst-free intramolecular cyclization occurring between an amide and a primary aliphatic amine for the construction of imidazoline molecules.

Antibacterial property, corrosion and discoloration resistance of pure copper containing Zn or Ni.

This study focused on the effects of Zn and Ni addition on the antibacterial properties and corrosion resistance of copper alloys. The antimicrobial properties of copper and copper alloys were evaluated using Escherichia coli ATCC 8739 bacterial strain by employing the overlay and plate counting methods. X-ray photoelectron spectroscopy (XPS) was used to analyze the surface composition of the alloy after contact with bacteria. A salt spray method was used to simulate an artificial sweat contact environment to test the discoloration and corrosion resistance of the alloy, and scanning electron microscopy (SEM) was used to analyze the film layer and surface material composition of the corroded samples. The addition of Ni reduced the antibacterial performance of pure copper; however, the antibacterial performance of the alloy remained fast and efficient after the addition of Zn. Moreover, the addition of Zn and Ni significantly improved the corrosion resistance and surface discoloration of copper alloys in artificial sweat environments. This study provided support for the future application of copper alloys as antimicrobial surface-contact materials with safer public and medical environments in the face of diseases spread by large populations. Supplementary Information: The online version contains supplementary material available at 10.1007/s12598-022-02098-8.

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignancy of immature T cells. Recently, the next-generation sequencing approach has allowed systematic identification of molecular features in pediatric T-ALL. Here, by performing RNA-sequencing and other genomewide analysis, we investigated the genomic landscape in 61 adult and 69 pediatric T-ALL cases. Thirty-six distinct gene fusion transcripts were identified, with SET-NUP214 being highly related to adult cases. Among 18 previously unknown fusions, ZBTB16-ABL1, TRA-SALL2, and involvement of NKX2-1 were recurrent events. ZBTB16-ABL1 functioned as a leukemogenic driver and responded to the effect of tyrosine kinase inhibitors. Among 48 genes with mutation rates >3%, 6 were newly found in T-ALL. An aberrantly overexpressed short mRNA transcript of the SLC17A9 gene was revealed in most cases with overexpressed TAL1, which predicted a poor prognosis in the adult group. Up-regulation of HOXA, MEF2C, and LYL1 was often present in adult cases, while TAL1 overexpression was detected mainly in the pediatric group. Although most gene fusions were mutually exclusive, they coexisted with gene mutations. These genetic abnormalities were correlated with deregulated gene expression markers in three subgroups. This study may further enrich the current knowledge of T-ALL molecular pathogenesis.

Hydrogen Sulfide Switch Phenomenon Regulating Autophagy in Cardiovascular Diseases.

Hydrogen sulfide (H2S), a novel gaseous signaling molecule, is a vital physiological signal in mammals. H2S protects the cardiovascular system via modulation of vasodilation, vascular remodeling, and inhibition of vascular calcification, and also has anti-atherosclerosis properties. Autophagy is a lysosomal-mediated intracellular degradation mechanism for excessive or abnormal proteins and lipids. The contribution of autophagy to normal and disease-state cell physiology is extremely complicated. Autophagy acts as a double-edged sword in the cardiovascular system. It can defend against damage to cells caused by environmental changes and it can also induce active cell death under certain conditions. In recent years, accumulating evidence indicates that H2S can up- or downregulate autophagy in many pathological processes, thereby switching from a harmful to a beneficial role. In this review, we summarize progress on understanding the mechanism by which H2S regulates autophagy in cardiovascular disease. We also discuss a H2S switch phenomenon that regulates autophagy and provides protection in cardiovascular diseases.

CXCL2, a new critical factor and therapeutic target for cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Previous studies have shown that inflammatory chemokines are involved in the physiological functions of cytoskeletal reorganization, cell migration, adhesion and immune responses. However, in the past decade, there have been studies showing that inflammatory chemokines play a key role in CVD. Importantly, CXC motif chemokine ligand 2 (CXCL2) has been shown to be involved in the pathogenesis of cardiovascular disease. CXCL2 exerts its effects on the cardiovascular system by mediating inflammatory responses, but the specific signaling pathways by which CXCL2 exerts its effects in CVD remain unknown and need to be further investigated. This review aims to investigate the expression changes of CXCL2 in acute myocardial infarction (AMI), atherosclerosis (AS), obesity, diabetes and ischemic stroke (IS) and its potential key role in cardiovascular disease in order to provide new ideas for the prevention and treatment of cardiovascular diseases.

Rapid and sensitive detection of the phenoxy acid herbicides in environmental water samples by magnetic solid-phase extraction combined with liquid chromatography-tandem mass spectrometry.

Phenoxy acid herbicides are widely used herbicides that play an important role in improving the yield and quality of crops. However, some research has shown that this kind of herbicide is poisonous to human and animals. In this study, a rapid and sensitive method was developed for the detection of seven phenoxy acid herbicides in water samples based on magnetic solid-phase extraction followed by liquid chromatography and tandem mass spectrometry. Magnetic amino-functionalized multiwalled carbon nanotubes were prepared by mixing bare magnetic Fe3 O4 nanoparticles with commercial amino-functionalized multiwalled carbon nanotubes in water. Then the amino-functionalized multiwalled carbon nanotubes were used to enrich phenoxy acid herbicides from water samples based on hydrophobic and ionic interactions. The effects of experimental variables on the extraction efficiency have been studied in detail. Under the optimized conditions, the method validation was performed. Good linearities for seven phenoxy acid herbicides were obtained with squared regression coefficients ranging from 0.9971 to 0.9989. The limits of detection ranged from 0.01 to 0.02 µg/L. The method recoveries of seven phenoxy acid herbicides spiked at three concentration levels in a blank sample were from 92.3 to 103.2%, with inter- and intraday relative standard deviations less than 12.6%.

PI3K/Akt/FoxO3a signaling mediates cardioprotection of FGF-2 against hydrogen peroxide-induced apoptosis in H9c2 cells.

Cardiovascular disease is a growing major global public health problem. Oxidative stress is regarded as one of the key regulators of pathological physiology, which eventually leads to cardiovascular disease. However, mechanisms by which FGF-2 rescues cells from oxidative stress damage in cardiovascular disease is not fully elucidated. Herein this study was designed to investigate the protective effects of FGF-2 in H2O2-induced apoptosis of H9c2 cardiomyocytes, as well as the possible signaling pathway involved. Apoptosis of H9c2 cardiomyocytes was induced by H2O2 and assessed using methyl thiazolyl tetrazolium assay, Hoechst, and TUNEL staining. Cells were pretreated with PI3K/Akt inhibitor LY294002 to investigate the possible PI3K/Akt pathways involved in the protection of FGF-2. The levels of p-Akt, p-FoxO3a, and Bim were detected by immunoblotting. Stimulation with H2O2 decreased the phosphorylation of Akt and FoxO3a, and induced nuclear localization of FoxO3a and apoptosis of H9c2 cells. These effects of H2O2 were abrogated by pretreatment with FGF-2. Furthermore, the protective effects of FGF-2 were abolished by PI3K/Akt inhibitor LY294002. In conclusion, our data suggest that FGF-2 protects against H2O2-induced apoptosis of H9c2 cardiomyocytes via activation of the PI3K/Akt/FoxO3a pathway.

Rapid and sensitive detection of fipronil and its metabolites in edible oils by solid-phase extraction based on humic acid bonded silica combined with gas chromatography with electron capture detection.

Solid-phase extraction based on humic acid bonded silica followed by gas chromatography with electron capture detection was developed to determine fipronil and its metabolites in edible oil. To achieve the best extraction performance, we systematically investigated a series of solid-phase extraction parameters. Under the optimized conditions, the method was validated according to linearity, recovery, and precision. Good linearities were obtained with R(2) more than 0.9996 for all analytes. The limits of detection were between 0.3 and 0.5 ng/g, and the recoveries ranged from 83.1 to 104.0% at three spiked concentrations with intra- and interday relative standard deviation values less than 8.7%. Finally, the proposed method was applied to determine fipronil and its metabolites in 11 edible oil samples taken from Wuhan markets. Fipronil was detectable in four samples with concentrations ranging from 3.0 to 5.2 ng/g. In China, the maximum residue limits of fipronil in some vegetables and maize are 20 and 100 ng/g (GB/T 2763-2014), respectively. The residues of fipronil and its metabolites in commercial edible oils might exhibit some potential threat to human health as a result of high consumption of edible oil as part of daily intake.

Cajaninstilbene acid derivatives conjugated with siderophores of 3-hydroxypyridin-4(1H)-ones as novel antibacterial agents against Gram-negative bacteria based on the Trojan horse strategy.

The low permeability of the outer membrane of Gram-negative bacteria is a serious obstacle to the development of new antibiotics against them. Conjugation of antibiotic with siderophore based on the "Trojan horse strategy" is a promising strategy to overcome the outer membrane obstacle. In this study, series of antibacterial agents were designed and synthesized by conjugating the 3-hydroxypyridin-4(1H)-one based siderophores with cajaninstilbene acid (CSA) derivative 4 which shows good activity against Gram-positive bacteria by targeting their cell membranes but is ineffective against Gram-negative bacteria. Compared to the inactive parent compound 4, the conjugates 45c or 45d exhibits significant improvement in activity against Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae and especially P. aeruginosa (minimum inhibitory concentrations, MICs = 7.8-31.25 µM). The antibacterial activity of the conjugates is attributed to the CSA derivative moiety, and the action mechanism is by disruption of bacterial cell membranes. Further studies on the uptake mechanisms showed that the bacterial siderophore-dependent iron transport system was involved in the uptake of the conjugates. In addition, the conjugates 45c and 45d showed a lower cytotoxic effects in vivo and in vitro and a positive therapeutic effect in the treatment of C. elegans infected by P. aeruginosa. Overall, our work describes a new class and a promising 3-hydroxypyridin-4(1H)-one-CSA derivative conjugates for further development as antibacterial agents against Gram-negative bacteria.

In vivo imaging reveals a synchronized correlation among neurotransmitter dynamics during propofol and sevoflurane anesthesia.

General anesthesia is widely applied in clinical practice. However, the precise mechanism of loss of consciousness induced by general anesthetics remains unknown. Here, we measured the dynamics of five neurotransmitters, including γ-aminobutyric acid, glutamate, norepinephrine, acetylcholine, and dopamine, in the medial prefrontal cortex and primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from a neurotransmitter perspective. Results revealed that the concentrations of γ-aminobutyric acid, glutamate, norepinephrine, and acetylcholine increased in the cortex during propofol-induced loss of consciousness. Dopamine levels did not change following the hypnotic dose of propofol but increased significantly following surgical doses of propofol anesthesia. Notably, the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness. Furthermore, the neurotransmitter dynamic networks were not synchronized in the non-anesthesia groups but were highly synchronized in the anesthetic groups. These findings suggest that neurotransmitter dynamic network synchronization may cause anesthetic-induced loss of consciousness.

W-Shaped π-Extended Double Undecabenzo[7]helicene.

A chiral W-shaped fully π-extended double [7]helicene (ED7H) has been synthesized and fully characterized. It displays fluorescence emission (λem = 636 nm) with a quantum yield (Φf) of 0.10. In comparison to its X-shaped and monomict π-extended [7]helicene analogues, enantiopure W-shaped ED7H exhibited superior chiral optical characteristics, including distinct circular dichroism signals from 400 to 650 nm, a good dissymmetric emission factor |glum| of 4 × 10-3, and a circularly polarized luminescence brightness value BCPL of 42 M-1 cm-1.

Transcutaneous auricular vagal nerve stimulation for consciousness recovery in patients with prolonged disorders of consciousness (TAVREC): study protocol for a multicenter, triple-blind, randomized controlled trial in China.

INTRODUCTION: Prolonged disorders of consciousness (pDoC) are a catastrophic condition following brain injury with few therapeutic options. Transcutaneous auricular vagal nerve stimulation (taVNS), a safe, non-invasive intervention modulating thalamo-cortical connectivity and brain function, is a possible treatment option of pDoC. We developed a protocol for a randomised controlled study to evaluate the effectiveness of taVNS on consciousness recovery in patients with pDoC (TAVREC). METHODS AND ANALYSIS: The TAVREC programme is a multicentre, triple-blind, randomised controlled trial with 4 weeks intervention followed by 4 weeks follow-up period. A minimum number of 116 eligible pDoC patients will be recruited and randomly receive either: (1) conventional therapy plus taVNS (30 s monophasic square current of pulse width 300 µs, frequency of 25 Hz and intensity of 1 mA followed by 30 s rest, 60 min, two times per day, for 4 weeks); or (2) conventional therapy plus taVNS placebo. Primary outcome of TAVREC is the rate of improved consciousness level based on the Coma Recovery Scale-Revised (CRS-R) at week 4. Secondary outcomes are CRS-R total and subscale scores, Glasgow Coma Scale score, Full Outline of UnResponsiveness score, ECG parameters, brainstem auditory evoked potential, upper somatosensory evoked potential, neuroimaging parameters from positron emission tomography/functional MRI, serum biomarkers associated with consciousness level and adverse events. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Reference number: 2023-SR-392). Findings will be disseminated in a peer-reviewed journal and presented at relevant conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073950.

Cellular angiolipoma: a case report and review of the literature.

Cellular angiolipoma is a rare subtype of angiolipoma, with vascular density approaching 95%. This case report describes a 55-year-old female that presented for treatment of a mass in her left breast that had been tender to slightly painful on palpation for nearly 2 years The patient underwent surgical excision of the mass, which was pathologically confirmed as a cellular angiolipoma. As of the 3-year follow-up, the patient reported no recurrence of the lesion. It is important to report this case and refresh knowledge of this and similar lesions to raise awareness of this diagnosis and treatment and improve future management of cellular angiolipoma cases.

[HMGB1-mediated activation of TLR4 signaling in hepatic stellate cells].

To determine the potential of the high mobility group box-1 protein 1 (HMGB1) to activate Toll-like receptor 4 (TLR4) signaling in hepatic stellate cells (HSCs) and investigate the subsequent transition of HSC towards the inflammatory phenotype. Three immortalized mouse HSC cell lines, wild-type (JS1), TLR4-/- (JS2) and MyD88-/- (JS3), were subcultured in plates and divided into groups of normal control (untreated), postive control (lipopolysaccaride, LPS treatment), and experimental (HMGB1 treatment). All groups were transfected with luciferase reporter plasmids carrying responsive elements for either the nuclear factor-kappa B (NF-kB) or activator protein-1 AP-1 transcription factors. Following stimulation with normal saline, LPS (100 ng/mL) or HMGB1 (100 ng/mL), the activation of NF-kB or AP-1 was detected by a dual-luciferase reporter assay system. The induction of monocyte chemotactic protein-1 (MCP-1) transcription was determined by measuring the mRNA levels using real time quantitative reverse transcription PCR (qRT-PCR). The secreted protein levels of MCP-1 were determined by enzyme-linked immunosorbent assay (ELISA) of the culture supernatants. Activation of NF-kB- and AP-1-responsive reporters was significantly up-regulated in JS1 cells treated with HMGB1 or LPS, and the activation was coincident with markedly up-regulated transcription and secretion of MCP-1. However, HMGB1 and LPS treatment produced no responsive of the NF-kB and AP-1 reporters, and no increase in expression or secretion of MCP-1, in JS2 or JS3 cells. As an endogeous ligand of TLR4, HMGB1 may activate TLR4 signaling and the TLR4-mediated inflammatory response of HSC.

[Study on the healing effect of pneumoconiosis with tetrandrine and massive whole-lung lavage].

OBJECTIVE: To study the healing effect of pneumoconiosis with tetrandrine and massive whole-lung lavage. METHODS: Choose 34 confirmed pneumoconiosis patients as drug treatment group and complex treatment group, and 17 tested workers as control group. Collected the content of TGF-beta1 and P III P which in these three investigated groups. RESULTS: Drug treatment group and complex treatment group of patients improved the clinical symptoms and lung function Compared with Pretreatment, the FVC, FEV1.0, FEV1.0/FVC, MVV was obviously higher than those before treatment (P < 0.05). Complex treatment group than in the drug treatment group increased more significantly (P < 0.05). The level of TGF-beta1 and P III P was reduced after complex treatment (P < 0.05). Moreover,the level of TGF-beta1 and P III P in these patients are lower than in those patients treated with tetrandrine combined with whole lung lavage (P < 0.05). CONCLUSION: Tetrandrine combined with whole-lung lavage could significantly retard the development of pneumoconiosis by lessening the TGF-beta1 and P III P in serum.