Experimental study on failure mode and fracture evolution characteristics of red shale in Kaiyang Phosphorus mining area.

In order to study the failure mode and fracture evolution characteristics of red shale in Kaiyang Phosphorus mining area, conventional triaxial compression mechanical tests of red shale with different bedding dip angles were carried out by using DSTD-1000 electro-hydraulic servo rock mechanics experiment system. Based on the laboratory test results, the conventional triaxial particle flow simulation of red shale samples with different bedding dip angles was carried out using discrete element PFC2D. The results show that: (1) the failure mode of red shale is controlled by bedrock when the bedding dip angle is 0° and 60° ~ 90°. When the bedding dip angle is 15° ~ 45°, the rock failure mode is controlled by bedding. The compressive strength of rock is the minimum when the bedding dip angle is 30°and the maximum at 0°, which is about 2 times of the minimum. (2) In the failure process of red shale, the cracks with different bedding dip angles show slow growth stage, accelerated growth stage and stable stage with axial strain. The whole failure process is dominated by tensile cracks, accompanied by a few shear cracks. (3) The type of displacement field varies with the bedding dip angle: tensile failure and shear failure are the main displacement field types at 15° ~ 45°, and mixed failure is often the main mode at 60° ~ 90°and 0°. The research results provide the basis and reference for the safety control of red shale roadway.

Distribution of Nosocomial Pathogens and Antimicrobial Resistance among Patients with Burn Injuries in China: A Comprehensive Research Synopsis and Meta-Analysis.

INTRODUCTION: Over the past decade, numerous studies have described the types of pathogens and their antibiotic resistance patterns in patients with burn injuries in China; however, the findings have generally been inconsistent. We conducted a literature search and meta-analysis to summarize the infection spectra and antimicrobial resistance patterns in patients with burn injuries. METHODS: We searched the PubMed, Embase, Web of Science, China National Knowledge Infrastructure, China Biomedical Literature, Wanfang, and Weipu databases for relevant articles published between January 2010 and December 2023. The DerSimonian-Laird random-effects model was used to estimate the proportions and 95% confidence intervals (CIs) of pathogens among Chinese patients with burn injuries. Meta-regression analyses were performed to explore differences in the proportions of pathogens among different subgroups and their resistance patterns. This study was registered with PROSPERO (CRD42024514386). RESULTS: The database searches yielded 2017 records; after removing duplicates and conducting initial screening, 219 articles underwent full-text screening. Ultimately, 60 studies comprising a total of 62,819 isolated strains reported the proportions of pathogens in patients with burn injuries and were included in this meta-analysis. Meta-analyses were conducted on 18 types of pathogens. The most common pathogens causing infections in Chinese patients with burn injuries were Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Staphylococcus epidermidis. Similar results were observed in the subgroup analysis focusing on wound infections. Since 2015, there has been a significant decrease in the proportion of Pseudomonas aeruginosa (R2 = 4.89%) and a significant increase in the proportion of Klebsiella pneumoniae (R2 = 9.60%). In terms of antibiotic resistance, there has been a significant decrease in the resistance of Staphylococcus aureus to multiple antibiotics and an increasing trend in the resistance of Klebsiella pneumoniae. CONCLUSIONS: We systematically summarized the epidemiological characteristics and antibiotic resistance patterns of pathogens among individuals suffering from burns in China, thus providing guidance for controlling wound infections and promoting optimal empirical antimicrobial therapy. The observed high levels of antibiotic resistance underscore the need for ongoing monitoring of antibiotic usage trends.

[Hg Content Characteristics and Safe Planting Zoning of Paddy Soil and Rice in Guizhou Province].

Guizhou Province ranks first in terms of Hg reserves and production in the country, and rice is its largest grain crop. In order to study the characteristics and pollution causes of soil-rice Hg content at the provincial level in Guizhou and to carry out safe planting zoning, 1 564 pairs of soil-rice samples, 470 natural soil samples, and 203 individual paddy soil samples were collected to test their Hg content and basic physical and chemical properties of the soil. The results showed that:① Paddy soil was mainly neutral and acidic, the paddy soil ω (Hg) range was 0.005-93.06 mg·kg-1, and the geometric mean was 0.864 mg·kg-1. The Hg content of paddy soil in Guizhou Province was significantly higher than that in natural soil (0.16 mg·kg-1,P < 0.05). Compared with the filtered value and control value, the soil samples exceeded the standard by 63.25% and 14.71%, respectively. Among them, the soil Hg pollution in Danzhai County of Qiandongnan Prefecture, Wuchuan County of Zunyi City, Zhenfeng County of Qianxinan Prefecture, and Wanshan District of Tongren City was more prominent. ② Rice ω(Hg) ranged from 0.000 5 to 0.52 mg·kg-1, and the geometric mean was 0.010 mg·kg-1, the percentage of rice Hg content exceeding the standard was 25.87%, and the exceeding points were mainly distributed in Suiyang County of Zunyi City, Zhenfeng County of Qianxinan Prefecture, Xixiu District of Anshun City, Bijiang District of Tongren City, and other industrial and mining activity-intensive areas. ③ The majority of the study area was in the priority protection category (74.75%); the safe use category accounted for (24.62%); and the strictly controlled category (0.93%) was scattered in Danzhai County at the border between Qiannan Prefecture and Qiandongnan Prefecture, Zhenfeng County in Qianxinan Prefecture, and Wanshan District in Tongren. It is not recommended to plant rice, which can be used as feed for reproduction.

Latent tuberculosis infection and infection-associated risk factors for miner workers with silicosis in eastern China.

OBJECTIVES: Silicosis people are at high risk of developing pulmonary tuberculosis. Whether silica exposure increases the likelihood of latent tuberculosis infection (LTBI) was not well understood, and potential factors involved in LTBI risk among silicosis people were not evaluated before. Thus, LTBI among silicosis people and potential risk factors for LTBI among silicosis people were evaluated in this study. METHODS: A cross-sectional study was undertaken for 130 miner workers with silicosis. The QFT-GIT was performed for LTBI detection. RESULTS: The LTBI was high to 31.6% (36/114) for silicosis participants, and 13.1% (13/99) had a history of tuberculosis. Drinking was associated with LTBI risk (OR = 6.92, 95%CI, 1.47-32.66, P = 0.015). Meanwhile, tunneling work was associated with an increased risk of LTBI compared with other mining occupations (OR = 3.91,95%CI,1.20-12.70, P = 0.024). CONCLUSIONS: The LTBI rate of silicosis participants was high and more than 10% had a history of tuberculosis. Drinking alcohol and tunneling were independent risk factors for LTBI in silicosis participants.

Unlocking the power of activated carbon-mediated peracetic acid activation for efficient antibiotics abatement in groundwater: Coupling the processes of electron transfer, radical production, and adsorption.

The activation of peracetic acid (PAA) by activated carbon (AC) is a promising approach for reducing micropollutants in groundwater. However, to harness the PAA/AC system's potential and achieve sustainable and low-impact groundwater remediation, it is crucial to quantify the individual contributions of active species. In this study, we developed a combined degradation kinetic and adsorption mass transfer model to elucidate the roles of free radicals, electron transfer processes (ETP), and adsorption on the degradation of antibiotics by PAA in groundwater. Our findings reveal that ETP predominantly facilitated the activation of PAA by modified activated carbon (AC600), contributing to ∼61% of the overall degradation of sulfamethoxazole (SMX). The carbonyl group (CO) on the surface of AC600 was identified as a probable site for the ETP. Free radicals contributed to ∼39% of the degradation, while adsorption was negligible. Thermodynamic and activation energy analyses indicate that the degradation of SMX within the PAA/AC600 system requires a relatively low energy input (27.66 kJ/mol), which is within the lower range of various heterogeneous Fenton-like reactions, thus making it easily achievable. These novel insights enhance our understanding of the AC600-mediated PAA activation mechanism and lay the groundwork for developing efficient and sustainable technologies for mitigating groundwater pollution. ENVIRONMENTAL IMPLICATION: The antibiotics in groundwater raises alarming environmental concerns. As groundwater serves as a primary source of drinking water for nearly half the global population, the development of eco-friendly technologies for antibiotic-contaminated groundwater remediation becomes imperative. The innovative PAA/AC600 system demonstrates significant efficacy in degrading micropollutants, particularly sulfonamide antibiotics. By integrating degradation kinetics and adsorption mass transfer models, this study sheds light on the intricate mechanisms involved, emphasizing the potential of carbon materials as sustainable tools in the ongoing battle for clean and safe groundwater.

A novel mycelial pellet applied to remove polycyclic aromatic hydrocarbons: High adsorption performance & its mechanisms.

Mycelial pellets formed by Penicillium thomii ZJJ were applied as efficient biosorbents for the removal of polycyclic aromatic hydrocarbons (PAHs), which are a type of ubiquitous harmful hydrophobic pollutants. The live mycelial pellets were able to remove 93.48 % of pyrene at a concentration of 100 mg/L within 48 h, demonstrating a maximum adsorption capacity of 285.63 mg/g. Meanwhile, the heat-killed one also achieved a removal rate of 65.01 %. Among the six typical PAHs (pyrene, phenanthrene, fluorene, anthracene, fluoranthene, benzo[a]pyrene), the mycelial pellets preferentially adsorbed the high molecular weight PAHs, which also have higher toxicity, resulting in higher removal efficiency. The experimental results showed that the biosorption of mycelial pellets was mainly a spontaneous physical adsorption process that occurred as a monolayer on a homogeneous surface, with mass transfer being the key rate-limiting step. The main adsorption sites on the surface of mycelia were carboxyl and N-containing groups. Extracellular polymeric substances (EPS) produced by mycelial pellets could enhance adsorption, and its coupling with dead mycelia could achieve basically the same removal effect to that of living one. It can be concluded that biosorption by mycelial pellets occurred due to the influence of electrostatic and hydrophobic interactions, consisting of five steps. Furthermore, the potential applicability of mycelial pellets has been investigated considering diverse factors. The mycelia showed high environmental tolerance, which could effectively remove pyrene across a wide range of pH and salt concentration. And pellets diameters and humic acid concentration had a significant effect on microbial adsorption effect. Based on a cost-effectiveness analysis, mycelium pellets were found to be a low-cost adsorbent. The research outcomes facilitate a thorough comprehension of the adsorption process of pyrene by mycelial pellets and their relevant applications, proposing a cost-effective method without potential environmental issues (heat-killed mycelial pellets plus EPS) to removal PAHs.

CRISPR/Cas Technology: The Unique Synthetic Biology Genome-Editing Tool Shifting the Paradigm in Viral Diagnostics, Defense, and Therapeutics.

The emergence of the COVID-19 pandemic has starkly exposed our significantly limited ability to promptly identify and respond to emergent biological threats. Consequently, there is an urgent need to advance biotechnological methods for addressing both known and unforeseen biological hazards. Recently, the CRISPR/Cas system has revolutionized genetic engineering, enabling precise and efficient synthetic biology applications. Therefore, this review aims to provide a comprehensive introduction to the fundamental principles underlying the CRISPR/Cas system and assess the advantages and limitations of various CRISPR/Cas-based techniques applicable to the detection of, defense against, and treatment of viral infections. These techniques include viral diagnostics, the development of antiviral vaccines, B cell engineering for antibody production, viral activation/interference, and epigenetic modifications. Furthermore, this review delves into the challenges and bioethical considerations associated with use of the CRISPR/Cas system. With the continuous evolution of technology, the CRISPR/Cas system holds considerable promise for addressing both existing and unforeseen biological threats. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 26 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Natural product Kaji-ichigoside F1 exhibits rapid antidepression via activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway.

BACKGROUND: Depression is a common and recurrent neuropsychiatric disorder. Recent studies have shown that the N-methyl-d-aspartate (NMDA) receptor (NMDAR) is involved in the pathophysiology of depression. Previous studies have found that Kaji-ichigoside F1 (KF1) has a protective effect against NMDA-induced neurotoxicity. However, the antidepressant mechanism of KF1 has not been confirmed yet. PURPOSE: In the present study, we aimed to evaluate the rapid antidepressant activity of KF1 and explore the underlying mechanism. STUDY DESIGN: First, we explored the effect of KF1 on NMDA-induced hippocampal neurons and the underlying mechanism. Second, depression was induced in C57BL/6 mice via chronic unpredictable mild stress (CUMS), and the immediate and persistent depression-like behavior was evaluated using the forced swimming test (FST) after a single administration of KF1. Third, the contributions of NMDA signaling to the antidepressant effect of KF1 were investigated using pharmacological interventions. Fourth, CUMS mice were treated with KF1 for 21 days, and then their depression-like behaviors and the underlying mechanism were further explored. METHODS: The FST was used to evaluate immediate and persistent depression-like behavior after a single administration of KF1 with or without NMDA pretreatment. The effect of KF1 on depressive-like behavior was investigated in CUMS mice by treating them with KF1 once daily for 21 days through the sucrose preference test, FST, open field test, and tail suspension test. Then, the effects of KF1 on the morphology and molecular and functional phenotypes of primary neuronal cells and hippocampus of mice were investigated by hematoxylin-eosin staining, Nissl staining, propidium iodide staining, TUNEL staining, Ca2+ imaging, JC-1 staining, ELISA, immunofluorescence analysis, RT-PCR, and Western blot. RESULTS: KF1 could effectively improve cellular viability, reduce apoptosis, inhibit the release of LDH and Ca2+, and increase the mitochondrial membrane potential and the number of dendritic spines numbers in hippocampal neurons. Moreover, behavioral tests showed that KF1 exerted acute and sustained antidepressant-like effects by reducing Glu-levels and ameliorating neuronal damage in the hippocampus. Additionally, in vivo and in vitro experiments revealed that PSD95, Syn1, α-amino-3­hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and brain-derived neurotrophic factor (BDNF) were upregulated at the protein level, and BDNF and AMPA were upregulated at the mRNA level. NR1 and NR2A showed the opposite trend. CONCLUSION: These results confirm that KF1 exerts rapid antidepressant effects mainly by activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway. This study serves as a new reference for discovering rapid antidepressants.

Multi-ecosystem services differently affected by over-canopy and understory nitrogen additions in a typical subtropical forest.

Obtaining a holistic understanding of the impacts of atmospheric nitrogen deposition on multiple ecosystem services of forest is essential for developing comprehensive and sustainable strategies, particularly in heavy N deposition regions such as subtropical China. However, such impacts remain incompletely understood, with most previous studies focus on individual ecosystem function or service via understory N addition experiments. To address this knowledge gap, we quantified the effects of over-canopy and understory N additions on multiple ecosystem services based on a 7-year large-scale field experiment in a typical subtropical forest. Our results showed continued over-canopy N addition with 50 kg ha-1 year-1 over a period of 4-7 years significantly increased plant nutrient retention, but did not affect the services of soil nutrient accumulation, water yield, C sequestration (in plants and soil), or oxygen release. There were trade-offs between the soil and plant on providing the services of nutrient accumulation/retention and C sequestration under over-canopy N addition. However, without uptake and retention of tree canopy, the trade-off between soil and plant were more weaken under the understory N addition with 50 kg ha-1 year-1 , and their relationships were even synergetic under the understory N addition with 25 kg ha-1 year-1 . The results suggest that understory N addition cannot accurately simulate the effects of atmospheric N deposition on multiple services, along with mutual relationships. Interestingly, the services of plant N, P retention, and C sequestration exhibited a synergetic increase under the over-canopy N addition but a decrease under the understory N addition. Our results also found tree layer plays a primary role in providing plant nutrient retention service and is sensitive to atmospheric N deposition. Further studies are needed to investigate the generalized effects of forest canopy processes on alleviating the threaten of global change factors in different forest ecosystems.

Unleashing the power of acetylacetone: Effective control of harmful cyanobacterial blooms with ecological safety.

Harmful algal blooms resulting from eutrophication pose a severe threat to human health. Acetylacetone (AA) has emerged as a potential chemical for combatting cyanobacterial blooms, but its real-world application remains limited. In this study, we conducted a 42-day evaluation of AA's effectiveness in controlling blooms in river water, with a focus on the interplay between ecological community structure, organism functional traits, and water quality. At a concentration of 0.2 mM, AA effectively suppressed the growth of Cyanobacteria (88 %), Bacteroidia (49 %), and Alphaproteobacteria (52 %), while promoting the abundance of Gammaproteobacteria (5.0 times) and Actinobacteria (7.2 times) that are associated with the degradation of organic matter. Notably, after dosing of AA, the OD680 (0.07 ± 0.02) and turbidity (8.6 ± 2.1) remained at a satisfactory level. AA induced significant disruptions in two photosynthesis and two biosynthesis pathways (P < 0.05), while simultaneously enriching eight pathways of xenobiotics biodegradation and metabolism. This enrichment facilitated the reduction of organic pollutants and supported improved water quality. Importantly, AA treatment decreased the abundance of two macrolide-related antibiotic resistance genes (ARGs), ereA and vatE, while slightly increased the abundance of two aminoglycoside-related ARGs, aacA and strB. Overall, our findings establish AA as an efficient and durable algicide with favorable ecological safety. Moreover, this work contributes to the development of effective strategies for maintaining and restoring the health and resilience of aquatic ecosystems impacted by harmful algal blooms.

Double-Shelled Open Hollow Metal-Organic Frameworks for Efficient Aqueous Zn-Ion Batteries.

Multi-shelled hollow metal-organic frameworks (MH-MOFs) are highly promising as electrode materials due to their impressive surface area and efficient mass transfer capabilities. However, the fabrication of MH-MOFs has remained a formidable challenge. In this study, two types of double-shelled open hollow Prussian blue analogues, one with divalent iron (DHPBA-Fe(II)) and the other with trivalent iron (DHPBA-Fe(III)), through an innovative inner-outer growth strategy are successfully developed. The growth mechanism is found to involve lattice matching growth and ligand exchange processes. Subsequently, DHPBA-Fe(II) and DHPBA-Fe(III) are employed as cathodes in aqueous Zn-ion batteries. Significantly, DHPBA-Fe(II) demonstrated exceptional performance, exhibiting a capacity of 92.5 mAh g-1 at 1 A g-1, and maintaining remarkable stability over an astounding 10 000 cycles. This research is poised to catalyze further exploration into the fabrication techniques of MH-MOFs and offer fresh insights into the intricate interplay between electronic structure and battery performance.

An XAS study of Hg(II) sorption to Al-based drinking water treatment residuals.

Drinking water treatment residuals (DWTRs) are produced from the coagulation and flocculation processes in conventional drinking water treatment. The abundant metal oxide content of these materials resulting from the use of coagulants, like alum and ferric chloride, has driven strong research interest into the reuse of DWTRs as sorptive materials. Using a suite of aluminum-based DWTRs, we provide new insights into Hg(II) sorption mechanisms. Experiments performed at circum-neutral pH show that sorption capacities are related to the amount of organic carbon/matter present in DWTRs. We found that carbon rich samples can scavenge about 9000 mg/kg of Hg, in contrast to 2000 mg/kg for lime based DWTRs. X-ray absorption spectroscopy (XAS) at the Hg L3 edge further characterizes mercury coordination. X-ray absorption near edge structure (XANES) and extended x-ray absorption fine structure (EXAFS) results point to a partial association of mercury with sulfur at low mass loadings, transitioning to a full association with oxygen/carbon at higher concentrations of sorbed Hg(II) and in DWTRs with limited sulfur content. These results suggest that sorption of Hg(II) is primarily controlled by the carbon/organic matter fraction of DWTRs, but not by the coagulants.

Behind the Indolent Facade: Uncovering the Molecular Features and Malignancy Potential in Lung Minimally Invasive Adenocarcinoma by Single-Cell Transcriptomics.

The increased use of low-dose computed tomography screening has led to more frequent detection of early stage lung tumors, including minimally invasive adenocarcinoma (MIA). To unravel the intricacies of tumor cells and the immune microenvironment in MIA, this study performs a comprehensive single-cell transcriptomic analysis and profiles the transcriptomes of 156,447 cells from fresh paired MIA and invasive adenocarcinoma (IA) tumor samples, peripheral blood mononuclear cells, and adjacent normal tissue samples from three patients with synchronous multiple primary lung adenocarcinoma. This study highlights a connection and heterogeneity between the tumor ecosystem of MIA and IA. MIA tumor cells exhibited high expression of aquaporin-1 and angiotensin II receptor type 2 and a basal-like molecular character. Furthermore, it identifies that cathepsin B+ tumor-associated macrophages may over-activate CD8+ T cells in MIA, leading to an enrichment of granzyme K+ senescent CD8+ T cells, indicating the possibility of malignant progression behind the indolent appearance of MIA. These findings are further validated in 34 MIA and 35 IA samples by multiplexed immunofluorescence. These findings provide valuable insights into the mechanisms that maintain the indolent nature and prompt tumor progression of MIA and can be used to develop more effective therapeutic targets and strategies for MIA patients.

Study on Matrix Damage and Control Methods of Fracturing Fluid on Tight Sandstone Gas Reservoirs.

Hydraulic fracturing is a highly effective method for stimulating the development of gas reservoirs. However, the process of pumping fracturing fluid (FF) into the reservoir unavoidably causes damage to the surrounding matrix, leading to a decrease in the overall stimulation effect. To assess the extent of matrix permeability damage caused by the intrusion of FF, as well as its impact on the pore throat structure, and to propose appropriate measures to control this damage, we conducted a series of experimental studies on tight gas reservoirs. These studies included mercury intrusion, core flow, nitrogen adsorption, linear expansion, and contact angle measurements. The findings revealed that the damage inflicted on matrix permeability by FF was significantly greater than that caused by its gel-breaking counterpart. Surprisingly, the damage rate of the rejecting fluid to the matrix was found to be comparable to that of its gel-breaking counterpart. The fractal dimension (D2) was observed to have a strong correlation with surface area, pore volume, and mean pore size, making it an effective means of characterizing pore structure characteristics. After the rock samples were displaced by the formation water, the D2 value decreased, leading to a decrease in the complexity of the pore throat structure and an increase in matrix permeability. Conversely, the displacement of the FF increased the D2 value, indicating a gradual complication of the pore throat structure and a more uneven distribution of pore sizes. The inclusion of polyamide in antiexpansion FF, as well as its gel-breaking counterpart, proved to be effective in inhibiting the hydration and expansion of clay minerals, thereby reducing water-sensitive damage. Additionally, the use of surfactants with low surface tension enhanced the flowback rate of FF by increasing the contact angle and reducing the work of adhesion. This, in turn, helped to decrease the apparent water film thickness and expand gas flow channels, ultimately improving gas permeability.

Electron transport, ferroelectric, piezoelectric and optical properties of two-dimensional In2Te3: a first-principles study.

Two-dimensional (2D) materials have garnered significant interest in the fields of optoelectronics and electronics due to their unique and diverse properties. In this work, the electron transport, ferroelectric, piezoelectric, and optical properties of 2D In2Te3 were systematically investigated using first-principles based on density functional theory. The analysis of the phonon spectrum and elastic modulus of the Born effective criterion indicates that the structure of the novel 2D In2Te3 is dynamically stable. The calculation results show that 2D In2Te3 exhibits a carrier mobility as high as 3680.99 cm2 V-1 s-1 (y direction), a high in-plane polarization of 2.428 × 10-10 C m-1, and an excellent ferroelectric phase transition barrier (52.847 meV) and piezoelectric properties (e11 = 1.52 × 10-10 C m-1). The higher carrier mobility is attributed to the band degeneracy and small carrier effective mass. In addition, biaxial strain is an effective way to modulate the band gap and optical properties of 2D In2Te3. These properties indicate that 2D In2Te3 is a promising candidate material for flexible electronic devices and ferroelectric photovoltaic devices.

Matching-Adjusted Indirect Comparisons of Brexucabtagene Autoleucel with Alternative Standard Therapies for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Adult Patients.

INTRODUCTION: Brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, is approved for relapsed/refractory B-cell precursor acute lymphoblastic leukemia in adults aged 18+/26+ years in the US/European Union (EU), based on efficacy results from the single-arm ZUMA-3 trial. This study aimed to estimate the relative treatment effects of brexu-cel versus inotuzumab ozogamicin (InO), blinatumomab (blina), and chemotherapies using unanchored matching-adjusted indirect comparison (MAIC) methods. METHODS: Individual patient data from ZUMA-3 and published aggregate level data from two randomized controlled trials, INO-VATE (InO versus chemotherapy) and TOWER (blina versus chemotherapy), were used. Patient-level data from ZUMA-3 were weighted to match the mean of the following prognostic variables at baseline, which were pre-specified based on clinical input, for each comparator population: primary refractory disease, duration of first remission < 12 months, prior stem-cell transplantation, age, performance status, salvage status, bone marrow blast, complex karyotype, and Philadelphia chromosome status. The base case analysis was conducted using the modified intention-to-treat population (i.e., received brexu-cel) from ZUMA-3. Relative treatment effects for overall survival (OS) and event-free survival (EFS) were expressed as hazard ratios (HR) and differences in restricted mean survival time (RMST) with 95% confidence intervals (CI). RESULTS: The base case MAIC results suggested brexu-cel improved OS and EFS compared to blina (OS HR 0.46 [95% CI 0.28, 0.75]; EFS HR 0.37 [95% CI 0.25, 0.56]) and pooled INO-VATE/TOWER chemotherapy (OS HR 0.32 [95% CI 0.18, 0.56]; EFS HR 0.27 [0.18, 0.40]). Brexu-cel also improved OS compared to InO (HR 0.45 [95% CI 0.24, 0.85]). The point estimate for EFS favored brexu-cel over Ino but the difference was not statistically significant (HR 0.67 [95% CI 0.41, 1.10]). Findings were consistent between the HR and RMST analyses. CONCLUSION: Despite limitations, these MAIC results suggest that brexu-cel may improve OS and EFS versus currently used therapies in this population.

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3.

BACKGROUND: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. METHODS: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×106 CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. RESULTS: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). CONCLUSIONS: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

Design, synthesis and evaluation of novel 1-phenyl-pyrrolo[1,2-b]isoquinolin-3-one derivatives as antagonists for the glycine binding site of the NMDA receptor.

A new series of 1-phenyl-pyrrolo[1,2-b]isoquinolin-3-one derivatives were designed, synthesized and demonstrated to act as antagonists for the glycine binding site of the NMDA receptor. These new derivatives protected PC12 cells against NMDA-induced injury and cell apoptosis in vitro, among which compound 13b exhibited excellent cytoneuroprotective potency and shown a dose-dependent prevention. The increased intracellular Ca2+ influx caused by NMDA in PC12 cells was reversed when pretreated with compound 13b. Furthermore, the interaction between compound 13b and the glycine binding site of the NMDA receptor was validated via MST assay. It was observed that the stereochemistry of compound 13b did not influence the binding affinity, which was consistent with the neuroprotective result. Molecular docking study confirmed the observed activity of compound 13b by virtue of their Pi-stacking, cation-Pi, H-bonding and Pi-electron interactions with the key amino acids in the glycine binding pocket. These results confirm the potential of 1-phenyl-pyrrolo[1,2-b]isoquinolin-3-one derivatives as neuroprotective agents targeting the glycine binding site of the NMDA receptor.

LncRNA BBOX1-AS1 Contributes to the Development of Nasopharyngeal Carcinoma via miR-204-5p/MUC4 Axis.

OBJECTIVE: Dysregulation of long non-coding RNAs (lncRNAs) is common in nasopharyngeal carcinoma (NPC) progression, and it is important to have an in-depth understanding of their functions in NPC. This study is the first to explore the role of the lncRNA BBOX1-AS1 in NPC development. METHODS: The expression of lncRNA BBOX1-AS1, MUC4, or miR-204-5p was measured in NPC cell lines or tissues via RT-qPCR and western blotting. Wound healing assays and CCK-8 were used to identify cell migration and cell viability, respectively. The protein expression of Bax and Bcl-2 was measured by western blotting. The tumorigenic effect of NPC cells in vivo was verified using xenograft tumors in nude mice. Luciferase reporter and RIP assays were conducted to clarify the association between miR-204-5p and lncRNA BBOX1-AS1 or MUC4. RESULTS: lncRNA BBOX1-AS1 upregulation was observed in NPC cells and tissues. Silencing lncRNA BBOX1-AS1 suppressed the migration and viability of C666-1 and TW03 cells while promoting cell apoptosis. Knockdown of the lncRNA BBOX1-AS1 repressed tumor growth in vivo. Moreover, the tumor suppression effect of silenced lncRNA BBOX1-AS1 might be reversed with the help of the miR-204-5p inhibitor. lncRNA BBOX1-AS1 targets miR-204-5p and regulates MUC4 expression in NPC. MUC4 is a miR-204-5p target and exerts a function similar to that of lncRNA BBOX1-AS1. CONCLUSION: These observations highlight that lncRNA BBOX1-AS1 is an essential NPC progression promoter and suggest that the lncRNA BBOX1-AS1/miR-204-5p/MUC4 axis is a potential therapeutic target in NPC.

High-fat diet impairs gut barrier through intestinal microbiota-derived reactive oxygen species.

Gut barrier disruption is a key event in bridging gut microbiota dysbiosis and high-fat diet (HFD)-associated metabolic disorders. However, the underlying mechanism remains elusive. In the present study, by comparing HFD- and normal diet (ND)-treated mice, we found that the HFD instantly altered the composition of the gut microbiota and subsequently damaged the integrity of the gut barrier. Metagenomic sequencing revealed that the HFD upregulates gut microbial functions related to redox reactions, as confirmed by the increased reactive oxygen species (ROS) levels in fecal microbiota incubation in vitro and in the lumen, which were detected using in vivo fluorescence imaging. This microbial ROS-producing capability induced by HFD can be transferred through fecal microbiota transplantation (FMT) into germ-free (GF) mice, downregulating the gut barrier tight junctions. Similarly, mono-colonizing GF mice with an Enterococcus strain excelled in ROS production, damaged the gut barrier, induced mitochondrial malfunction and apoptosis of the intestinal epithelial cells, and exacerbated fatty liver, compared with other low-ROS-producing Enterococcus strains. Oral administration of recombinant high-stability-superoxide dismutase (SOD) significantly reduced intestinal ROS, protected the gut barrier, and improved fatty liver against the HFD. In conclusion, our study suggests that extracellular ROS derived from gut microbiota play a pivotal role in HFD-induced gut barrier disruption and is a potential therapeutic target for HFD-associated metabolic diseases.