PASS-ALL study of paediatric-inspired versus adult chemotherapy regimens on survival of high-risk Philadelphia-negative B-cell acute lymphoblastic leukaemia with allogeneic haematopoietic stem cell transplantation.

This PASS-ALL study was designed to explore the effect of paediatric-inspired versus adult chemotherapy regimens on survival of adolescents and young adults (AYA) with high-risk Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia (HR PH-ve B-cell ALL) eligible for allogeneic haematopoietic stem cell transplantation (allo-HSCT). The PASS-ALL study is a multicentre, observational cohort study, and 143 patients with HR B-cell PH-ve ALL were enrolled from five centres-77 patients allocated in the paediatric-inspired cohort and 66 in the adult cohort with comparable baseline characteristics. Of the 143 patients, 128 cases underwent allo-HSCT. Three-year leukaemia-free survival (LFS) in the paediatric-inspired cohort was 72.2% (95% CI 60.8%-83.6%) compared with 44.6% (95% CI 31.9%-57.3%; p = 0.001). Furthermore, time-to-positive minimal residual disease (TTP-MRD) post-HSCT was marked different, 3-year cumulative incidence of relapse was 25.9% (95% CI 15.8%-37.2%) in paediatric cohort and 45.4% (95% CI 40.0%-57.9%) in adult cohort (p = 0.026). Finally, the 3-year OS rate was 75.3% (95% CI 64.9%-85.7%) for the paediatric-inspired cohort and 64.1% (95% CI 51.8%-76.4%) for the adult cohort (p = 0.074). On a multivariate analysis, paediatric-inspired regimen is a predictive factor for LFS (HR = 2.540, 95% CI 1.327-4.862, p = 0.005). Collectively, our data suggest that paediatric-inspired chemotherapy pre-HSCT results in deeper and durable MRD response reduces relapse post-HSCT and improves survival in HR B-cell PH-ve ALL patients with allo-HSCT.

Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma.

REIIBP is a lysine methyltransferase aberrantly expressed through alternative promoter usage of NSD2 locus in t(4;14)-translocated multiple myeloma (MM). Clinically, t(4;14) translocation is an adverse prognostic factor found in approximately 15% of MM patients. The contribution of REIIBP relative to other NSD2 isoforms as a dependency gene in t(4;14)-translocated MM remains to be evaluated. Here, we demonstrated that despite homology with NSD2, REIIBP displayed distinct substrate specificity by preferentially catalyzing H3K4me3 and H3K27me3, with little activity on H3K36me2. Furthermore, REIIBP was regulated through microRNA by EZH2 in a Dicer-dependent manner, exemplifying a role of REIIBP in SET-mediated H3K27me3. Chromatin immunoprecipitation sequencing revealed chromatin remodeling characterized by changes in genome-wide and loci-specific occupancy of these opposing histone marks, allowing a bidirectional regulation of its target genes. Transcriptomics indicated that REIIBP induced a pro-inflammatory gene signature through upregulation of TLR7, which in turn led to B-cell receptor-independent activation of BTK and driving NFkB-mediated production of cytokines such as IL-6. Activation of this pathway is targetable using Ibrutinib and partially mitigated bortezomib resistance in a REIIBP xenograft model. Mechanistically, REIIBP upregulated TLR7 through eIF3E, and this relied on eIF3E RNA-binding function instead of its canonical protein synthesis activity, as demonstrated by direct binding to the 3'UTR of TLR7 mRNA. Altogether, we provided a rationale that co-existence of different NSD2 isoforms induced diversified oncogenic programs that should be considered in the strategies for t(4;14)-targeted therapy.

Mutations of epigenetic modifier genes predict poor outcome in adult acute lymphoblastic leukemia.

Epigenetic modifier (EM) genes play important roles in the occurrence and progression of acute lymphoblastic leukemia (ALL). However, the prognostic significance of EM mutations in ALL has not yet been thoroughly investigated. This retrospective study included 205 adult patients with ALL engaged in a pediatric-type regimen. Based on targeted next-generation sequencing, they were divided into EM mutation group (EM-mut, n = 75) and EM wild-type group (EM-wt, n = 130). The EM-mut group showed a higher positive rate of minimal residual disease (MRD) on treatment day24 and before consolidation therapy (P = 0.026, 0.020). Multivariate Cox regression analysis showed that EM-mut was an independent adverse factor for overall survival (OS) and event-free survival (EFS) (HR = 2.123, 1.742; P = 0.009, 0.007). Survival analysis revealed that the OS and EFS rates were significantly lower in the EM-mut group than in the EM-wt group (3-year OS rate, 45.8% vs. 65.0%, P = 0.0041; 3-year EFS rate, 36.7% vs. 53.2%, P = 0.011). In conclusion, EM was frequently mutated in adult ALL and was characterized by poor response to induction therapy and inferior clinical outcomes.

Cold plasma turns mixed-dye-contaminated wastewater bio-safe.

The excessive and uncontrollable discharge of diverse organic pollutants into the environment has emerged as a significant concern, presenting a substantial risk to human health. Among the advanced oxidation processes used for the purification of wastewater, cold plasma technology is superior in fast and effective decontamination but often fails facing mixed pollutants. To address these issues, here we develop the new conceptual approach, plasma process, and proprietary reactor that ensure, for the first time, that the efficiency of treatment (114.7%) of two mixed organic dyes, methylene blue (MB) and methyl orange (MO), is higher than when the two dyes are treated separately. We further reveal the underlying mechanisms for the energy-efficient complete degradation of the mixed dyes. The contribution of plasma-induced ROS and the distinct degradation characteristics and mechanism of pollutants in mixed treatment are discussed. The electron transfer pathway revealed for the first time suggest that the mixed pollutants reduce the overall redox potentials and facilitate electron transfer during the plasma treatment, promoting synergistic degradation effects. The integrated frameworks including both direct and indirect mechanisms provide new insights into the high-efficiency mixed-contaminant treatment. The degradation products for mixed degradation are revealed based on the identification of intermediate species. The plasma-treated water is proven safe for living creatures in waterways and sustainable fishery applications, using in vivo zebrafish model bio-toxicity assay. Overall, these findings offer a feasible approach and new insights into the mechanisms for the development of highly-effective, energy-efficient technologies for wastewater treatment and reuse in agriculture, industry, and potentially in urban water networks.

Visible-Light-Induced Tandem Radical Brominative Addition/Cyclization of Activated Alkynes with CBr4 for the Synthesis of 3-Bromocoumarins.

A visible-light-induced tandem radical brominative addition/spiro-cyclization/1,2-ester migration of activated alkynes with CBr4 is developed. This protocol features good functional group tolerance, operational simplicity, and mild reaction conditions without the use of catalysts and external additives, providing easy access to valuable 3-bromocoumarins in generally high yields.

Bactericidal effect of low-temperature atmospheric plasma against the Shigella flexneri.

BACKGROUND: Shigella flexneri (S. flexneri) is a common intestinal pathogenic bacteria that mainly causes bacillary dysentery, especially in low socioeconomic countries. This study aimed to apply cold atmospheric plasma (CAP) on S. flexneri directly to achieve rapid, efficient and environmentally friendly sterilization. METHODS: The operating parameters of the equipment were determined by plasma diagnostics. The plate count and transmission electron microscope were employed to calculate bacterial mortality rates and observe the morphological damage of bacterial cells. Measurement of intracellular reactive oxygen species (ROS) and superoxide anions were detected by 2,7-dichlorodihydrofluorescein (DCFH) and Dihydroethidium fluorescence probes, respectively. The fluorescence intensity (a. u.) reflects the relative contents. Additionally, the experiment about the single effect of temperature, ultraviolet (UV), and ROS on bacteria was conducted. RESULTS: The peak discharge voltage and current during plasma operation were 3.92kV and 66mA. After discharge, the bacterial mortality rate of 10, 20, 30 and 40 s of plasma treatment was 60.71%, 74.02%, 88.11% and 98.76%, respectively. It was shown that the intracellular ROS content was proportional to the plasma treatment time and ROS was the major contributor to bacterial death. CONCLUSION: In summary, our results illustrated that the plasma treatment could inactivate S. flexneri efficiently, and the ROS produced by plasma is the leading cause of bacterial mortality. This highly efficient sterilization method renders plasma a highly promising solution for hospitals, clinics, and daily life.

Inverse design of an ultra-compact and large-bandwidth bent subwavelength grating wavelength demultiplexer.

Inverse design has attracted significant attention as a method to improve device performance and compactness. In this research, we employed a combination of forward design and the inverse algorithm using particle swarm optimization (PSO) to design a bent ultra-compact 1310/1550 nm broadband wavelength demultiplexer assisted by a subwavelength grating (SWG). Through the phase matching at 1550 nm and the phase mismatch at 1310 nm, we rapidly designed the width parameters of SWG in the forward direction. Then the PSO algorithm was used to optimize the SWG parameters in a certain range to achieve the best performance. Additionally, we introduced a new bent dimension significantly reducing the device length while maintaining low insertion loss (IL) and high extinction ratios (ERs). It has been verified that the length of the device is only 7.8 µm, and it provides a high ER of 24 dB at 1310 nm and 27 dB at 1550 nm. The transmitted spectrum shows that the IL values at both wavelengths are below 0.1 dB. Meanwhile, the 1 dB bandwidth exceeds 150 nm, effectively covering the entire O-band and C-band. This approach has been proven successful in enhancing performance and significantly reducing the device footprint.

All-optical spiking neural network and optical spike-time-dependent plasticity based on the self-pulsing effect within a micro-ring resonator.

In this paper, we proposed an all-optical version of photonic spiking neurons and spike-time-dependent plasticity (STDP) based on the nonlinear optical effects within a micro-ring resonator. In this system, the self-pulsing effect was exploited to implement threshold control, and the equivalent pulse energy required for spiking, calculated by multiplying the input pulse power amplitude with its duration, was about 14.1 pJ. The positive performance of the neurons in the excitability and cascadability tests validated the feasibility of this scheme. Furthermore, two simulations were performed to demonstrate that such an all-optical spiking neural network incorporated with STDP could run stably on a stochastic topology. The essence of such an all-optical spiking neural network is a nonlinear spiking dynamical system that combines the advantages of photonics and spiking neural networks (SNNs), promising access to the high speed and lower consumption inherent to optical systems.

A Meaningful Attempt: Applying Dielectric Barrier Discharge Plasma to Induce Polarization of Macrophages.

Macrophage polarization plays an important role in many macrophage-related diseases. This study was designed to preliminarily explore the effects of dielectric barrier discharge (DBD) plasma on the polarization direction and cell activity of macrophages with different phenotypes (ie, M0, M1, and M2). The M1 macrophage marker inducible nitric oxide synthase (iNOS) and M2 macrophage marker cluster of differentiation 206 (CD206) were detected by western blot (WB). The effects of DBD plasma on macrophage viability were analyzed by using a cell counting kit-8 detection kit. M0, M1, and M2 macrophages exhibited a decrease in iNOS expression and an increase in CD206 expression after the DBD plasma intervention. Additionally, the decrease in macrophage viability remained non-significant after initiating the intervention. DBD plasma can promote the transformation of M0 and M1 macrophages to M2 macrophages, and can further enhance the expression of the M2 macrophage phenotype marker CD206. Our study not only demonstrates the potential therapeutic value of DBD plasma for macrophage-related diseases, but it also provides a new direction for research to improve the treatment of macrophage-related diseases. © 2023 Bioelectromagnetics Society.

UniPath: a uniform approach for pathway and gene-set based analysis of heterogeneity in single-cell epigenome and transcriptome profiles.

Recent advances in single-cell open-chromatin and transcriptome profiling have created a challenge of exploring novel applications with a meaningful transformation of read-counts, which often have high variability in noise and drop-out among cells. Here, we introduce UniPath, for representing single-cells using pathway and gene-set enrichment scores by a transformation of their open-chromatin or gene-expression profiles. The robust statistical approach of UniPath provides high accuracy, consistency and scalability in estimating gene-set enrichment scores for every cell. Its framework provides an easy solution for handling variability in drop-out rate, which can sometimes create artefact due to systematic patterns. UniPath provides an alternative approach of dimension reduction of single-cell open-chromatin profiles. UniPath's approach of predicting temporal-order of single-cells using their pathway enrichment scores enables suppression of covariates to achieve correct order of cells. Analysis of mouse cell atlas using our approach yielded surprising, albeit biologically-meaningful co-clustering of cell-types from distant organs. By enabling an unconventional method of exploiting pathway co-occurrence to compare two groups of cells, our approach also proves to be useful in inferring context-specific regulations in cancer cells. Available at https://reggenlab.github.io/UniPathWeb/.

Relationship between long non-coding RNA PCAT-1 expression and gefitinib resistance in non-small-cell lung cancer cells.

BACKGROUND: Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been used as first-line treatment for advanced non-small-cell lung cancer (NSCLC). However, during treatment, cancer cells often develop resistance to gefitinib, the mechanisms of which are not fully understood. This study was designed to elucidate the expression and role of long non-coding RNA (lncRNA)-PCAT-1, a potential biomarker for drug resistance and a therapeutic target for NSCLC, in gefitinib resistance in NSCLC cells. METHODS: In this study, we verified differential PCAT-1 expression in NSCLC gefitinib-resistant tissues or cells. PCAT-1 knockdown, clone formation, Transwell, flow cytometry, and immunofluorescence assays were used to verify the correlation between PCAT-1 and gefitinib sensitivity. A nude mouse tumor-bearing model verified that PCAT-1 can reverse gefitinib resistance in vivo. Then, a PI3K/Akt agonist was used to verify the possible mechanism of PCAT-1 action. RESULTS: PCAT-1 is highly expressed in gefitinib-resistant NSCLC tissues and cells. PCAT-1 knockdown enhanced gefitinib sensitivity and gefitinib-induced apoptosis in H1299/GR cells. PCAT-1 knockdown reduced tumor volume and weight, and reversed acquired gefitinib resistance in vivo. PCAT-1 knockdown inhibited AKT and GSK3 phosphorylation in H1299/GR cells. A PI3K/AKT agonist reversed PCAT-1 knockdown-mediated enhancement of gefitinib sensitivity in H1299/GR cells CONCLUSION: PCAT-1 knockdown improves sensitivity to gefitinib by inhibition of AKT and GSK3 phosphorylation in NSCLC. PCAT-1 is as potential target for improving the clinical efficacy of gefitinib.

Advances in Artificial Layers for Stable Lithium Metal Anodes.

Lithium (Li) metal is considered as the most promising anode material for rechargeable high-energy batteries. Nevertheless, the practical implement of Li anodes is significantly hindered by the growth of Li dendrites, which can cause severe safety issues. To inhibit the formation of Li dendrites, coating an artificial layer on the Li metal anode has been shown to be a facile and effective approach. This review mainly focuses on recent advances in artificial layers for stable Li metal anodes. It summarizes the progress in this area and discusses the different types of artificial layers according to their mechanisms for Li dendrite inhibition, including regulation of uniform deposition of Li metal and suppression of Li dendrite growth. By doing this, it is hoped that this contribution will provide instructional guidance for the future design of new artificial layers.

Droplet Directional Movement on the Homogeneously Structured Superhydrophobic Surface with the Gradient Non-Wettability.

The surface with the gradient non-wettability intensely appeals to researchers because of its academic significance and applications for directional droplet movement. Herein, we developed a homogeneous structure superhydrophobic surface with the gradient non-wettability by a combination strategy of chemical etching and vapor diffusion modification. As a consequence, the as-prepared surface exhibits a remarkable gradient characteristic of water repellency, and the water contact angle is mainly located within the range of 162 ± 0.5 to 149 ± 0.4°. Meanwhile, the sliding angle also exhibits a corresponding change from 3 to 11°. On this basis, the gradient characteristic of non-wettability induces the distinguishing droplet adhesion on the surface, that is, from 19 µN for the most hydrophobic end to 57 µN for the opposite one. Because of the difference of the water adhesion force, droplets on the as-prepared surface can well roll alongside a specific direction (i.e., gradient direction of non-wettability). In terms of dynamic impact droplets, they can rapidly rebound off the sample surface with the short contact time of 12.8 ms, and the finally fallen droplets mainly deviate toward weaker regions because of water repellency. To analyze this phenomenon, it is found that the asymmetric mechanic behavior is mainly caused by the unbalanced retraction force between the both ends of the impact droplet. This work provides a novel strategy to construct the homogeneous structure superhydrophobic surface with the gradient non-wettability for the applications in the droplet movement control or transport.

Controllable Fabrication of Inhomogeneous Microcapsules for Triggered Release by Osmotic Pressure.

Inhomogeneous microcapsules that can encapsulate various cargo for controlled release triggered by osmotic shock are designed and reported. The microcapsules are fabricated using a microfluidic approach and the inhomogeneity of shell thickness in the microcapsules can be controlled by tuning the flow rate ratio of the middle phase to the inner phase. This study demonstrates the swelling of these inhomogeneous microcapsules begins at the thinnest part of shell and eventually leads to rupture at the weak spot with a low osmotic pressure. Systematic studies indicate the rupture fraction of these microcapsules increases with increasing inhomogeneity, while the rupture osmotic pressure decreases linearly with increasing inhomogeneity. The inhomogeneous microcapsules are demonstrated to be impermeable to small probe molecules, which enables long-term storage. Thus, these microcapsules can be used for long-term storage of enzymes, which can be controllably released through osmotic shock without impairing their biological activity. The study provides a new approach to design effective carriers to encapsulate biomolecules and release them on-demand upon applying osmotic shock.

An Interfacial Layer Based on Polymers of Intrinsic Microporosity to Suppress Dendrite Growth on Li Metal Anodes.

The performance and safety of lithium (Li) metal batteries can be compromised owing to the formation of Li dendrites. Here, the use of a polymer of intrinsic microporosity (PIM) is reported as a feasible and robust interfacial layer that inhibits dendrite growth. The PIM demonstrates excellent film-forming ability, electrochemical stability, strong adhesion to a copper metal electrode, and outstanding mechanical flexibility so that it relieves the stress of structural changes produced by reversible lithiation. Importantly, the porous structure of the PIM, which guides Li flux to obtain uniform deposition, and its strong mechanical strength combine to suppress dendrite growth. Hence, the electrochemical performance of the anode is significantly enhanced, promising excellent performance and extended cycle lifetime for Li metal batteries.

Toxicity of Six Insecticides on Codling Moth (Lepidoptera: Tortricidae) and Effect on Expression of Detoxification Genes.

The codling moth, Cydia pomonella (L.), is a key worldwide fruit pest that has evolved high levels of resistance to almost all classes of conventional insecticides. Neonicotinoids, a new reduced-risk biorational insecticide class, have remained an effective control approach. In this study, the toxicity and sublethal effect of conventional and reduced-risk biorational insecticides on transcripts abundance of three detoxification genes in codling moth were determined. Bioassays on a codling moth laboratory strain suggested that acetamiprid had the highest oral toxicity against the third-instar larvae compared with the other five pesticides. Results also indicated that acetamiprid exhibits long-term efficacy against codling moth even at 120 h post feeding. Real-time quantitative polymerase chain reaction showed that the detoxification genes CYP9A61, CpGST1, and CpCE-1 were differentially induced or suppressed by deltamethrin, cypermethrin, methomyl, carbaryl, and imidacloprid, depending on the type of insecticides; in contrast, no significant difference in CYP9A61, CpGST1, and CpCE-1 expressions were observed after acetamiprid exposure, when compared with the control. These results suggest that the reduced-risk biorational insecticide acetamiprid is an effective insecticide with no induction of detoxification genes and can be integrated into the management of codling moth.

Finite element simulation of lower limb injuries to the driver in minibus frontal collisions.

PURPOSE: This study aims to explore the biomechanical mechanism of lower limb injuries to the driver by establishing a finite element (FE) simulation model of collisions. METHODS: First a minibus FE model was integrated with a seat belt system. Then it was used to rebuild two collisions together with the total human model for safety (THUMS) provided by Toyota Motor Corporation: a rear-end collision between a minibus and a truck and a head-on collision of a minibus to a rigid wall. The impact velocities of both collisions were set at 56 km/h. The vehicle dynamic response, vehicle deceleration, and dashboard intrusion in the two collisions were compared. RESULTS: In the minibus rear-end truck collision, the peak values of the von Mises equivalent stress at the tibia and the femur were 133 MPa and 126 MPa respectively; while in the minibus head-on rigid wall collision, the data were 139 MPa and 99 MPa. Compared with the minibus head-on rigid wall collision, the vehicle deceleration was smaller and the dashboard intrusion was larger in the minibus rear-end truck collision. CONCLUSION: The results illustrate that a longer dashboard incursion distance corresponds to a higher von Mises equivalent stress at the femur. The simulation results are consistent with the driver's autopsy report on lower limbs injuries. These findings verify that FE simulation method is reliable and useful to analyze the mechanisms of lower limb injuries to the driver in minibus frontal collisions.

The Toxicology and Biochemical Characterization of Cantharidin on Cydia pomonella.

Cantharidin, a natural toxin produced by beetles in the families Meloidae and Oedemeridae, reported to be toxic to some pests, is being developed as a biopesticide in China. This study evaluates the toxicity and biochemical characterization of cantharidin on the codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae), an economically important fruit pest, under both laboratory and field conditions. Laboratory dose response bioassays showed that the LC50 value of cantharidin against neonate larvae was 0.057 mg ml(-1). Exposure of the larvae to 0.024 and 0.057 mg ml(-1) of cantharidin resulted in significant reduction in larval body weight. Neonate larvae exposed to LC10 of cantharidin showed increased glutathione S-transferase activity and significantly reduced the carboxylesterase and cytochrome P450-dependent mixed-function oxidase activities. Results also showed 16 and 25% ovicidal activity at concentrations of 0.057 and 0.14 mg ml(-1) of cantharidin, respectively. Field trials demonstrated cantharidin has a significant effect on both the first and second generations of C. pomonella larvae, but it exhibits a lower control efficiency than the chemical reference emamectin benzoate. Cantharidin may be considered a valuable tool for the control of codling moth.