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Abstract The combination of fingerprint positioning and 5G (the 5th Generation Mobile Communication Technology) offers broader application prospects for indoor positioning technology, but also brings challenges in real-time performance. In this paper, we propose a fingerprint positioning method based on a deep convolutional neural network (DCNN) using a classification approach in a single-base station scenario for massive multiple input multiple output-orthogonal frequency division multiplexing (MIMO-OFDM) systems. We introduce an angle-delay domain fingerprint matrix that simplifies the computation process and increases the location differentiation. The cosine distance is chosen as the fingerprint similarity criterion due to its sensitivity to angular differences. First, the DCNN model is used to determine the sub-area to which the mobile terminal belongs, and then the weighted K-nearest neighbor (WKNN) matching algorithm is used to estimate the position within the sub-area. The positioning performance is simulated in a DeepMIMO indoor environment, showing that the classification DCNN method reduces the positioning time by 77.05% compared to the non-classification method, with only a 1.08% increase in average positioning error.

Abstract The present study employed dictator game and ultimatum game to investigate the effect of facial attractiveness, vocal attractiveness and social interest in expressing positive (“I like you”) versus negative signals (“I don’t like you”) on decision making. Female participants played against male recipients in dictator game and ultimatum game while played against male proposers in ultimatum game. Results showed that participants offered recipients with attractive faces more money than recipients with unattractive faces. Participants also offered recipients with attractive voices more money than recipients with unattractive voices, especially under the positive social interest condition. Moreover, participants allocated more money to recipients who expressed positive social interest than those who expressed negative social interest, whereas they would also expect proposers who expressed positive social interest to offer them more money than proposers who expressed negative social interest. Overall, the results inform beauty premium for faces and voices on opposite-sex economic bargaining. Social interest also affects decision outcomes. However, the beauty premium and effect of social interest varies with participants’ roles.

The presence of microplastics in surface waters poses potential hazards to both organisms and human health. Traditional water treatment processes have proven to be inadequate in effectively removing microplastics. Besides, previous studies have often utilized disinfectant dosages that surpass those commonly employed in drinking water treatment plants (DWTPs), and the biotoxicity changes induced by microplastics after disinfection remain largely unexplored. To address these knowledge gaps, our study aimed to investigate the impact of practical disinfectant dosages on the leaching of organic compounds from microplastics and the formation of disinfection byproducts (DBPs). Furthermore, the resulting acute and genetic toxicity was evaluated through bioassays. Our findings revealed an elevated release of dissolved organic matter (DOM) derived from microplastics. Additionally, both acute and genetic toxicity increased following various disinfection processes. Specifically, chlorination exhibited the highest level of toxicity in short-term disinfection, while the pretreatment of ozonation followed by residual chlorination demonstrated the highest toxicity in the long-term disinfection, which was correlated with the concentration of CHCl3 formed. These findings will advance our understanding of the potential risks associated with microplastics during various disinfection processes, with the ultimate goal of safeguarding water supplies. HIGHLIGHTS Toxicity increased following various disinfection processes.; Chlorination exhibited the highest level of toxicity in short-term disinfection.; Pretreatment of ozonation followed by residual chlorination demonstrated the highest toxicity in the long-term disinfection.; CHCl3 concentration was correlated with both acute and genetic toxicity.;

Abstract MYCN amplification is an independent poor prognostic factor in patients with high-risk neuroblastoma (NB). Further exploring the molecular regulatory mechanisms in MYCN-amplified NB will help to develop novel therapy targets. In this study, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) was identified as the differentially expressed gene (DEG) highly expressed in MYCN-amplified NB, and it showed a positive correlation with MYCN and was associated with a poor prognosis of NB patients. Knockdown of MTHFD1 inhibited proliferation and migration, and induced apoptosis of NB cells in vitro. Mouse model experiments validated the tumorigenic effect of MTHFD1 in NB in vivo. In terms of the mechanism, ChIP-qPCR and dual-luciferase reporter assays demonstrated that MTHFD1 was directly activated by MYCN at the transcriptional level. As an important enzyme in the folic acid metabolism pathway, MTHFD1 maintained the NADPH redox homeostasis in MYCN-amplified NB. Knockdown of MTHFD1 reduced cellular NADPH/NADP+ and GSH/GSSG ratios, increased cellular reactive oxygen species (ROS) and triggered the apoptosis of NB cells. Moreover, genetic knockdown of MTHFD1 or application of the anti-folic acid metabolism drug methotrexate (MTX) potentiated the anti-tumor effect of JQ1 both in vitro and in vivo. Taken together, MTHFD1 as an oncogene is a potential therapeutic target for MYCN-amplified NB. The combination of MTX with JQ1 is of important clinical translational significance for the treatment of patients with MYCN-amplified NB.

ABSTRACTT/NK cell-based immunotherapy has achieved remarkable success in adult cancers but has limited efficacy in pediatric malignancies including high-risk neuroblastoma (NB). Immune defects of NB tumor microenvironment are poorly understood compared with adults. Here, we described the unique characteristics of NB immune contexture and determined the phenotype signatures of PD-L1-expressing CD8+ T and NK cells in NB tumors by systemically analyzing the spatial distribution of T and NK cells and the distinct expression of programmed death 1 (PD-1) and its ligand (PD-L1) in patients with NB. We found that PD-L1-expressing CD8+ T and NK cells in NB tumors were highly activated and functionally competent and associated with better clinical outcomes. Intratumoral NK cells were a favorable prognostic biomarker independent of CD8+ T cells, PD-1/PD-L1 expression, tumor stage, MYCN amplification, and risk classification. NK cells combined with anti-PD-1/PD-L1 antibodies showed potent antitumor activity against both MYCN-amplified and non-amplified NBs in vitro and in vivo, and PD-L1-expressing NK cells associated with improved antitumor efficacy. Collectively, we raise novel insights into the role of PD-L1 expression on CD8+ T-cell and NK-cell activation. We highlight the great potential of intratumoral NK cells in better defining risk stratification, and predicting survival and response to anti-PD-1/PD-L1 therapy in NB. These findings explain why single anti-PD-1/PD-L1 therapy may not be successful in NB, suggesting its combination with NK cell-adoptive cellular therapy as a promising strategy for relapsing/refractory NB. This study provides a potential prospect that patients with PD-L1-expressing NK cells may respond to anti-PD-1/PD-L1 therapy.

BackgroundHigh-intensity chemotherapy can cause life-threatening complications in pediatric patients. Therefore, this study investigated safety and efficacy of long-acting pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF; Jinyouli®) in children undergoing high-intensity chemotherapy.MethodsTreatment-naive patients received post-chemotherapy PEG-rhG-CSF as primary prophylaxis for two cycles. The primary endpoints were drug-related adverse events (AEs) and bone pain scores. Secondary endpoints included grade 3–4 neutropenia, duration of neutropenia recovery, absolute neutrophil count changes, febrile neutropenia (FN), reduced chemotherapy intensity, antibiotic usage, and AE severity. The cost-effectiveness of PEG-rhG-CSF was compared with that of rhG-CSF (Ruibai®).ResultsHere, 307 and 288 patients underwent one and two PEG-rhG-CSF cycles, respectively. Ninety-one patients experienced drug-related AEs, primarily bone pain (12.7%). Moreover, Grade 3–4 neutropenia and FN were observed. Median FN durations were 3.0 days in both cycles. No drug-related delays were observed during chemotherapy. One patient experienced grade 4 neutropenia-induced reduction in chemotherapy intensity during cycle 2. In total, 138 patients received antibiotics. PEG-rhG-CSF exhibited superior cost-effectiveness compared to rhG-CSF.ConclusionOur findings indicate that PEG-rhG-CSF is safe, efficient, and cost-effective in pediatric patients undergoing high-intensity chemotherapy, providing preliminary evidence warranting further randomized controlled trials.

Summary: Background: The combined vincristine, pegylated liposomal doxorubicin (PLD), and cyclophosphamide (VPC) regimen has never been studied in pediatric patients. Methods: This open-label, single-center, single-arm phase I study utilizing a “3 + 3” design enrolled children with relapsed/refractory (R/R) solid tumors. Three dose levels of PLD (Duomeisu®) were studied (30, 40, or 50 mg/m2) in combination with cyclophosphamide (1500 mg/m2), mesna (1500 mg/m2), and vincristine (1.5 mg/m2, maximum 2 mg) once every 3 weeks. The primary endpoints included safety, the maximum tolerated dose (MTD) of PLD (Duomeisu®), and the recommended phase 2 dose (RP2D) of PLD (Duomeisu®) for further phase 2 investigation. The secondary endpoints were objective response rate (ORR) and disease control rate (DCR). This study is registered with ClinicalTrials.gov, NCT04213612. Findings: Between January 7, 2020, and November 18, 2021, 34 patients were eligible and evaluable for toxicity, while 26 patients were evaluable for response. The MTD of PLD (Duomeisu®) was 30 mg/m2. The most common adverse event (AE) was grade 3 or 4 neutropenia (61.8%). The most common grade 1 or 2 non-hematologic AE and cardiotoxicity effects were vomiting (35.3%) and abnormal electrocardiogram T waves (20.6%), respectively. ORR and DCR to VPC regimen after two cycles were 50.0% and 92.3%, respectively. Targeted gene panel sequencing revealed the activation of TP53 mutation may be an adverse prognostic factor. Interpretation: The VPC regimen showed a promising safety profile and had preliminary efficacy in children with R/R solid tumors. The RP2D for PLD (Duomeisu®) combined with cyclophosphamide and vincristine is 30 mg/m2 once every 3 weeks. Funding: CSPC Ouyi Pharmaceutical Co., Ltd., Shijiazhuang, the National Key Research and Development Program of China [No. 2022YFC2705005], the National Natural Science Foundation of China [No. 82203303], and the Basic and Applied Basic Research Foundation of Guangdong Province [No. 2021A1515110234].

Abstract The aim of this phase I study is to evaluate, for the first time, the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent malignancies. During the dose escalation phase, patients received a single intravenous infusion of sintilimab at varying doses of 1, 3, and 10 mg/kg. The primary endpoints included the identification of dose-limiting toxicities (DLTs) as well as the evaluation of safety and tolerance. Secondary endpoints focused on assessing objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A total of 29 patients were enrolled, including 10 individuals diagnosed with Hodgkin lymphoma (HL) and 19 patients with various other tumor categories. Notably, diverse pathological types such as thymoma, choroid plexus carcinoma, and NK/T-cell lymphoma were also included in the study cohort. By the safety data cutoff, most adverse events were grade 1 or 2, with grade 3 or higher treatment-related adverse events (TRAE) occurring in 10% of patients. Among the 27 evaluated subjects, four achieved confirmed complete response (CR) while seven patients exhibited confirmed partial response (PR). Additionally, seven patients maintained disease (SD) during the study period. Notably, sintilimab demonstrated remarkable tolerability without DLTs and exhibited promising anti-tumor effects in pediatric HL. Whole-exome sequencing (WES) was conducted in 15 patients to assess the mutational landscape and copy number variation (CNV) status. The completion of this phase I study establishes the foundation for potential combination regimens involving sintilimab in childhood cancer treatment. The trial is registered on ClinicalTrials.gov with the identifier NCT04400851.

Abstract Approximately 20% of aged captive giant pandas (Ailuropoda melanoleuca) have cataracts that impair their quality of life. To identify potential biomarkers of cataract formation, we carried out a quantitative proteomics analysis of 10 giant pandas to find proteins differing in abundance between healthy and cataract-bearing animals. We identified almost 150 proteins exceeding our threshold for differential abundance, most of which were associated with GO categories related to extracellular localization. The most significant differential abundance was associated with components of the proteasome and other proteins with a role in proteolysis or its regulation, most of which were depleted in pandas with cataracts. Other modulated proteins included components of the extracellular matrix or cytoskeleton, as well as associated signaling proteins and regulators, but we did not find any differentially expressed transcription factors. These results indicate that the formation of cataracts involves a complex post-transcriptional network of signaling inside and outside lens cells to drive stress responses as a means to address the accumulation of protein aggregates triggered by oxidative damage. The modulated proteins also indicate that it should be possible to predict the onset of cataracts in captive pandas by taking blood samples and testing them for the presence or absence of specific protein markers.

Abstract Background Pegylated recombinant human granulocyte colony‐stimulating factor (PEG‐rhG‐CSF) can be used in pediatric patients. This study assessed the safety and efficacy of PEG‐rhG‐CSF as a primary prophylactic drug against neutropenia after chemotherapy in pediatric patients with solid tumors or non‐Hodgkin lymphoma (NHL). Patients and Methods This phase II study (between October 2020 and March 2022) enrolled pediatric patients with solid tumors or NHL treated with high‐intensity chemotherapy and with grade ≥3 myelosuppression for at least 14 days during chemotherapy. Prophylactic PEG‐rhG‐CSF was given at 100 μg/kg body weight (maximum total dosage of 6 mg) once 24–48 h following chemotherapy for two cycles. The primary endpoint was the incidence of PEG‐rhG‐CSF‐related adverse events (AEs). The key secondary endpoints were the rates of grade 3/4 neutropenia and febrile neutropenia (FN). Results This study included 160 pediatric patients with a median age of 6.22 (0.29, 18.00) years. Fifty‐eight patients (36.25%) were diagnosed with sarcoma. AEs potentially related to PEG‐rhG‐CSF included bone pain (n = 32), fatigue (n = 21), pain at the injection site (n = 21), and myalgia (n = 20). The rates of grade 3/4 neutropenia and FN during treatment were 57.28% and 29.45%, respectively. Conclusion PEG‐rhG‐CSF is well tolerated and effective in pediatric patients with solid tumors or NHL. These findings should be substantiated with further trials. Clinical Trial Registration ClinicalTrials.gov identifier: NCT04547829.

ABSTRACT Toxoplasmosis is a global health issue; however, there is a lack of safe and effective drugs and vaccines. Herein, we developed a novel mRNA vaccine, TGGT1_278620 mRNA-lipid nanoparticle (LNP), and evaluated its safety and efficacy in BALB/c mice. The vaccine elicited a significant increase not only immunoglobulin (Ig)G and IgG subclasses (IgG2a and IgG1) antibodies but also interleukin (IL)-12, interferon-gamma, IL-4, and IL-10 cytokines. We showed that specific cellular immunity and humoral immunity were activated by combining splenocyte proliferation, cytotoxic T-cell activity, and T-cell surface molecule CD8 and CD4 ratios. Dendritic cell signaling pathway members interferon regulatory factor 8, T-Box 21, and nuclear factor kappa B were analyzed at the mRNA and protein levels, and increased differentiation and maturation were observed by examining dendritic cell surface molecules (CD83, CD86, MHC-I, and MHC-II) using flow cytometry. Finally, the survival time of the vaccinated mice was significantly prolonged after Toxoplasma gondii RH challenge, and the adoptive transfer of splenocytes and sera from the vaccinated mice also significantly prolonged survival. These findings suggested that the TGGT1_278620 mRNA-LNP vaccine might be a promising candidate for further development in anti-toxoplasmosis therapy. IMPORTANCE Toxoplasma gondii, an obligate intracellular eukaryotic parasite, can infect about one-third of the world’s population. One vaccine, Toxovax, has been developed and licensed commercially; however, it is only used in the sheep industry to reduce the losses caused by congenital toxoplasmosis. Various other vaccine approaches have been explored, including excretory secretion antigen vaccines, subunit vaccines, epitope vaccines, and DNA vaccines. However, current research has not yet developed a safe and effective vaccine for T. gondii. Here, we generated an mRNA vaccine candidate against T. gondii. We investigated the efficacy of vaccination with a novel identified candidate, TGGT1_278620, in a mouse infection model. We screened T. gondii-derived protective antigens at the genome-wide level, combined them with mRNA-lipid nanoparticle vaccine technology against T. gondii, and investigated immune-related factors and mechanisms. Our findings might contribute to developing vaccines for immunizing humans and animals against T. gondii.

Calibration transfer between near infrared (NIR) spectrometers is a subtle issue in the chemometrics and process industry. Similar instruments may generate strongly different spectral responses, and regression models developed on a first NIR system can rarely be used with spectra collected by a second apparatus. In this work, two novel methods based on Structural Equation Modeling (SEM), called Enhanced Feature Extraction Approaches for factor analysis (EFEA-FA) and Enhanced Feature Extraction Approaches for spectral space transformation (EFEA-SST), were proposed to perform calibration transfer between NIR spectrometers. They were applied to a NIR nondestructive testing model for solid wood panels mechanical properties. Four different standardization algorithms were evaluated for transferring solid wood panels quality databases between a portable NIRS (InGaAs)-array spectrometer (NIRquest512) and a HSI Camera (SPECIM FX17). The results showed that EFEA-SST yielded the best model evaluation metrics (R2 and Root Mean Square Error of Prediction (RMSEP)) values for tensile strength (RMSEP=11.309, R2=0.865) parameters, while EFEA-FA gave the best fit for flexural strength (RMSEP=10.653, R2=0. 912). These results suggest the potential of two novel quality parameters prediction methods based on spectral databases transferred between diverse NIRS spectrometers.

Abstract Background Compared with other pediatric tumors, little advances were achieved in studies on the stratified treatment in localized Ewing sarcoma. Most pediatric oncology groups treated Ewing sarcoma according to whether there was an existing metastasis, without involving more prognostic factors. In this study, patients with localized Ewing sarcoma were divided into resectable and unresectable groups at diagnosis and received chemotherapy with different intensity, for the purpose of achieving good efficacy, avoiding overtreatment and reducing unnecessary toxicity. Methods A total of 143 patients with a median age of 10 years old diagnosed with localized Ewing sarcoma in this retrospective study were divided into two cohorts (Cohort 1, n = 42; Cohort 2, n = 101) and patients in Cohort 2 received chemotherapy with different intensity (Regimen 1, n = 52; Regimen 2, n = 49). Outcomes were analyzed using the Kaplan–Meier method to estimate event‐free survival (EFS) and overall survival (OS), and the curves were compared using the log‐rank test. Results The 5‐year EFS and 5‐year OS for all the patients were 69.0% and 77.5%. The 5‐year EFS for Cohort 1 and Cohort 2 were 76.0% and 66.1% (p = 0.31), and the 5‐year OS were 83.0% and 75.1% (p = 0.30), respectively. In Cohort 2, the 5‐year EFS rate of patients treated with Regimen 2 was significantly higher than that of patients treated with Regimen 1 (74.5% vs. 58.3%, p = 0.03). Conclusions According to whether a grossly complete resection was received at the time of diagnosis, localized Ewing sarcoma patients in this study were stratified into two groups and received different intensities of chemotherapy, which achieved good efficacy and avoided overtreatment and reduced unnecessary toxicity.

Abstract The application of totally implantable access ports (TIAPs) reduces treatment-related discomfort; however, the existence of catheter may cause side effects, with the most common one being the occurrence of TIAPs-associated thrombosis. The risk factors for TIAPs-associated thrombosis in pediatric oncology patients have not been fully described. A total of 587 pediatric oncology patients undergoing TIAPs implantation at a single center over a 5-year period were retrospectively analyzed in the present study. We investigated the risk factors for thrombosis, emphasizing the internal jugular vein distance, by measuring the vertical distance from the highest point of the catheter to the upper border of the left and right extremitas sternalis claviculae on chest X-ray images. Among 587 patients, 143 (24.4%) had thrombosis. Platelet count, C-reactive protein, and the vertical distance from the highest point of the catheter to the upper border of the left and right extremitas sternalis claviculae were demonstrated to be the main risk factors for the development of TIAPs-associated thrombosis. TIAPs-associated thrombosis, especially asymptomatic events, is common in pediatric cancer patients. The vertical distance from the highest point of the catheter to the upper border of the left and right extremitas sternalis claviculae was a risk factor for TIAPs-associated thrombosis, which deserved additional attention.

This study systematically developed a deep transfer network for near-infrared spectrum detection using convolutional neural network modules as key components. Through meticulous evaluation, specific modules and structures suitable for constructing the near-infrared spectrum detection model were identified, ensuring its effectiveness. This study extensively analyzed the basic network components and explored three unsupervised domain adaptation structures, highlighting their applications in the nondestructive testing of wood. Additionally, five transfer networks were strategically redesigned to substantially enhance their performance. The experimental results showed that the Conditional Domain Adversarial Network and Globalized Loss Optimization Transfer network outperformed the Direct Standardization, Piecewise Direct Standardization, and Spectral Space Transformation models. The coefficients of determination for the Conditional Domain Adversarial Network and Globalized Loss Optimization Transfer network are 82.11% and 83.59%, respectively, with root mean square error prediction values of 12.237 and 11.582, respectively. These achievements represent considerable advancements toward the practical implementation of an efficient and reliable near-infrared spectrum detection system using a deep transfer network.

The gut microbiota is a complex ecosystem that interacts with many other factors to affect the health and disease states of the host. The common kestrel (Falco tinnunculus) is protected at the national level in China. However, the available sequencing data of the gut microbiota from the feces of wild common kestrels, especially for being rescued individuals by professional organization, remains limited. In the present study, we characterized the fecal bacterial communities of healthy and injured common kestrels, and compared the structure of their fecal microbiota by analyzing the V3–V4 region of the 16S rRNA gene using high-throughput sequencing technology with the Illumina MiSeq platform. We found that Firmicutes, Proteobacteria and Actinobacteria were the most predominant phyla in common kestrels. Further, the beta diversity analysis showed that changes in gut microbes were associated with injuries to the common kestrel. The Bacteroides/Firmicutes ratio was significantly lower in the injured group. At the genus level, Glutamicibacter showed significant difference in the two groups. The aim of our current study was to characterize the basic bacterial composition and community structure in the feces of healthy common kestrels, and then compare the differences in the fecal microbiota between healthy and injured individuals. Patescibacteria, Spirochaetes, and Glutamicibacter may be studied as potential biomarkers for certain diseases in raptors. The results could provide the basic data for additional research on the fecal microbiota of common kestrels and contribute to the rescue of wild raptors in the future.

The vegetative insecticidal proteins (Vip3A) secreted by some Bacillus thuringiensis (Bt) strains during vegetative growth are regarded as a new generation of insecticidal toxins. Like insecticidal crystal proteins, they are also used in transgenic crops to control pests. However, their insecticidal mechanisms are far less defined than those of insecticidal crystal protein. Prohibitin 2 (PHB2) is a potential Vip3Aa binding receptor identified from the membrane of Sf9 cells in our previous work. In this paper, we demonstrated the interaction between Vip3Aa and PHB2 using pull-down, dot blotting, microscale thermophoresis, and co-immunoprecipitation assays. PHB2 is distributed on the cell membrane and in the cytoplasm, and the co-localization of PHB2 and Vip3Aa was observed in Sf9 cells using a confocal laser scanning microscope. Moreover, PHB2 could interact with scavenger receptor-C via its SPFH (stomatin, prohibitin, flotillin, and HflK/C) domain. Downregulation of phb2 expression reduced the degree of internalization of Vip3Aa, exacerbated Vip3Aa-mediated mitochondrial damage, and increased Vip3Aa toxicity to Sf9 cells. This suggested that PHB2 performs two different functions: Acting as an interacting partner to facilitate the internalization of Vip3Aa into Sf9 cells and maintaining the stability of mitochondria. The latter has a more important influence on the virulence of Vip3Aa.

Abstract Despite recent major advances in developing effective vaccines against toxoplasmosis, finding new protective vaccination strategies remains a challenging and elusive goal as it is critical to prevent the disease. Over the past few years, various experimental approaches have shown that developing an effective vaccine against T. gondii is achievable. However, more remains unknown due to its complicated life cycle, difficulties in clinical translation, and lack of a standardized platform. This minireview summarizes the recent advances in the development of T. gondii vaccines and the main obstacles to developing a safe, effective and durable T. gondii vaccine. The successes and failures in developing and testing vaccine candidates for the T. gondii vaccine are also discussed, which may facilitate the future development of T. gondii vaccines.

ABSTRACT The rapid acquisition of antibiotic resistance of Pseudomonas aeruginosa has been a complex problem in clinics. Two meropenem-resistant P. aeruginosa isolates were collected from the same patient on May 24, 2021, and June 4, 2021, respectively. The first was susceptible to aztreonam, while the second displayed resistance. This study aimed to identify the genetic differences between two P. aeruginosa isolates and uncover alterations formed by the within-host bacterial evolution leading to aztreonam resistance during therapy. Strains were subjected to antimicrobial susceptibility testing using the broth microdilution method. Genomic DNAs were obtained to identify their genetic differences. The relative mRNA levels of β-lactam-resistance genes were determined by real-time PCR. Both isolates belonged to ST 773 high-risk clones with the same antibiotic resistance genes, eliminating the possibility of horizontally obtaining resistance genes. Reverse transcription (RT)-PCR results showed that the blaPDC-16 mRNA level in the second one was about 1,500 times higher than that in the first one. When 3-aminophenyl boronic acid was added, the second strain recovered its susceptibility to aztreonam, which confirmed that the overexpression of blaPDC-16 was the main reason for the isolate’s resistance to aztreonam. Compared to the first strain, the second showed a single amino acid substitution in AmpR located upstream of blaPDC-16, which may contribute to the upregulation of blaPDC-16 and lead to aztreonam resistance. AmpR plays an essential role in regulating antibiotic resistance in P. aeruginosa, and there is a need to be alert to clinical treatment failures associated with mutations in ampR. IMPORTANCE Pseudomonas aeruginosa is notorious for being highly resistant to antimicrobial agents. In this study, two P. aeruginosa strains isolated from the same patient with different susceptibility to aztreonam were used to illustrate the within-host resistance evolution process of P. aeruginosa. Both isolates, which belonged to a ST773 high-risk clone, had the same β-lactam resistance genes (blaPDC-16, blaIMP-45, blaOXA-1, and blaOXA-395), which means the second isolate might have been derived from the first isolate by gaining aztreonam resistance via mutations associated with aztreonam resistance relative genes. Subsequently, we found that mutation in ampR may be the cause of aztreonam resistance in the second isolate. Mutation in ampR leads to its loss of control over blaPDC-16, allowing overexpression of blaPDC-16 and further resistance to aztreonam. This study revealed that ampR plays an essential role in regulating antibiotic resistance in P. aeruginosa. There is a need to be alert to clinical treatment failures associated with mutations in ampR.

BackgroundProgrammed death receptor 1 (PD-1) inhibition has shown durable response and mild adverse events (AEs) in adult malignancies. However, data on the clinical activity of PD-1 inhibition in pediatric patients are lacking. We comprehensively assessed the efficacy and safety of PD-1 inhibitor-based regimens for pediatric malignancies.MethodsWe conducted a real-world, multi-institutional, retrospective analysis of pediatric malignancies treated with PD-1 inhibitor-based regimens. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints included disease control rate (DCR), duration of response (DOR), and AEs. The Kaplan–Meier method was used to calculate PFS and DOR. The National Cancer Institute Common Toxicity Criteria for AEs (version 5.0) were used to grade toxicity.ResultsA total of 93 and 109 patients were evaluated for efficacy and safety, respectively. For all efficacy-evaluable patients, PD-1 inhibitor monotherapy, combined chemotherapy, combined histone deacetylase inhibitor, and combined vascular endothelial growth factor receptor tyrosine kinase inhibitor cohorts, the ORR and DCR were 53.76%/81.72%, 56.67%/83.33%, 54.00%/80.00%, 100.00%/100.00%, and 12.50%/75.00%, respectively; the median PFS and DOR were 17.6/31.2 months, not achieved/not achieved, 14.9/31.2 months, 17.6/14.9 months, and 3.7/1.8 months, respectively; the incidence rate of AEs were 83.49%, 55.26%, 100.00%, 80.00%, and 100.00%, respectively. One patient in the PD-1 inhibitor-combined chemotherapy cohort discontinued treatment due to diabetic ketoacidosis.ConclusionsThis largest retrospective analysis demonstrate that PD-1 inhibitor-based regimens are potentially effective and tolerable in pediatric malignancies. Our findings provide references for future clinical trials and practice of PD-1 inhibitors in pediatric cancer patients.

Terahertz sensing has an important position in biochemical detection due to its unique advantages. In this work, we design a sensor with tunable analytes refractive index interval using graphene/dielectric multilayer structured hyperbolic metamaterials (GMHMM). We use the attenuated total reflection method to match the bulk high k waves mode in the GMHMM and derive dispersion relation of the bulk resonance mode in combination with waveguide mode analysis. By tuning the graphene Fermi energy level and incidence angle, the sensor can detect analytes with different refractive indices with a maximum sensitivity of 20.5 THz/RIU and an average sensitivity of 11.05 THz/RIU in the band of 2.4 THz. We believe that the proposed structure can be applied to biochemical molecule detection in the terahertz band and contribute to the development of hyperbolic metamaterial sensors from laboratory research to practical applications.

Introduction: Metronomic maintenance therapy (MMT) has significantly improved the survival of patients with high-risk rhabdomyosarcoma in clinical trials. However, there remains a lack of relevant data on its effectiveness in real-world situations.Methods: We retrospectively retrieved data of 459 patients < 18 years of age diagnosed with rhabdomyosarcoma at Sun Yat-sen University Cancer Center from January 2011 to July 2020 from our database. The MMT regimen was oral vinorelbine 25–40 mg/m2 for twelve 4-week cycles on days 1, 8, and 15, and oral cyclophosphamide 25–50 mg/m2 daily for 48 consecutive weeks.Results: A total of 57 patients who underwent MMT were included in the analysis. The median follow-up time was 27.8 (range: 2.9–117.5) months. From MMT to the end of follow-up, the 3-year PFS and OS rates were 40.6% ± 6.8% and 58.3% ± 7.2%, respectively. The 3-year PFS was 43.6% ± 11.3% in patients who were initially diagnosed as low- and intermediate-risk but relapsed after comprehensive treatment (20/57), compared with 27.8% ± 10.4% in high-risk patients (20/57) and 52.8% ± 13.3% in intermediate-risk patients who did not relapse (17/57). The corresponding 3-year OS for these three groups was 65.8% ± 11.4%, 50.1% ± 12.9%, and 55.6% ± 13.6%, respectively.Conclusion: We present a novel study of MMT with oral vinorelbine and continuous low doses of cyclophosphamide in real-world pediatric patients with RMS. Our findings showed that the MMT strategy significantly improved patient outcomes and may be an effective treatment for high-risk and relapsed patients.

Abstract With the intensive therapeutic strategies, diffuse large B-cell lymphoma (DLBCL) is still a fatal disease due to its progressive characteristics. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator that catalyzes the commitment step of the kynurenine pathway in the immune system, its aberrant activation may contribute to malignant cell escape eradication. However, the role of IDO1 in DLBCL progression remains elusive. Our study showed IDO1 expression was upregulated in DLBCL and was associated with a poor prognosis and low overall survival. Inhibition of IDO1 suppressed DLBCL cell proliferation in vitro and impeded xenograft tumorigenesis in vivo. RNA-seq analyses revealed MDM2 was downregulated while TP53 was upregulated in IDO1 inhibition OCI-Ly10 cells. Mechanistically, IDO1 inhibition decreased the expression of MDM2, a major negative regulator of p53, and restored p53 expression in OCI-Ly3 and OCI-Ly10 cells, resulting in cell cycle arrest and apoptosis. IDO1 inhibition induced cell apoptosis coupled with PUMA and BAX upregulation, as well as BCL2 and BCL-XL downregulation. In addition, p21, a p53 transcriptional target, was upregulated in cell cycle arrest. Taken together, this study revealed IDO1 is essential for the proliferation of DLBCL cells and may be a potential therapeutic target for the treatment of DLBCL.

Background: Pancreatic cancer is one of the most deadly malignancies in the world. It is characterized by rapid progression and a very poor prognosis. The five-year survival rate of pancreatic cancer in China is only 7.2%, which is the lowest among all cancers and the use of combined paclitaxel albumin, capecitabine, and digital has been the clinical standard treatment for advanced pancreatic cancer since 1997. Also, the application of multidrug combinations is often limited by the toxicity of chemotherapy. Therefore, there is an urgent need for a more appropriate and less toxic treatment modality for pancreatic cancer.Case presentation: The patient was a 79-year-old woman, admitted to the hospital with a diagnosis of unresectable locally advanced pancreatic cancer (T3N0M0, stage IIA), with its imaging showing overgrowth of SMV involvement and unresectable reconstruction of the posterior vein after evaluation. As the patient refused chemotherapy, lenvatinib (8 mg/time, qd) and icaritin soft capsules (three tablets/time, bid) were recommended according to our past experience and a few clinical research cases. The tumor lesion was greatly reduced by 57.5% after the treatment, and the extent of vascular involvement also decreased. The aforementioned medication resulted in a significant downstaging of the patient’s tumor.Conclusion: Better results were achieved in the treatment with icaritin soft capsules and lenvatinib in this case. Because of its less toxic effect on the liver and kidney and bone marrow suppression, it was suitable to combine icaritin soft capsules with targeted drugs for treating intermediate and advanced malignancies, which brings hope to patients who cannot or refuse to take chemotherapy.

Toxoplasma gondii, a specialized intracellular parasite, causes a widespread zoonotic disease and is a severe threat to social and economic development. There is a lack of effective drugs and vaccines against T. gondii infection. Recently, mRNA vaccines have been rapidly developed, and their packaging materials and technologies are well established. In this study, TGGT1_216200 (TG_200), a novel molecule from T. gondii, was identified using bioinformatic screening analysis. TG_200 was purified and encapsulated with a lipid nanoparticle (LNP) to produce the TG_200 mRNA-LNP vaccine. The immune protection provided by the new vaccine and its mechanisms after immunizing BABL/C mice via intramuscular injection were investigated. There was a strong immune response when mice were vaccinated with TG_200 mRNA-LNP. Elevated levels of anti-T. gondii-specific immunoglobulin G (IgG), and a higher IgG2a-to-IgG1 ratio was observed. The levels of interleukin-12 (IL-12), interferon-γ (IFN-γ), IL-4, and IL-10 were also elevated. The result showed that the vaccine induced a mixture of Th1 and Th2 cells, and Th1-dominated humoral immune response. Significantly increased antigen-specific splenocyte proliferation was induced by TG_200 mRNA-LNP immunization. The vaccine could also induce T. gondii-specific cytotoxic T lymphocytes (CTLs). The expression levels of interferon regulatory factor 8 (IRF8), T-Box 21 (T-bet), and nuclear factor kappa B (NF-κB) were significantly elevated after TG_200 mRNA-LNP immunization. The levels of CD83, CD86, MHC-I, MHC-II, CD8, and CD4 molecules were also higher. The results indicated that TG_200 mRNA-LNP produced specific cellular and humoral immune responses. Most importantly, TG_200 mRNA-LNP immunized mice survived significantly longer (19.27 ± 3.438 days) than the control mice, which died within eight days after T. gondii challenge (P< 0.001). The protective effect of adoptive transfer was also assessed, and mice receiving serum and splenocytes from mice immunized with TG_200 mRNA-LNP showed improved survival rates of 9.70 ± 1.64 days and, 13.40 ± 2.32 days, respectively (P< 0.001). The results suggested that TG_200 mRNA-LNP is a safe and promising vaccine against T. gondii infection.

Recent studies have shown that microtransplant (MST) could improve outcome of patients with elderly acute myeloid leukemia (EAML). To further standardize the MST therapy and improve outcomes in EAML patients, based on analysis of the literature on MST, especially MST with EAML from January 1st, 2011 to November 30th, 2022, the International Microtransplant Interest Group provides recommendations and considerations for MST in the treatment of EAML. Four major issues related to MST for treating EAML were addressed: therapeutic principle of MST (1), candidates for MST (2), induction chemotherapy regimens (3), and post-remission therapy based on MST (4). Others included donor screening, infusion of donor cells, laboratory examinations, and complications of treatment.

Toxoplasma gondii (T. gondii) can infect almost all warm-blooded animals and is a major threat to global public health. Currently, there is no effective drug or vaccine for T. gondii. In this study, bioinformatics analysis on B and T cell epitopes revealed that TGGT1_316290 (TG290) had superior effects compared with the surface antigen 1 (SAG1). TG290 mRNA-LNP was constructed through the Lipid Nanoparticle (LNP) technology and intramuscularly injected into the BALB/c mice, and its immunogenicity and efficacy were explored. Analysis of antibodies, cytokines (IFN-γ, IL-12, IL-4, and IL-10), lymphocytes proliferation, cytotoxic T lymphocyte activity, dendritic cell (DC) maturation, as well as CD4+ and CD8+ T lymphocytes revealed that TG290 mRNA-LNP induced humoral and cellular immune responses in vaccinated mice. Furthermore, T-Box 21 (T-bet), nuclear factor kappa B (NF-kB) p65, and interferon regulatory factor 8 (IRF8) subunit were over-expressed in the TG290 mRNA-LNP-immunized group. The survival time of mice injected with TG290 mRNA-LNP was significantly longer (18.7 ± 3 days) compared with the survival of mice of the control groups (p

Abstract Ewing sarcoma (EwS) is an aggressive tumor that affects children and young adults. Patients with relapsed/refractory diseases have limited treatment options. Targeting the driver fusion oncoproteins of EwS remains a technical problem. Epigenetic mechanisms have been pointed out as key players and alternative therapeutic targets in EwS. Here, we reported that lysine demethylase 5B (KDM5B), a histone demethylase that specifically demethylates tri- and di-methylated H3 Lys-4 (H3K4), was upregulated in EwS and overexpressed KDM5B was correlated with poor outcomes of patients. KDM5B knockdown and KDM5B inhibitor AS-8351 suppressed EwS cell proliferation and induced cell cycle arrest. Bioinformatics analysis revealed that KDM5B mainly influenced the cell cycle pathways in EwS. In mechanistic studies, we found that overexpression of KDM5B resulted in increased CCNE1 protein level, but did not affect the mRNA level of CCNE1. KDM5B upregulation blocked the degradation pathway of CCNE1 by reducing the expression of FBXW7. KDM5B downregulated FBXW7 gene by demethylation of H3K4me3 at promoter region. Moreover, AS-8351 could inhibit tumor growth in nude mice models, indicating the antitumor effect of targeting KDM5B in EwS. Our study uncovered that KDM5B in EwS attenuated FBXW7 transcription and accumulated CCNE1 protein, leading to malignant proliferation of EwS. Epigenetic drug targeting KDM5B could be a potential treatment for EwS.

Analytical chemistry relies on the qualitative and quantitative analysis of multivariate data obtained from various measurement techniques. However, artifacts such as missing data, noise, multiplicative and additive effects, and peak shifts can adversely affect the accuracy of chemical measurements. To ensure the validity and accuracy of results, it is crucial to preprocess the data and correct for these artifacts. This paper proposes a fusion recalibration algorithm, called Spectral Offset Recalibration (SOR), that combines the Extended Multiplicative Signal Correction (EMSC) and Correlation-Optimized Warping (COW) algorithms to address both multiplicative and additive effects and peak shifts. The algorithm incorporates prior spectroscopic knowledge to down-weight or disregard spectral regions with strong absorption or significant distortion caused by peak alignment algorithms. Experimental validation on wood NIR datasets and simulated datasets demonstrates the effectiveness of the proposed method. The fusion recalibration approach offers a comprehensive solution for accurate analyses and predictions in analytical chemistry by mitigating the impact of artifacts.

Aiming at the problems of complex structure parameters and low feature extraction ability of U-Net used in vegetation classification, a deep network with improved U-Net and dual-way branch input is proposed. Firstly, The principal component analysis (PCA) is used to reduce the dimension of hyperspectral remote sensing images, and the effective bands are obtained. Secondly, the depthwise separable convolution and residual connections are combined to replace the common convolution layers of U-Net for depth feature extraction to ensure classification accuracy and reduce the complexity of network parameters. Finally, normalized difference vegetation index (NDVI), gray level co-occurrence matrix (GLCM) and edge features of hyperspectral remote sensing images are extracted respectively. The above three artificial features are fused as one input, and PCA dimension reduction features are used as another input. Based on the improved U-net, a dual-way vegetation classification model is generated. Taking the hyperspectral remote sensing image of Matiwan Village, Xiong’an, Beijing as the experimental object, the experimental results show that the precision and recall of the improved U-Net are significantly improved with the residual structure and depthwise separable convolution, reaching 97.13% and 92.36% respectively. In addition, in order to verify the effectiveness of artificial features and dual-way branch design, the accuracy of single channel and the dual-way branch are compared. The experimental results show that artificial features in single channel network interfere with the original hyperspectral data, resulting in reduction of the recognition accuracy. However, the accuracy of the dual-way branch network has been improved, reaching 98.67%. It shows that artificial features are effective complements of network features.

Pine cones are important forest products, and the picking process is complex. Aiming at the multi-objective and dispersed characteristics of pine cones in the forest, a machine vision detection model (EBE-YOLOV4) is designed to solve the problems of many parameters and poor computing ability of the general YOLOv4, so as to realize rapid and accurate recognition of pine cones in the forest. Taking YOLOv4 as the basic framework, this method can realize a lightweight and accurate recognition model for pine cones in forest through optimized design of the backbone and the neck networks. EfficientNet-b0 (E) is chosen as the backbone network for feature extraction to reduce parameters and improve the running speed of the model. Channel transformation BiFPN structure (B), which improves the detection rate and ensures the detection accuracy of the model, is introduced to the neck network for feature fusion. The neck network also adds a lightweight channel attention ECA-Net (E) to solve the problem of accuracy decline caused by lightweight improvement. Meanwhile, the H-Swish activation function is used to optimize the model performance to further improve the model accuracy at a small computational cost. 768 images of pine cones in forest were used as experimental data, and 1536 images were obtained after data expansion, which were divided into training set and test set at the ratio of 8:2. The CPU used in the experiment was Inter Core i9-10885@2.40Ghz, and the GPU was NVIDIA Quadro RTX 5000. The performance of YOLOv4 lightweight design was observed based on the indicators of precision (P), recall (R) and detection frames per second (FPS). The results showed that the measurement accuracy (P) of the EBE-YOLOv4 was 96.25%, the recall rate (F) was 82.72% and the detection speed (FPS) was 64.09F/S. Compared with the original YOLOv4, the precision of detection had no significant change, but the speed increased by 70%, which demonstrated the effectiveness of YOLOv4 lightweight design.

High-risk neuroblastoma (NB) is sensitive to chemotherapy but susceptible to chemoresistance. In this study, we aimed to analyze the incidence of chemoresistance in high-risk NB patients and to explore the role of autophagy in NB chemoresistance. We retrospectively analyzed the incidence of changing the chemotherapy regimen due to disease stabilization or disease progression during induction chemotherapy in high-risk NB patients, which was expressed as the chemoresistance rate. The autophagy levels were probed in tumor cells exposed to first-line chemotherapy agents. The sensitivity of tumor cells to chemotherapy agents and apoptosis rate were observed after inhibiting autophagy by transfection of shRNA or chloroquine (CQ). This study included 247 patients with high-risk NB. The chemoresistance rates of patients treated with cyclophosphamide + adriamycin + vincristine (CAV) alternating with etoposide + cisplatin (EP) (Group 1) and CAV alternating with etoposide + ifosfamide + cisplatin (VIP) (Group 2) was 61.5% and 39.9% (P = 0.0009), respectively. Group 2 had better survival rates than group 1. After exposure to cisplatin, cyclophosphamide, and etoposide, the autophagy-related proteins LC3-I, LC3-II, and Beclin-1 were upregulated, and the incidence of autophagy vesicle formation and the expression of P62 were increased. Chemotherapeutic agents combined with CQ significantly increased the chemotherapeutic sensitivity of tumor cells and increased the cell apoptosis. The downregulated expression of Beclin-1 increased the sensitivity of tumor cells to chemotherapeutics. Our results suggest that increasing the chemotherapy intensity can overcome resistance to NB. Inhibition of autophagy is beneficial to increase the sensitivity of NB to chemotherapy agents.

ABSTRACT Nucleoside transport is essential for maintaining intracellular nucleoside and nucleobase homeostasis for living cells. Here, we identified an uncharacterized GntR/HutC family transcriptional regulator, NagR2, renamed NupR (nucleoside permease regulator), that mainly controls nucleoside transport in the Bacillus thuringiensis BMB171 strain. The deletion or overexpression of nupR affected the bacteria's utilization of guanosine, adenosine, uridine, and cytidine rather than thymidine. We further demonstrated that zinc ion is an effector for the NupR, dissociating NupR from its target DNA. Moreover, the expression of nupR is inhibited by NupR, ComK, and PurR, while it is promoted by CcpA. Also, a purine riboswitch located in its 5′ noncoding region influences the expression of nupR. Guanine is the ligand of the riboswitch, reducing the expression of nupR by terminating the transcription of nupR in advance. Hence, our results reveal an exquisite regulation mechanism enabling NupR to respond to multiple signals, control genes involved in nucleoside transport, and contribute to nucleoside substance utilization. Overall, this study provides essential clues for future studies exploring the function of the NupR homolog in other bacteria, such as Bacillus cereus, Bacillus anthracis, Klebsiella pneumoniae, and Streptococcus pneumoniae. IMPORTANCE The transport of nucleosides and their homeostasis within the cell are essential for growth and proliferation. Here, we have identified a novel transcription factor, NupR, which, to our knowledge, is the first GntR family transcription factor primarily involved in the regulation of nucleoside transport. Moreover, responding to diverse intracellular signals, NupR regulates nucleoside transport. It is vital for utilizing extracellular nucleosides and maintaining intracellular nucleoside homeostasis. NupR may also be involved in other pathways such as pH homeostasis, molybdenum cofactor biosynthesis, nitrate metabolism, and transport. In addition, nucleosides have various applications, such as antiviral drugs. Thus, the elucidation of the transport mechanism of nucleosides could be helpful for the construction of engineered strains for nucleoside production.

Defects in wood growth affect the product’s quality and grade. At present, the research on texture defects of wood mainly focuses on defect localization, ignoring the splicing problem of maintaining texture consistency. In this paper, we designed the MRS-Transformer network and introduced image inpainting to the field of solid wood board splicing. First, we proposed an asymmetric encoder-decoder based on Vision Transformer, where the encoder uses a fixed mask(M) strategy, discarding the masked patches and using only the unmasked visual patches as input to reduce model calculations. Second, we designed a reverse Swin (RS) module with multi-scale characteristics as the decoder to adjust the divided image patches’ size and complete the restoration from coarse to fine. Finally, we proposed a weighted L2 loss (MSE, mean square error), which assigns different weights to the unmasked region according to the distance from the defective region, allowing the model to make full use of the effective pixels to repair the masked region. To demonstrate the effectiveness of the designed modules, we used MSE (mean square error), LPIPS (learned perceptual image patch similarity), PSNR (peak signal to noise ratio), SSIM (structural similarity), and FLOPs (floating point operations) to measure the quality of the model generated wood texture images and the model computational complexity, we designed relevant ablation experiments. The results show that the MSE, LPIPS, PSNR, and SSIM of the wood images restored by the MRS-Transformer reached 0.0003, 0.154, 40.12, 0.9173, and the GFLOPs is 20.18. Compared with images generated by the Vision Transformer, the MSE and LPIPS were reduced by 51.7% and 30%, PSNR and SSIM were improved by 12.2% and 7.5%, and the GFLOPs were reduced by 38%. To verify the superiority of MRS-Transformer, we compared the image inpainting algorithms with Deepfill v2 and TG-Net, respectively, in which the MSE was 47.0% and 66.9% lower; the LPIPS was 60.6% and 42.5% lower; the FLOPs was 70.6% and 53.5% lower; the PSNR was 16.1% and 26.2% higher; and the SSIM was 7.3% and 5.8% higher. MRS-Transformer repairs a single image in 0.05 s, nearly five times faster than Deepfill v2 and TG-Net. The experimental results demonstrate that the RSwin module effectively alleviates the sense of fragmentation caused by the division of images into patches, the proposed weighted L2 loss improves the semantic consistency of the edges of the missing regions and makes the generated wood texture more detailed and coherent, and the adopted asymmetric encoder-decoder effectively reduces the computational effort of the model and speeds up the training.

Due to the complex structure of high-canopy-density forests, the traditional individual tree segmentation (ITS) algorithms based on ALS point cloud, which set segmentation threshold manually, is difficult to adequately cover a variety of complex situations, so the ITS accuracy is unsatisfactory. In this paper, a top-down segmentation strategy is adopted to propose an adaptive segmentation method based on extreme offset deep learning, and the ITS set aggregation strategy based on gradient change criterion is designed for the over-segmentation generated by random offset, and the precise ITS is realized. Firstly, the segmentation sub-plot is set as 25 m × 25 m, the regional point cloud and its treetop are marked, and the offset network is trained. Secondly, the extreme offset network is designed to carry out spatial transformation of the original point cloud, and each point is offset to the position near the treetop to obtain the offset point cloud with a high density at the treetop, which enhances the discrimination among individual trees. Thirdly, the self-adaptive mean shift algorithm based on average neighboring distance is designed to divide and mark the offset point cloud. Fourthly, the offset point cloud, after clustering, is mapped back to the original space to complete the preliminary segmentation. Finally, according to the gradient change among different canopies, the ITS aggregation method is designed to aggregate adjacent canopies with a gentle gradient change. In order to investigate the universality of the proposed method on different stand structures, two coniferous forest plots (U1, U2) in the Blue Ridge area of Washington, USA, and two mixed forest plots (G1, G2) in Bretten, Germany, are selected in the experiment. The learning rate of the deep network is set as 0.001, the sampled point number of the sub-plot is 900, the transformer dimension is 512 × 512, the neighboring search number of points is 16, and the number of up-sampling blocks is 3. Experimental results show that in mixed forests (G1, G2) with complex structures, the F-score of the proposed method reaches 0.89, which is about 4% and 7% higher than the classical SHDR and improved DK, respectively. In high-canopy-density areas (U2, G2), the F-score of the proposed method reaches 0.89, which is about 3% and 4% higher than the SHDR and improved DK, respectively. The results show that the proposed method has high universality and accuracy, even in a complex stand environment with high canopy density.

Cylindrical vector beams (CVBs) are the product of polarization modulation of optical fields, and possess both unique focusing characteristics and excellent properties applicable to machining, imaging, communication and other fields. Mode selection couplers comprise a promising new method to realize the long-term stable output of cylindrical vector beam all-fiber lasers. Mode selection couplers have the advantages of a simple structure, high mode conversion efficiency and high mode purity. However, the production process of conventional asymmetric mode selection couplers is more complicated. Therefore, in this paper, a symmetric two-mode coupler with a 1 μm band is designed and fabricated using the finite element method, beam propagation method and fused pull-cone method, and a set of all-fiber passive mode-locked lasers based on symmetric dual-mode couplers are constructed. Finally, we obtain cylindrical vector beam outputs with central wavelengths of 1038.97 nm/1067.72 nm, a repetition rate of 8.78 MHz, pulse durations of 660 ps/656 ps, maximum average powers of 5.25 mW/5.2 mW, and the high mode purity of TM (transverse magnetic)01 mode and TE (transverse electric)01 mode is 97.18% and 97.07%, respectively.

ABSTRACT Importance Burkitt lymphoma with bone marrow involvement and Burkitt leukemia behave aggressively. Thus far, there are limited data concerning survival and toxicity in Chinese children with Burkitt lymphoma or Burkitt leukemia who have undergone treatment with the non‐Hodgkin’s lymphoma Berlin‐Frankfurt‐Münster‐90/95 (NHL‐BFM‐90/95) protocol. Objective To analyze outcomes and toxicity in pediatric patients who exhibit Burkitt lymphoma with bone marrow involvement or Burkitt leukemia following treatment with the NHL‐BFM‐90/95 protocol. Methods Patients aged

Abstract Neuroblastoma (NB) is the most common extracranial solid malignancy in children and its mortality rate is relatively high. However, driver genes of NB are not clearly identified. Using bioinformatics analysis, we determined the top 8 differentially expressed genes (DEGs) in NB, including GFAP, PAX6, FOXG1, GAD1, PTPRC, ISL1, GRM5, and GATA3. Insulin gene enhancer binding protein 1 (ISL1) is a LIM homeodomain transcription factor which has been found to be highly expressed in a variety of malignant tumors, but the function of ISL1 in NB has not been fully elucidated. We identified ISL1 as an oncogene in NB. ISL1 is preferentially upregulated in NB tissues compared with normal tissues. High ISL1 expression is significantly associated with poor outcome of NB patients. Knockdown of ISL1 markedly represses proliferation and induces cell apoptosis in vitro, and suppresses tumorigenicity in vivo, while overexpression of ISL1 has the opposite effects. Mechanistically, we demonstrate that ISL1 promotes cell proliferation and EMT transformation through PI3K/AKT signaling pathway by upregulating Aurora kinase A (AURKA), a serine-threonine kinase that is essential for the survival of NB cells. The blockade of AURKA attenuates the function of ISL1 overexpression in the regulation of cell proliferation and migration, Conclusively, this study showed that ISL1 targeted AURKA to facilitate the development of NB, which provided new insights into the tumorigenesis of NB. Thus, ISL1 may be a promising therapeutic target in the future.

Leather wastewater harms the ecological environment and human health. In this study, a modified bio-flocculant was prepared to facilitate treatment of leather wastewater. A bio-flocculant produced by Bacillus cereus was combined with amphoteric starch and modified using a cerium ammonium nitrate initiator. Single factor optimization and orthogonal optimization were used to determine the optimal preparation conditions as follows: amphoteric starch-to-flocculant ratio = 22:30; reaction temperature = 64 °C; initiator dosage = 2.00%; reaction time = 15 min; stirring speed = 600 rpm; and flocculation system pH = 8.0. At a dosage of 1 g/L added to simulated leather industry wastewater, the flocculation efficiency (98.17%) and the total nitrogen removal efficiency (100.00%) of modified bio-flocculant was superior to that achieved by 1 g/L of unmodified bio-flocculant (72.16% and 50.00%, respectively), amphoteric starch (8.50% and 0.00%) and polyacrylamide (95.55% and 75.00%). Analysis of natural and flocculated precipitates in the wastewater showed that the modified bio-flocculant significantly changed several characteristics of the flocculated particles; in addition, it promoted the removal of nitrogenous substances in the process of denitrification. These changes helped explain the material's flocculating ability. The results confirmed that the modified bio-flocculant was an effective additive for treating leather wastewater. HIGHLIGHTS A modified biological flocculant was successfully prepared by using biological flocculant and amphoteric starch.; The modified biological flocculant has an excellent treatment effect on leather wastewater.; The flocculation rate of leather wastewater can reach 98.17%, and the removal rate of total nitrogen can reach 100%.;

This paper presents a theoretical model of lossy mode resonance (LMR) prism refractive index sensor based on the SBS (sensing medium/black phosphorus/sensing medium) structure. By using the sensing medium as the matching layer and the black phosphorus (BP) as the lossy layer, the sensor’s performance under angular interrogation is effectively improved. In addition, the implications on the reflectance of changes in the sensor structure are investigated in detail and the principles for the design of the device are summarized in this paper. Results show that the device has a refractive index detection range of 1.33–1.49, with different sensing properties under TE and TM polarized light. This LMR sensor has a high sensitivity under TE polarized light with a sensitivity range of 83–420 °/RIU and a maximum quality factor of 9.9×105 RIU−1 under TM polarized light. We believe that the proposed structure can be broadly applied to chemical biomolecular detection, environmental monitoring, medical diagnosis, and other fields.

IRAK1 is an active kinase which plays a critical role in IL-1/TLR signaling pathway involved in inflammation and innate immune response. Recently, increasing evidence supports a potential role of IRAK1 in cancer progression. However, no immunological pan-cancer analysis of IRAK1 is available. We aimed to explore the prognostic value and the immunological functions of IRAK1. A series of datasets including The Cancer Genome Atlas, GEPIA2, cBioPortal, HPA, TIMER2.0 were performed to explore the oncogenic and immunological roles of IRAK1, including the relationship between IRAK1 and prognosis, genetic mutation, GO and KEGG enrichment pathway analysis, immune state of different tumors, The results showed that IRAK1 levels were upregulated in more than 20 types of cancers compared to the normal tissues. IRAK1 expression was associated with poorer prognosis in different cancer types. For the most frequent DNA alteration of IRAK1 is amplification. And the result of the enrichment analysis suggested that IRAK1 related to immune checkpoint pathway in cancer. IRAK1 inhibitor pacritinib inhibit proliferation and upregulate PD-L1 expression in different cancer cell lines. Moreover, the patients who receiving anti-PD-L1 therapy with low IRAK1 expression had a better prognosis, and the objective response rate to anti-PD-L1 therapy was higher in the low IRAK1 group than in the high IRAK1 group in IMvigor210 cohort. Our study reveals that IRAK1 can function as a prognostic marker in various malignant tumors. And pacritinib upregulated PD-L1 expression in several cancer cell lines, which indicating that IRAK1 can be used as a reliable marker to predict the efficacy of immunotherapy.

Abstract High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) is still a consolidation treatment choice for relapsed/refractory B-cell non-Hodgkin’s lymphoma (NHL) patients and some aggressive B-cell NHL as frontline therapy. Due to the shortage of carmustine, we switched to idarubicin-substituted BEAC (IEAC) conditioning regimen. We retrospectively compared the outcomes of 72 aggressive B-cell NHL patients treated with IEAC or BEAC regimens followed by ASCT as upfront consolidative treatment. The median time to neutrophil and platelet reconstitution showed no difference between IEAC and BEAC groups. IEAC regimen was well tolerated without increase of adverse events. Transplant-related mortality didn’t occur. The overall survival (OS) and progression-free survival (PFS) of IEAC group (33 and 23 months) were a little longer than that of BEAC group (30 and 18 months). However, due to the small sample numbers, there’s no significant difference in OS and PFS between IEAC and BEAC group with DLBCL or MCL. Multivariate analysis showed that AnnArbor staging, IPI score, lactate dehydrogenase level, remission of disease, modified regimen were related with PFS and OS. In conclusion, IEAC regimen was well tolerated and replacement with idarubicin could be an alternative when carmustine was not available.

With the development of communication technology, there is a more urgent demand for enhancing the security of data transmission. In order to improve the security of the traditional chaotic laser communication system, we propose a new scheme by the introduction of wavelength-hopping technology based on tunable lasers. In our new scheme, due to the hopping of wavelengths and the pseudo-randomness of the wavelength-hopping sequence, it is difficult for the eavesdropper to intercept the information and predict to which wavelength the hopping station will hop. The numerical simulation results show that the average bit error rate of eavesdropping is about five orders of magnitude higher than that of working normally. This indicates that the introduction of wavelength-hopping technology can improve the difficulty of message decoding and improve the confidentiality of the system. This scheme can be used to realize a high level of privacy in the design of chaotic laser communication systems in the future.

PurposeThe combination of irinotecan, temozolomide and vincristine has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination for patients with relapsed and refractory neuroblastoma (NB).Patients and MethodsIn this retrospective study, forty-six patients with relapsed or refractory NB were treated with the combination of vincristine (1.5 mg/m2 i.v. day 1), irinotecan (50 mg/m2/day i.v. days 1–5) and temozolomide (100 mg/m2/day p.o. days 1–5) (VIT) during the period 2011–2019. All toxicities were documented.ResultsA total of 251 cycles (median 6 cycles/patient) were administered. A complete response (CR) was achieved in 5 patients, partial response (PR) in 27 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 6 patients, with an overall objective response rate (CR+PR) of 69.6%. Eighteen patients developed diarrhea with Grade 3 or less. Grade 1-2 hematologic toxicity occurred in 10 patients. Grade 3-4 hematologic toxicity developed in 32 patients. VIT was an effective regimen for different metastatic sites. UGT1A*28 genotyping performed in 7 patients revealed wild type. Diarrhea occurred in 4 of them.ConclusionThe shorter, 5-day VIT regimen is an active and well-tolerated salvage regimen in relapse/refractory NB.

Objective: Refractory or recurrent pediatric solid tumors lack effective treatments, and are associated with dismal outcomes. Hence, there is an urgent need for a novel therapeutic strategy. This study aimed to evaluate the efficacy and safety of anlotinib, a novel oral multi-kinase angiogenesis inhibitor, in pediatric patients with refractory or recurrent solid tumors.Methods: This single-institutional, observational retrospective study was conducted in Sun Yat-sen University Cancer Center, China. Refractory or recurrent pediatric solid tumor patients treated with anlotinib between 2018 and 2020 were evaluated.Results: Forty-one and 30 patients were enrolled to evaluate the efficacy and safety of anlotinib, respectively. There was partial response in five patients, stable disease in 22 patients, no patient with complete response, with an objective response ratio of 12.2% (5/41; 95% CI 1.7-22.7). The disease control rate was 65.9% (27/41; 95% CI 50.7-81) and the median progression-free survival was 2.87 months (95% CI 0.86-4.88). The incidence rates of any grade and grade 3–4 adverse events were 80% (24/30) and 23.3% (7/30), respectively. Bleeding (20%, 6/30), hand-foot syndrome (16.7%, 5/30), and diarrhea (13.3%, 4/30) were the most common adverse events. Grade 3–4 adverse events included hypertension, hand-foot syndrome, diarrhea, anemia, and thrombocytopenia. There were no adverse events-related deaths.Conclusion: For heavily pretreated pediatric solid tumors, anlotinib monotherapy and its combination with chemotherapy may be an effective treatment option with tolerable adverse events. It is necessary to monitor blood pressure when using anlotinib in children.

To verify the feasibility of Brillouin optical time domain reflector (BOTDR) applied in space station, three kinds of commercial fibers, YOFC fiber (about 1 km), Corning fiber (about 1 km) and Fujikura fibers (about 1.5 km), have been radiated by Co60 in radiation experiment. Based on the Brillouin Gain Spectrum (BGS) along sensing fiber, we analyze power curve of Brillouin backscattered light, Brillouin Frequency Shift (BFS) along sensing fiber and spatial resolution carefully. The results indicate that radiation has little effect on BFS when signal-to-noise ratio (SNR) is large enough. However, since radiation will lead to radiation-induced attenuation, the amplitude of BGS will decrease accordingly. And if the SNR becomes small enough, the accurate BFS cannot be obtained. For the stressed fiber section of BOTDR, the result shows that radiation has little effect on the strain coefficient at the total radiation dose of 200 Gy, but radiation will deteriorate the spatial resolution of BOTDR with the increase of radiation dose. These results are good references for the introduction of BOTDR to space station.