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Abstract Invasive fungal infections (IFIs) pose a significant threat to immunocompromised individuals, leading to considerable morbidity and mortality. Prompt and accurate diagnosis is essential for effective treatment. Here we develop a rapid molecular diagnostic method that involves three steps: fungal enrichment using affinity-magnetic separation (AMS), genomic DNA extraction with silicon hydroxyl magnetic beads, and detection through a one-pot system. This method, optimized to detect 30 CFU/mL of C. albicans in blood and bronchoalveolar lavage (BAL) samples within 2.5 h, is approximately 100 times more sensitive than microscopy-based staining. Initial validation using clinical samples showed 93.93% sensitivity, 100% specificity, and high predictive values, while simulated tests demonstrated 95% sensitivity and 100% specificity. This cost-effective, highly sensitive technique offers potential for use in resource-limited clinical settings and can be easily adapted to differentiate between fungal species and detect drug resistance.

Abstract Background Recent studies have shown that both metabolic syndrome and circadian rhythm syndrome are firmly associated with the occurrence of cardiovascular disease (CVD), with insulin resistance playing a significant role. The estimated glucose disposal rate (eGDR) is considered to be a reliable surrogate marker for insulin resistance. However, the relationship between eGDR and CVD under different metabolic and circadian rhythm states has not been thoroughly studied, and large-scale prospective cohort studies are needed to clarify this relationship. Methods This study is based on the China Health and Retirement Longitudinal Study (CHARLS), recruiting individuals aged 45 and above with complete eGDR data. The eGDR was calculated by the formula: eGDR(mg/kg/min) = 21.158 − (0.09 × WC) − (3.407 × hypertension) − (0.551 × HbA1c) [WC (cm), hypertension (yes = 1/no = 0), and HbA1c (%)] (Zabala et al. in Cardiovasc Diabetol 20(1):202; 2021).Participants were divided into four subgroups based on the quartiles (Q) of eGDR.The cumulative incidence rates and hazard ratios (HR) with 95% confidence intervals (CI) were calculated, with the lowest eGDR quartile (representing the highest degree of insulin resistance) as the reference. Participants were further divided into subgroups based on the diagnosis of Metabolic syndrome (MetS) or circadian syndrome (CircS) to explore the relationship between eGDR and CVD under different metabolic and circadian rhythm conditions. The dose–response relationship between eGDR and CVD incidence was investigated using a restricted cubic spline (RCS) based on a Cox regression model. Receiver operating characteristic (ROC) curves were generated to assess the predictive value of eGDR for CVD incidence. A clinical decision curve analysis (DCA) was also conducted to assess the clinical utility of the basic model. Results 6507 participants were included, with a median age of 58 years [52 years, 64 years], and 55% were female. Over a median follow-up duration of 87 months, 679 first-episode CVD events were recorded, including heart disease and stroke. The RCS curves demonstrated a significant dose–response relationship between eGDR and the incidence of first-presentation CVD in different metabolic and circadian rhythm subgroups (all P-values 0.05). eGDR exhibited a significant linear relationship with all outcomes (non-linearity P

Abstract Background Spontaneous intracerebral hemorrhage (SICH) is a severe stroke with high mortality and disability rates. Endoscopic surgery is an increasingly widely used minimally invasive method for the treatment of SICH. However, the impact of fever on patient outcomes remains unclear. Methods We retrospectively included patients aged 18 years or older with supratentorial SICH confirmed by CT, who underwent endoscopic hematoma evacuation within 48 h of symptom onset. The primary outcome was the modified Rankin Scale (mRS) score at 3 months. Secondary outcomes included hospital and neurosurgical intensive care unit (NSICU) stays, and perioperative complications. We analyzed the association between postoperative fever (highest temperature within 24 h after surgery) and these outcomes using multivariate analysis, generalized additive models, and segmented regression analysis. Results Of the 56 patients, 38 had favorable outcomes (mRS ≤ 3) and 18 had unfavorable outcomes (mRS > 3) at 3 months. A threshold effect at 38.2 °C was observed between postoperative body temperature and clinical outcomes. The mean age was 56 years (SD = 9) for the > 38.2 °C group and 58 years (SD = 8) for the ≤ 38.2 °C group, with a similar proportion of male patients (63% vs. 69%, P = 0.635). Patients with postoperative fever had larger hematoma volumes (65 vs. 56 mL; P = 0.008). Other characteristics were similar between the groups. Postoperative fever (> 38.2 °C) was independently associated with a 4.99-fold increased risk of unfavorable outcomes (95% CI = [1.13 to 25.90]; P = 0.040), which remained significant after excluding patients with postoperative complications (adjusted RR = 16.03, 95% CI = [1.69 to 417.24]; P = 0.033). The association was consistent across subgroups with different Glasgow Coma Scale scores, hematoma volumes, and intraventricular extension. Postoperative fever was also associated with longer NSICU stays (3.1 vs. 2.3 days; P = 0.023), longer hospital stays (17.2 vs. 13.6 days; P = 0.010), more residual hematoma, and greater edema volume. Different antipyretic therapies did not affect outcomes. Conclusions This study identifies a temperature threshold (38.2 °C) associated with poor outcomes in SICH patients undergoing endoscopic surgery. Further research is needed to mitigate postoperative fever and improve patient outcomes.

ObjectiveThis study aims to explore the structural strength deterioration mechanism of pipelines with corrosion defects in hydrogen-blended environments.MethodsBased on the experimental data, an analysis is made of the load bearing performance of X52 steel under different levels of hydrogen blending , and the structural strength failure mechanism of an X52 hydrogen-blended natural gas pipeline under different corrosion defects is described using the nonlinear finite element method. ResultsWhen the hydrogen blend level increases to 50.0%, under a combined load, the pipeline reaches minimum displacement failure at 2.58 mm, and the structural toughness deteriorates to a greater degree; at a hydrogen blend level of 25.0%, the defect depth is greater and the degree of structural failure more serious; comparing square and circular defects, the maximum stress of the square defects is higher than that of the circular defects. ConclusionsThe material property-based defective pipeline model can realize the assessment of the structural bearing capacity deterioration of natural gas pipelines under different hydrogen-blending conditions, providing engineering suggestions for the design and health monitoring of new energy pipelines.

Abstract Background Gastric cancer (GC) is a major contributor to cancer-related mortality. Glycolysis plays a pivotal role in tumor microenvironment (TME) reprogramming. In this research, the functions of glycolysis-associated genes (GRGs) were evaluated to predict the outcome and reveal the characteristics of the immune microenvironment in individuals with stomach cancer. Methods The Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD) cohort provided gene expression and clinical data for gastric cancer (GC) patients, which were further authenticated using datasets sourced from the Gene Expression Omnibus (GEO). By referencing the Molecular Signatures Database (MSigDB), a total of 326 GRGs were pinpointed. The various subtypes of GC were outlined through consensus clustering, derived from the expression patterns of these GRGs. Utilizing multivariate Cox regression analysis, a multigene risk score model was formulated. Both the CIBERSORT and ESTIMATE algorithms played a pivotal role in assessing the immune microenvironment. To delve into the biological functions of the key genes, wound healing, transwell invasion, and MTT assays were conducted. Results Based on the expression patterns of GRGs, patients were categorized into two distinct groups: the metabolic subtype, designated as cluster A, and the immune subtype, labeled as cluster B. Patients belonging to cluster B exhibited a poorer prognosis. A prognostic risk score model, formulated upon the expression levels of six key GRGs — ME1, PLOD2, NUP50, CXCR4, SLC35A3, and SRD35A3 — emerged as a viable tool for predicting patient outcomes. The downregulation of CXCR4 notably diminished the glycolytic capacity of gastric cancer (GC) cells, alongside their migratory, invasive, and proliferative capabilities. Intriguingly, despite the adverse prognostic implications associated with both the immune subtype (cluster B) and the high-risk cohort, these groups exhibited a favorable immune microenvironment coupled with elevated expression of immune checkpoint genes. Our investigations revealed a positive correlation between high CXCR4 expression and low ME1 expression with the infiltration of CD8+ T cells, as well as an enhanced responsiveness to treatment with an anti-PD-1 immune checkpoint inhibitor. Conclusions In this study, we discovered that the expression profiles of GRGs hold the potential to forecast the prognosis of gastric cancer (GC) patients, thereby possibly aiding in clinical treatment decision-making.

Abstract Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1–14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8–89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

Abstract Recent evidence has shed light on the significant role of FANCD2 in cancer initiation, development, and progression. However, a comprehensive pan-cancer analysis of FANCD2 has been lacking. In this study, we have conducted a thorough investigation into the expression profiles and prognostic significance of FANCD2, as well as its correlation with clinicopathological parameters and immune cell infiltration, using advanced bioinformatic techniques. The results demonstrate that FANCD2 is significantly upregulated in various common cancers and is associated with prognosis. Notably, higher expression levels of FANCD2 are linked to poor overall survival, as indicated by Cox regression and Kaplan-Meier analyses. Additionally, we have observed a decrease in the methylation of FANCD2 DNA in some cancers, and this decrease is inversely correlated with FANCD2 expression. Genetic alterations in FANCD2 predominantly manifest as mutations, which are associated with overall survival, disease-specific survival, disease-free survival, and progression-free survival in certain tumor types. Moreover, FANCD2 exhibits a strong correlation with infiltrating cell levels, immune checkpoint genes, tumor mutation burden (TMB), and microsatellite instability (MSI). Enrichment analysis further highlights the potential impact of FANCD2 on Fanconi anemia (FA) pathway and cell cycle regulation. Through this comprehensive pan-cancer analysis, we have gained a deeper understanding of the functions of FANCD2 in oncogenesis and metastasis across different types of cancer.

ABSTRACTMany biological processes related to cell function and fate begin with chromatin alterations, and many factors associated with the efficacy of immune checkpoint inhibitors (ICIs) are actually downstream events of chromatin alterations, such as genome changes, neoantigen production, and immune checkpoint expression. However, the influence of genes as chromatin regulators on the efficacy of ICIs remains elusive, especially in gastric cancer (GC). In this study, thirty out of 1593 genes regulating chromatin associated with a favorable prognosis were selected for GC. CHAF1A, a well-defined oncogene, was identified as the highest linkage hub gene. High CHAF1A expression were associated with microsatellite instability (MSI), high tumor mutation burden (TMB), high tumor neoantigen burden (TNB), high expressions of PD-L1 and immune effector genes, and live infiltration of immune cells. High CHAF1A expression indicated a favorable response and prognosis in immunotherapy of several cohorts, which was independent of MSI, TMB, TNB, PD-L1 expression, immune phenotype and transcriptome scoring, and improved patient selection based on these classic biomarkers. In vivo, CHAF1A knockdown alone inhibited tumor growth but it impaired the effect of an anti-PD-1 antibody by increasing the relative tumor proliferation rate and decreasing the survival benefit, potentially through the activation of TGF-β signaling. In conclusion, CHAF1A may be a novel biomarker for improving patient selection in immunotherapy.

Background: To evaluate the efficacy and safety of allogenic CD8 + natural killer T (CD8+ NKT) immunotherapy combined with gefitinib in the treatment of advanced or metastatic EGFR mutant non-small cell lung cancer (NSCLC). Methods: This study is prospective. The NSCLC patients with exon 19 (Ex19del) or exon 21 L858R point mutations, and response to gefitinib treatment were enrolled into the trial to be randomly assigned into the gefitinib arm and the gefitinib/NKT arm. Allogenic CD8+ NKT cells were cultured in vitro and adaptive transferred into the patients via vein in the gefitinib/NKT arm. The primary endpoint was progression-free survival (PFS). Secondary endpoint analysis included time to disease progression (TTP), overall survival (OS), levels of serum tumour markers for carcinoembryonic antigen (CEA) and alanine aminotransferase (ALT) in the blood, the response rate and safety. From July 2017 to June 2021, 19 patients were randomly assigned to the gefitinib arm (n = 8) and the gefitinib/NKT arm (n = 11). Results: The estimated median survival PFS in the gefitinib/NKT arm was significantly longer than that of the gefitinib arm (12 months vs 7 months). Similar results were also observed for the median TTP. Moreover, the gefitinib/NKT arm had better CEA control than the gefitinib arm. Clinical grade 3 adverse reactions occurred in 64% and 39% of patients in the gefitinib/NKT arm and the gefitinib arm, respectively. The most common grade 3 adverse events in the gefitinib/NKT arm included abnormal liver function in 8 cases (73%) and diarrhoea in 1 case (9%), both of which resolved after drug intervention. Conclusion: The PFS of EGFR-mutated advanced NSCLC treated with allogenic CD8+ NKT cells combined with gefitinib was longer than that of gefitinib alone. No obvious serious adverse reactions occurred, and the patients compliance and survival status were good.

Facial expression recognition (FER) is an important task in human emotion analysis. Though researchers have made great progress in FER, the semantic information lying in facial landmarks has not been fully exploited. In this paper, we propose a landmark-based adaptive graph convolutional network (LBAGCN) for FER. It takes facial landmarks as input in both phases of model training and inference and thus preserves sensitive privacy information well. Based on the facial landmark sequence extracted from a video clip, we define landmark motion sequence, muscle sequence and muscle motion sequence. Correspondingly, we construct four facial graphs with learnable topologies, named landmark graph, landmark motion graph, muscle graph and muscle motion graph. Each of the facial graphs contains useful semantic information relevant to facial expressions. The proposed LBAGCN consists of four parallel adaptive graph convolutional networks (AGCNs), each of which employs well-designed adaptive graph convolution blocks and multi-branch temporal convolutional network blocks to learn the spatial and temporal features from a facial graph automatically. The class scores of AGCNs are fused to boost the FER accuracy. Extensive experiments have been carried out to validate the proposed LBAGCN on the recognized CK+ dataset and Oulu CASIA dataset. Compared with state-of-the-art methods, the proposed LBAGCN achieves competitive FER accuracy especially on the challenging Oulu CASIA dataset. Testing results on practical platforms confirm that the proposed LBAGCN can be a feasible solution for real-time FER applications.

Recognizing emotional states from speech is essential for human-computer interaction. It is challenging to realize effective speech emotion recognition (SER) on platforms with limited memory capacity and computing power. In this paper, we propose a lightweight multi-scale deep neural network architecture for SER, which takes Mel Frequency Cepstral Coefficients (MFCCs) as input. In order to realize effective multi-scale feature extraction, we propose a new Inception module, named A_Inception. A_Inception combines the merits of Inception module and attention-based rectified linear units (AReLU) and thus can learn multi-scale features adaptively with low computational cost. Meanwhile, to extract most important emotional information, we propose a new multiscale cepstral attention and temporal-cepstral attention (MCA-TCA) module. The idea of MCA-TCA module is to focus on the key cepstral components and the key temporal-cepstral positions. Furthermore, a loss function combining Softmax loss and Center loss is adopted to supervise the model training so as to enhance the model’s discriminative power. Experiments have been carried out on IEMOCAP, EMO-DB and SAVEE datasets to verify the performance of the proposed model and compare with the state-of-the-art SER models. Numerical results reveal that the proposed model has a small number of parameters (0.82 M) and much lower computational cost (81.64 MFLOPs) than compared models, and achieves impressive accuracy on all datasets considered.

Deep reinforcement learning (DRL) methods have emerged as a feasible solution for addressing the power resource allocation problem in ultra-dense small-cell networks (UDSCNs). In this paper, we propose a novel actor-critic-based low-coupling policy optimization (LCPO) framework. Our framework aims to achieve practicality by employing a design that consists of training and execution modules with low coupling. By adopting policy optimization methods, including advantage actor-critic (A2C) and proximal policy optimization (PPO) with state-dependent exploration (SDE) technique, LCPO demonstrates stable performance. In this study, we define the research problem of power resource allocation in UDSCNs and present the mathematical algorithm employed in the LCPO framework. We compare the performance of LCPO with other algorithms, such as deep deterministic policy gradient (DDPG) and fractional programming (FP) algorithms. Through extensive simulations, our proposed LCPO framework outperforms DDPG and FP algorithms in terms of both performance and execution time. Furthermore, to provide an up-to-date overview of the current state-of-the-art, we incorporate recent research papers in the field. The inclusion of these papers enhances the relevance of our study and allows readers to gain insights into the latest advancements in power resource allocation in UDSCNs. The results of our research highlight the effectiveness of the LCPO framework in addressing the power resource allocation problem in UDSCNs. The proposed framework offers superior performance compared to existing algorithms, making it a promising solution for optimizing power allocation in UDSCNs.

Abstract Background Novel biomarkers are required in gastric cancer (GC) treated by immunotherapy. Epstein-Barr virus (EBV) infection induces an immune-active tumor microenvironment, while its association with immunotherapy response is still controversial. Genes underlying EBV infection may determine the response heterogeneity of EBV + GC. Thus, we screened hub genes associated with EBV infection to predict the response to immunotherapy in GC. Methods Prognostic hub genes associated with EBV infection were screened using multi-omic data of GC. EBV + GC cells were established and confirmed by EBV-encoded small RNA in situ hybridization (EBER-ISH). Immunohistochemistry (IHC) staining of the hub genes was conducted in GC samples with EBER-ISH assay. Infiltrating immune cells were stained using immunofluorescence. Results CHAF1A was identified as a hub gene in EBV + GC, and its expression was an independent predictor of overall survival (OS). EBV infection up-regulated CHAF1A expression which also predicted EBV infection well. CHAF1A expression also predicted microsatellite instability (MSI) and a high tumor mutation burden (TMB). The combined score (CS) of CHAF1A expression with MSI or TMB further improved prognostic stratification. CHAF1A IHC score positively correlated with the infiltration of NK cells and macrophages M1. CHAF1A expression alone could predict the immunotherapy response, but its CS with EBV infection, MSI, TMB, or PD-L1 expression showed better effects and improved response stratification based on current biomarkers. Conclusions CHAF1A could be a novel biomarker for immunotherapy of GC, with the potential to improve the efficacy of existing biomarkers.

This study presents a theoretical investigation into the voltammetric behavior of bipolar interfacial nanopores due to the effect of potential scan rate (1–1000 V/s). Finite element method (FEM) is utilized to explore the current–voltage (I–V) properties of bipolar interfacial nanopores at different bulk salt concentrations. The results demonstrate a strong impact of the scan rate on the I–V response of bipolar interfacial nanopores, particularly at relatively low concentrations. Hysteresis loops are observed in bipolar interfacial nanopores under specific scan rates and potential ranges and divided by a cross-point potential that remains unaffected by the scan rate employed. This indicates that the current in bipolar interfacial nanopores is not just reliant on the bias potential that is imposed but also on the previous conditions within the nanopore, exhibiting history-dependent or memory effects. This scan-rate-dependent current–voltage response is found to be significantly influenced by the length of the nanopore (membrane thickness). Thicker membranes exhibit a more pronounced scan-rate-dependent phenomenon, as the mass transfer of ionic species is slower relative to the potential scan rate. Additionally, unlike conventional bipolar nanopores, the ion current passing through bipolar interfacial nanopores is minimally affected by the membrane thickness, making it easier to detect.

The dust in the main well tower seriously affects the health of the staff in the well tower and the safe and stable operation of the equipment. In order to reduce the dust diffusion effect in the well tower and further reduce the dust concentration in the well tower, the dust migration trajectory in the main hoisting shaft of Dongtan Coal Mine was studied, and the Eulerian-Lagrange method was used to study the gas-solid phase in the well tower. The average error of the numerical calculation method is 5% compared with the actual measured data in the field, and the numerical simulation method is reliable. The study found that the airflow in the tower produced swirling flow, and the static pressure of the airflow was clearly demarcated on the 8th floor. With the increase of floors, the proportion of PM2.5 gradually increased, especially in the 7th floor area, the proportion of PM2.5 was as high as 90%.

Saccharides, being one of the fundamental molecules of life, play essential roles in the physiological and pathological functions of cells. However, their intricate structures pose challenges for detection. Nanopore technology, with its high sensitivity and capability for single-molecule-level analysis, has revolutionized the identification and structural analysis of saccharide molecules. This review focuses on recent advancements in nanopore technology for carbohydrate detection, presenting an array of methods that leverage the molecular complexity of saccharides. Biological nanopore techniques utilize specific protein binding or pore modifications to trigger typical resistive pulses, enabling the high-sensitivity detection of monosaccharides and oligosaccharides. In solid-state nanopore sensing, boronic acid modification and pH gating mechanisms are employed for the specific recognition and quantitative analysis of polysaccharides. The integration of artificial intelligence algorithms can further enhance the accuracy and reliability of analyses. Serving as a crucial tool in carbohydrate detection, we foresee significant potential in the application of nanopore technology for the detection of carbohydrate molecules in disease diagnosis, drug screening, and biosensing, fostering innovative progress in related research domains.

With the widespread deployment of surveillance cameras, automatic violence detection has attracted extensive attention from industry and academia. Though researchers have made great progress in video-based violence detection, it is still a challenging task to realize accurate violence detection in real time, especially with limited computing resources. In this paper, we propose a lightweight 2D CNN-based violence detection scheme, which takes advantage of frame-grouping to reduce data redundancy greatly and, meanwhile, enable short-term temporal modeling. In particular, a lightweight 2D CNN, named improved EfficientNet-B0, is constructed by integrating our proposed bi-directional long-term motion attention (Bi-LTMA) module and a temporal shift module (TSM) into the original EfficientNet-B0. The Bi-LTMA takes both spatial and channel dimensions into consideration and captures motion features in both forward and backward directions. The TSM is adopted to realize temporal feature interaction. Moreover, an auxiliary classifier is designed and employed to improve the classification capability and generalization performance of the proposed model. Experiment results demonstrate that the computational cost of the proposed model is 1.21 GFLOPS. Moreover, the proposed scheme achieves accuracies of 100%, 98.5%, 91.67%, and 90.25% on the Movie Fight dataset, the Hockey Fight dataset, the Surveillance Camera dataset, and the RWF-2000 dataset, respectively.

Objective. Immunotherapy has proven effective in treating advanced gastric cancer (AGC), yet its benefits are limited to a subset of patients. Our aim is to swiftly identify prognostic biomarkers using cytokines to improve the precision of clinical guidance and decision-making for PD-1 inhibitor-based cancer immunotherapy in AGC. Materials and Methods. The retrospective study compared 36 patients with AGC who received combined anti-PD-1 immunotherapy and chemotherapy (immunochemotherapy) with a control group of 20 patients who received chemotherapy alone. The concentrations of TNF-α, IL-1β, IL-2R, IL-6, IL-8, IL-10, and IL-17 in the serum were assessed using chemiluminescence immunoassay at three distinct time intervals following the commencement of immunochemotherapy. Results. When compared to controls, patients undergoing immunochemotherapy demonstrated a generalized rise in cytokine levels after the start of treatment. However, patients who benefited from immunochemotherapy showed a decrease in IL-6 or IL-8 concentrations throughout treatment (with varied trends observed for IL-1β, IL-2R, IL-10, IL-17, and TNF-α) was evident in patients benefiting from immunochemotherapy but not in those who did not benefit. Among these markers, the combination of IL-6, IL-8, and CEA showed optimal predictive performance for short-term efficacy of immunochemotherapy in AGC patients. Conclusion. Reductions in IL-6/IL-8 levels observed during immunochemotherapy correlated with increased responsiveness to treatment effectiveness. These easily accessible blood-based biomarkers are predictive and rapid and may play a crucial role in identifying individuals likely to derive benefits from PD-1 blockade immunotherapy.

N6-methyladenosine (m6A) methylation modification is a ubiquitous RNA modification involved in the regulation of various cellular processes, including regulation of RNA stability, metabolism, splicing and translation. Gastrointestinal (GI) cancers are some of the world’s most common and fatal cancers. Emerging evidence has shown that m6A modification is dynamically regulated by a complex network of enzymes and that the catalytic subunit m6A-METTL complex (MAC)-METTL3/14, a core component of m6A methyltransferases, participates in the development and progression of GI cancers. Furthermore, it has been shown that METTL3/14 modulates immune cell infiltration in an m6A-dependent manner in TIME (Tumor immune microenvironment), thereby altering the response of cancer cells to ICIs (Immune checkpoint inhibitors). Immunotherapy has emerged as a promising approach for treating GI cancers. Moreover, targeting the expression of METTL3/14 and its downstream genes may improve patient response to immunotherapy. Therefore, understanding the role of MAC in the pathogenesis of GI cancers and its impact on immune cell infiltration may provide new insights into the development of effective therapeutic strategies for GI cancers.

Abstract The tumormicroenvironment (TME) plays a key role in tumor progression. Tumor-associated macrophages (TAMs), which are natural immune cells abundantin the TME, are mainly divided into the anti-tumor M1 subtype and pro-tumor M2 subtype. Due to the high plasticity of TAMs, the conversion of the M1 to M2 phenotype in hypoxic and hypoglycemic TME promotes cancer progression, which is closely related to lipid metabolism. Key factors of lipid metabolism in TAMs, including peroxisome proliferator-activated receptor and lipoxygenase, promote the formation of a tumor immunosuppressive microenvironment and facilitate immune escape. In addition, tumor cells promote lipid accumulation in TAMs, causing TAMs to polarize to the M2 phenotype. Moreover, other factors of lipid metabolism, such as abhydrolase domain containing 5 and fatty acid binding protein, have both promoting and inhibiting effects on tumor cells. Therefore, further research on lipid metabolism in tumors is still required. In addition, statins, as core drugs regulating cholesterol metabolism, can inhibit lipid rafts and adhesion of tumor cells, which can sensitize them to chemotherapeutic drugs. Clinical studies on simvastatin and lovastatin in a variety of tumors are underway. This article provides a comprehensive review of the role of lipid metabolism in TAMs in tumor progression, and provides new ideas for targeting lipid metabolism in tumor therapy.

The sensitivity and accuracy of nanopore sensors are severely hindered by the high noise associated with solid-state nanopores. To mitigate this issue, the deposition of organic polymer materials onto silicon nitride (SiNx) membranes has been effective in obtaining low-noise measurements. Nonetheless, the fabrication of nanopores sub-10 nm on thin polymer membranes remains a significant challenge. This work proposes a method for fabricating nanopores on polymethyl methacrylate (PMMA) membrane by the local high electrical field controlled breakdown, exploring the impact of voltage and current on the breakdown of PMMA membranes and discussing the mechanism underlying the breakdown voltage and current during the formation of nanopores. By improving the electric field application method, transient high electric fields that are one–seven times higher than the breakdown electric field can be utilized to fabricate nanopores. A comparative analysis was performed on the current noise levels of nanopores in PMMA-SiNx composite membranes and SiNx nanopores with a 5 nm diameter. The results demonstrated that the fast fabrication of nanopores on PMMA-SiNx membranes exhibited reduced current noise compared to SiNx nanopores. This finding provides evidence supporting the feasibility of utilizing this technology for efficiently fabricating low-noise nanopores on polymer composite membranes.

BackgroundAberrant metabolism is a major hallmark of cancers and hereditary diseases. Genes associated with inborn metabolic errors may also play roles in cancer development. This study evaluated the overall impact of these genes on gastric cancer (GC).MethodsIn total, 162 genes involved in 203 hereditary metabolic diseases were identified in the Human Phenotype Ontology database. Clinical and multi-omic data were acquired from the GC cohort of the Affiliated Hospital of Jiangsu University and other published cohorts. A 4-gene and 32-gene signature was established for diagnosis and prognosis or therapeutic prediction, respectively, and corresponding abnormal metabolism scores (AMscores) were calculated.ResultsThe diagnostic AMscore showed high sensitivity (0.88-1.00) and specificity (0.89-1.00) to distinguish between GC and paired normal tissues, with area under the receiver operating characteristic curve (AUC) ranging from 0.911 to 1.000 in four GC cohorts. The prognostic or predictive AMscore was an independent predictor of overall survival (OS) in five GC cohorts and a predictor of the OS and disease-free survival benefit of postoperative chemotherapy or chemoradiotherapy in one GC cohort with such data. The AMscore adversely impacts immune biomarkers, including tumor mutation burden, tumor neoantigen burden, microsatellite instability, programmed death-ligand 1 protein expression, tumor microenvironment score, T cell receptor clonality, and immune cell infiltration detected by multiplex immunofluorescence staining. The AUC of the AMscore for predicting immunotherapy response ranging from 0.780 to 0.964 in four cohorts involving GC, urothelial cancer, melanoma, and lung cancer. The objective response rates in the low and high AMscore subgroups were 78.6% and 3.2%, 40.4% and 7%, 52.6% and 0%, and 72.7% and 0%, respectively (all p

Abstract Background Effective therapeutics and vaccines for coronavirus disease 2019 (COVID-19) are currently lacking because of the mutation and immune escape of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the propagation characteristics of SARS-CoV-2, rapid and accurate detection of complete virions from clinical samples and the environment is critical for assessing infection risk and containing further COVID-19 outbreaks. However, currently applicable methods cannot achieve large-scale clinical application due to factors such as the high viral load, cumbersome virus isolation steps, demanding environmental conditions, and long experimental periods. In this study, we developed an immuno molecular detection method combining capture of the viral spike glycoprotein with monoclonal antibodies and nucleic acid amplification via quantitative reverse transcription PCR to rapidly and accurately detect complete virions. Results After constructing a novel pseudovirus, screening for specific antibodies, and optimizing the detection parameters, the assay achieved a limit of detection of 9 × 102 transduction units/mL of viral titer with high confidence (~ 95%) and excellent stability against human serum and common virus/pseudovirus. The coefficients of variation were 1.0 ~ 2.0% for intra-assay and inter-assay analyses, respectively. Compared with reverse transcription-PCR, the immunomolecular method more accurately quantified complete virions. SARS-CoV-2/pseudovirus was more stable on plastic and paper compared with aluminum and copper in the detection of SARS-CoV-2 pseudovirus under different conditions. Complete virions were detected up to 96 h after they were applied to these surfaces (except for copper), although the titer of the virions was greatly reduced. Conclusion Convenient, inexpensive, and accurate complete virus detection can be applied to many fields, including monitoring the infectivity of convalescent and post-discharge patients and assessing high-risk environments (isolation rooms, operating rooms, patient living environments, and cold chain logistics). This method can also be used to detect intact virions, including Hepatitis B and C viruses, human immunodeficiency virus, influenza, and the partial pulmonary virus, which may further improve the accuracy of diagnoses and facilitate individualized and precise treatments. Graphical Abstract

The low sensitivity of radiotherapy is the main cause of tumor tolerance against ionizing radiation (IR). However, the molecular mechanisms by which radiosensitivity is controlled remain elusive. Here, we observed that high expression of pellino E3 ubiquitin protein ligase 1 (PELI1) was correlated with improved prognosis in human esophageal squamous cell carcinoma stage III patients that received adjuvant radiotherapy. Moreover, we found PELI1‐mediated IR‐induced tumor cell apoptosis in vivo and in vitro. Mechanistically, PELI1 mediated the lysine 48 (Lys48)–linked polyubiquitination and degradation of NF‐κB–inducing kinase (NIK; also known as MAP3K14), the master kinase of the noncanonical NF‐κB pathway, thereby inhibiting IR‐induced activation of the noncanonical NF‐κB signaling pathway during radiotherapy. As a consequence, PELI1 inhibited the noncanonical NF‐κB–induced expression of the anti‐apoptotic gene BCL2 like 1 (Bclxl; also known as BCL2L1), leading to an enhancement of the IR‐induced apoptosis signaling pathway and ultimately promoting IR‐induced apoptosis in tumor cells. Therefore, Bclxl or NIK knockdown abolished the apoptosis‐resistant effect in PELI1‐knockdown tumor cells after radiotherapy. These findings establish PELI1 as a critical tumor intrinsic regulator in controlling the sensitivity of tumor cells to radiotherapy through modulating IR‐induced noncanonical NF‐κB expression.

BackgroundCancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are critical for immune suppression by restricting immune cell infiltration in the tumor stromal zones from penetrating tumor islands and changing their function status, particularly for CD8+ T cells. However, assessing and quantifying the impact of CAFs on immune cells and investigating how this impact is related to clinical outcomes, especially the efficacy of immunotherapy, remain unclear.Materials and methodsThe TME was characterized using immunohistochemical (IHC) analysis using a large-scale sample size of gene expression profiles. The CD8+ T cell/CAF ratio (CFR) association with survival was investigated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) lung cancer cohorts. The correlation between CFR and immunotherapeutic efficacy was computed in five independent cohorts. The correlation between CFR and objective response rates (ORRs) following pembrolizumab monotherapy was investigated in 20 solid tumor types. To facilitate clinical translation, the IHC-detected CD8/α-SMA ratio was applied as an immunotherapeutic predictive biomarker in a real-world lung cancer cohort.ResultsCompared with normal tissue, CAFs were enriched in cancer tissue, and the amount of CAFs was overwhelmingly higher than that in other immune cells. CAFs are positively correlated with the extent of immune infiltration. A higher CFR was strongly associated with improved survival in lung cancer, melanoma, and urothelial cancer immunotherapy cohorts. Within most cohorts, there was no clear evidence for an association between CFR and programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB). Compared with TMB and PD-L1, a higher correlation coefficient was observed between CFR and the ORR following pembrolizumab monotherapy in 20 solid tumor types (Spearman’s r = 0.69 vs. 0.44 and 0.21). In a real-world cohort, patients with a high CFR detected by IHC benefited considerably from immunotherapy as compared with those with a low CFR (hazard ratio, 0.37; 95% confidence interval, 0.19–0.75; p < 0.001).ConclusionsCFR is a newly found and simple parameter that can be used for identifying patients unlikely to benefit from immunotherapy. Future studies are needed to confirm this finding.

Abstract Background Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, have achieved good efficacy in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients, but eventual drug resistance is inevitable. Thus, new TKI-based combination therapies should be urgently explored to extend the overall survival time of these patients. CD8 + CD56+ natural killer T (NKT) cells are a natural and unique subset of lymphocytes in humans that present characteristics of T and NK cells and exert cytotoxicity on tumour cells in a granzyme B-dependent manner. The aim of this trial was to explore the efficacy and safety of CD8 + CD56+ NKT cell immunotherapy combined with gefitinib in patients with advanced EGFR-mutated NSCLC. Methods The study was designed as a prospective, randomized, controlled, open-label, phase I/II trial that includes 30 patients with EGFR mutation-positive stage III/IV NSCLC. All patients will be randomized in blocks at a 1:1 ratio and treated with gefitinib 250 mg/day monotherapy or combination therapy with allogeneic CD8 + CD56+ NKT cell infusions twice per month for 12 cycles or until disease progression occurs. The effectiveness of this treatment will be evaluated based on by progression-free survival (PFS), the time to progression (TTP), overall response rate (ORR), disease control rate (DCR) and overall survival (OS). The safety of the trail is being assessed based on adverse events (AEs). Recruitment and data collection, which started in December 2017, are ongoing. Discussion Although immunotherapy, including programmed death-1/programmed death-1 ligand (PD-1/PD-L1) immunotherapy, has been used for NSCLC treatment with or without EGFR-TKIs, its clear efficacy still has not been shown. Assessing the safety and therapeutic potential of allogeneic CD8 + CD56+ NKT killer cells in combination with EGFR-TKIs in NSCLC will be of great interest. Trial registration This trial (Phase I/II Trails of NKT Cell in Combination With Gefitinib For Non Small Cell Lung Cancer) was registered on 21 November 2017 with www.chictr.org.cn , ChiCTR-IIR-17013471 .

Gastric cancer (GC) is the third-leading cause of cancer mortality worldwide. The aim of this study was to develop a nomogram that estimates 1-year, 3-year, and 5-year survival probability of GC patients after D2 gastrectomy combined with adjuvant chemotherapy. The results showed that median age is 58 (range: 18-85) years in the training cohort and 59 (range: 32-85) years in the validation cohort. On multivariate analysis, four factors were found to be significantly associated with worse overall survival (OS): late TNM stage, positive resection margin, preoperative carcinoembryonic antigen (CEA) level, and single chemotherapy regimens compared with multiple chemotherapy regimens. All of these findings were validated in the validation cohort. Furthermore, the four factors were included in the final nomogram for the prediction of 1-year, 3-year, and 5-year survival probability, with accurate calibration and reasonable discrimination (C-index = 0.676 for training cohort, and C-index = 0.664 for validation cohort). The AUC values analyzed by the ROC analysis demonstrated a good predictive accuracy of the nomogram for OS (1-year, 3-year, and 5-year OS were 94.43%, 77.42%, and 73.03% in the training cohort, respectively; 96.95%, 81.54%, and 73.41% in the validation cohort, respectively). In conclusion, the proposed nomogram may be used to objectively and accurately predict survival probability of GC patients in a multi-institutional clinical setting.

A practical solution to the power allocation problem in ultra-dense small cell networks can be achieved by using deep reinforcement learning (DRL) methods. Unlike traditional algorithms, DRL methods are capable of achieving low latency and operating without the need for global real-time channel state information (CSI). Based on the actor–critic framework, we propose a policy optimization of the power allocation algorithm (POPA) for small cell networks in this paper. The POPA adopts the proximal policy optimization (PPO) algorithm to update the policy, which has been shown to have stable exploration and convergence effects in our simulations. Thanks to our proposed actor–critic architecture with distributed execution and centralized exploration training, the POPA can meet real-time requirements and has multi-dimensional scalability. Through simulations, we demonstrate that the POPA outperforms existing methods in terms of spectral efficiency. Our findings suggest that the POPA can be of practical value for power allocation in small cell networks.

Abstract Background In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer. Case presentation Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months. Conclusions We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.

PurposeImmune checkpoint inhibitors plus antiangiogenic tyrosine kinase inhibitors may offer a first-line treatment for advanced hepatocellular carcinoma (HCC). In this phase 2 trial [registered with clinicaltrials.gov (NCT04052152)], we investigated the safety and efficacy of first-line anti-PD-1 antibody sintilimab plus antiangiogenic TKI anlotinib for advanced HCC.Methods and MaterialsPathologically-proven advanced HCC patients received sintilimab (200 mg) on day 1 and anlotinib (12 mg) once daily on days 1 to 14 every 3 weeks, with a safety run-in for the first six participants to assess dose-limiting toxicities (DLTs). The primary endpoints were safety and objective response rate (ORR) per RECIST v1.1.ResultsTwenty advanced HCC patients were enrolled. No DLTs occurred in the safety run-in. All patients had treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 8 (40.0%) patients, the most common being decreased platelet count (10.0%) and increased γ-glutamyl transferase (10.0%). No grade 4/5 TRAEs occurred. Five (25%) patients developed immune-related AEs. The ORR was 35.0% (95%CI 15.4%-59.2%) per RECIST v1.1 and 55.0% (95%CI 31.5%-76.9%) per modified RECIST. At data cutoff (March 31, 2021), the median progression-free survival was 12.2 months (95%CI, 3.8 to not reached). The median PFS was significantly longer in patients with lower LDH levels (not reached [NR], 95% CI, 8.7 to NR vs. higher LDH levels 5.2 months, 95% CI 3.4 to NR; P=0.020) and a CONUT score ≤2 (NR, 95% CI 5.1 to NR vs. CONUT score >2 6.2 months, 95% CI 1.8 to NR; P=0.020). Furthermore, patients showing tumor response had a significantly higher median proportion of CD16+CD56+ NK cells than patients who had stable or progressive disease (21.6% vs. 14.6%; P=0.026).ConclusionSintilimab plus anlotinib showed promising clinical activities with manageable toxicity as first-line treatment of advanced HCC.

Background: The immunotherapy efficacy in gastric cancer (GC) is limited. Cancer-associated fibroblasts (CAFs) induce primary resistance to immunotherapy. However, CAF infiltration in tumors is difficult to evaluate due to the lack of validated and standardized quantified methods. This study aimed to investigate the impact of infiltrating CAFs alternatively using fibroblast-associated mutation scoring (FAMscore).Methods: In a GC cohort from Affiliated Hospital of Jiangsu University (AHJU), whole exon sequencing of genomic mutations, whole transcriptome sequencing of mRNA expression profiles, and immunofluorescence staining of tumor-infiltrating immune cells were performed. GC data from The Cancer Genome Atlas were used to identify genetic mutations which were associated with overall survival (OS) and impacted infiltrating CAF abundance determined by transcriptome-based estimation. FAMscore was then constructed through a least absolute shrinkage and selection operator Cox regression model and further validated in AHJU. The predictive role of FAMscore for immunotherapy outcomes was tested in 1 GC, one melanoma, and two non-small-cell lung cancer (NSCLC-1 and -2) cohorts wherein participants were treated by immune checkpoint inhibitors.Results: FAMscore was calculated based on a mutation signature consisting of 16 genes. In both TCGA and AHJU, a high FAMscore was an independent predictor for poor OS of GC patients. FAMscore was associated with immune-associated genome biomarkers, immune cell infiltration, and signaling pathways of abnormal immunity. Importantly, patients with high FAMscore presented inferiority in the objective response rate of immunotherapy compared to those with low FAMscore, with 14.6% vs. 66.7% (p

Objectives: The aim of this study was to investigate the molecular mechanisms of imipenem resistance in Enterobacteriaceae and to assess the antimicrobial activities of ceftazidime/avibactam (CAZ/AVI) and aztreonam/avibactam (ATM/AVI) against imipenem-resistant clinical isolates in a tertiary hospital in China. Methods: A total of 91 imipenem-resistant Enterobacteriaceae were collected and genes encoding carbapenemases, ESBLs, AmpC β-lactamases and porins were detected using PCR. MICs and susceptibility were determined using in-house-prepared broth microdilution panels and were interpreted according to CLSI breakpoints. Results: Imipenem-resistant isolates comprising 54 Klebsiella pneumoniae, 18 Escherichia coli, 8 Enterobacter cloacae, 6 Serratia marcescens, 3 Klebsiella oxytoca and 2 Klebsiella aerogenes were collected independently. Five different carbapenemase genes were identified, namely blaKPC-2 (n = 60), blaNDM-5 (n = 14), blaNDM-1 (n = 11), blaKPC-3 (n = 4) and blaIMP-4 (n = 1). Among the 91 carbapenem-resistant Enterobacteriaceae (CRE), 85 isolates harboured at least one ESBL and/or AmpC gene, including 5 strains without carbapenemase-encoding genes. Moreover, 31 K. pneumoniae carried ompK35 and/or ompK36 mutations. MLST results showed that the K. pneumoniae belonged to 12 different STs, with ST11 being predominant (29/54; 53.7%). Overall, 17.6%, 25.3%, 41.8%, 65.9% and 100% of the CRE strains were susceptible to amikacin, trimethoprim/sulfamethoxazole, tetracycline, CAZ/AVI and ATM/AVI, respectively. Conclusion: This study revealed that CRE isolates differ significantly in their species, STs, porins and carbapenemase genes in a single Chinese hospital. ATM/AVI exhibited potent activity against CRE isolates, even for the most notorious double-carbapenemase-producers with porin defects, whereas CAZ/AVI was active against all the non-metallo-β-lactamase-producing isolates.

ABSTRACTHepatitis B virus (HBV) is a partially double-stranded DNA virus that replicates by reverse transcription. We previously demonstrated that the host restriction factor-APOBEC3B (A3B) inhibited HBV replication which was dependent on its deaminase activity during reverse transcription. However, the host factors involved in the process of regulating the anti-HBV function of A3B are less known. In this research, to obtain a comprehensive understanding of the interaction networks of A3B, we conducted coimmunoprecipitation and mass spectrometry to identify A3B-interacting proteins in the presence of HBV. By this approach, we determined that DExD/H-box helicase 9 (DHX9) suppressed the anti-HBV effect of A3B, and this suppression was dependent on their interaction. Although DHX9 did not affect the deamination activity of A3B in vitro assay or the viral DNA editing of A3B in HepG2-NTCP cells that support HBV infection, it inhibited the binding of A3B with pgRNA. These data suggest that DHX9 can interact with A3B and attenuate the anti-HBV efficacy of A3B.Abbreviations: 3D-PCR: differential DNA denaturation PCR; APOBEC3: apolipoprotein B mRNA-editing catalytic polypeptide 3; cccDNA: covalently closed circular DNA; co-IP: coimmunoprecipitation; DDX: DExD-box RNA helicases; HBc: HBV core protein; HBV: hepatitis B virus; HepAD38: HepG2 cell line stably transfected with HBV DNA; HepG2-NTCP: HepG2 cell line stably transfected with Na+/taurocholate cotransporter polypeptide; Huh7: human hepatoma cell line; pgRNA: pregenomic RNA; PPI: protein–protein interactions; RC DNA: relaxed circular DNA.

Gallium Nitride High Electron Mobility Transistors (GaN HEMTs) enable higher efficiency, higher power density, and smaller passive components resulting in lighter, smaller and more efficient electrical systems as opposed to conventional Silicon (Si) based devices. This paper investigates the detailed benefits of using GaN devices in transportation electrification applications. The material properties of GaN including the applications of GaN HEMTs at different switch ratings are presented. The challenges currently facing the transportation industry are introduced and possible solutions are presented. A detailed review of the use of GaN in the Electric Vehicle (EV) powertrain is discussed. The implementation of GaN devices in aircraft, ships, rail vehicles and heavy-duty vehicles is briefly covered. Future trends of GaN devices in terms of cost, voltage level, gate driver design, thermal management and packaging are investigated.

The introduction of IPsec into software-defined networking (SDN) can secure communication in an SDN southbound interface, i.e., communication between the controllers and the switches. However, due to the static configuration of IPsec cryptographic algorithms, the invocation of these algorithms cannot dynamically self-adapt to traffic fluctuations in SDN southbound communication. To address the contradiction between link security and communication performance incurred by IPsec encryption, an evaluation model to find a trade-off between communication performance and link security is presented in this paper. An invocation mechanism based on the Free-to-Add (FTA) method is also proposed to optimize the invocation mode of cryptographic algorithms in traditional IPsec. Based on the real-time network status and the impact of the IPsec encryption process on the network latency and throughput, a feedback-based scheduling scheme is designed to enable the IPsec algorithms in use to be flexibly replaced and synchronously switched, and two policies are applied to determinate the appropriate encryption algorithm(s). The validity and effectiveness of the FTA-based mechanism are verified and evaluated on an SDN/OpenFlow platform in which IPsec security gateways are deployed. The feedback-based scheduling scheme is evaluated in terms of packet processing latency, distribution of optional encryption intensity, and the hit rate of encryption intensity.

BackgroundHER2 is one of the most extensively studied oncogenes in solid tumors. However, the association between tumor microenvironment (TME) and HER2 mutation remains elusive, and there are no specific therapies for HER2-mutated tumors. Immune checkpoint inhibitors (ICIs) have been approved for some tumor subgroups that lack targeted therapies, while their effects are still unclear in HER2-mutated tumors. We examined whether HER2 mutation impacts treatment outcomes of ICIs in solid tumors via its association with anticancer immunity.MethodsMulti-omics data of solid tumors from The Cancer Genome Atlas (TCGA), the Asian Cancer Research Group and the Affiliated Hospital of Jiangsu University were used to analyze the association between HER2 mutations and tumor features. Data of patients with multiple microsatellite-stable solid tumors, who were treated by ICIs including antibodies against programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) in eight studies, were collected to investigate the effects of HER2 mutations on immunotherapy outcomes.ResultsThe mutation rate of HER2 varied in solid tumors of TCGA, with an overall incidence of 3.13%, ranged from 0.39% to 12.2%. Concurrent HER2 mutations and amplifications were rare (0.26%). HER2 mutation was not associated with HER2 protein expression but was positively associated with microsatellite instability, tumor mutation and neoantigen burdens, infiltrating antitumor immune cells, and signal activities of antitumor immunity. Of 321 ICI-treated patients, 18 carried HER2 mutations (5.6%) and showed improved objective response rates compared with those with HER2 wild-type (44.4% vs. 25.7%, p=0.081), especially in the anti-PD-1/anti-PD-L1 subgroup (62.5% vs. 28.4%, p=0.04). Heterogeneity was observed among tumor types. Patients with HER2 mutations also had superior overall survival than those with HER2 wild-type (HR=0.47, 95%CI: 0.23-0.97, p=0.04), especially in the presence of co-mutations in ABCA1 (HR = 0.23, 95% CI: 0.07-0.73, p=0.013), CELSR1 (HR = 0.24, 95% CI: 0.08-0.77, p=0.016), LRP2 (HR = 0.24, 95% CI: 0.07-0.74, p=0.014), or PKHD1L1 (HR = 0.2, 95% CI: 0.05-0.8, p=0.023).ConclusionsHER2 mutations may improve the TME to favor immunotherapy. A prospective basket trial is needed to further investigate the impacts of HER2 mutations on immunotherapy outcomes in solid tumors.

In order to understand the wake characteristics for the circular cylinder with the V-groove surface, the Particle Image Velocimetry (PIV) and Proper Orthogonal Decomposition (POD) technology are used to measure and analyze the flow field velocity and the flow characteristic of the wake flow of the circular cylinder with the V-groove surface. This study focuses on the length of the velocity gradient, the Reynolds stress, the turbulent kinetic energy, the vortex shedding process, and the velocity fluctuating characteristics of flow field with POD technology. Compared with the smooth cylinder, the velocity gradient of the circular cylinder with the V-groove surface are larger. The peak values of Reynolds stress of the circular cylinders with the V-groove surface (the peak values are 0.33, 0.28 and 0.24) is lower than that of the smooth cylinder (0.39), and the peak values of turbulent kinetic energy are also lower. The recirculation region of the circular cylinders with the V-groove surface is larger, the length of the recirculation region are increased by 5.9%, 13.0% and 16.1% respectively, and it implies the suppression of vortex by the V-groove structure. Otherwise, the correlation of POD mode coefficients is disturbed for the circular cylinders with the V-groove surface, further proving that the effect of V-groove structure on vortex shedding.

It is of great significance to study the seepage characteristics of heavy oil reservoirs, which are conducive to the efficient development of resources. Boundary layer effect (BLE) exists in the pore-scale flow process of macromolecular fluid media, which is different from the flow law of conventional fluid in the pore, yet the influence of BLE is ignored in the previous pore-scale simulation. Conventional porous media simulations have difficulty analyzing the mass transfer law of small-scale models under the influence of microfractures. Based on the CT scanning data and thin section data of the real core in the target area, the rock skeleton and flow space were extracted according to the maximum ball algorithm, and the pore network model representing the complex structure was constructed. The microscale effect of macromolecules in the flow process in the pores was characterized by modifying the effective flow. The effects of the BLE on the effective connectivity, displacement process, and oil distribution law were analyzed. The seepage characteristics of different wettability conditions and different water cut stages were compared. The results show that BLE reduces the effective flow space and leads to deviations in the relative permeability curve and capillary curve. For fractured porous media, the irregular shape of porous media was characterized by the morphological method, and the mass transfer process was analyzed by the equivalent flux method. The influence of the porous media shape on the macromass transfer process was compared. This study provides a solution to the problem of BLE in pore-scale simulation.

Fluorescent sensor has demonstrated to be a facile and effective method to detect heavy metal ions owing to its unique characteristics such as simplicity, ease of operation and cost-effectiveness. In this work, a novel fluorescent probe with aggregation-induced emission (AIE) feature that contains an amide ligand base on the tetraphenylethylene (TPE) dye was designed and successfully synthesized. The utilization of the AIE-active fluorescent probe (named as FDPA) for detection of Cu2+ in aqueous solution has also been examined. We demonstrated that the resultant AIE-active molecule displays amphiphilic property and can self-assemble in aqueous solution with remarkable enhancement of fluorescent intensity owing to its AIE feature. The detection limit of probe for Cu2+ determination is 6.11 × 10−9 M and shows excellent selectivity in the presence of competitive ions. This work provides a useful route to overcome the fluorescence quenching of conventional fluorescent probes in aqueous solution and an elegant way to prepare fluorescent probes with better fluorescence properties.

ObjectivesTo assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing Enterobacterales (CPE) clinical isolates and 6 in vitro selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants.MethodsMICs of imipenem, ceftazidime-avibact8am (CAZ-AVI), ATM-AVI, CAZ-AVI-AUR and ATM-AVI-AUR were determined via the broth microdilution method. Genetic background and carbapenemase genes were determined by PCR and Sanger sequencing.ResultsAUR alone showed little antibacterial activity with AUR MICs were greater than 64 μg/mL for all the 88 clinical CPE isolates. The addition of AUR (16 μg/mL) resulted in an 3-folding dilutions MIC reduction of ATM-AVI MIC50 (0.5 to 0.0625 μg/mL) and a 2-folding dilutions MIC reduction of MIC90 (1 to 0.25 μg/mL) against all 88 clinical CPE isolates, respectively. Notably, the reduced ATM-AVI MIC values were mainly found in MBL-producers, and the MIC50 and MIC90 reduced by 2-folding dilutions (0.25 to 0.0625 μg/mL) and 3-folding dilutions (2 to 0.25 μg/mL) respectively by AUR among the 51 MBL-producers. By contrast, the addition of AUR did not showed significant effects on ATM-AVI MIC50 (0.0625 μg/mL) and MIC90 (0.125 μg/mL) among single KPC-producers. Interestingly, the addition of AUR restored the ATM-AVI susceptibility against the 6 in vitro selected ATM-AVI-resistant CMY-16 Tyr150Ser and Asn346His mutants or transfromants, with the MICs reduced from ≥32 μg/mL (32->256 μg/mL) to ≤8 μg/mL (0.0625-8 μg/mL).ConclusionsOur results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates in vitro. Importantly, AUR restored the ATM-AVI activity against ATM-AVI resistant mutant strains. As a clinically approved drug, AUR might be repurposed in combination with ATM-AVI to treat infections caused by highly resistant MBL-producing Enterobacterales.

Erianin, a natural product derived from Dendrobium chrysotoxum Lindl, has been proved to play antitumor activity in various cancers. However, the effects and molecular mechanisms of erianin in bladder cancer cells remain unexplored. In this study, we found that erianin triggered cell death and cell cycle arrest in bladder cancer cells. Then we demonstrated that erianin could promote the accumulation of lethal lipid-based reactive oxygen species (ROS) and the depletion of glutathione (GSH), suggesting the induction of ferroptosis. In the further study, the ferroptosis inhibitor deferoxamine (DFO), N-Acetylcysteine (NAC) and GSH but not necrostatin-1, CQ or Z-VAD-FMK rescued erianin-caused cell death, showing ferroptosis played a major role in erianin-caused cell death. In vivo, we also showed that erianin suppressed the tumor growth by inducing ferroptosis. Mechanistically, we demonstrated that nuclear factor E2-related factor 2 (NRF2) inactivation was a key determinant of ferroptosis caused by erianin. In bladder cancer cells, the compound tert-butylhydro-quinone (TBHQ), an activator of NRF2, suppressed erianin-induced ferroptosis. Whereas, NRF2 inhibition used shRNA augmented the ferroptosis response induced by erianin treatment. In conclusion, our data provide the first evidence that erianin can initiate ferroptosis-like cell death and lipid peroxidation in bladder cancer, which will hopefully become a promising anticancer compound for the treatment of bladder cancer.

Nanopore detection technology has now developed into an indispensable tool for single molecule experiments, in which useful information on molecular properties can be obtained from the ion current flow induced by individual molecules, but the relatively high background noise affects the data analysis. Therefore, a nanopore signal noise reduction method based on wavelet transform and Kalman filter is proposed, which can achieve multi-scale decomposition and optimal estimation of the nanopore signal. The real measurement shows that the Kalman filter based on the wavelet mode maxima method reduces the root mean square (RMS) of the background noise by 17.8%, and the noise reduction effect is better than the traditional Kalman filter method.

The morbidity and mortality of lung cancer is the first in the world, immunotherapy has become a important treatment strategy in addition to chemotherapy, radiotherapy and targeted therapy. In recent years, the US Food and Drug Administration (FDA) has successively approved immunological checkpoint inhibitors as standard programs for non-small cell lung cancer (NSCLC) in second-line or first-line treatment. The National Comprehensive Cancer Network (NCCN) also recommends immunological checkpoint inhibitors as the standard treatment for small cell lung cancer (SCLC). Now, the treatment for lung cancer has entered the era of precision treatment, it is very important to select effective and reliable biomarker for the dominant populations of lung cancer to receive immunotherapy. A large number of researchs indicated that tumor mutation burden (TMB) may be an independent predicted biomarker for immunotherapy, but with limitations. This article reviewed the predictive value of TMB and its limitations in the field of immunotherapy for lung cancer.

Oesophageal cancer is a malignant tumor with high morbidity and mortality. Surgical treatment, radiotherapy, and chemotherapy are the most common treatment methods for oesophageal cancer. However, traditional chemotherapy drugs have poor targeting performance and cause serious adverse drug reactions. In this study, a GSH-sensitive material, ATRA-SS-HA, was developed and self-assembled with curcumin, a natural polyphenol antitumor drug, into nanomicelles Cur@ATRA-SS-HA. The micelles had a suitable particle size, excellent drug loading, encapsulation rate, stability, biocompatibility, and stable release behaviour. In the tumor microenvironment, GSH induced disulfide bond rupture in Cur@ATRA-SS-HA and promoted the release of curcumin, improving tumor targeting. Following GSH-induced release, the curcumin IC50 value was significantly lower than that of free curcumin and better than that of 5-FU. In vivo pharmacokinetic experiments showed that the drug-loaded nanomicelles exhibited better metabolic behaviour than free drugs, which greatly increased the blood concentration of curcumin and increased the half-life of the drug. The design of the nanomicelle provides a novel clinical treatment for oesophageal cancer.